Chemotherapeutic Agents

/Antimicrobial Drugs/

Antiseptics & Disinfectants

© 2023 Takele Beyene, AAU-CVMA

 Learning objectives

At the end of this Lecture students should be

able to:
– Differentiate antiseptics and disinfectants with
their mode of application

© 2023 Takele Beyene, AAU-CVMA

 Definitions
• Sterilization
– Freeing of an article, surface or medium by
removing or klling all micro-organisms
including vegetative form of bacteria, spores,
viruses and fungi
• Disinfection
– Destruction or inhibition of growth of all
pathogenic organisms (bacteria, viruses,
fungi) on non living surfaces
– Is spores are also killed - sterilization

© 2023 Takele Beyene, AAU-CVMA

 Antiseptics and Disinfectants
• Antiseptics
– Chemicals that kill or inhibit the growth of
microorganisms on living surfaces/animate objects: skin
and mucous membrane (a biocide applied to living
tissue)
• Disinfectants
– Chemicals that kill or inhibit the growth of
microorganisms on inanimate objects
• Ideally these agents should:
– Be easy to apply, Fast action
– Activity in the presence of organic material
– Not damage- non absorbable
– Non staining and good odour
– Be nonirritating (low toxicity) – non sensitizing
– Have the broadest possible spectrum of activity
– Be affordable
© 2023 Takele Beyene, AAU-CVMA
 General MoA
• Oxidation of bacterial protoplasm
– Potassium permanganate, H2O2, Halogens

• Coagulation (denaturation) of bacterial

proteins and disrupt cell membrane
– Phenols, chlorhexidine, alcohols, aldehydes

• Detergent like action increase cell m/m

permeability
– Cetrimide, soaps
© 2023 Takele Beyene, AAU-CVMA
Types of Disinfecting Agents

© 2023 Takele Beyene, AAU-CVMA

 Phenols
– Destroy the selective permeability of cell
membranes, & denature bacterial proteins
– Effective against G+ve & G-ve bacteria, fungi,
and some enveloped viruses
– Oldest antiseptic-no longer use
– Has severe toxicity-
• injures tissues and cells-skin burn at high conc.
• Extremely irritating, corrosive
– E.g. Sodium phenylphenol
– Cresol- substituted phenols, more bactericidal,
less toxic and caustic than phenols
– Bisphenol (Triclosan), Hexachlorophene

© 2023 Takele Beyene, AAU-CVMA

 Oxidizing agents
• Potassium permanganate
– Liberates oxygen which oxidizes bacterial
protoplasm
– Used for gargling, irritating wounds
– High conc cause burns
– Also used to disinfect water ponds
– Stomach wash in alkaloidal poisoning
• Hydrogen peroxide
– damages proteins and is used to kill anaerobic bacteria;
– can cause tissue damage (3%), so its use is limited
– oxidizes necrotic matter & bacteria
– Helps in loosening & removing slough, ear wax, etc
• Benzyl peroxide- widely used for acne
Quaternary ammonium compounds
(QACs)
– Work by concentrating at the cell membrane and
dissolving lipids in the cell walls and membranes
– Effective against gram-positive and gram-negative
bacteria, fungi, and enveloped viruses

– They are often found in dis- infectants and in cleaning

products that are used in hospitals, day care centers,
restaurants, and homes.
– benzalkonium chlorides and didecyl dimethyl
ammonium chloride
– Cetrimide, or alkyltrimethylammonium bromide, is an antiseptic which is
a mixture of three quaternary ammonium compounds: tetradonium bromide
(TTAB or MITMAB), cetrimonium bromide (CTAB), and laurtrimonium bromide
(DTAB or LTAB).
 Aldehydes
– Work by affecting protein structure
– Effective against gram-positive and gram-
negative bacteria, fungi, viruses, and bacterial
spores
– High level disinfectant
• E.g. Formaldehyde & Glutaraldehyde (GLT)
– Formaldehyde-
• Effective but slow bactericide, virucide, fungicide
requiring 6-12 hrs contact time
– GLT
• Better bactericide, sporicidal, virucide, fungicide
activity
• Short contact time: <2minutes for veg. bacteria, 10
min for fungi, 3hrs for spore forming bacteria

© 2023 Takele Beyene, AAU-CVMA

 Halogens
– Work by interfering with proteins and enzymes of the
microbe (interfere with metabolic reactions & by
disrupting protein and NA structure & synthesis)
❑Chlorine
– Potent germicide: kills bacteria, fungi, viruses,
protozoas, and spores
– Disinfect urban water supplies 0.1-0.25ppm
❑Chlorophores
– Chlorinated lime (bleaching powder)
• Disinfect drinking water
– Na- or Ca-hypochlorites
• Powerful disinfectant used in dairy (milk cans)
• Irritant to use as atiseptics
• Root canal therapy in dentistry
 Halogens…cont’d
❑Iodine
– kills most classes of microbes if used at
the proper concentration and exposure
times
– Iodinating and oxidizing microbial
protoplasm
– Used for cuts, degerming skin before
surgery
– ADR: burns and blisters
– Tincture iodine = 1-2% iodine soln in
70% ethyl alcohol
© 2023 Takele Beyene, AAU-CVMA
 Halogens…cont’d

❑Iodophores: Povidone iodine

– Non toxic, non-staining prolonged
action
– Used on boils, burns, ulcers, tinea,
surgical scrub, disinfecting surgical
instruments, non specific vaginitis

© 2023 Takele Beyene, AAU-CVMA

 Alcohols
– Antiseptic and cleansing agent at 40-90% conc
– act by coagulating proteins and dissolving
membrane lipids
– Effective against G+ve and G-ve bacteria, fungi,
and enveloped viruses
– Most commonly used: ethyl and isopropyl alcohol
– They are lipid solvents and protein denaturants
– 70% ethyl or 50% isopropyl are effective
– Effective on clean skin, but the presence of
organic materials: blood, mucous, excreta reduce
its effectiveness (irritant on open wound/ulcers)
– Used for low level disinfection

© 2023 Takele Beyene, AAU-CVMA

 Biguanides

– Kill the bacteria by disrupting the cell m/m and

precipitating cell contents (denaturing proteins)
– Effective against gram-positive and gram-
negative bacteria, fungi, and enveloped viruses
– E.g. Chlorhexidine (0.1% aqueous), PHMB
(polyhexamethylene biguanide)
– Longest residual effect: 5-6 hrs
– Has activity in the presence of blood and other
organic materials
– Commonly used as antiseptics (presurgical, wound
flash, teat dip)

© 2023 Takele Beyene, AAU-CVMA

 Ethylene oxide (gas)
– Works by destroying DNA and proteins
– Is a gas used for chemical sterilization
– Effective against gram-positive and gram-
negative bacteria, fungi, viruses, and bacterial
spores.

© 2023 Takele Beyene, AAU-CVMA

 Combinations

– Savlon: cetrimide + chlorhexidine

• Other agents
– Soaps and detergents
• Anionic detergents
• have limited bactericidal activity (only G+ve
bacteria)
• Washing with soap+warm water- effective in
preventing disease transmission
 Factors affecting the efficacy of
antiseptics/ disinfectants
• Concentration-
– Mostly inverse r/ship (as the time to effectively kill the
Mos).
• E.g. QACs, aldehydes, chlorhexidine
– Alcohol activity is very concentration dependent
• Temperature
– Direct relationship
• pH
– Increase PH decrease activity of hypochlorite
– GDH-more potent at alkaline pH
• Contamination
• Organism type
• Formation of biofilms- less sensitive
– an adherent slimy layer of organic polymer matrix in
which the microbes are embedded.
 Use in veterinary medicine
Antiseptics
– Skin cleansers
– Wound scrubs
– Teat dips
• Disinfectants
– Hospital disinfectants on floors, tables, walls surgical
equipment and other equipments before storage
– Disinfection of animal housing facilities

• Read about Actions and uses of

disinfecting agents
© 2023 Takele Beyene, AAU-CVMA
 Antiseptics and Disinfectants
❑ Things to Keep in Mind When Choosing/Using
Products
• the surface it will be applied to
• the range of organisms you want to eliminate
• Products may be less effective in the presence of
organic waste (must be applied to a thoroughly
clean surface)
• Read the package insert for dilution
recommendations and special use instructions
• Contact time is critical to the efficacy of the
product
• Keep MSDS on all products

© 2023 Takele Beyene, AAU-CVMA

 Antiseptics and Disinfectants
❑ Material Safety Data Sheets

• Always request and keep MSDS

• Filing of MSDS and container labeling are

important components of each facility’s hazard
communication plan
• Hazard Communication Standard was enacted in
1988 to educate and protect employees who
work with potentially hazardous material

© 2023 Takele Beyene, AAU-CVMA

 Antiseptics and Disinfectants
❑ Information on MSDS
– Product name and chemical identification
– Name, address, and telephone number of the
manufacturer
– List of all hazardous ingredients
– Physical data for the product
– Fire and explosion information
– Information on potential chemical reactions
when the product is mixed with other materials
– Outline of emergency and cleanup procedures
– Personal protective equipment required when
handling the material
– A description of any special precautions
necessary when using the material

© 2023 Takele Beyene, AAU-CVMA

 Thank you!

© 2023 Takele Beyene, AAU-CVMA

 Lecture 3-5

Antimicrobial Drugs

Antibacterial Drugs

© 2023 by Takele B. Tufa, AAU-CVMA.

 Learning objectives

• At the end of this topic students should be able

to:
– Understand the spectrum of activity,
mechanism of action, PK and ADR of each
antibacterial agents

– Select commonly used antibiotics in veterinary

medicine to treat bacterial infections

© 2023 by Takele B. Tufa, AAU-CVMA.

 Antibiotics
• Antibiotics work only on bacteria and are
described by their spectrum of action:
– Narrow-spectrum
• work only on either gram-positive or gram-negative
bacteria (not both)
– Broad-spectrum
• work on both gram-positive and gram-negative
bacteria (but not necessarily all)

• Antibiotics can be classified as bactericidal or

bacteriostatic
– Bactericidal kill the bacteria
– Bacteriostatic inhibit the growth or replication of
bacteria

© 2023 by Takele B. Tufa, AAU-CVMA.

 Antibiotics…cont’d
❑ Source of Antibiotics
• Most modern antibiotics come
from species of microorganisms
that live in the soil

• To commercially produce
antibiotic:
1. Select strain and grow in
broth
2. When maximum antibiotic
concentration reached,
extract from medium
3. Purify
4. Chemical alter to make it
more stable

© 2023 by Takele B. Tufa, AAU-CVMA.

 MoA of Antibacterial Drugs

1. Inhibit cell wall synthesis

2. Damage to plasma membrane
3. Inhibit protein synthesis
4. Inhibit synthesis of essential
metabolites
5. Inhibit nucleic acid synthesis

© 2023 by Takele B. Tufa, AAU-CVMA.

MoA

https://www.youtube.com/watch?v=Cj9UADDIidI

© 2023 by Takele B. Tufa, AAU-CVMA.

 Classes of Antibiotics

❑ Based on mechanism of action (MoA)

1. Cell wall synthesis inhibitors
2. Damage to plasma membrane
3. Protein synthesis Inhibitors
4. Essential metabolites synthesis inhibitors
5. Nucleic acid synthesis Inhibitors

© 2023 by Takele B. Tufa, AAU-CVMA.

 Lecture 3-5
❑Cell wall inhibitors

❑Membrane disrupting agents

❑Protein synthesis inhibitors

❑Essential metabolites synthesis

inhibitors

© 2023 by Takele B. Tufa, AAU-CVMA.

 1. Cell Wall Inhibitors

• Irreversibly inhibit enzymes involved in the final

steps of cell wall synthesis
• These enzymes mediate formation of peptide
bridges between adjacent stands of peptidoglycan
▪ b-lactam ring is similar in structure to normal
substrate of enzyme
• Drug binds to a series of enzymes involved in the
final stage of cell wall synthesis, competitively
inhibit enzymatic activity.
• Leads to the formation of defective cell walls that
are osmotically unstable and cell death usually
results from lysis
• Some bacteria produce b-lactamase- enzyme that
breaks the critical b-lactam ring
© 2023 by Takele B. Tufa, AAU-CVMA.
b-Lactam Drugs

© 2023 by Takele B. Tufa, AAU-CVMA.

 b-Lactam Drugs
❑ Penicillins
▪ Most widely effective and the least toxic drugs
▪ Only effective against rapidly growing organisms
that synthesize a peptidoglycan cell wall
▪ MoA:
▪ Have b-lactam structure that interferes with
bacterial cell wall synthesis by:
• Binding to Penicillin binding proteins (PBPs) of the
bacterial enzyme.
• Inhibition of transpeptidase
• Production of autolysin
▪ Identified by the –cillin ending in the drug name

© 2023 by Takele B. Tufa, AAU-CVMA.

 b-Lactam Drugs
• Penicillins (…cont’d)
▪ Spectrum of activity depends on the type of
penicillin
– Narrow-spectrum penicillin
• for gram +ve bacteria
• Penicillin G is given parenterally
• Penicillin V is given orally
– Broader/extended-spectrum penicillin
• are semi-synthetic
• For both Gram +ve and G-ve bacteria
• E.g. Aminopenicillin (Amoxicillin & ampicillin),
• Antistaphylococcal penicillin (oxacillin, cloxacillin,
dicloxacillin, methicillin, nafcillin)

© 2023 by Takele B. Tufa, AAU-CVMA.

 b-Lactam Drugs
❑ Penicillins (…cont’d)
▪ b-lactamase resistant penicillin
• E.g. Methicillin, oxacillin, dicloxacillin, cloxacillin, and
floxacillin

– Extended spectrum penicillins (Antipseudomonas

penicillins)
• Carbenicillin and ticarcillin

– Potentiated penicillins
• chemically combined with another drug to enhance the
effects of both
• E.g. Amoxicillin and clavulanic acid combination
(which binds to beta-lactamase to prevent the beta-
lactam ring from being destroyed)
– Ampicillin-Sulbactam
– Piperacillin-tazobactam
– Ticarcillin-clavulanic acid
© 2023 by Takele B. Tufa, –
AAU-CVMA.
 b-Lactam Drugs
• Penicillins (…cont’d)
• PK:
– Crystalline penicillin: Na+ and K+ penicillin salts
suspended in inert oil prolong absorption from site of
injection for 18 hrs
– Oil based preparation of procaine penicillin G prolongs
absorption for > 24 hrs
– Benzathine pen G is a repository salt form and
absorption prolongs up to >7 days
– High concentrations are achieved in kidney, liver & lung
– Do not enter the CNS unless there is inflammation
– Metabolites are inactive and excreted in the urine

© 2023 by Takele B. Tufa, AAU-CVMA.

 b-Lactam Drugs
❑ Penicillins (…cont’d)
• Resistance:
▪ b-lactamase activity
▪ Decreased permeability to the drug
▪ Altered PBPs
• ADR:
– Hypersensitivity
– Diarrhea- due to disruption of normal flora
– Nephritis- acute interstitial nephritis by Methicillin
– Neurotoxicity- irritates neural tissue, aggravate seizure
– Hematological disorders- decreased coagulation
– Cation toxicity- Na+ or K+ salts of penicillin

© 2023 by Takele B. Tufa, AAU-CVMA.

 b-Lactam Drugs
❑ Cephalosporins
– Are semi-synthetic, broad-spectrum antibiotics
– are closely related both structurally and functionally to the
penicillins
• Have the beta-lactam ring
• The same mode of action as penicillins
• Can be identified by the ceph- or cef- prefix in the drug
name
▪ Antibacterial activity:
– Are classified into four generations- 1st, 2nd, 3rd & 4th
generation, based largely on their bacterial susceptibility
patterns and resistance to b-lactamase

© 2023 by Takele B. Tufa, AAU-CVMA.

Unique features of cephalosporins

NB: In general, as the number of the generation increases, the

spectrum of activity broadens (but becomes less effective
against gram-positive bacteria)
© 2023 by Takele B. Tufa, AAU-CVMA.
List of cephalosporins generation

Source: Riviere and Papich, 2018

 b-Lactam Drugs
❑ Cephalosporins…(cont’d)
▪ PK:
– IV or IM administration:- poor oral absorption
– Distribute very well into body fluids e.g. CSF
– All cross the placenta
– Elimination via tubular secretion (cautions)
▪ Resistance
– The same as penicillins
– Susceptible to extended spectrum b-
lactamases (ESBLs)
▪ ADRs:
– Allergic effects similar to penicillins
• Approved for VM: cephalexin, Ceftiofur, cefotaxime,
cephapirin etc (Cefquinome-4th gen)
© 2023 by Takele B. Tufa, AAU-CVMA.
 b-Lactam Drugs
❑ Carbapenems
o Penems include imipenem, doripenem, ertapenem, and
meropenem.
o Broadest antibacterial action in comparison to other β-lactams,
even surpassing 3rd gen cepha
o Becoming valuable antibiotics because of a broad spectrum that
includes many bacteria resistant to other drugs
o Not active against MRSA or resistant strains of Enterococcus
faecium.
o The high activity due to its stability against most of the β-
lactamases (including ESBL) and ability to penetrate porin
channels that usually exclude other drugs
o More bactericidal than other β-lactam antibiotics against G-ve bacteria
because they affect PBP-1 and PBP-2 and produce post-antibiotic
effects (PAE) that are not seen with other β-lactams.

© 2023 by Takele B. Tufa, AAU-CVMA.

 Cell wall inhibitors…cont’d
❑ Vancomycin
▪ MOA:
✓ inhibits synthesis of bacterial cell wall phospholipids &
peptidoglycan polymerization
▪ Antibacterial spectrum:
▪ Effective against many gram-positive bacteria; MDR
organisms e.g., MRSA & enterococci
▪ Resistance:
✓ Plasmid mediated changes in permeability to drugs
✓ Decreased binding of vancomycin to receptor
molecules
▪ PK:
✓ Not absorbed from GIT
✓ Slow iv infusion for systemic use
✓ Inflammation allows to penetrate into meninges
© 2023 by Takele B. Tufa, AAU-CVMA.
 Cell wall inhibitors…cont’d
❑ Bacitracin
– Isolated from Bacillus subtilis
– Inhibits the early stage in peptidoglycan
synthesis, i.e. disrupts the bacterial cell wall
– is effective against G+ve bacteria
– Forms complex with mammalian cell
membrane lipids
– Poorly absorbed from orally
• Used topically (skin, mucous membranes, eyes) and
as a feed additive
• Because of its potential nephrotoxicity with systemic
use

© 2023 by Takele B. Tufa, AAU-CVMA.

 Summary
Beta-lactams: MoA and MoR

Listen a lecture video and take a summary note

from the link:

https://youtu.be/qBdYnRhdWcQ

© 2023 by Takele B. Tufa, AAU-CVMA.

 Lecture 4

1. Cell wall synthesis inhibitors

2. Plasma membrane disrupting
agents
3. Protein synthesis inhibitors
4. Essential metabolites synthesis
inhibitors
5. Nucleic acid synthesis inhibitors

© 2023 by Takele B. Tufa, AAU-CVMA.

2. Cell Membrane Disrupting Agents
❑ Polymyxin B

– Works by attacking the cell membrane of bacteria

– Binds to membrane of G-ve bacteria and alters
permeability
• This leads to leakage of cellular contents and cell death
– Effective for meningitis, pneumonia, sepsis & UTIs
– But, this drug also bind to eukaryotic cells to some
extent, which limits their use to topical
applications ~ Highly toxic (absence of selective
toxicity)
– Is a narrow-spectrum, G-ve antibiotic
• Not absorbed when taken orally or applied
topically
• Used as an ointment or wet dressing
© 2023 by Takele B. Tufa, AAU-CVMA.
 3. Protein Synthesis Inhibitors
❑ Aminoglycosides
– Amikacin, gentamycin, neomycin, streptomycin,
tobramycin, kanamycin
❑ Tetracyclines
– Tetracycline, oxytetracycline, doxycycline,
minocycline, chlortetracycline
❑ Macrolides
– Azithromycin, clarithromycin, Dirithromycin,
Erythromycin, Tilmicosin, Tylosin, Gamithromycin,
Tulathromycin, Tildipirosin
❑ Chloramphenicol
❑ Lincosamides (lincomycin, clindamycin,
pirlimycin),
❑ Linezolid
© 2023 by Takele B. Tufa, AAU-CVMA.
 Protein Synthesis Inhibitors
Target ribosomes of bacteria

Protein Synthesis Inhibitors antibiotics animation video - YouTube

© 2023 by Takele B. Tufa, AAU-CVMA.

 Protein Synthesis …cont’d
❑Aminoglycosides

▪ Source:
– Produced from strains of Streptomyces spp. & other
bacteria
▪ MoA:
– Irreversibly binding to 30S subunit of rRNA causing it
to distort and malfunction; blocks initiation of translation
(interfering with mRNA) of bacteria
▪ Antibacterial activity
– broad spectrum of activity, used for gram-ve bacteria
– Pseudomonas, Acintobacter, Enterobacter,
Mycobacteria,
▪ Resistance:
– Decreased drug uptake
– Plasmid-associated synthesis of enzymes
(acetyltransferase, nucleotidyltransferases &
phosphotransferases) that modify & inactivate the drug
© 2023 by Takele B. Tufa, AAU-CVMA.
 Protein Synthesis …cont’d
❑ Aminoglycosides …(cont’d)
• PK:
– Excellent water, but poor lipid, solubility
– Not absorbed well from the GI tract, so are
given parenterally
– Stable over a wide ranges of pH and
temperatures
– Inadequate concentration in CSF
– High concentration in renal cortex & inner ear
– All of them cross the fetal membranes

➢ May be recognized by –micin or –mycin ending in

drug name
E.g., Gentamicin, Amikacin, Streptomycin,
Spectinomycin, Neomycin, Amikacin, Paromycin,
Tobramycin, © 2023 by Takele B. Tufa, AAU-CVMA.
 Protein Synthesis …cont’d

• Aminoglycosides …(cont’d)

• SE:
– potentially nephrotoxic when given systemically and
ototoxic due to binding to proximal tubules & inhibition
of mitochondrial functions, respectively.
– Neuromuscular paralysis
– Allergic rxns- contact dermatitis for topically applied

© 2023 by Takele B. Tufa, AAU-CVMA.

 Protein Synthesis …cont’d
❑Tetracyclines
▪ MOA: Bind reversibly to 30S subunit of bacterial
ribosomes, thereby blocking attachment of tRNA to
mRNA-ribosome complex at receptor site
– Interfere with bacterial protein synthesis

▪ Antibacterial spectrum:
o Broad
• wide variety of bacteria, intracellular organism:
Mycoplasma, Chlamydia & Rickettsia
• Bacteriostatic

E.g., Tetracycline, oxytetracycline,

chlortetracycline, doxycycline and
minocycline
© 2023 by Takele B. Tufa, AAU-CVMA.
 Protein Synthesis …cont’d

▪ Tetracyclines…(cont’d)

▪ Resistance:
▪ Widespread resistance development
▪ Active efflux pump, mediated by plasmid-
encoded resistance protein, TetA
▪ Enzymatic inactivation
▪ Production of bacterial proteins that prevent
TTC from binding to the ribosome

© 2023 by Takele B. Tufa, AAU-CVMA.

 Protein Synthesis …cont’d
❑ Tetracyclines…(cont’d)
▪ PK:
– Can bind to divalent ions: calcium and be deposited in
growing bones and teeth,
– or bind components of antacids and other mineral-
containing compounds/foods (dairy products)
– Complex formation (chelation) limits absorption
– Adequate penetration into most body fluids
– All of them cross the placenta barrier
– Metabolized and conjugated to form soluble
glucuronides
– Parent &/or metabolites are secreted into the bile and
most undergo enterohepatic circulation
– Are recognized by –cycline ending in drug name
▪ SE:
▪ GIT signs, hepatotoxicity, and superinfection

© 2023 by Takele B. Tufa, AAU-CVMA.

 Protein Synthesis …cont’d
❑Macrolides
▪ MoA:
✓ Inhibits protein synthesis by reversibly binding to the P
site on 50S subunit of bacterial ribosome- prevent
peptidyltransferase from binding the growing peptide
attached to tRNA to the next AA as well as (-) ribosomal
translation.
▪ Antibacterial spectrum:
– a broad-spectrum of activity- mainly Gram+ve
• Used to treat penicillin-resistant infections or in
animals that have allergic reactions to penicillins
• Bacteriostatic at therapeutic concentration, but can
be slowly bactericidal, especially against
Streptococci
• Mycoplasma, mannheimia, pneumococci,
staphylococci, enterococci, and some rikettsia
© 2023 by Takele B. Tufa, AAU-CVMA.
 Protein Synthesis …cont’d
Macrolides… (cont’d)
▪ Resistance:
– Unable to enter into or presence of efflux pump
– Decreased affinity to 50S ribosomal subunit
– Presence of Plasmid-mediated erythromycin estrase

▪ PK:
– Weak bases that are poorly absorbed
– Has a large molecular structure
– CYP 450 enzyme inhibitor
– Variable distribution between the drugs
– Primarily concentrated & excreted in active form in the bile
– Optimum antibacterial pH is 8
• Acidic environment: abscess, necrotic tissue or urine
suppress its antibacterial activity

© 2023 by Takele B. Tufa, AAU-CVMA.

 Protein Synthesis …cont’d
▪ Macrolides… (cont’d)
• Use:
– Bovine resp. diseases and enzootic pneumonia in
sheep
– Immunomodulating activity
▪ ADR
– Epigastric distress-oral based
– Cholestatic jaundice
– Ototoxicity
• CI
– Non ruminant herbivores: horses and rabbits
– Cause rapid rxn- fatal digestive disturbances
▪ Macrolides used in animals:
▪ Erythromycin, tylosin, Tilmicosin, Azithromycin,
Gamithromycin, Tildipirosin, Tulathromycin
© 2023 by Takele B. Tufa, AAU-CVMA.
 Protein Synthesis …cont’d
❑ Others
❑Chloramphenicol
– Inhibits protein synthesis by its action on the ribosome
of both bacterial and mammalian cells
– Is a synthetic, has a broad-spectrum of activity that
penetrates tissues and fluids well (including the eyes
and CNS)
– Metabolized in liver & CYP-450 inhibitor
– Has toxic SE:
• Bone marrow depression that extremely limit use
– Its use is strictly controlled in food-producing animals
• Drug residue effects –aplastic anemia in susceptible
individuals
• Its effect is not concentration dependent
– Chloramphenicol is the only drug in this category
– Its derivatives: Thiamphenicol, Florfenicol

© 2023 by Takele B. Tufa, AAU-CVMA.

 Protein Synthesis …cont’d
❑Florfenicol
– Inhibits protein synthesis by its action on the
ribosome of bacterial cells
– Is a synthetic, broad-spectrum antibiotic
– Currently recommended for resp. infections
caused by M. haemolytica and P. multocida,
foot rot.
– Enteric septicemia in fish, colibacillosis in broiler
SE:
✓ local tissue reaction (possible loss of tissue at
slaughter), inappetence, decreased water
consumption, and diarrhea
– is the only drug in this category
– Recently approved for use in food animals & dogs
 Protein Synthesis …cont’d
❑Lincosamides (clindamycin)
– Inhibits protein synthesis by binding to the ribosome
of bacterial cells
– Bacteriostatic
– Are narrow-spectrum, gram-positive infections where
there is resistance or intolerance to penicillins
(MRSA)
– Not for G-ve bacteria (unable to pass via porins)
– Penetrate bone well, hence are indicated in
• Osteomyelitis and periodontitis
– Toxic in small mammals, where they trigger a
clostridial overgrowth
– SE: GI problems (Pseudomembranous colitis)
– E.g. Clindamycin, pirlimycin, & lincomycin
© 2023 by Takele B. Tufa, AAU-CVMA.
 Protein Synthesis …cont’d
❑Streptogramins
– Bind to the P site of the 50S and inhibit protein
synthesis– prevent tRNA binding, elongation
of protein chains & release of incomplete
peptides
– Bactericidal – Streptococcus and Staph
– Bacteriostatic- E. faecium
– Effective for Gram +ve bacteria only
– For VRSA and VRE.facium but not for VRE.
Fecalis
– Not used….still may be as feed additives

© 2023 by Takele B. Tufa, AAU-CVMA.

 Protein Synthesis …cont’d

❑Linezolid
– Inhibit initiation of complex formation
– Bacteriostatic
– Bactericidal only for Streptococcus
– G +ve bacteria: MRSA, VRSA, VRE. feacalis
– Use: Skin and soft tissue infection
– SE: GI, bone marrow suppression

© 2023 by Takele B. Tufa, AAU-CVMA.

 Lecture 5
1. Cell wall synthesis inhibitors
2. Plasma membrane disrupting agents
3. Protein synthesis inhibitors
4. Essential metabolites synthesis
inhibitors (antimetabolites)
5. Nucleic acid synthesis inhibitors
6. Miscellaneous antibiotics

© 2023 by Takele B. Tufa, AAU-CVMA.

 4. Antimetabolites
• Antibacterial drugs that inhibit synthesis of essential
metabolites
• Competitive inhibition by substance that resembles normal
substrate of enzyme
• Folate is essential for the synthesis of purines &
pyrimidines (precursors of RNA & DNA)& necessary
for cellular growth and replication
• Hence, absence of folate, cells cannot grow or divide.
• Humans/animals obtain preformed folate in the form
of folic acid (FA) as a vitamin from diet.
• However, many bacteria are impermeable to FA, and
therefore, must rely on de novo folate synthesis.
• In many MOs, DHFA is synthesized from PABA,
pteridine & glutamate

© 2023 by Takele B. Tufa, AAU-CVMA.

 Inhibition of THF synthesis by sulfonamides and
trimethoprim
Pteridine precursor + PABA

Microorganisms
Dihydropteroate
Sulfa drugs synthetase

Glutamate
Dihydrofolic acid
(DHFA)
Dihydrofolate
Trimethoprim reductase

Tetrahydrofolic
Purine acid (THFA)
synthesis Thymidine
synthesis
© 2023 by Takele B. Tufa, AAU-CVMA. Amino acid synthesis
 Antimetabolites…cont’d
❑ Sulfonamides
• MoA:
– Sulfa drugs are synthetic analogs of PABA
– The drug compete for bacterial enzyme:
dihydropteroate synthetase. Thus, inhibit the synthesis
of bacterial DHFA, and, thereby, the formation of its
essential co-factor forms.
– Antimetabolites, interfering with normal production of
RNA, protein synthesis & microbial replication
mechanisms
– Inhibit metabolism by interfering with the synthesis of
FA (needed for the growth of many organisms)
– Bacteriostatic

• Broad antibacterial activity:

– many bacteria, Coccidia, Chlamydia, protozoa including
Toxoplasma

© 2023 by Takele B. Tufa, AAU-CVMA.

 Antimetabolites…cont’d

❑ Sulfonamides (cont’d)

• Resistance:
✓ Natural resistance
o Bacteria that can obtain folate from environment
✓ Acquired resistance- plasmid transfer or random mutation
o Altered dihydropteroate synthetase
o Decreased cellular permeability
o Enhanced production of the substrate, PABA

© 2023 by Takele B. Tufa, AAU-CVMA.

 Antimetabolites…cont’d

Sulfonamides (cont’d)

• PK:
o Some are designed to stay in the GI tract
(sulfasalazine);
o Some are absorbed by the GI tract and penetrate
tissues
o Acetylation in the liver and lungs is the main route of
metabolism
o Metabolites excreted via the kidneys

© 2023 by Takele B. Tufa, AAU-CVMA.

 Antimetabolites…cont’d
Sulfonamides (…cont’d)
– May be potentiated with
• trimethoprim or ormetoprim; reduce the MIC needed of both
drugs & therefore reduce SE.
• Anticoagulant effect of warfarin- it displaces from binding to
albumin.

➢ Indications:
• Urinary, CNS, joint, respiratory, prostate infections
– Trimethoprim distribute to most tissues of the body
(lipophilic) & concentrates in tissues with greater acidity than
plasma (e.g., prostate)
– Sulfasalazine (Salazopyrin)
• Used to treat IBD (inflammatory bowel disease) as one of its
metabolites has a local anti-inflammatory effect in the colon

© 2023 by Takele B. Tufa, AAU-CVMA.

 Antimetabolites…cont’d
❑ Cotrimoxazole (Trimethoprim + sulfamethoxazole)
– Greater antibacterial activity than equivalent quantities of
either drug used alone
– Synergistic activity
▪ MoA:
▪ inhibits two sequential steps in the synthesis of THFA
✓ SMZ inhibits the incorporation of PABA into DHFA
precursors
✓ TMP prevents reduction of DHF to THF
▪ Antibacterial activity
✓ Broader spectrum than the sulfa drugs

▪ Resistance:
✓ Less frequent than either of the drugs alone

© 2023 by Takele B. Tufa, AAU-CVMA.

 Antimetabolites…cont’d

▪ SE:
✓ Dermatologic reactions (skin rashes)
✓ GIT problems,
✓ Hematologic (Megaloblastic anemia, leukopenia)
✓ crystalluria,

© 2023 by Takele B. Tufa, AAU-CVMA.

 Thank you!
takele.beyene@aau.edu.et
takelebeyene@gmail.com

© 2023 by Takele B. Tufa, AAU-CVMA.

VETERINARY PHARMACOLOGY
AND
THERAPEUTICS I
For 3rd DVM Students

Compiled By Dr Lishan A 1
 INTRODUCTION
❑History of pharmacology
• Knowledge of drugs and their use in disease is as old as history
of mankind, but as a science Pharmacology is quite a young one.

• The birth date of pharmacology is not as clear-cut.

• Primitive men gathered the knowledge of healing and medicine
by:-
➢Observing the nature,
➢Noticing animals while ill and
➢Personal experiences after consuming certain herbs and
berries as remedies.
Compiled By Dr Lishan A 2
Cont……… History:

• Ancient civilizations discovered that extracts

from plants, animals, and minerals had
medicinal effects on body tissue. These
discoveries became the foundation of
pharmacology.

Compiled By Dr Lishan A 3
 A. Early History:
• Kahun Papyrus (2000 BC) is an oldest Egyptian document containing
information about veterinary medicines and uterine diseases of women.
• Hippocrates (460-375 BC) A Greek physician consider “father of
Medicine”.
➢ He was the first person who recognize disease as abnormal reaction of body.

➢ He introduce use of metallic salts for the treatment of disease.

• Theophrastus (380-287 BC) a great philosopher called father of

Pharmacognosy.
➢ He classified medicinal plants on the base of medicinal characteristics.

Compiled By Dr Lishan A 4
Cont. …. Early History

• Pedanius Dioscorides [1st century (AD 57)] (anno

Domini, in the year of our Lord), a Greek
physician:
➢He was one of the 1st author of Materia Medica of
approximately 500 plants and remedies.

➢This work encompassed botanical terminology as well

as how herbs and plants could be used in medicine.

Compiled By Dr Lishan A 5
 Cont. …. Early History
• Examples of ancient pharmacological(medical substances)
known documentation (records) are:-
✓ Indian Ayurvedic treatise from the 6th century BC.
✓ Unani (a system of healing used in south Asia )
✓ Chinese(2500 BC)(PAN TSAO-CHINESE MATERIA MEDICA)

✓ Papyri from ancient Egyptian(1500BC) (EBERS PAPYRUS-

EGYPTIAN MATERIA MEDICA)

❖ MATERIA MEDICA = list of symptoms and corresponding

remedies.
Compiled By Dr Lishan A 6
 B. In medieval times
• Apothecaries, in a way crude pharmacists of their day,
➢ Used to prepare all sort of strange concoctions, including those
of herbs, in order to treat their patients.

➢ They not only prepared drugs but also prescribed them.

• In the early 1800s, however, some apothecaries decided

they had no interest in treating patients and were more
interested in preparing medical compounds instead.

Compiled By Dr Lishan A 7
 Cont. ……medieval times
• By the end of the century, scientists using new advances in
chemistry and biology, across various disciplines; at the time:
✓ Isolated, purified, and even standardized some drugs like morphine
✓ Conducted experiments on animals to show what effects a drug
may exert upon the body, how, and why.

➢ Pharmacology as we know it today became a scientific

discipline in the early 19th century, when a number of
physiologists began to perform pharmacologic studies.

Compiled By Dr Lishan A 8
 C. Modern History
❖ Conversion of old medicines into the modern pharmacology start taking
shape following the introduction of animal experimentation and
isolation of active ingredients from plants.

• Francois Megendie (1783-1855) a first pharmacologist established the

foundation of modern pharmacology. He developed experiment to
elucidate the physiological processes and action of drugs on the body.

• Oswald Schmiedeberg (1838–1921) “Father of Pharmacology”

established pharmacology as an independent discipline. He start
teaching Pharmacology in University of Strasbourg (France).

Compiled By Dr Lishan A 9
Cont. …………Modern History
• L. mayer Jones (1912-2002) regarded as father of modern
veterinary pharmacology. He authored first book of veterinary
pharmacology and therapeutics in 1954.

• The origins of veterinary pharmacology and therapeutics are the

same as those of the equivalent human disciplines, laying in the
administration of and responses to plants and extracts of plants
containing pharmacologically active compounds.

Compiled By Dr Lishan A 10
 Cont. …………Modern History

•The field of pharmacology grew rapidly in the 20th and 21st

centuries, increasing in the number of new drugs that would
improve the human condition tremendously.

• Many drugs, from lifesaving antibiotics, vaccines, to important

hormonal compounds like insulin (to treat diabetes) were
developed.
• Likewise, there has been great progress in the treatment of
chronic conditions like diabetes, hypertension, and depression.

Compiled By Dr Lishan A 11
 Definition of terms
❖ Pharmacology is the science of drugs (Greek pharmakos,

medicine or drug; and logos, study/science).

➢ It is the study of substances that interact with living systems
through chemical processes, especially through binding to
regulatory molecules and activating or inhibiting normal body
processes.
➢ Experimental science dealing with the properties of drugs and their effects
on / interactions with/ living systems.
▪ Wide term which includes:
➢ The investigation of the biochemical and physiological effects of drugs
➢ The study of drug absorption; distribution; metabolism and excretion
➢ The knowledge about the history; sources; physical and chemical properties
and therapeutic uses of drugs.
Compiled By Dr Lishan A 12
 What is a Drug?
• Drug: French: Drogue – a dry herb:
➢ A single active chemical entity present in a medicine that is used for
diagnosis, mitigation, prevention and treatment of diseases.
✓ Articles other than food intended to affect the structure or function of the
body.

• WHO:
➢ “Drug” is any substance or product that is used or intended to be
used to modify or explore physiological system or pathological states
for the benefit of the recipient.
• FDA approved definition of drugs
➢ A chemical substance that is mainly used to treat, control, prevent, or
diagnose a specific disease or to prevent pregnancy!!!
Compiled By Dr Lishan A 13
 Human Pathophysiological
/ Animal Process=Disease

Management
Drugs

Compiled By Dr Lishan A 14
Drug and Medicine

• Drug:- a chemical substance of known structure, other than

a nutrient or an essential dietary ingredient, when
administered to living organism, produce a biological effect

• Medicine:- a chemical preparation which usually but not

necessary contain one or more drugs
➢ Substance that have medical importance or therapeutic values

➢ Mostly, Drug + additives

Compiled By Dr Lishan A 15
 Cont. ….. Defn of terms
• Xenobiotic : is a compound foreign to the body
✓ Not produced within the body

✓ Physiologically, endocrinologically, or pharmacologically active

• Dose: quantity of medication to be administered at one time.

• Dosage regimen: is the Manner in which a drug is taken.

• Dosing frequency – The time interval between Doses.

• Pharmaceutics: large-scale manufacture of drugs.

• Steady state: is achieved when the Rate of administration =
Rate of elimination.
Compiled By Dr Lishan A 16
 Cont. ….. Defn of terms

• Drug therapy:- the proper administration of drugs used

to treat disease.

• Indication – the use of that drug for treating a particular

disease.
✓ Example: insulin is indicated for the treatment of diabetes.

❖ Over-the-counter(OTC)/Nonprescription drugs:- sold without a

prescription in a pharmacy.

Compiled By Dr Lishan A 17
 Cont. ….. Defn of terms
• Placebo: Drug dosage form such as a tablet/capsule that
has no pharmacologic activity because the dosage form
has no active ingredients

• Contraindication: Are factors in a patient condition

that make the use of a drug dangerous. e.g.
✓ Renal failure, pregnancy, hypertension, diabetes.

✓ Camels do not tolerate the trypanocidal drugs diminazine

aceturate and isometamidium chloride, at doses harmless to
other ruminants.
Compiled By Dr Lishan A 18
 Cont. ….. Defn of terms
• Bioequivalence:- indicates/shows that the drug
products, when given to the same patient in the same
dosage regimen, result in equivalent concentrations of
drug in plasma and tissues.
• Therapeutic equivalence:- indicates that drug products,
when given to the same patient in the same dosage
regimen, have the same therapeutic and adverse effects.

Compiled By Dr Lishan A 19
 Sub Fields Of Pharmacology
• Pharmacokinetics: It deals with Absorption, Distribution,
Metabolism and Excretion (ADME) of drugs.
➢ What our body does to a drug.
❖ Pharmacodynamics: is the study of the :
✓ Biochemical and physiological effect of the drugs on our body,
parasites and micro-organisms,
➢ what a drug does to our body.

✓ Mechanism of action.
✓ Relation between drug concentration and its therapeutic effect.

Compiled By Dr Lishan A 20
 Cont. ……..Sub Fields
• Pharmacy:- It is the art and science of compounding and
dispensing drugs or preparing suitable dosage forms for
administration of drugs in man and animals.
✓ It also includes identification, selection, collection,
purification, isolation, standardization and quality control of
medicinal substances.

• Experimental Pharmacology: It deals with the study of

drugs action in animals under laboratory conditions.

Compiled By Dr Lishan A 21
 Cont. ……..Sub Fields
• Pharmacotherapeutics: study the use of drug in the treatment
and prevention of disease.
✓ Which among the drugs would be most effective or appropriate for a
specific disorder or what dose would be required.
➢ Using or depending upon the information of drug obtained by
pharmacodynamics studies

✓ Use of drugs and clinical indications of drugs to prevent and treat

disease (clinical management of diseases)
▪ Pharmacogenetics / Pharmacogenomics: It deals with the
study of genetic variations that cause difference in drug
response among different individuals.
Compiled By Dr Lishan A 22
 Cont. ……..Sub Fields
• Toxicology:- Study of the harmful effect of drugs and
chemicals.
➢ It deals with the symptoms, mechanisms, treatment and
detection of poisoning caused by different chemical
substances.

➢ For toxicology, main criterion is the dose.

➢ A medicine(any chemical substance) in high dose/excess can

be a poison (including those beneficial in lower doses) while a
poison in low dose can be a medicine.

Compiled By Dr Lishan A 23
 Cont. ……..Sub Fields

• Posology: is the study of how medicines are dosed. It also

depends upon various factors including age, weight, and sex.
❖ Clinical pharmacology it is the controlled evaluation of the
efficacy and safety of drug therapy in animal patients.

❖ Chemotherapy: A branch of pharmacology dealing with drugs

that selectively inhibit or destroy specific agents of diseases
such as bacteria, viruses, fungi and other parasites. It also
includes the drugs used in malignancy/ neoplastic diseases.

Compiled By Dr Lishan A 24
 Cont. ……..Sub Fields
• Pharmacoeconomics: Study of cost effectiveness of drug
treatment.
• Pharmacognosy: is the study of identification/source of drugs.
❖ Pharmacopoeia: It is an official code containing a selected list
of the established drugs and medicinal preparations with
descriptions of their physical properties and tests for their
identity, purity and potency.
➢ Define the standards of preparations. Examples- BP, USP, IP an EP

Compiled By Dr Lishan A 25
 Cont. ……..Sub Fields
❖Pharmaco-epidemiology
✓It deals with the study of effects of drugs on a large population.
✓It includes trial studies on healthy and diseased individuals and collecting the
opinion of physicians prescribing a drug.
❖Comparative Pharmacology
✓It deals with the comparison of different drugs of same or different uses.
❖Animal Pharmacology
✓It deals with different properties of drugs in animals.

❖ Immuno pharmacology: It deals with the immunological actions of

drugs in immune system and development of antibodies in response to a
drug.

Compiled By Dr Lishan A 26
 Sources of Drugs
• Drugs are obtained from many sources.
1. Natural sources

❖ Plants = Roots, bark, sap, leaves, flowers, seeds were sources for
drugs. E.g. Morphine, digoxin, atropine, castor oil, etc
❖ Minerals = acids, bases, iron, kaolin , liquid paraffin, salts like
Epsom salt, etc
❖ Microorganisms = Natural penicillin from mold, streptomycin and
many other antibiotics.
❖ Animals = Insulin from the pancreases of pigs and cattle, thyroid
extract, heparin and antitoxin sera, etc..

Compiled By Dr Lishan A 27
 Cont. …….Sources of Drugs
2. Synthetic / Semi-synthetic
➢ Synthetic drugs: are created artificially. E.g. aspirin
➢ Semi-synthetic: contain both natural and synthetic
components. E.g. ampicillin, diacetylmorphine etc.
3.Radiopharmaceuticals: are diagnostic or therapeutic drugs
containing radioactive isotopes.
4.Genetic engineering (Altering DNA):
➢ Human insulin, human growth hormone etc.
❖ Out of all the above sources, majority of the drugs currently used
in therapeutics are from synthetic source.

Compiled By Dr Lishan A 28
 Dosage Forms Of Drug
• Dosage form of drug is medicated product specially designed
/preparations of drugs compounded/ for administration depending
upon the routes to the patient for diagnosis and treatment of disease.

❖ The dosage form is broadly divided into:

• Solid dosage (Bolus, Tablets. Powder, capsule etc )

• Semi-solid dosage (Cream, Ont, gel) which are,

used both
• Liquid dosage (Solutions, suspension)
internally as
• Inhalations well as,
externally

Compiled By Dr Lishan A 29
 1. Solid Dosage Forms
• Tablets:
➢ A mixture of active drug and inert binding materials or
excipients, usually in powder form, pressed or compacted into a
solid.
➢ Is a compressed product (AP/AI + excipients)
• Granule: is a dosage form consisting of powder particles that
have been aggregated to form a larger mass.
• Patches : Disk-shaped piece of material that is worn on the skin
and contains a substance (as a drug) that is absorbed at a
constant rate through the skin into the bloodstream.
Compiled By Dr Lishan A 30
❖Powder
• Drug dosage form in fine particles.
• Could be sprinkled on feed or dissolved in drinking water.
• It is commonly used in poultry.

❖Suppository:
• Is drug in the form of a small plug that is inserted into a bodily
cavity, especially:
➢ The rectum (rectal suppository), vagina (vaginal suppository/
Pessaries), or urethra (urethral suppository), where it melts at
body temperature to deliver the drug.
• Used to deliver both systematically- and locally-acting medications.

Compiled By Dr Lishan A 31
 ❖Capsule: can be
• Hard gelatin. e.g. ampicillin capsule for dry powdered
ingredients or miniature/small pellets.
• Soft gelatin. e.g. garlic capsule
➢ Primarily used for oil & for AI that are dissolved or suspended in oil.
➢ AP/AI + excipients - enclosed in the hard/soft water soluble container
made of gelatin.
➢ Consist of cap and body – filled with powders, pellets, granules
(paste, oil)
✓ In the GIT gelatin shell softens, swells and dissolve – particles are
dispersed → disintegration → AP/AI dissolution → absorption
➢ Hygroscopic

Compiled By Dr Lishan A 32
 2. Semi-solid Dosage Form:
• Examples are ointments, creams and gels commonly
used to treat dermatological diseases.
• Ointments are homogenous, viscous, semi-solid, greasy,
thick oil, intended for external application to skin or
mucous membranes.
• A paste is a 2-component semi-solid in which drug is
dispersed as a powder in an aqueous or fatty base.

Compiled By Dr Lishan A 33
 3. Liquid dosage forms
❖ Suspension:
✓ Formulation of two-phase system composed of a finely divided
solid that is dispersed in a liquid phase, which is usually water.
✓ They are common as oral drug preparations.
✓ Never administer intravenously.
❖ Emulsion:
✓ Aqueous suspension of insoluble liquid substance usually with
emulsifying agent to stabilize the preparation.
✓ Usually administered orally or topically.

Compiled By Dr Lishan A 34
❖Solutions
• Oral Solution: is aqueous preparation of drug for
oral use. The drug is in true solution.

• Parenteral Solution: sterile and pyrogen free

aqueous preparation for injection. Drugs may also
be dissolved in oil for prolonged absorption.

• Ophthalmic Solution: sterile hypotonic aqueous

solution of drug for administration into eye.

Compiled By Dr Lishan A 35
❖Liniment:
• Liquid preparation of a drug in which the drug is dissolved or
suspended in dilute alcohol or water.

• Often contain dissolved or emulsified oils and are applied to the

skin by rubbing or massage.

❖Lotion:
• Usually an oil in water base which contains insoluble medicinal
agents in Suspension and

• Is applied to the skin without rubbing following which the solvent

evaporate leaving a film of drug.

Compiled By Dr Lishan A 36
❖Tincture:

• Tinctures vary in strength. Example are

tinctures of alcohol, iodine, opium, and

digitalis.

Compiled By Dr Lishan A 37
 4. Aerosol Dosage Forms
• The drug exists as liquid or solid particle so small
as to remain suspended in air for long periods.

• Aerosol generators may produce particles in 1-5µm

ranges.

• For therapeutic purpose, aerosols are introduced

in the body by inhalation.

Compiled By Dr Lishan A 38
 Storage and Handling of Cytotoxic and
Hazardous Drugs
• Storage??
✓Pharmacological
✓Alphabetical
✓Dosage forms

❖Utilization of stored chemicals

✓Based on expiration date (LIFO/FIFO Method)

Compiled By Dr Lishan A 39
 Safe Handling of Hazardous Drugs
❖What Are Hazardous Medications?
• Medications that are known or suspected to cause
adverse health effects from exposures in the
workplace.
• They include:
✓Antiviral medications, hormones, antibacterial, & other
miscellaneous medications.
✓Chemicals for ecto-parasites

Compiled By Dr Lishan A 40
 Potential Risks to Health Care Workers
• Working with or near hazardous medications in health
care settings can potentially cause:
✓Skin rashes
✓Infertility
✓Miscarriage
✓Birth defects
✓Organ toxicities
✓Leukemia or other cancers

Compiled By Dr Lishan A 41
Adverse Health Effects of Occupational
Exposure to Hazardous Drugs on specific system

• Integumenary/Mucosal • Reproductive
– Skin irritation or contact
dermatitis – Infertility
– Mouth and nasal sores – Prolonged time to conception
– Partial alopecia*; hair thinning – Premature delivery/low birth weight
• Neurologic
– Ectopic pregnancy
– Headaches
– Dizziness – Spontaneous abortions/miscarriages
• Respiratory – Stillbirths
– Dyspnea
– Learning disabilities in offspring
• Gastrointestinal
– Nausea and vomiting • Malignancies
– Abdominal pain – Leukemia
• Hypersensitivity – Non-Hodgkin’s lymphoma
– Allergic asthma
– Bladder cancer
– Eye irritation
–
Compiled By Dr Lishan A
Liver cancer 42
 How Do Staff Come in Contact With Hazardous
Medications?
Direct contact Indirect Contact

• Primary physical contact with • Secondary contact with a

a hazardous medication hazardous medication from
during: body fluids, bed linens,
✓ Preparation or medical equipment, etc.
✓ Administration or

✓ When managing a hazardous

medication spill/fall.

Compiled By Dr Lishan A 43
 Exposure Risks
Studies show:
• Chronic (repeated exposure during preparation or
administration of chemotherapy drugs without the use of
protective gloves) low-level exposure to HDs can lead to
absorption.
➢ Chronic low-level absorption may cause significant long-term
side effects.
❖ The use of personal protective equipment (PPE) reduces
the risk of absorption.

Compiled By Dr Lishan A 44
Types of Exposure

• Absorption (through skin, eyes, or mucous

membranes)

• Injection (accidental needle sticks)

• Ingestion

• Inhalation (sprays, aerosolization, drug dust, spills)

Compiled By Dr Lishan A 45
 Controls to Exposure
• Work Practice Controls (procedures performed to
reduce exposure)
─ Prime IV tubing in the Biologic safety cabinets (BSC) , with
saline/locking connections

• Administrative Controls
– Provide clear policy/procedure, education, training, and
evaluation.*

• Personal Controls
─ Personal Protective Equipment – known as “PPE”

Compiled By Dr Lishan A 46
Guidelines for PPE

Compiled By Dr Lishan A 47
 When Should PPE Be Used?
• Introducing or withdrawing needles from vials

• Transferring drugs from vials to other containers using needles or syringes

• Opening ampoules

• Expelling air from a drug-filled syringe

• Administering HDs by any route

• Spiking IV bags containing HDs and changing IV tubing

• Disposing of HDs and items contaminated by HDs

• Handling the body fluids of a patient who received HDs in the past 48 hours

• Cleaning HD spills/fall/leak

Compiled By Dr Lishan A 48
 Disposal of HDs
• Place in leak-proof container.
• Label as hazardous. Put sharps in a puncture-proof
container.
• Seal containers when full.
• Decontaminate reusable equipment (IV poles).
• Keep HDs away from pets and children.
• Follow local regulations regarding disposal.*

Compiled By Dr Lishan A 49
 Spill Management
• Prevent spills as much as possible!

• Be prepared for one if it happens (spill kit).

• Post signs where spill is located; evacuate area.

• If clothes or skin are contaminated, remove clothes; wash

skin with soap and water; get medical attention.

• Wear full PPE, including respirator mask and shoe covers,

before attempting to control spill.

Compiled By Dr Lishan A 50
Mgt of Acute Accidental Cytotoxic Exposure:

❖Skin ❖Inhalation
– Remove contaminated – Move away from area of
garments. exposure.
– Immediately wash skin – Seek emergency treatment.
with soap and water. – Refer to emergency department.
– Refer to emergency
department.
❖Ingestion
– Do not induce vomiting.
❖Eye – Seek emergency treatment.
– Immediately flush eye(s). – Refer to emergency department.
– Seek emergency treatment.
– Refer to emergency
department.

Compiled By Dr Lishan A 51
Naming of drugs/ Nomenclature
 Names of drugs a source of confusion to the novice and include;
 3 Type Of Naming System

Compiled By Dr Lishan A 52
 Cont. ……Nomenclature
❖Generic name:
✓ International non proprietary names (INN)- describe the common name of
drug
✓ Product must have this name
✓ Accepted internationally
✓ Only one generic name for a drug
❖Brand name(Trade Name):
✓ Name by manufacture company
✓ Several name for single drug may occur and have letter ®
✓ Expensive
➢ The difference b/n generic product and brand product is only the
additives but not active ingredient
❖Chemical name (Scientific Name):
✓ Is based on molecular structure of drugs.
✓ Interest of chemists
✓ Indicate the chemical entity present in the drug
Compiled By Dr Lishan A 53
 Cont. …….. Name of
o Example:- Paracetamol

❖ Chemical name: N-(4-hydroxyphenyl)acetamide.

❖ Non-proprietary name:
✓ Approved Name: British Approved Name (BAN): paracetamol

✓ United States Adopted Name (USAN): acetaminophen

✓ Official Name: Acetaminophen

❖ Proprietary name: panadol, calpol, adol

Compiled By Dr Lishan A 54
 Prescription writing
❖ A written order issued by a physician or other qualified practitioner that
authorizes a pharmacist to supply a specific medication for a patient,
with instructions on its use. (written order for medicine)
1. The date of writing the prescription
2. Patient/owner Information (patient’s full name, age, and current address.)
3. The superscription, Rx Symbol
4. The inscription lists the names and amounts of drugs
5. The signatura (Sig. or S.)
6. The subscription gives the instructions to the pharmacist.
7. The signature of the practitioner

Compiled By Dr Lishan A 55
 ❖Superscription (i.e., heading)
• Is an abbreviation of the Latin word (Symbol = R)
recipe meaning “take thou of”.

• It highlights the beginning of your instructions for

dispensing the medication.

Compiled By Dr Lishan A 56
 The inscription:-Medication prescribed
➢ Lists the names and amounts of drugs to prescribed
➢ Where you include details about the specific drug and percentage
you want to prescribe.
➢ It is always best to avoid abbreviations (to make things perfectly
clear for the pharmacist).
• The inscription should include the following:
✓ Drug name – can be generic or trade name
✓ Drug strength – especially if the drug comes in more than one
strength
✓ Drug formulation

Compiled By Dr Lishan A 57
 ❖Signatura – sig for short: Patient use directions
• is where you lay out the nitty-gritty(essential) details for how and
when the patient will use the prescribed medication.

• Here are some things to include:

✓ Amount of drug to take each time
✓ When to take the medication (frequency, duration)
✓ Route of administration
➢ How to administer the medication
✓ When to discontinue use = duration

Compiled By Dr Lishan A 58
 Subscription:- Dispensing directions
➢ Gives the instructions to the pharmacist.

• This is where you will let the pharmacist know what

exactly to hand over to the patient.

• Write the amount the pharmacist will dispense, preceded

by “dispense,” “disp,” or “#”
➢ Always spell numbers out to prevent confusion and possible
alterations
➢ Include the bottle size, ointment tube size, or number of tablets
or capsules.

Compiled By Dr Lishan A 59
 Cont. ……prescription

• Names of drugs to be included in the

prescription
✓Should not be abbreviated but

✓ Written out in full to avoid possible errors

✓Written out in generic name

✓Chemical formulas must not be used

Compiled By Dr Lishan A 60
Abbreviations used in prescription writing
Abbreviation Latin Meaning
ad lib ad libitum freely as required
à à ana for each
a.c. ante cibum before meals
à ante before
aq. aqua water
b.i.d (BID) bis I die twice a day
cap. capula capsule
dos. dosis a dose
eq. pts. equalis parties equal parts
gtt. gutta a drop
haust haustus drench
h. hora hour
no. numero number
n.r non repetatur not to be repeated
o.d omne die every day
per os orally
p.c post cibum after meals
prn pro re nata as occasion requires
qid quater in die four times a day
s.o.s si opus sit if necessay
tab tabella a tablet
t.i.d (TID) ter in die three times a day
Compiled By Dr Lishan A 61
 Cont………..Abbreviations
• p.o. Take by mouth, orally. From the Latin term per os.
• p.r.n. Take as necessary or when needed. From the Latin term pro re nata.
• q.d. Take once per day. From the Latin term quaque die.
• q.h. Take once every hour. From the Latin term quaque (every) and the
abbreviation for hours.
• q.2h Take once every 2 hours.
• q.3h Take once every 3 hours.

❖ Note
➢ Dose calculation:- usually using units of mg, ml, and IU per
kg body weight.
➢ Percentage(wt/v, v/v, wt/wt)
➢ Dilution formula Compiled By Dr Lishan A 62
 Routes of drug administration
• Drugs can be administered by various routes.

• Most Commonly used routs:

1. Topical Routes: to produce local effects, drugs are applied

topically to skin or mucous membranes.

✓ Skin: the dosage forms applied locally to skin are powders,

paste, lotions, ointments, creams, plasters and jellies.

▪ They are used for their antiseptic, antipruritic, analgesic, local

anesthetic and other effects.

Compiled By Dr Lishan A 63
 Routes. ……cont’d
✓ Mucous membranes: the topical application is also used on the
mucous membranes.

❖ i.e. nose, throat, eye, ear, bronchi, urethra, vagina and rectum.

2. Systemic routes: to produce systemic effects

➢ Drugs are administered orally, rectally, parentally or by inhalation route.

➢ The drug administered through systemic route is absorbed into the blood,
distributed along through the circulation and produces their desired effects.

Compiled By Dr Lishan A 64
 Routes. ……cont’d
✓ Oral route: this is the most commonly used route of drug
administration.

Advantage
✓ It is the safest, most convenient and economical.

Disadvantage
✓ Drug action is slow, thus not suitable for emergencies.

✓ Incapability to absorb some drugs, due to their physical characteristics i.e.

polarity of the drug.

✓ Unpalatable and other irritant drugs cannot be administered.

Compiled By Dr Lishan A 65
Routes. ……cont’d

• May not be useful in the presence of vomiting and diarrhea.

• Cannot be used for unconscious and uncooperative patients.

• Drugs, which can be destroyed by digestive juices, cannot be

administered orally.

• The absorption of certain drugs is negligible. i.e streptomycin

Compiled By Dr Lishan A 66
Routes. ……cont’d

✓ Parenteral route: the administration of drug by injection

directly into the tissue fluid or blood without having to cross
the intestinal mucosa.
➢ The most important parenteral route includes: intramascular (IM),
intravenous(IV), intramamammary, intrathecal, Ipidural,
subcutaneous(SC), IA, IP, ID, Intra Arthcular, etc.

Advantage
✓ Rapid action of drug.

✓ Can be employed in unconscious/ uncooperative patients.

Compiled By Dr Lishan A 67
Routes. ……cont’d

• Drugs, which are modified by alimentary juices and liver, can

be given by this route.

• Drugs, which are not absorbed in small intestine or irritate the

stomach can be administered.

Disadvantage

• Less safe, more expensive.

• Inconvenient (painful) for patient.

• Chances of local injury at the site of injection.

Compiled By Dr Lishan A 68
Routes. ……cont’d

✓ Inhalation route: the volatile liquids and gasses are given by

inhalation route.

❖ Drugs given by this route are quickly absorbed, which takes

place from the vast surface of alveoli and produce rapid action.

Compiled By Dr Lishan A 69
Summary and other route of drug administration

Compiled By Dr Lishan A 70
Compiled By Dr Lishan A 71
Compiled By Dr Lishan A 72
 Fate of Administered Drug
• Most drugs after administered to the body they undergo 2
major process
❑ Pharmacokinetics (PK) process :- process that involve
absorption, distribution, metabolism, excretion.
❑ Pharmacodynamics (PD) process:- process that involve
receptor – drug interaction which determines types and
selectivity of the drug effect and quantitative
determination of drug effect

Compiled By Dr Lishan A 73
 Drug administered
(oral, Iv, rectal…)

Absorption
Storage in tissue
Site of action (eg- body fat)
( receptors…)
distribution
distribution Plasma compartment

Free drug bound drug

distribution

Metabolism
(eg- liver, GI. Lung…)
Unwanted site distribution
( side effect..)

Excretion
( eg- kidney, lung,
sweat…)
Compiled By Dr Lishan A 74
 PHARMACOKINETICS
• Pharmacokinetics (PK) is derived from ancient
Greek. Pharmakon means 'drug' and kinetikos means
'moving or putting in motion.'
• PK is the effects of the body on drug delivery to its site of
action.
➢ “The journey of medication through the body”
• Pharmacokinetic aspects are determined by the following
general processes, such as absorption, distribution,
metabolism and renal elimination (ADME).
Compiled By Dr Lishan A 75
 1. Absorption
• Absorption is the transfer of the drug from the site of
administration to the general circulation.
• With the exception of direct intravenous or intra-
arterial injections, a drug must cross at least one
membrane in its movement from the site of
administration into the general circulation.
• Drugs acting at intracellular sites must also cross the
cell membrane to exert an effect.
Compiled By Dr Lishan A 76
Cell Membrane

+ve
charged

Hydrophobic
heads

Compiled By Dr Lishan A 77
❖Mechanisms of the drug transfer across the membrane

• The main mechanisms by which drugs can cross

membranes from site of administration are:
❖Passive Diffusion / Simple diffusion
❖Transport Mediated By Membrane Proteins
✓Facilitated diffusion /Carrier-mediated processes
✓Active Transport

❖ Through pores or ion channels

❖ By Endocytosis (phagocytosis and pinocytosis) and
exocytosis
Compiled By Dr Lishan A 78
Fig. The passage of drugs (D) across membrane bilayers.
Compiled By Dr Lishan A 79
❖Simple Diffusion: Pass through the phospholipid bilayer
• Simple diffusion is defined as the movement of substances like ions,
atoms, and molecules from an area of their higher concentration to
lower concentration without the involvement of any other molecules
like a carrier protein.
✓ Small, non-polar molecules (such as O2, CO2, N2) and
✓ Uncharged polar molecules (such as urea, ethanol, and small organic acids)
• The direction of net movement is always ‘downhill’, along the
concentration gradient, from high to low concentration in a solution
through a semi permeable membrane to attain equilibrium on both
sides. → Attain equilibrium.

Compiled By Dr Lishan A 80
 Characteristics of Simple Diffusion
• Occurs across a semi permeable membrane
• Requires a concentration gradient across the cell membrane
➢ Concentration gradient across a membrane is the driving force.
• Does not need a carrier transport protein
• Cannot be inhibited by an inhibitor molecule because of the absence of carrier
proteins
• A comparably slow process than other forms of diffusion
• Require no energy expenditure
- Major mechanism by which drugs enter the body.
- Lipid soluble drugs move across by dissolving into the membrane’s
lipid layers
➢ The only requirement for passive diffusion is that the drug should
be lipid soluble
Compiled By Dr Lishan A 81
 Cont. ………….simple diffusion
/ Passive

Time

Compiled By Dr Lishan A 82
 Transport Mediated By Membrane Proteins
• Transport of larger, polar molecules, such as amino acids or sugars,
into a cell requires the involvement of membrane proteins known as
transporters.
➢ Also called porters, permeases, translocases, or carrier proteins.

• The term ‘carrier’ is also applied to iono-phores, which move passively

across the membrane together with the bound ion.

• Transporters are as specific as are enzymes for their substrates, and

work by one of two mechanisms:
✓ Facilitated diffusion or

✓ Active transport.

Compiled By Dr Lishan A 83
Facilitated Diffusion/Carrier-mediated processes:

✓ Movement of a substrate through a membrane down a

concentration gradient /from high to low concentration

✓ Requires a carrier, no energy required. → a passive

transport

• In contrast, active transport is a process in which substrates

are transported uphill, against their concentration gradient.

• Active transport must be coupled to an energy-producing

reaction.
Compiled By Dr Lishan A 84
Cont…………..Facilitated Diffusion

• The rate of facilitated diffusion is generally much greater than that of

simple diffusion.

• In contrast to simple diffusion, in which the rate of transport is

directly proportional to the substrate concentration, facilitated
diffusion is a saturable process, characterized by a maximum
transport rate, Tmax.

• When the concentration of extracellular molecules (transport

substrates) becomes very high, the Tmax is achieved by saturation of
the transporter proteins with substrate.

Compiled By Dr Lishan A 85
 Cont…………..Facilitated Diffusion

• The transport process is usually highly specific:

✓Each transporter transports only a single species of
molecules or structurally related compounds.

• E.g., The red blood cell GLUT-1 transporter has:

➢A high affinity for D-glucose, but
➢10–20 times lower affinity for D-mannose & D-galactose.
➢The L-glucose is not transported; its affinity is more than
1000 times less than that of the D-form.

Compiled By Dr Lishan A 86
• There are a number of relatively non-specific carriers which can
transport drugs out of cells, such as

✓ P-glycoprotein (PGP),

✓ Organic anion transporters (OAT1 to OAT4) and

✓ Organic cation transporters (OCT1 and OCT2).

• Drugs that bind to carrier proteins but are released only slowly act
as inhibitors of the carrier; for example, probenecid inhibits the
secretion of anions, such as penicillins, by the renal tubule.

Compiled By Dr Lishan A 87
Facilitated diffusion

Protein channel

Compiled By Dr Lishan A 88
 Facilitated Vs Simple Diffusion In Tabular Form
BASIS OF
COMPARI FACILITATED DIFFUSION SIMPLE DIFFUSION
SON
Simple diffusion entails movement
Facilitated diffusion entails
of particles from a region of high
movement of substances across a
Description concentration to a region of low
biological membrane through a
concentration across a membrane
concentration gradient by means of a
without the assistance of carrier
carrier molecule.
molecules.
Facilitated diffusion can be inhibited
No inhibitor molecule can inhibit
Inhibition by specific inhibitor which binds to
the process of simple diffusion.
the carrier molecules.
ATP
Facilitated diffusion may or may not Simple diffusion does not require
Requireme
nt require energy from ATP. energy from ATP.
Through facilitated diffusion large or Through simple diffusion small,
Molecules polar particles are transported across non-polar molecules are passed
the plasma membrane. through a plasma membrane.
Compiled By Dr Lishan A 89
 Facilitated diffusion occurs
Simple diffusion occurs
through specific facilitator
Occurrence directly through the cell
molecules referred to as trans-
membrane.
membrane integral proteins.
Rate of
At low solute concentration, the At low solute concentration,
Diffusion At
rate of facilitated diffusion is the rate of simple diffusion is
Low
relatively high when compared to relatively low when compared
Concentratio
that of simple diffusion. to that of facilitated diffusion.
n Gradient
Facilitated diffusion is always Simple diffusion is not solute
Specificity
solute specific. specific.
The rate of simple diffusion
Factors
The rate of facilitated diffusion depends on the membrane
Affecting
depends on the kinetics of carrier- permeability, size of molecules
The Rate of
mediated transport. and the concentration gradient
Diffusion
across the membrane.

Compiled By Dr Lishan A 90
Kind Of Facilitated diffusion can be active Simple diffusion is normally
Process or a passive process. passive.

Simple diffusion takes place

Type Of Facilitated diffusion takes place
through the phospholipid
Membrane through trans-membrane proteins.
bilayer.

✓Co-transport of sodium together

with glucose, galactose, fructose, Diffusion of gasses across the
amino acids. respiratory membrane. Diffusion
Examples
✓The counter-transport of of molecules from the blood to
chloride/bicarbonate in renal cells through interstitial fluid.
tubular cells.

Compiled By Dr Lishan A 91
 Active transport
• Cells may need to move molecules against concentration gradient.
• The change in shape of transport membrane transports solute from
one side of membrane to other.
• It is mechanism of an energy-dependent in the form of ATP. ±
carrier.

• The proteins involved in transport are also known as protein

pump.
• E.g. Na + / K+ pumps, Ca2+ pump in muscle, SER pumps
and Proton pump in mitochondria etc.

Compiled By Dr Lishan A 92
❖Passage Through Membrane Pores or Ion Channels:

• Movement occurs down a concentration gradient and

can only occur for extremely small water-soluble
molecules (<100 Da).

• This is applicable to therapeutic ions such as lithium

and radioactive iodide.

Compiled By Dr Lishan A 93
Compiled By Dr Lishan A 94
 Transport of large molecules
• They move into and out of cell membrane through vesicles &
vacuoles by various mechanism.

✓ Endocytosis:- cell membrane engulfs the drug molecule

and transports into the cell
✓ by “pinching” off the drug filled vesicle.

➢ Two mechanisms Endocytosis:-

A. Pinocytosis (fluid particles)
B. Phagocytosis (solid particles)
C. Receptor mediated endocytosis

Compiled By Dr Lishan A 95
Cont. ………..Endocytosis

A. Pinocytosis also known as “cellular drinking” is the most

common form of endocytosis. It takes in dissolved
molecules as a vesicle.
✓ Cell forms an invagination dissolve in water to be brought into
cell. It is non specific process.
B. Phagocytosis is also known as “cellular eating”.
✓ It used to engulf large particles such as food, bacteria, etc.
into vesicles which are then lead to fuse with lysosomes for
digestion.

Compiled By Dr Lishan A 96
Cont. ………..Endocytosis

C. Receptor mediated endocytosis:-

✓ In this process, some integral proteins have

receptors on their surface to recognize & take
in hormones, cholesterol, etc into the cell.

✓ These are triggered by molecular signals.

Compiled By Dr Lishan A 97
Figure 3: Various methods of Endocytosis

Compiled By Dr Lishan A 98
 ❖Exocytosis
• It is the opposite of endocytosis.

• Large molecules that are manufactured in the cell are released

through the cell membrane.

• Molecules are moved out of the cell by vesicles that fuse with the
plasma membrane. E.g.
✓ Hormones E.g. Nor-adrenaline being released from cells.

✓How nerve cells communicate with one another.

E.g. Ach being released from cells.

Compiled By Dr Lishan A 99
Figure 4: Mechanism of Exocytosis

Compiled By Dr Lishan A 100

 Factors affecting absorption of a drug
• A number of factors can affect the rate and extent to which a

drug is absorbed and into the general circulation.

❑ Drug structure (PH and Ionization):

• Drug structure is a major determinant of absorption, distribution

and elimination.

• Drugs need to be lipid soluble to be absorbed from the gut.

➢ Therefore, highly polar acids and bases absorbed only slowly and

incompletely, with much of the dose voided in the faeces.

Compiled By Dr Lishan A 101

…cont’d
• High polarity may be useful for delivery of the drug to
the lower bowel.

• The structure of some drugs can make them unstable

either at :
✓ Too low pH of the stomach, for example penicillin G, or

✓ In the presence of digestive enzymes, for example insulin.

Compiled By Dr Lishan A 102

❑ Drug Formulation:
• Drugs cannot be absorbed until the administered tablet/ capsule disintegrates
and the drug is dissolved in the gastrointestinal contents to form a molecular
solution.

• Most tablets disintegrate and dissolve rapidly and completely and all the
entire dose is rapidly available for absorption but others may not..

➢ The rate at which the drug is absorbed is limited by the rate of release
and dissolution of drug from the formulation, rather than by the
transfer of the dissolved drug across the gut wall.

Compiled By Dr Lishan A 103

❑Administration route

• Can either be:-

➢Enteral (by in the GI tract, such as by mouth,
feeding tube, or rectal suppository) or

➢Parenteral (not in the GI tract, such as an

injection or topical medication).

Compiled By Dr Lishan A 104

 ❑ Gastric emptying:

• The rate of gastric emptying determines the rate at which a drug is delivered to

the small intestine (SI).

• A delayed gastric emptying delay the detection of the drug in the circulation

after oral dosing. E.g.,

• Co-administration of Antimuscarinics, → Slow Gastric Emptying → Can alter

the rate of drug absorption.

• Food has a complex effect on drug absorption since

✓ It reduces the rate of gastric emptying and delays absorption,

✓ It can also alter the total amount of drug absorbed.

Compiled By Dr Lishan A 105

❖Total surface area for absorption:
✓ The greater the surface area the greater the rate of
absorption.

✓ The intestine has a very large surface area, making it an

ideal target for drug absorption.

❖Blood flow to absorbing site. The better the blood

supply to the area the greater the rate of absorption.
✓ Drugs are absorbed faster in the muscle than subcutaneously.

Compiled By Dr Lishan A 106

 ❑ Solubility of the drug:
• How soluble is the drug in body fluids?
➢ Drugs can dissolve readily in the body water.
➢ However, certain drugs do not dissolve into small enough particles to ensure
rapid absorption.

❑ Barriers of the body: some barriers are harder to cross than others.

• Example: blood brain barrier, blood bronchus, prostatic, mammary

gland and placenta.

➢ They are harder to cross as the gaps between cells are smaller than other

capillary membranes.

Compiled By Dr Lishan A 107

 …cont’d

• Many lipophilic drugs are able to cross these barriers.

• Lipophobic agents usually can only cross these barriers

if there is a transport molecular or when the barriers are
inflamed resulting in an increase in the distance between
the cells.

Compiled By Dr Lishan A 108

 ❑Time of arrival and contact time at absorption site.

• The longer the drug is in contact with the absorbing

surface the greater the rate of absorption.

➢ This is why if a patient is suffering from diarrhoea the

chances of a drug given orally being absorbed
completely are lowered and other means of
administration must be considered.

Compiled By Dr Lishan A 109

 ❑Chemical stability

➢Will it break down readily?

❑Lipid to water partition coefficient.

• Is it more fat soluble than water soluble?

• As cells are made up of a phospho-lipid layer,

➢Any drug that can dissolve well in lipids will pass
through tissues far more rapidly.

Compiled By Dr Lishan A 110

 2. Distribution of drug
The transport / dispersion of a drug through the body's
fluids and tissues by the bloodstream as it travel to its site
of action.
Factors affecting Drug Disn:-
➢ Bind of drug to plasma proteins and tissue macromolecules
➢ The physicochemical properties of the drug (pKa, lipid solublity, molecular
weight).
➢ Blood flow to the tissue
➢ The presence of anatomic barriers.

• Goal: is for the drug to reach the target tissue or

intended site of action.
Compiled By Dr Lishan A 111
 ❖Distribution reflects two phases:-
❑The initial phase of drug distribution reflects cardiac
out put and regional blood flow, so that well-perfused
organs receive most of the drug.
❖Order of perfusion:
➢Brain > Lungs > Liver > Heart > Kidneys > Skeletal Muscle >
Adipose Tissue, Skin and Viscera
➢Areas of rapid distribution: heart, liver, kidneys, brain

❑A second phase reflects movement of the drug into

interstitial space or cellular compartments.
➢ Areas of slow distribution: muscle, skin, fat
Compiled By Dr Lishan A 112
113
 3. Metabolism

• Drug metabolism also known as xenobiotic

metabolism is the biochemical modification of
pharmaceutical substances by living organisms, usually
through specialized enzymatic systems.

• The purpose of biotransformation is to facilitate renal or

biliary excretion of drugs by rendering it more polar.

Compiled By Dr Lishan A 114

 …con’t
• The rate of metabolism determines the duration and
intensity of a drug's pharmacological action
• Site: every tissue has the ability to metabolize drugs, the
liver is the principal organ of drug metabolism.

• Drug metabolism helps to:

✓Reduce the drug effect

✓Often inactivates the drug but can activate also

✓Converts lipophilic chemical compounds into more readily

excreted hydrophilic products → makes the drug more polar
Compiled By Dr Lishan A 115
Cont‘d. …….Metabolism/Biotransformation

❖Delayed drug metabolism results in:

✓ Accumulation of drugs

✓ Prolonged action of the drugs

❖Stimulating drug metabolism causes:

✓ Diminished pharmacologic effects

116
 …cont (Reading Assignment)
❖ The enzymes responsible for drug biotransformation are primarily
found in the smooth endoplasmic reticulum of liver and to limited
extent, in GIT, kidneys, and lung.
❖ Chemical reaction involved in drug metabolism are classified
as:
• phase I functionalization reactions(modification)
• phase II biosynthetic (conjugation) reactions.
✓ These reaction often, but not always, occur sequentially and mostly takes
place in liver.
✓ Both phases decrease lipid solubility and, thus increase renal elimination.

Compiled By Dr Lishan A 117

 Phase I functionalization reactions
• Phase I reaction converts the drug to more polar
metabolites by oxidation, reduction and hydrolysis.

• The products are often more chemically reactive and

inactive metabolites, and hence sometimes are more
toxic or carcinogenic than the parent agent (pro-drug).

• It primarily occur in liver.

Compiled By Dr Lishan A 118

 …cont

❖Oxidation: involves the introduction of oxygen or

removal of a hydrogen atom or hydroxylation,
dealkaylation, of drug molecule.
✓Is quantitatively most important phase I reaction.
❖It involves the following enzymatic reactions:
➢Cytochrome P450 monooxygenase system
➢Flavin-containing monooxygenase system
➢Alcohol dehydrogenase and
➢aldehyde dehydrogenase enzymes
➢Monoamine oxidase
➢Co-oxidation by peroxidases
Compiled By Dr Lishan A 119
…cont
❖ Reduction: takes place by the enzyme reductase which
catalyze the azo (-N=N-) and nitro (-NO2)compounds.
o eg. Prontosil converted to sulfonamides.

➢ NADPH-cytochrome P450 reductase

❖ Hydrolysis: drug metabolism by hydrolysis is limited to

esters and amines (by Esterases and Amidase) are found
in plasma and other tissues like liver, GIT.
✓ It means splitting of drug after adding water.

➢Epoxide hydrolase
Compiled By Dr Lishan A 120
 Phase II reaction
• Phase II reaction, which are called conjugation,
couple the more polar metabolites with
Glucuronide, sulfates, acetate, glutathione, or an
amino acid.
❖This phase involve the following reactions:
✓Glucuronidation
✓Sulfate conjugation
✓Acetylation
✓Glycine conjugation and methylation reactions.
Compiled By Dr Lishan A 121
 …cont

• Parent drugs or their phase I metabolites that

contain suitable chemical group (hydroxyl,
carboxyl, amino or sulfhydryl) often undergo
coupling reaction with endogenous.

❖The products of phase II reaction are:-

✓Highly hydrophilic
✓More rapidly undergo elimination in the urine, and
✓Almost always inactive.
Compiled By Dr Lishan A 122
 …cont

❖Phase II reaction requires specific enzymes. Such as :

✓Glucuronyl transferase (deficient in cats)
✓Acetyl transferase (kupffer cells)(deficient in dogs)
✓Methyl transferase
✓Sulfo transferase(deficient in pigs)
✓Glutathione S transferase

Compiled By Dr Lishan A 123

❖Factors affecting drug metabolism

✓ Species differences

✓ Genetic differences

✓ Age (Impaired hepatic enzyme activity: elderly v prematurely)

✓ Gender difference

✓ Co-existing disease(e.g. liver disease)

✓ Drug- drug interaction (Either enzyme inducer/inhibitor)

✓ Dietary factors(may induce enzyme).

Compiled By Dr Lishan A 124

 ❖Enzyme Inducing Drugs
✓ Enhance the (production of) liver enzymes which break down drugs
✓ Faster rate of drug breakdown
✓ Larger dose of affected drug needed to get the same clinical effect

❖ Enzyme Inhibiting Drugs

✓ Inhibit the enzymes which break down drugs
✓ Decreased rate of drug breakdown
✓ Smaller dose of affected drug needed to produce the same clinical
effect

Compiled By Dr Lishan A 125

 4. Drug excretion
The elimination of drugs / its chemical byproducts from the body
• Kidneys (main organ)
• Liver
• Bowel
– Biliary excretion: drugs are taken up by the liver, released into bile,
and eliminated in the feces.

– Enterohepatic circulation: drugs in the bile are reabsorbed into the

bloodstream, returned to the liver, and secreted a second time into the bile

▪ Other routes include: lungs, saliva, sweat, breast

milk, tear, genital secretion
126
 Cont. ………..Drug excretion

➢ Primary organ responsible for excretion is the

kidney, most common mechanism for the
elimination of polar drugs or their metabolites.

• For most drugs it involves filtration of non protein-

bound drugs at the glomerular and subsequent tubular
excretion.

Compiled By Dr Lishan A 127

Renal drug elimination depends on:
✓Blood flow to kidney (normal 1500ml/min)
➢Glomerular filtration rate (normal 120mls/min)

✓Urine flow rate and pH which indirectly alter

➢Passive reabsorption
➢Active tubular secretion

❖Patients with poor renal function will not

eliminate renally excreted drugs very well
Compiled By Dr Lishan A 128
 1. Glomerular filtration
o Agents <2000 MW diffuse into the glomerular filtrate.

➢ As plasma albumin is 6800MW, agents bound to plasma

protein do not pass through the glomerulus.

Compiled By Dr Lishan A 129

 2. Tubular secretion and reabsorption

• The majority of agents undergo renal secretion.

➢ Secretion is the process whereby agents cross from afferent renal
capillaries into the renal tubules and thus into the urinary filtrate.
➢ Reabsorption is the opposite process whereby substance in the
urinary filtrate cross the tubular cells into the renal capillaries.

❖ These process may be depending on passive, facilitated or

active.
❖ Tubular secretion is potentially the most effective
mechanism for agent elimination by the kidney.

Compiled By Dr Lishan A 130

 3. Passive diffusion across tubular epithelium

• Agents with high lipid solubility → high tubular

permeability can passively diffuse from the urinary filtrate

across the tubular epithelium → are excreted slowly.

• However, weak acid or weak base change their

degree of ionization according to the difference

between plasma and urinary pH and this markedly

affect renal excretion.

Compiled By Dr Lishan A 131
…cont
❖The non-trapping effect means that:-
➢A weak base is more rapidly eliminated when
excreted into acidic urine, because the low pH within
the tubule favors ionization and thus inhibits
reabsorption.

➢Acidic agents are more rapidly eliminated when

excreted if the urine is alkaline.

Compiled By Dr Lishan A 132

 Bowel Drug Elimination
• Routes of drug elimination via biliary and fecal excretion.
• Drugs excreted in bile enters the intestine, where they are either
excreted in the feces or passively reabsorbed.
• Glucuronide conjugates of drugs that enter the intestinal tract
may undergo hydrolysis by intestinal ß-glucuronidases and the
lipid soluble parent drug reabsorbed.

• This process is called enterohepatic cycling and may significantly

prolong the action of some drugs.
• Species difference in the extent of biliary excretion exist. Dogs,
cats, and humans are considered good, fair, and poor biliary
excrators, respectively.
Compiled By Dr Lishan A 133
 Pharmacokinetic Models
✓ One Compartment Open Model IV bolus

✓ Two Compartment Model / Multi Compartment Model

Compiled By Dr Lishan A 134

 Pharmacokinetic parameters
❖The four parameters governing drug disposition are:
✓ Clearance

✓ Volume of distribution

✓ Half-life (t1/2)

✓ Bioavailability.

Compiled By Dr Lishan A 135

❖ Clearance
• Is the volume of blood cleared of a drug per unit of time.
• The total clearance of a drug is the sum of clearance from
each organ of elimination such as the liver, kidney, and lungs.
❖ Clearance may be influenced by:
➢ plasma protein binding
➢ Organ perfussion
➢ Drug-metabolizing enzyme ability
➢ The efficiency of renal excretion.

Compiled By Dr Lishan A 136

Cont. …. clearance

• Clearance= rate of drug elimination

serum drug concentration

Compiled By Dr Lishan A 137

 ❖ Volume of distribution (Vd)
• Is a measure of the apparent space in the body available
to contain the drug.

• The Vd is a quantitative estimate of the extent of drug

distribution.

• It represents the theoretical volume in which the total

amount of drug would have to be uniformly distributed to
give the observed plasma concentration.

Compiled By Dr Lishan A 138

• It reflects a drug’s affinity for plasma and tissue binding.

• High level of plasma protein binding limit a drug’s Vd to the

plasma volume.

• Drug binding to tissues increases a drug’s Vd.

• Vd is a proportionality constant that relates the amount of drug in

the body to the concentration of drug in the blood.

Compiled By Dr Lishan A 139

Vd= Total amount of drug in the body
Serum drug concentration at steady
state (Css)

Compiled By Dr Lishan A 140

 Half-life (t1/2)
• Half life refers to the time required to
reduce the plasma concentration of
a drug to half of its original value .
• It gives an estimate of the duration of
drug effects in the body.
❖ The t1/2 is a derived parameter
dependent on both clearance and Vd.

T1/2= 0.693 Vd
clearance
Compiled By Dr Lishan A 141
 ❖Bioavailability
• The fraction of the administered dose of the unchanged drug that
reaches the systemic circulation available to have an effect.
• Any factor that affects drug absorption influence drug bioavailability.
❖ Example: Affected by:
✓ Drug food interaction

✓ Drug-Drug interaction concomitantly in absorption

✓ Intestinal motility/Gastric emptying rate

✓ Physical properties of the drug (hydrophobicity, pKa, solubility)

✓ The drug formulation (immediate release, excipients used, manufacturing

methods, modified release – delayed release, extended release, sustained
release, etc.)
Compiled By Dr Lishan A 142
 Other factors of Bioavailability
❖First-pass hepatic metabolism
• When an oral drug is absorbed across the GI tract, it first
enters the portal circulation before the systemic
circulation
• If the drug is rapidly metabolized, less of the active
ingredient will reach the systemic circulation
❖Example: nitroglycerine (90% is cleared through passage
through the liver)
➢ It is Given sublingually

143
Cont. …… First pass Metabolism
❖It can happen in
➢Liver
➢Gut wall
➢GIT Lumen

The results of first pass metabolism

✓Low bioavailability of drugs = low serum level of active

drug that can produce action.

✓Short duration of action of drugs (t ½).

144
Cont. ….. Bioavailability

❖Drug administered IV bioavailability is 100%.

➢ Administered via other routes (such as orally),
bioavailability decreases (due to incomplete absorption and
first-pass metabolism) or may vary from patient to patient.

Compiled By Dr Lishan A 145

PHARMACODYNAMICS

Compiled By Dr Lishan A 146

 Dose of drug
administered

ABSORPITION

Drug concentration DISTRIBUTION Drug in PHARMACOKINETICS

in systemic tissue of
circulation distribution
ELIMINATION
Drug metabolized
Drug
or excreted
concentration at
the site of action

Pharmacologic effect
PHARMACODYNAMICS
Clinical response
Toxicity Efficacy
Compiled By Dr Lishan A 147
Fig. 2 pharmacokinetics and pharmacodynamics
Pharmacodynamics (PD) :

• Is how the drug affects the body

• Is the study of the biochemical and physiological effects of

drug and their mechanism of action.
• Pharmacodynamics places particular emphasis on the
study of dose–response relationships, that is, the
relationships between drug concentration and effect.
• Provides the basis for –
➢ Rational/Normal therapeutic use of a drug and,

➢ Design of new and superior therapeutic agents.

Compiled By Dr Lishan A 148
 Mechanism of Action
• Ways in which a drug can produce a therapeutic effect

• Once the drug hits its “site of action” it can modify the
rate at which a cell or tissue functions.
❖The effects of drugs = drug + macromolecular components of
the organism = Drug-receptor complex (interaction)

❖Interactions → alter function of the pertinent component →

biochemical and physiological changes that are
characteristic of the response to the drug.

149
Cont. ……… Mechanism of Action
• A Receptor is a specific macromolecule, usually a
protein, with which the appropriate ligand can interact or
bind and initiates its effects
• Some drug-receptor interaction are highly specific
(Pharmacological receptors are involved) &
• Some are non-specific (receptors are not involved).
➢ Not all drugs exert their pharmacological action via receptor-
mediated mechanisms. Drugs act via:
➢ Pharmacological receptors
➢ Without receptors

150
❖Examples of None receptor based MOA
✓Osmotic diuretics,
✓Purgatives,
✓Antiseptics,
✓Antacids,
✓Chelating agents
✓Urinary acidifying and alkalinizing agent- is
attributed to the physiochemical properties.

151
Cont. ……… Mechanism of Action
❖There are numerous different mechanisms by
which agents exert an effect. Such as:-

➢Action on receptor

➢Action on an enzyme

➢Cytotoxic action

➢Action on membrane ionic channel

152
 1. Drug-Receptor Interaction
• Most drugs exert their effects by interacting with receptors
• Receptors bind drugs and initiate events leading to alterations in
biochemical and/or biophysical activity of a cell
• Drugs interact with receptors in many different ways, may bind
to enzymes, nucleic acids, or membrane receptors
• The formation of the drug–receptor complex leads to a biologic
response
• The magnitude of the response is proportional to the number of
drug–receptor complexes
Cont. ……..Drug-Receptor Interactions
✓ Mimic actions of neurotransmitter at same site (agonist)

✓ Bind to nearby site and facilitate neurotransmitter binding (agonist)

✓ Block actions of neurotransmitter at same site (antagonist)

154
 Cont. ………Action on receptor ()
➢ The reactive site, situated either in cell membranes or within
the cell; on a cell or tissue.

• Once a specific substance [appropriate ligands: drugs or naturally

occurring substances (such as neurotransmitters or hormones)],
binds to and interacts with the receptor, a pharmacologic effect/
response is produced

155
 Structure-Activity Relationship (SAR)
❖ Interaction between a drug and its receptor is defined as affinity
of the drug for the receptor

❖ Ligands: a substance that attaches and interacts with a receptor.

▪ The ligand is thought of as a “key” fitting into the “lock” which is

the receptor.
▪ The ligand usually fits the receptor as its 3D molecular structure
corresponds to the 3D structure of the receptor.

❖Ligands: can refer to an endogenous substance.

➢ e.g. acetylcholine is a ligand that binds to nicotinic or
muscarinic receptors.
➢ Also refers to exogenous substance; e.g. drug. 156
 Cont. ….. Structure-Activity Relationship

• The strength of the reversible interaction between a drug

and its receptor, as measured by their dissociation constant,

is defined as the affinity of one for the other.

• Both the affinity of a drug for its receptor and its intrinsic

activity are determined by its chemical structure.

157
 Cont. ….. Structure-Activity Relationship
• The chemical structure of a drug determines its affinity
for the receptor and ability to elicit a response (I.e.,
intrinsic activity).
• Structure-activity relationships are exploited in drug
design.
➢ SAR led to the synthesis of valuable therapeutic agents
• Relatively minor modifications to drug structure may
result in more favorable therapeutic profiles and/or
pharmacokinetic properties.

158
 Terms Define Drug Receptor mediated activity:-
• Affinity: affinity is a measure of the attraction of the ligand for the
receptor. Affinity is determined by the chemical structure

• Selectivity: a drug's ability to preferentially produce a particular effect.

• Is related to the structural specificity of drug binding to receptors.

• Efficacy
– Degree to which a drug is able to produce the desired response
– “The greater the magnitude of the response, the greater the agent’s
efficacy”.
– measure thee effectiveness of drug (potency, agonist & antagonist)

159
• Potency: is a measure of concentration
– Used to compare compounds within classes of drugs
– A potent drug requires a lesser concentration to exert an effect.

– Potency of an agent varies inversely with the dose; “the lower

the dose required the more potent the drug”.

160
• Agonists: Drugs / chemical that binds to a receptor and
elicits an appropriate response.
➢ Drug binds to receptor → there is a response (e.g. Adrenergic
Agents)

• Partial agonists: Agents that are only partly as effective

as agonists no matter the dose employed.

• Inverse agonists: Those that stabilize the receptor in its

inactive conformation.

161
• Antagonists:
➢A chemical that binds to a receptor but elicits no
response and blocks access to the receptor by an
agonist. Or
➢ Blocks the binding of the endogenous agonist.

➢Drug binds to receptor → no response → prevents

binding of agonists (e.g. Alpha & Beta Blockers)

162
Drug-Receptor Specificity
• Alterations to a drug’s chemical structure may
influence potency
– e.g., amphetamine vs. methamphetamine

• Many drugs have multiple sites of action

– Some sites of action are responsible for side effects

– e.g., tricyclic antidepressants: sedation, dry mouth,

blurred vision
163
Cont. …….drug-receptor specificity

164
 Where do you find the receptors
(their location)???
❖Location: found
❖ On / In ion channels,
❖ Adjacent to ion channel,
❖ On enzymes,
❖ Associated with carrier molecules,
❖ Within the cell cytoplasm or
❖ Within the cell nucleus.
➢ Receptors are not only found in animal host, they can also
be found in parasites, bacteria, viruses, and fungi etc.

165
2. Action on an Enzyme
• Enzymes are substances that catalyze nearly every
biochemical reaction in a cell

• Like receptors, they are protein macromolecules with

which substrate interacts to produce activation or
inhibition.

✓ Drugs can interact with enzyme systems to alter a response.

❖ Inhibits action of enzymes → Protects target cell from

enzyme’s action (ACE Inhibitors)
166
3. Cytotoxic actions:

✓Drugs used in cancer or in the treatment of infection may:

➢kill malignant cells or micro-organisms.

4. Action on membrane ionic channel:

➢The conduction of impulse in nerve tissues and
➢Electromechanical coupling in muscle depend on the
movement of ions, particularly Na+, Ca++ and K+, through
membrane channels.
Eg. Furosemide inhibits Na/K/Cl co-transport in the
ascending limb of the loop of Henle.

167
 Dose response relationships and curves
• Pharmacodynamics= concentration of a drug + response.

✓ Individual patients may respond to smaller concentrations, or

✓ Require concentrations that are much greater to obtain a

therapeutic effect.

• Thus, we start by plotting a drug response curve where the

concentration of the drug is along the X-axis and the magnitude of
the effect is along the Y-axis.

168
Dose response relationships curves
169
 Medication Dose Responses
• Except when administered IV, medicines take time to enter
bloodstream
• The quantity & distribution of medicine in different body
compartments change constantly
❖ Goal is to keep constant blood level within a safe
therapeutic range
• Repeated doses are required to achieve a constant
therapeutic concentration of a medicine because a portion of
med is always being excreted.
170
Onset, Peak, and Duration

Onset
✓ The time it takes for the drug to elicit a
therapeutic response

Peak
✓ The time it takes for a drug to reach its maximum therapeutic
response

Duration
✓ The time a drug concentration is sufficient to elicit a therapeutic
response

171
 Loading and Maintenance Dose
• Loading Dose (DL) = a dose of drug sufficient to produce a plasma
concentration of drug that would fall within the therapeutic window
after only one or very few doses over a very short interval.

• It is larger than the dose rate needed to maintain the concentration

within the window and would produce toxic concentrations if given in
repeated doses.

• Maintenance Dose (DM) = The dose needed to maintain the

concentration within the therapeutic window when given repeatedly at
a constant interval.

172
 Loading Doses

• Loading doses allow rapid

40
achievement of therapeutic 35
30
serum levels
25 w/ bolus
• Same loading dose used 20
w/o
15 bolus
regardless of metabolism 10

/elimination dysfunction 5
0

173
Dose-Response Functions

➢Efficacy (ED50 = median effective dose)

➢Lethality (LD50 = median lethal dose)
➢Therapeutic Index = LD 50 /ED 50

174
The therapeutic index(TI):
• It is the ratio of the dose that results in an undesired effect to that which
results in a desired effect.

• Lethal dose 50 (LD50): is a dose that kills 50% of the animals/subject.

• Effective dose 50 (ED 50): a dose that produce the desired effect in 50% of
the subject.

• Therapeutic Index
– Measure/ guide of the safety of a drug

– Calculation: LD50/ED50

– It is desirable that the TI be large.

175
❖The dose of a drug can be increased progressively until
a desired response is achieved.
✓ However if it is further increased, no additional desired
effects are achieved and unwanted effects can be seen.

❖Drugs with a narrow therapeutic index:

✓ Can be difficult to use in clinical practice and

✓ Often require monitoring of plasma concentration in order to

prevent toxicity.

176
 Cont. ……………..TI
❖ Some e.gs. Of Drugs with a narrow therapeutic index
✓ Digoxin, Gentamicin, Carbamazepine, Phenytoin, Lithium,
Theophylline, Warfarin, Amphoteracin B,
❖ Therapeutic window: Difference between the minimum
effective concentrations (MEC) required for a desired response
and one that produces an adverse effect.

❖Margin of Safety (MOS)

– Margin between the therapeutic and lethal doses of a drug
– MOS is ratio of toxic dose to 1% of population (TD01) to the
dose that is 99% effective to the population (ED99).

177
178
 Signal Transduction Pathways
❖ Signal Transduction = Cellular Communication
➢ Cells must communicate with one another at either a distance or nearby • Autocrine
• Paracrine
➢ Communication is determined by chemical signals and cellular receptors • Endocrine

• Physiological receptors on the surface of cells have two major functions,

✓ Ligand binding and

✓ Message propagation (i.e., transmembrane and intracellular signaling).

• These functions imply the existence of at least two functional domains

within the receptor: a LBD and an Effector Domain.
• The receptor, its cellular target, and any intermediary molecules are referred to as a
receptor-effector system or signal transduction pathway.

Compiled By Dr Lishan A 179

Cont. ………Signal Transduction Pathways

❖ A signal transduction pathway is a series of steps by which a

signal on a cell’s surface is converted into a specific cellular
response.

➢ Activated by the binding of ligands

➢Receptors and their associated effector and transducer proteins

→ act as integrators of information
✓B/c they coordinate signals from multiple ligands with each other
and with the differentiated activity of the target cell.

180
 Cont. ………Signal Transduction Pathways
• Drugs act as signals, and their receptors act as signal detectors.
• Many receptors signal their recognition of a bound drug by
initiating a series of reactions that ultimately result in a specific
intracellular response.

181
 ❖ Signal Transduction by GPCRs
✓ GPCRs control many different aspects of cell function by acting on a variety of different
signal transduction mechanisms.

✓ The link between the membrane receptor and the first stage of the signal transduction
cascade is established through the G-proteins.

❖ G-Proteins
✓ These are the most abundant type of receptors membrane receptors coupled to
intracellular effectors systems via a G-protein, changes the concentration of intracellular
second messenger
✓ They are called as G-proteins because of their interaction with the guanine nucleotides GTP
and GDP.

✓ The G-protein is a membrane protein comprising three subunits (alpha, beta, gamma), the
alpha-subunit possessing GTPase activity.

✓ There are three main classes of G-proteins (Gs, Gi, Gq).

▪ The extracellular domain of this receptor contains the ligand-binding area.

Cont. …………..G-Proteins
▪ Intracellularly, these receptors are linked to a G protein (Gs, Gi, and
others) having three subunits, an α subunit that binds guanosine
Diphosphate (GDP) and a β-γ subunit

▪ Binding of the appropriate ligand to the extracellular region of the

receptor activates the G protein so that GTP replaces guanosine
diphosphate (GDP) on the α subunit

▪ Dissociation of the G protein occurs, and the α-GTP subunit interact

with other cellular effectors, usually an enzyme or an ion channel to
give the biological effect

▪ Example: mAChR, adrenergic receptors (Adrenoceptors)

 Cont. Signal
….G-Protein-Coupled
Transduction Receptors
by GPCRs(GPCRs)

The GTP-bound form of G protein then dissociates from the receptor and can engage
downstream mediators
184
 Second Messenger
✓ Second messengers are essential in conducting and amplifying
signals coming from GPCRs
✓ G protein activates adenylate cyclase, which converts ATP to
cAMP.
➢ cAMP is one of the second messenger that regulates protein
phosphorylation.
✓ G proteins also activate phospholipase C, which is responsible
for the generation of two other second messengers, inositol-1,4,5-
trisphosphate (IP3) and diacylglycerol.

✓ G protein activates guanylate cyclase, which converts GTP to

cGMP, a fourth second messenger that stimulates protein kinase
 TARGETS FOR G-PROTEINS
• The main targets for G-protein through which GPCRs control different aspects
of cell function are:
➢ Adenylate Cyclase : the enzyme responsible for cAMP formation.

➢ Phospholipase C: the enzyme responsible for inositol phosphate and diacyglycerol formation.

➢ Ion channels: particularly calcium and potassium channels.

❖ The Adenylate Cyclase / cAMP system

✓ cAMP is a nucleotide synthesized within the cell from ATP by the action of
a membrane bound enzyme adenylate cyclase.

✓ cAMP is produced continuously and inactivated by hydrolysis to 5’-AMP

through the action of phosphodiesterases.
• Many different drug, hormones and neurotransmitters act on
GPCRs and produce their effects by increasing or decreasing
the catalytic activity of adenylate cyclase, thus raising or
lowering the concentration of cAMP within the cell.
Compiled by Lishan A (Dr) 1
 Introduction
• Anthelmintic are drugs used to either kill (vermicide) or expel
(vermifuge) the parasitic worms or helminths (Cestodes,
Trematodes and Nematodes), which inhabit the:-

✓ Alimentary tract and associated structures

✓ Organs such as liver, lungs and the blood circulation.

• They help to reduce worm burdens and control worm larvae on

the pasture or eggs in the environment.

Compiled by Lishan A (Dr) 2

 Ideal Anthelmintic
• Should have high efficacy:

o Ideally it should have high level of anthelmintic activity.

o The efficacy is said to be good if it removes 95% of a gastro-

intestinal nematodes from ruminant spp.

o If it removes only 70% of the worm burden it is considered as a

poor anthelmintic.

o It should have effect on both adult and larval stages of worms.

o If it is effective only against adult worms it is repeated to eliminate

adult worms that were unaffected during the first dose.

Compiled by Lishan A (Dr) 3

 Cont. ………..“Ideal” x-tic of Anthelmintic:-
❖ Broad spectrum of activity:

o The anthelmintic compound should have activity against

o Both mature and immature parasites including larvae.
o Tissue and luminal dweller

❖ Safe to use:-
➢ Large TI
✓ Minor variation in calculation of dosage should not produce any toxicity in host
✓ Anthelmintics must be selectively toxic to the parasite and

➢ Be compatible with other compounds,

➢ Not discolor tissue,
➢ Short withdrawal period,
➢ Not toxic to host and environment.

Compiled by Lishan A (Dr) 4

 Cont. ………..“Ideal” x-tic of Anthelmintic:-
❖ Convenient to use
o Be easy to administer (easily administered to large number of animals).

o single Rx should be effective and Inhibit re-infection for extended periods of time,
no fasting is required

❖ Be cost effective: should be low cost, low cost administering instrument.

❖ Residue :
• It should be eliminated from the body without any residual problems.

• The anthelmintics possessing a long withdrawal time will create human

health hazards after consumption of milk, meat and other animals produce.

• The anthelmintics having a short withdrawal time are much safer.

Compiled by Lishan A (Dr) 5

 ❖Modern Anthelmintics Generally Have:-
✓ A wide margin of safety,
✓ Considerable activity against immature (larval) and mature
stages of helminths, and
✓ A broad spectrum of activity.
❖ The label should always be read before using any drug.
➢ Any modification of the recommended dose rate must be
discouraged, b/c it likely result:
➢In lowered efficacy and

➢Possibly increased pressure for development of resistance

Compiled by Lishan A (Dr) 6

 Route
❖Oral- given in bolus, solution, suspension and feed
additive form

❖Parenthral- not convinient, risk of vital organs,

introduction of microorganisms.

❖Topical- cause environmental pollution. E.g., dipping,

wound spray, etc

Compiled by Lishan A (Dr) 7

 Aim of usage
❖Therapeutic use:-
✓In order to improve clinical signs

✓Kill or reduce the burden of pathogenic organisms

❖Chemoprophylaxis:-
✓Prevent the occurance of infection

➢Usually those drugs which has long residual effect, they

should stay to act for longer period when given SC.

Compiled by Lishan A (Dr) 8

 General Mechanisms of Action
• Parasites must also maintain homeostasis despite host immune
reactions.
❖ Most anthelmintic can be classified into two major categories on
the basis of their mechanism of actions.
✓ Drug affecting the energy production of the parasites

✓ Drugs Affecting the Neuromuscular System of the Parasites, (Paralysis)

❖ Which generally involves interference with the integrity of:-

✓ Parasite cells, neuromuscular coordination, or protective
mechanisms against host immunity,
➢ Which lead to starvation, paralysis, and expulsion of the
parasite.
Compiled by Lishan A (Dr) 9
 Cont. ………… Mechanisms of Action
• It need to now physiology of the parasite
• They have:- NS, DS
❖ Parasitic helminthes, nematodes and trematodes, to maintain an
appropriate energy state:
➢ Must actively ingest and move food through their digestive tracts;
➢ This and reproductive processes require proper neuromuscular coordination.
• Physiological coordination need
– Enzymatic aid
– Neurotransmission

❖ The antiparasitic drugs act on either of this two or on both.

Compiled by Lishan A (Dr) 10

 1. Drugs affect cellular integrity
• Bind to ꞵ-tubilin w/c are used for the formation of
microtubules w/c in-turn important for the movement of
cilia, flagella, transportation.

• They are cidal drugs

✓ E.g., Benzimedazole and probenzimedazoles

➢ Bind to ꞵ-tubulin and inhibit the formation of microtubules.

• Best effective for cattle and horse

Compiled by Lishan A (Dr) 11

Cont. ….. Interfere with cellular integrity

Compiled by Lishan A (Dr) 12

 2. Affecting energy metabolism
❖ Inhibit glucose transport:
➢ e.g. Mebendazole
❖ Disrupters of glycogen metabolism:
➢ e.g., Nitro-imidazoles- are anti-Coccidial drugs.
❖ Inhibit Glycolysis (inhibit source of energy):
– Tendency to bind with the sulfhydryl (- SH) groups
– alter the structure of proteins and the active sites of glycolytic enzymes of
the parasite and host. e.g.,
➢ Arsenicals: Thiacetarsamide
➢ Antitrematodal sulfonamide: Clorsulon

Compiled by Lishan A (Dr) 13

Inhibitors of electron transport mediated oxidative phosphorylation in the
mitochondria of the parasites:
• These drugs interfere with the electron transport in the mitochondria and
thereby inhibit the oxidative phosphorylation and generation of ATP. E.g.
✓Inhibit mitochondrial reaction:- mostly act on
fumarate reductase enzyme.
➢ E.g., Benzimidazole (except mebendazole)

✓ Inhibit phosphorelation – inhibit the H+ which is used for

phosphorelation. They are effective for cestodes and trematodes.

➢ E.g., Niclosamide (Yomesan)

• These drugs are mainly effective against flukes and tapeworms.
• These drugs are not effective against roundworms, because the drugs
cannot penetrate tissues of the intact roundworms.
Compiled by Lishan A (Dr) 14
3. Drug Affecting Neuromuscular system of the parasite

• The drugs affecting neuromuscular system are

classified as below:
✓ Cholinergic agonists

✓ Anticholinesterases

✓ Muscle hyperpolarizers

✓ Potentiation of inhibitory neurotransmitters (GABA

agonists).

✓ Others

Compiled by Lishan A (Dr) 15

Cont. ….. Drug affecting Neuromuscular system of the parasite

I. Those inhibit cholinesterase enzyme. are also has an

effect on the host, so has narrow therapeutic index.
➢ Cause inhibition of acetyl cholinesterase (AChE) enzyme
followed constant depolarization due to accumulation of excess
ACh at the neuromuscular junction.

o Interfere with neuromuscular transmission → paralysis and

expulsion the parasite, through enhanced intestinal peristalsis.
✓ E.g., Organophosphate-

Compiled by Lishan A (Dr) 16

II. Those cholinergic agonist drugs: Nicotine-like action,

• They act by competitive bind of the receptor of Ach.

• Stimulating and subsequently blocking the neuromuscular

junctions.

• Resulting sustained muscle contraction and spastic paralysis of

nematodes. E.g.,
✓ Imidazothiazoles: Butamisole, tetramisole and levamisole;

✓ Pyrimidines: Morantel, oxantel and pyrantel;

✓ Quaternary ammonium compounds: Bephenium and thenium etc. .

Compiled by Lishan A (Dr) 17

 III. Muscle hyperpolarizers:

• An anticholinergic action at the myo-neural junction in worms,

• Producing Competitive or non-depolarising type of

neuromuscular blockade like curarae.

• They cause the blockage of the action of Ach → hyperpolarization

of the muscle membrane → leading to flaccid paralysis,
facilitating expulsion
✓ E.g. Piperazine and avermectins

Compiled by Lishan A (Dr) 18

IV. Potentiation of inhibitory neurotransmitters (GABA agonists):

❖ These drugs act by potentiation of GABAergic transmission

(opening of chloride channels) between nerve and muscle.

o Potentiation of GABA leads to hyperpolarization of

postsynaptic cells leading to interference with
neurotransmission to muscles and consequent muscular
paralysis.

o E.g. Micro-cyclic lactones like Ivermectine and also

piperazine.

Compiled by Lishan A (Dr) 19

Cont. …. Drugs Affecting the Neuromuscular System of the Parasites

Compiled by Lishan A (Dr) 20

 V. Other MOA:
1. Drugs affecting parasite reproduction System:
✓ The drug either bind to the DNA of the parasite or inhibit protein
synthesis of the parasite or bind to macro-molecules.
➢ Such type of drugs are used for protozoan parasites.

2. Drugs affecting the permeability of the cells and cause

vacuolation of the tegument
• E.g. Praziqunatel and diamfenetide.

3.Drugs cause disruption of tegument of parasites:

• E.g. Bunamidine, epsiprantel and praziquantel.

Compiled by Lishan A (Dr) 21

 Anti-Nematodal Drugs (Anti-round worms)
❖The d/t classes include
➢Benzimidazoles
➢Probenzimidazoles
➢Imidazothiazoles,
➢Macrocyclic lactones

➢Tetrahydro-pyrimidins
➢Salicylanilides and substituted phenols,
➢Organophosphates

Compiled by Lishan A (Dr) 22

 1. Benzimidazoles
• Used to treat nematode and trematode infections in domestic animals.

• They are broad spectrum of activity against roundworms (nematodes), an

ovicidal effect, and a wide safety margin (no toxicity even when doubling
normal dose.).

• MOA:- Bind to B-tubules

➢ Inhibit microtubule polymerization

➢ Inhibit fumarate reductase enzyme in TCA cycle.

➢ Inhibit glucose transport - inhibition of energy generating mechanism.

❖ The drug include:- Thiabendazole, Albendazole, Mebendazole,

Cambendazole, Oxfendazole, Flubendazole, Oxibendazole, Fenbendazole,
Triclabendazole .

Compiled by Lishan A (Dr) 23

Cont. ............. Benzimidazoles

❖ Are also active against adult liver flukes and cestodes;

however, unlike all the other benzimidazoles,
triclabendazole has no activity against roundworms.

❖ Are less soluble and are slow release- this used for
effectiveness to the parasite.

• Route: PO as a suspension, paste, or bolus.

• Disadvantage: they have cross resistance.

• S/E: Have teratogenic effect during early pregnancy

Compiled by Lishan A (Dr) 24

 Albendazole
• Active against nematodes(adult and larvae stag), cestodes,
cocccidia and adult fasciola.

• Has very wide TI :- - possible to give 4-20x of normal

dose.

• Actual dose:- 5mg/kg – sheep & Horse (Route, PO???)

✓ 7.5mg/kg – cattle

• It is the most broader of the group.

Compiled by Lishan A (Dr) 25

❖ Cambendazole:-

• Primarily used in pigs.

• Beside nematodes used against cestodes

• Dose:- 20 – 40mg/kg for pigs

• 20mg/kg – cattle, sheep, horse.

• Has low therapeutic index compared to the group. – if you

increase 2 – 3x of the normal dose, it has a lethal effect.

Compiled by Lishan A (Dr) 26

 Fenbendazole (panacure®)
• Effective against all nematodes
• Used to treat the transmission of Toxocara canis in
bitches during late pregnancy.
• Dose:- Cattle → 7.5mg/kg
➢ Sheep → 5mg/kg
➢ Horse → 5-10mg/kg
➢ Dogs (toxocara) → 100mg/kg
✓ It is more commonly used for the treatment of lung
worm in horse.
➢ But it causes allergy due to the death of parasite in the lung.
Compiled by Lishan A (Dr) 27
❖Flubendazole
• Used in the pigs and human
• Dose:- 5mg/kg – pigs

❖Mebendazole:-
❖ MOA: inhibit glucose transport
✓ Highly soluble,
✓ Usually used in cattle

➢ Effective against adult and larvae of cestodes.

➢ Best for horse
✓ Dose:- 10-15mg/kg – sheep
✓ 5-10mg/kg - horse
Compiled by Lishan A (Dr) 28
❖Oxifendazole
• Can also be given by injection (directelly in to the rumen)

• Dose:- 4.5mg/kg – cattle

• 5mg/kg – sheep

• 10mg/kg – horse

❖Oxibendazole:-
• Usually for horse to treat nematodes and lung worms.

• Dose:- 10mg/kg – horse

• 5-10mg/kg – cattle

• 5mg/kg – sheep
Compiled by Lishan A (Dr) 29
❖Thiabendazole
• Active for adult and larval stage of nematodes.
❖ Not currently used due to developed resistance.
• Dose:- 50-75mg/kg – sheep
• 100mg/kg- cattle
• 50mg/kg – horse
• It requires zero withdrowal - can easily removed from the
system.
• Can be given for pregnant

Compiled by Lishan A (Dr) 30

 2. Pro-Benzimidazoles
• MOA:- inhibit fumarate reductase enzyme in kreb cycle.

• Well absorbed in animals and give raise to

Benzimidazole.

• Vet. Important of this group include:-

• Febant:- after administration, metabolized to:

➢ Oxifendazole and fenbendazole

➢ Effective against GIT nematodes

Compiled by Lishan A (Dr) 31

3. Imidazothiazoles

❖Tetramisole:- is a racemic mixture of two

levamisole

❖Levamisole (ketrax®)
✓ Commonly used in cattle, sheep, pigs, goats, and poultry to
treat nematode infections and is not ovicidal.

✓ Has no activity against flukes and tapeworms.

Compiled by Lishan A (Dr) 32

Cont. …………….Levamisole

❖Route: PO or SC. Topical preparations for cattle

have been developed.

❖MOA:- act on the functional group of Ach.

➢(acts on the roundworm nervous system )

– Cause continuous Ach stimulatory effect

– Their will be continuous contraction of the parasite –

result in spastic paralysis.

Compiled by Lishan A (Dr) 33

 Cont. …………….Levamisole
❖ Active against:
✓ GIT Nematodes, Lung worm, canine heart worm larvae (-microfilaria),

✓ Both adult and Immatures stages of Ascaris suum, adult swine nematodes,
except for Trichuris suis

✓ In poultry, levamisole is mainly used to remove Ascarid infections

✓ Used as an alternative to Benzimidazole resistance parasites.

✓ Dose:- 7.5mg/kg

❖ Has immuno-stimulant effects at dosage rates higher than those used

for anthelmintic activity.
➢ Used to increase cell mediated immunity– increase phagocytosis.

Compiled by Lishan A (Dr) 34

 4. Macro cyclic Lactones:
• The macro-cyclic lactones (avermectins and milbemycins) are
products, of soil microorganisms belonging to the genus Streptomyces.

• The avermectins in commercial use are ivermectin, abamectin,

doramectin, eprinomectin, and selamectin.

• Route: well absorbed when administered PO, parenterally, or as pour-

on formulations.

❖ Regardless of the route of administration, they are:

➢ Extensively distributed throughout the body and concentrate particularly in
adipose tissue.

➢ Effective levels are reached in the GI system, lungs, and skin

Compiled by Lishan A (Dr) 35

 Cont.………Macro cyclic Lactones / Macrolides

• A single therapeutic dose → can persist in concentrations sufficient to be

effective against susceptible nematode infections for prolonged periods.

• Sustained availability protects animals from re-infection by some

nematode (and arthropod) species for several weeks.

• Persistent efficacy mainly against the 3 major cattle nematodes,

✓ Ostertagia ostertagi

✓ Cooperia oncophora , and

✓ Dictyocaulus viviparus

➢ And the sheep nematode, Haemonchus contortus .

Compiled by Lishan A (Dr) 36

 Cont………Macrocyclic Lactons / Macrolids
• Highly potent and safe drug
• Has wide TI
• Effective against both internal and external parasites.
→All stages of nematodes and arthropods

• MOA:- Bind selectively and with high affinity to glutamate-gated chloride

ion channels which occur in invertebrate nerve and muscle cells. → leads
to an increase in the permeability of the cell membrane to chloride ions
with hyperpolarization of the nerve or muscle cell, resulting in paralysis
and death of the parasite.

• OR

Compiled by Lishan A (Dr) 37

Cont. ……….. Macrocyclic Lactons / Macrolids MOA
• It may also interact with other ligand-gated chloride channels →
cause increased ion transformation of chloride → trigger increase
excretion of gamma amino butyric acid, GABA, found b/n inter
neural junction of nematodes; and myo-neural junction in
arthropods. → cause hyper polarization →increased resting
potential mm. → inhibit impulse transmission → no muscle
contraction → results in flaccid paralysis of the parasite.
❖ It is not effective to treat cestodes & trematodes.
❖ It is not embryo toxin like albendazole
❖ GABA is important inhibitory NT in mammals, but ivermectin doesn’t affect
mammal
Compiled by Lishan A (Dr) 38
 Cattle
• Ivermectin, eprinomectin, abamectin, doramectin, and moxidectin are variously
available as PO, SC, and pour-on formulations for use in cattle.

• The SC and PO formulations are given at 0.2 mg/kg, whereas the pour-on
formulation is used at 0.5 mg/kg.

• 0.006mg/kg monthly for protection(prophylax)

• Due to their high potency and elimination through milk, the macrocyclic
lactones are not recommended for use in animals that produce milk for
human consumption.

• Eprinomectin and moxidectin are exceptions and have no milk withdrawal time
in many countries.

Compiled by Lishan A (Dr) 39

 Small Ruminants:
• Ivermectin, doramectin, and moxidectin are variously available as PO, SC, and
IM formulations for use in small ruminants.

• As for cattle, the macrocyclic lactones have a very high (>98%) efficacy
against all stages, including inactive forms, of the common sheep and goat
nematodes.

• There is cross-resistance between avermectins and milbemycins, but

moxidectin, still effective when resistance to ivermectin is present.

• Ivermectin controlled-release capsules have been used by sheep producers.

• The delivery rate, maintained for 100 days, is 0.8 mg ivermectin/day for sheep
20-40 kg in weight and 1.6 mg/day for sheep weighing 41-80 kg.

Compiled by Lishan A (Dr) 40

 Swine:
• In pigs, ivermectin and doramectin are given at 0.3
mg/kg body wt, SC, or

• Ivermectin is given in feed for 7 days at 0.1mg/kg body

wt/day for the treatment of all adult and larval stages of
the common swine parasites, including the kidney
worm Stephanurus.

• The exception is Trichuris suis , in which efficacy is

~80%.
Compiled by Lishan A (Dr) 41
 Horses:
• Ivermectin and moxidectin are the only macrocyclic lactones available for use
in horses.

• Dose:- Ivermectin is used at 200 μg/kg, whereas moxidectin is at 400 μg/kg.

• Both are effective against a broad range of adult and migrating larval stages of
nematode and arthropod parasites.

• These include the spirurid stomach worms ( Trichostrongylus axei , Parascaris

equorum , Oxyuris equi , and Strongyloides westeri ), bots ( Gasterophilus spp )

• Adult and immature large strongyles ( Strongylus vulgaris , S edentatus , and S

equinus ), and adult Cyathostominae.

Compiled by Lishan A (Dr) 42

 Dogs and Cats:
• Ivermectin, selamectin, moxidectin, and milbemycin-oxime:-

❖Used in dogs:-

➢for the prevention of heartworm disease and

➢control of GI roundworms.

• Ivermectin is used in dogs at only 6 μg/kg body wt, given

at 1-month intervals, to prevent development of
Dirofilaria immitis, the cause of heartworm disease.

Compiled by Lishan A (Dr) 43

 Cont. ……………….Dogs and Cats
❖ Milbemycin-oxime:- at a dosage of 0.5 mg/kg, PO,
➢ Used for prevention of heartworm infection and for treatment of
hookworms, ascarids, and whipworms in dogs.

❖ Moxidectin:- is also effective for the prevention of heartworm infection

at a dose rate of 3 mg/kg.

❖ Selamectin is also a true endectocide, as its activity encompasses most

of the common intestinal parasites (eg, Toxocara , Toxascaris ,
Uncinaria , Ancylostoma ), heartworms, and external parasites (fleas).

➢ Selamectin may also be given to pregnant and lactating bitches for

treatment and prevention of Toxocara canis infection.

Compiled by Lishan A (Dr) 44

 Environmental Effects
• The commercially available macrocyclic lactones are primarily
excreted in the feces, and a broad range of insecticidal activities
have been observed against dung-inhabiting insect species.

➢ Ivermectin in feces or soil degrades at a slow but significant

rate.
• Although highly toxic to aquatic organisms.
• They have little adverse effect on freshwater algae
• Milbemycins appear to be less harmful to fly and beetle larvae
tested than the avermectins.
Compiled by Lishan A (Dr) 45
• In most husbandry systems, a large proportion of the
feces will not contain residues of macrocyclic lactones,
thus providing a large reservoir of safe habitat for dung
insects.

• Therefore, it is unlikely that use of macrocyclic lactones

will have a significant ecotoxicologic impact on a global
or regional scale.

Compiled by Lishan A (Dr) 46

 5. Tetrahydro-pyrimidins
❖ Morantel, Pyrantel, Oxantel = Pyrimidine derivatives

❖ Pyrantel:- found in two forms

➢ P. pamoate

➢ P. tartrate – more soluble

• MOA:- Bind to & mimic Ach receptor → paralytic effect(spastic)

❖ P. pamoate /Pyrantel:-
✓ a broad-spectrum anthelmintic against GI nematodes of sheep
✓ also been used in cattle, horses, dogs, and pigs.
✓ Both pyrantel and morantel are effective against adult gut worms and
larval stages.

Compiled by Lishan A (Dr) 47

 Cont. ……………..Pyrimidine derivatives
❖ Pyrantel tartrate:-
➢ Ruminants:- broad spectrum limited to adult GI nematodes.
➢ Swine:- for the treatment of larval & adult Ascaris and Oesophagostomum.

❖ Pyrantel pamoate:-
➢ In Dogs and Cats is effective against the common GI nematodes, except for whipworms.

• In Horse:- Pyrantel is effective against:-

✓ Adult ascarids, large and small strongyles, pinworms, and
✓ At doubling the recommended dose, the ileocecal tapeworm Anoplocephala perfoliata.

❖ Oxantel:- combined with pyrantel preparations for dogs (and humans) to increase
activity against whipworms
❖ Dose(pyrantel):- 10mg/kg.

• Route: PO as a suspension, paste, drench, or tablets.

Compiled by Lishan A (Dr) 48

 6. Organophosphates
• Due to their relative toxicity, limited efficacy against
immature stages, narrow margin of safety, and
contamination of the environment through fecal excretion,
their use is declining.
• Haloxon, dichlorovon, trichlorison, coumaphos
• MOA:- They irreversably inhibit Ach-rase enzyme →
continuous contraction → spastic paralysis.
• Also they inhibit host Ach-rase enzyme.
• Low TI(Narrow safety margin)
Compiled by Lishan A (Dr) 49
 Cont. ………….Organophosphates

➢ Haloxon and naftalofos: → 1o OP used in cattle and sheep.

➢ Trichlorfon (metrifonate):- is still used in horses b/c of its high

degree of activity against stomach bots(Gasterophilus spp),
ascarids, and oxyurids.

➢ Dichlorvos:- is particularly useful in pigs against all major

adult nematodes and was one of the first broad-spectrum
anthelmintics to be used in this species. .
• Effective against larval stage.
• Dose:- 20-40mg/kg
Compiled by Lishan A (Dr) 50
 7. Substituted Piperazines
• Piperazines, Diethyl Carbamazine citrate
• MOA:- they cause hyper polarization of muscle → so, the
muscle not responsive to impulse(Ach) → no contraction →
flaccid paralysis
❖ Piperazine:-– Ascaris, Oxyuris of pigs and man.
• rapidly absorbed from the GI tract.
• Effective against :- largely ascarid in all animal species
(including humans) and Oxyuris of pigs
• The safety margin is wide.

Compiled by Lishan A (Dr) 51

 Cont. …………Substituted Piperazines
❖ DEC:- a derivative of piperazine = same MOA

➢ Effective against canine heart worm larval stage (micro-filarial) & used
for heartworm prevention in dogs.
❖In existing infections, the dogs must first be cleared of adult
heartworms and microfilariae to avoid reaction.

❖Then given DEC daily PO throughout the mosquito season to prevent

re-infection.

• DEC also used to treat prepatent Dictyocaulus viviparus in cattle.

• Route:- IM at 22 mg/kg body wt for 3 consecutive days, or

➢ 1 injection at 44 mg/kg provides better respiratory relief.

Compiled by Lishan A (Dr) 52

 Anti-Cestodes and Anti-Trematodes
❖ 1. Pyrazi-isoquinoline:-
✓ Praziquantel

✓ Epsiprantel
– Have high efficacy against cestode parasites but no effect on nematodes.

• Praziquantel is rapidly and almost completely absorbed from the GI tract.

– It has a wide safety margin.

✓ MOA:- Affect the outer layer and cause vacuolation → increase CM

permeability to Ca++, K+ → increased contraction (spastic paralysis) →
depletion of energy → Fail to attach to cm of host. OR

❖ Due to outer layer damage → increase susceptibility to host immune system.

Compiled by Lishan A (Dr) 53

 Praziquantel:-
• PO is highly effective against cestodes of:-
➢ Ruminants (eg, Moniezia spp , Stilesia), horses (Anoplocephala
perfoliata ), and poultry cestodes.
➢ At a dosage of 40 mg/kg is also effective against Schistosoma
infections in cattle (and humans).
➢ In dogs and cats PO (5 mg/kg) or SC (5.8 mg/kg) is 100% effective
against Taenia spp and Echinococcus granulosus (both adult and
immature forms).
➢ Larval stage in the intermediate host except the hydatid cyst
❖ Epsiprantel:- used for the treatment of the common tapeworms
of dogs and cats, including adult E. granulosus. Dose: 5 mg/kg
Compiled by Lishan A (Dr) 54
 2. Substituted phenols
✓ Nitroxinil

✓ Di-chlorphen

✓ Di-amphenthedines

❖ MOA:- Cause an increased permeability of H+ → leak into the inner

mitochondrial mm → cause inhibition of oxidative phospho-relation
→ block energy production.
❖ Diamphenthedines:- become active after biotransformation in the liver.
✓ Active against very young flukes, increased dose used for the adult.

✓ IM- sheep against fasciolosis

❖ Nitroxynil: only active when given parenteral, if given po, deactivated

by ruminal protozoan.
Compiled by Lishan A (Dr) 55
• Active against:-
✓ The adult fasciola and 6-8 wks larvae.

✓ Very effective for gape worm, like Syngumus trachae.

✓ Oestrus ovis

✓ Blood sucking nematodes (e.g. Hemoncuse)

✓ Dose:- 10mg/kg, po.

❖ Dichlorphen:- used to treat cestodes of dogs and cats. → Taenia and

Dipylidium, but no efficacy for Echinococcus.

• Dose:- 200mg/kg, po.

• S/E:- Usually cause vomiting.

Compiled by Lishan A (Dr) 56

 3. Salicylanilides
• Niclosamide, Oxyclozanide, Rafoxanide & Closantel.
• Active against:-
– Juvenile flukes(6-8wks of age)
– Blood sucking nematodes
– Tissue invading flies → oesry, hypoderma.

❖ MOA:- Same as substituted phenols.

❖ Closantel:- Effective against
✓ 6-8 wks & adult flukes, blood sucking nematodes, cestodes, mangemites,
tick
✓ Used in sheep and cattle

✓ Dose:- 5mg/kg, sc; 10mg/kg, po – for all spp of host.

Compiled by Lishan A (Dr) 57
 Niclosamide (YOMESAN®)
• Does not easily absorbed even if given parenterally.

• If it get absorbed, it easily decarboxilated in the liver /

easily metabolized/ and become inert amine.

❖ Effective against:- Taenia, Echinococcus, diplydium

caninum → in dogs and cats.

→Paramphistomum in ruminants (GIT Trematodes

larval stage is very pathogenic and treated by Niclosamide)

• Dose:- 150mg/kg, PO.

Compiled by Lishan A (Dr) 58
❖Oxyclosanide
• Active against only adult liver flukes
• Dose:- 10-15mg/kg, po – for shoats
❖Rafoxanide: - given po / parenteal
✓ Active against adult and young(6-10wks) age of:-
➢Blood sucking nematodes and oestrus ovis
➢Fly maggots

✓ Dose:- 7.5mg/kg, po –sheep and cattle

✓ 3mg/kg, sc - cattle

Compiled by Lishan A (Dr) 59

 4. Benzimidazole

❖Triclabendazole- choice for fasciolosis (acute or chronic)

• Inactive to nematodes but active to fasciola from day 1 to adult.
❖ MOA:- It bind to tubules → impairs polymerization of
microtubules → interfere transportation system (interfere the
removal of parasitic metabolites w/c later become toxic to the
parasite) → has protein syntesis inhibition.
• Dose:- 10mg/kg – sheep
12mg/kg - cattle

Compiled by Lishan A (Dr) 60

 5. Sulphanomides
❖ Clorsulon :- preferred from other sulfa drugs.
❖ MOA: It affect energy production by inhibiting two enzymes of the glycolytic
pathway. It bind to:-
→ phosphoglycerate kinase and phosphoglycerate mutase.

❑ Safety margin is wide,

→ Can be given po or parenteral (sc)
→ Active against:- adult and young (6-10wke) fluke.

❖ Dose:- 7mg/kg, po- sheep and cattle

✓ 4mg/kg, sc – for both spp

❖ Mainly for adult liver flukes in sheep and cattle and as a SC injection for cattle,
in combination with ivermectin.

Compiled by Lishan A (Dr) 61

 Resistance
• Resistance is becoming widespread because relatively
few chemically dissimilar groups of anthelmintics have
been introduced.
➢ Cross-resistance.

❖ Resistance to an anthelmintic is expressed by

– Passage of increased numbers of parasite eggs,
– Higher survival rates of adults in the host, and
– Greater numbers of larvae on the pasture after treatment than
would be seen if the parasites were susceptible to the drug.
Compiled by Lishan A (Dr) 62
 Res….
• Resistance to benzimidazoles, levamisole, and
macrocyclic lactones has been reported for nematodes of
cattle, the problem is still not considered to be serious.

• Nematodes resistant to levamisole are cross-resistant to

morantel due to the similarities of their mechanisms of
action. →Bind to & mimic Ach receptor

Compiled by Lishan A (Dr) 63

 Solution
• In parasite control, economic benefit is best obtained by
careful management practices.

• Planned treatment of a whole flock or herd should be

based on the biology, ecology, and epidemiology of the
parasite(s), with particular reference to climatic conditions.

Compiled by Lishan A (Dr) 64

Anti-Protozoan Drugs

Compiled by Lishan A (Dr) 65

 Antiprotozoal Drugs
• These are drugs used for the treatment and prevention of
protozoal diseases such as Coccidiosis, Babesiosis,
Trypanosomosis, Theileriosis and others.
• They include: -
1. Antitrypanosomial,
2. Antibabesials
3. Anticoccidials
4. Antitheilerials and
5. Miscellaneous antiprotozoals.
Compiled by Lishan A (Dr) 66
 Chemotherapy and Chemoprophylaxis in
Trypanosomosis
• Chemotherapy & chemoprophylaxis are essential in the control
of trypanosomosis, particularly in view of lack of effective
vaccines and the problems associated with vector control.

• Treatment of trypanosomosis is frequently complicated by

✓ Development of drug resistance,

✓ Toxicity and

✓ Damaging / dermo-necrosis produced by some of trypanocidal agents.

Compiled by Lishan A (Dr) 67

 Anti-Trypanosomal Drugs
• Before administering the drug, consider the ff:-
✓ Proper dx:- write drug for write spp
✓ Stage of the disease-
✓ Most drugs have narrow TI (Toxic to the host)
✓ Are mostly provided as dry form, so dissolve properly in
distilled water.
✓ Development of resistance- so it need proper dose, proper
estimation of the wt of the pt animal.

Compiled by Lishan A (Dr) 68

 Group of drugs used for Tryps Rx
1. Diamidines- aromatics
✓ Dimenazine aceturate(Berenil®)

✓ Phenamidine isoethionates

✓ Stilamiden

✓ Pentamidine

❖ MOA: It bind to the DNA of the Tryps.

❖ S/E:-
✓ Vasodilation effect- decrease BP lead to shock

✓ Increase muscle movement – result in vomiting and diarrhea

✓ Toxic to kidney and liver;- photosensitization

Compiled by Lishan A (Dr) 69

 ❖Diminazine aceturate (BERENIL®)-
➢ Diminazene aceturate was introduced for the treatment of babesiosis and
African trypanosomiasis
o Stable with very low toxicity
o Very active & effective against
✓ Trypanosomes resistant to other drugs and
✓ Piroplasmosis due to babesia bigemina.

❖ The x-ter is simillar for the group

✓ Active against T. congolense and T. vivax
✓ Soluble in water
❖ Recommended dose:
➢ 3·5 mg kg−1 body weight for T. congolense and T. vivax (7 mg kg−1 may be
recommended against resistant isolates) and
➢ 7 mg kg−1 is indicated for T. brucei and for surra,
➢ Administered by IM or SC injection.
➢ Those drugs are toxic to equine, dog and camel
❖ Diminazene is only applied as a curative agent

Compiled by Lishan A (Dr) 70

 DIMINAZENE MOA
• Its trypanocidal mode of action has not been completely elucidated.

❖ The compound binds the DNA

➢ In trypanosomes, the binding can cause inhibition of replication

❖ It also shown to interfere with the mitochondrial membrane potential

❖ It has been suggested that diminazene can also modulate the host
immune response by:
✓ Dampening pro-inflammatory cytokines and

✓ Excessive immune activation, which might also influence the in vivo effects of
the drug.
❖Phenamidine Isoethionate:
✓ Has the same MOA as the above→ bind to DNA
✓ Are best drug for babesia
✓ Soluble in water
✓ Dose 3.5mg/kg

❖Pentamidine: has actually been used to treat ‘early to late

stage’ HAT (Human African Trypanosomiasis: caused by sub
spp. of T. bruci; infect human: T. b. gambiense & rhodesiense)
but its movement across the blood–brain barrier is counteracted
by active efflux mechanisms, including Pglycoprotein and multi-
drug resistance transporters.

Compiled by Lishan A (Dr) 72

 2. Phenanthridine-based Trypanocidal Agents
(Amino-phenanthridium cpd)
➢ Homidium bromide (Ethidium)

➢ Homidium chloride (Novidium):

Homidium salts
➢ Isomethamidium chloride

❖ Homidium:-

➢ Widely used in Africa to treat T. congolense and T. vivax infections in cattle, sheep and
goats, in spite of its mutagenic and carcinogenic properties as intercalates a DNA

➢ Used as a curative and also possesses chemo-prophylactic properties (for 1month ), but
less pronounced than those of iso-metamidium.

➢ Homidium excretion is faster than isometamidium

❖ Dose: For both purposes, 1 mg kg−1 by a single, deep IM injection

• The use of homidium is today highly discouraged; due to:
✓ Its potential toxicity and Wide spread resistance to the drug
Compiled by Lishan A (Dr) 73
❖Isomethamidium Chloride (Samorine®, Trypamidium®)

• Synthesized by coupling homidium with the diazotized p-

aminobenzamide moiety of diminazene.

• It has both curative and prophylactic properties

• The di-substituted compound has poor trypanocidal activity but it
has a good prophylactic effect.
• Isometamidium is used primarily to treat and prevent T.
congolense and T. vivax infections in livestock in Africa.

• Can also be utilized against some T. b. evansi strains, although not

when these have reached the CNS, as it does not cross the BBB.

Compiled by Lishan A (Dr) 74

 Cont. ………Isometamidium
❖ Dose: cattle - single doses of 0·25–1·0 mg kg−1 for cure, and at
doses of 0·5–1 mg kg−1 for prophylaxis
✓ The dosage for T. b. evansi infections is generally 1–2 mg kg−1 , but in
horses it is recommended not to exceed 0·5 mg kg−1 due to toxicity issues

✓ Its resistant strains are susceptible to berenil.

• Duration of prophylactic: following IM in cattle is 2–3 or may
be up to 6 months.
❖ Persistence of isometamidium residues is much longer than
diminazene.
➢ Withdrawal period = 30 days for consumption of produce from cattle.

Compiled by Lishan A (Dr) 75

 3. Quinapyramines (Antrycides)
• Quinapyramine is a quinoline pyrimidine, as Isometamidium & diminazene, a
di-cation at physiological pH (homidium is monocationic).

• Are salts of chlorides and sulfate

• The chloride salts are less soluble in water and mostly used for prophylaxis.
– E.g., Quinapyramine chloride

• The sulfate salts are readily soluble in water, has fast action and used for
curative drug for cattle and small ruminants and given sc.
– E.g., Quinapyramine-methylsulfate (Trypacide)
• The pro-salt form of quinapyramine (a mixture of the soluble sulphate
and the insoluble chloride salts) was the first prophylactic drug
available for animal infections.
• Pro-salt suspension has both a curative and a prophylactic (up to 4
months) effect on T. b. evansi infections in horses and camels (at a 7·4
mg kg−1 dose)
Compiled by Lishan A (Dr) 76
Cont. ……………..Quinapyramines
• Effective against: T. congolense, T. vivax, T. evansi and T. equiperdum; less extent to
T. brucei

• As for the other charged trypanocides, quinapyramine is unable to cross the

bloodbrain barrier → failure to cure T. b. evansi in equids when the CNS is
affected.
• Best treatment in equine and camel
❖ Dose: 0.025mg/kg of 10% SC – prophylaxis (combination)
✓ 3-5 mg/kg sc - therapy
❖ As Quinapyramine resistant T. congolense trypanosomes show cross-resistance to isometamidium,

homidium and diminazene, the use of this compound to treat infections in cattle is
not recommended.
✓ There is lack of cross-resistance between diminazene and homidium, but

✓ Quinapyramine is cross-resistant to both.

Compiled by Lishan A (Dr) 77
❖Pyrithidium bromide (Prothidium):

✓ Basically used for prophylaxis in cattle, and both as a

curative and prophylactic drug for equine and dogs.

✓ It easily induces resistant trypanosomes with cross resistance

to ethidium and quinapyramine.

➢But susceptible to berenil and isometamedium.

Compiled by Lishan A (Dr) 78

4. Suramin sodium (Naganol)
• Suramin sodium is a symmetrical poly-anionic sulfonated naphthyl-amine

• Used for >65 yrs ago for sleeping sickness as a prophylactic drug in man.

• Used for the treatment of surra in camels

❖ Dose: 6–10 g per camel was described as 100% effective

• It also the standard treatment for equine trypanosomiasis (T. brucei spp.), being
more effective than diminazene and less toxic than quinapyramine .

• Suramin to be fully effective it dependent on the host’s immune response.

• It does not cross the blood–brain barrier; B/se of its large molecular size and
highly anionic nature,

• MOA:- Has effect on enzymes, especially on glycerophosphate oxidase enzyme.

Compiled by Lishan A (Dr) 79

 Cont. ………… Suramin
• Active against: T. evansi, T. equiperdum, T. brucei but not for T.
congolense and T. vivax
• It has good efficacy against T. simiae in pigs.
❖ Used as prophylactic agent when given SC as insoluble complex
with one of the cationic trypanocides e.g. with quinapyramine
(two cationic), in a 1:3 molecular proportion, resulting in
✓ 3–6 months protection at 40 mg kg−1 in pigs and
✓ >160 days protection in cattle

• This approach could be effective for the eradication of T. b.

gambiense in pigs, which acting as reservoir hosts of this species.
Compiled by Lishan A (Dr) 80
 Cont. ………… Suramin
• Has synergestic effect with phenanthridium salts and
Quinapyramine salts.
• Dose: treatment for camels and horses is 10 mg kg−1 , IV
• Used as curative not for prophylaxis
************************
❖ N.B: to overcome or reduce resistance, trypanocidals are used in
sequence or in combination. E. g. Quinapyramin with suramin
used against T. evansi in horses & T. simae in pigs.
➢ Pyrithidium →Homidium bromide (Ethidium) or Homidium chloride
(Novidium)→Isomethamidium → Diminazene (BERENIL).
Compiled by Lishan A (Dr) 81
Table: Summary of Currently Available Antitrypanocidals
Name Trade Aque Administ A Dosage (mg Vol.of Indication/ Adverse Treatm
Name ous ration cti Kg−1 ) b inj.solutio Animal effects/other ent of
soln route on n information relapse
s
Diminaz Berenil, 7% IM, SC T 3·5 (up to 8 T. congolense, Toxic to horses, Isometa
ene Veriben, cold for resistant T. vivax (less donkeys, dogs and midium
aceturat Pirocide, water trypanosomes, active on T. b. camels. Also chloride
e Ganaseg, 5–10 for T. b. 5ml/100kg brucei, T. b. babesicidal
Azidin, evansi) evansi)/Cattle,
Trypan sheep, goats,
dogs
Homidiu Ethidium 1- IM (deep, T, 1 10ml/100kg T. vivax, T. IM toxic to Diminaz
m Novidium 2.5% cattle), IV (P) congolense horses. ene
bromide Hot (sheep, (less active on Potentially aceturat
Homidiu water goats, T. b. carcinogenic e,
m pigs) brucei)/Cattle, Isometa
chloride sheep, goats, midium
pigs chloride
Isometa Trypamidi 10% IM (deep) P, 0·25 –1 (T), 2.5ml/100kg T. congolense, Toxic above 2 mg Diminaz
midium um, cold T 0·5 –1 (P) T. vivax (less Kg–1. Avoid ene
water 5-
chloride Samorin, active on T. b. subcutaneous aceturat
10ml/100kg
Veridium, brucei, T. b. administration. e
Securidium evansi)/Cattle, Highly irritant.
sheep, goats, Possible local
horses, camels reactions in
cattle.
 Table: Summary of Currently Available Antitrypanocidals
Name Trade Name Aqu Admi Act Dosage (mg Vol.of Indication/ Adverse Treatm
eous nistr ion Kg−1 ) b inj.soluti Animal effects/other ent of
soln ation on information relapse
route s
Quinapyr Antrycide, 10% SC T 3–5 (T) (20 5ml/100 T. b. evansi, T. Toxic at Isomet
amine Trypacide, cold –40 for T. kg vivax, T. high doses. amidiu
Methyl Noroquin, wate simiae) congolense, T. Fast m
sulphate Quintrycide r (Camels, brucei, T. b. resistance chlorid
Quinapyr , Tribexin, horses, pigs, equiperdum, acquisition e,
amine Triquin-S, dogs: dose T. Surami
sulphate: M7555, divided and simiae/Camels n
chloride Trypacide given at 6 h , horses, pigs, sodium
(3:2 w/w) prosalt intervals), dogs, cattle
7·4 (P) (discouraged)
Suramin Naganol, 10% IV T 10 (horses: 3 30- T. b. evansi, T. IM can Quinap
sodium Bayer 205, cold doses/1 40ml/An b. brucei, T. b. cause severe yramin
Germanin wate (P week) imal equiperdum/ necrosis at e
r ) Camels, injection sulphat
7- horses site. May be e
10ml/10 toxic to
0kg horses

IM, intramuscular; IV, intravenous; SC, subcutaneous; T, therapeutic action; P, prophylactic action.
Note. Products used in animals producing meat or milk for human consumption should only be used in
full compliance with product labels including withdrawal periods.
 Anti-Babesial Drugs
❖ Urea complex drugs:- of thee groups
➢ Amicarbacide istheonate
➢ Quinorunium sulphate
➢ Imidocarb dipropionate

❖ Amicarbacide istheonate
➢ Broad spectrum
➢ For the treatment of anaplasma
➢ Less effective for T. parva
❖ MOA:- Inhibit DNA replication
Compiled by Lishan A (Dr) 84
 Cont. ……….Amicarbacide istheonate
➢ It help to develop pre immunity, not remove the parasite .

➢ The animal remain as carrier.

➢ Dose: 8.8mg/kg, iv for two days; 5mg/kg IM, 10mg/kg for per
acute cases.

❖ S/E: Can cause local inflammation at site of injection.

❖Imidocarb dipropyonate/ Imizol: used for

prophylaxis and treatment of babesiosis and Anaplasmosis.

❖ MOA: Also bind to the DNA of parasite

➢ Vacuolation of cytoplasma

Compiled by Lishan A (Dr) 85

 Cont. ……..Imidocarb dipropyonate

❖S/E: Has an effect on host NS- Cause nervous sign

➢ Inhibit cholinestrase

• Dose:- 1.2, 2.4 and 6mg/kg for cattle, horse and dog

respectively; Route: sc, im

– Horse: 2.4mg/kg, cattle: 1.5mg/kg, dog 6mg/kg – Sc for

babesiosis therapy.

– Cattle: 3mg/kg, Sc/IM, for Anaplasmosis therapy or

babesiosis prophylaxis to protect for a month

Compiled by Lishan A (Dr) 86
❖ Quinurolium SO4 (Acopron®, Alopron®, Baboson®) -
Used for treatment of babesiosis, except B. bovis of cattle
and B.gibsoni of dog
❑Effect in wide range than the above two drugs

❑Usually used for curing of clinical signs.

❖ Dose:- Horse: 0.6-1mg/kg Sc, cattle, 1mg/kg Sc, Dog -

0.25mg/kg Sc.

✓ Route: sc only
Compiled by Lishan A (Dr) 87
❑ Other Babesiocidal Drugs
1) Trypan blue
➢ They are currently not on market b/c of their efficacy and toxicity.

➢ But effective for B. bigemina of cattle

➢ Route:- iv

2) Acriflavine- used for the treatment of babesiosis in

horse (B. equi) and cattle (B. begemina and B. bovis)
– Dose: cattle and horse- 2.2 mg/kg IV as 5% solution

Compiled by Lishan A (Dr) 88

3. Diminazinene aceturate – Trypanocide, babesicide and bactericide.
– Horse; 5mg/kg IM, cattle, shoat and dog: 3.5mg/kg SC or IM

– Dog: 6mg/kg, B.gibsoni.

4) Pentamidine isothionate: - used for treatment of babesiosis

✓ Cattle: 2mg/kg Sc, dog 4mg/kg Sc or IM

5) Phenamidine isothionate: - used to treat babesiosis.

✓ Horse- 8.8mg/kg/d Im for 2days, B.cabali, for 4-5 days B.equi

✓ Dog- 1.5mg/mg/d Sc for 2 days

Compiled by Lishan A (Dr) 89

 Anti-Coccidiosis
• They are used for prevention and treatment of coccidiosis caused by
Eimeria species in ruminants, birds and rabbits, and Isospora spp in
pig and dog.
• The natural development of immunity to coccidiosis may proceed
during the use of anticoccidials in the feed.
➢ In broiler, due to their short grow-out period of 37–44 days,
development of immunity may be of little consequence.
• In replacement layer pullets, natural immunity is important because
they are likely to be exposed to coccidial infections for extended periods
after termination of anticoccidial drugs.
• The drugs are given as prophylaxis
Compiled by Lishan A (Dr) 90
 Selecting Anti-coccidial
• Selection of an anticoccidial is based on:

1. The ability of the drug to improve weight and feed conversion and
to suppress the development of lesions.

2. Presence of drug residues in eggs and milk.

3. The emergence of drug resistant strains of coccidia

• Anti-coccidial drugs usually given as prophylaxis
which need for the development of immunity by

✓Lower dose of the drug

✓Intentionally infecting and treating

✓Attenuated vaccine

Compiled by Lishan A (Dr) 92

 Drug categories
• Anticoccidial drugs belong to one of two categories:
1. Polyether antibiotics or ionophores, which are produced by the
fermentation of Streptomyces spp. or Actinomadura spp.

❖ MOA: These drugs disrupt ion gradients across the cell

membrane of the parasite. Can be classified as:
a) Monovalent ionophores ( Monensin, Narasin, Salinomycin)
b) Monovalent glycosidic ionophores (Maduramicin, Semduramicin)
c) Divalent ionophore (Lasalocid)
 2. Synthetic compounds
• Popularly known as chemicals, produced by chemical
synthesis, often with a specific mode of action:
a) Inhibition of parasite mitochondrial respiration
(Decoquinate, Clopidol)
b) Inhibition of the folic acid pathway (Sulfonamides)
c) Competitive inhibition of thiamine uptake (Amprolium)
d) Unknown mode of action (e.g., Diclazuril, Halofuginone,
Nicarbazin, Robenidine)
 The ionophores
➢ Ionophorous Antibiotics are coccidiostatics obtained from
streptomyces species
➢ They are extensively used as anticoccidials.
➢ Commercially used Ionophores are:
✓ Monensin, Lasalocid and Salinomycin
➢ Monensin
➢ It is the 1st antibiotic used as an anticoccidials
➢ It is broad spectrum activity.
➢ It acts on trophozoites and 1st generation schizonts.
✓ Lack of development of drug resistance.

Compiled by Lishan A (Dr) 95

Cont. …………… Monensin
➢ It also increases the weight gain and feed conversion and in some
cases causes suppression of necrotic enteritis.

➢ It gives protection against all species at 0.01 - 0.121%

concentration in the feed (chicken).

➢ It is superior over amprolium, clopidol and zoalene in control of

coccidiosis.

• Dose:- (treatment)
✓ 100 – 200ppm- for chicken
✓ 16-33ppm - cattle
✓ 11-33ppm – sheep
 Mechanism of Action of Ionophores

❖ Interfere the transport of ions →Increase influx of Na+ ion

→Elevates the intracellular [Na+ ion] → Causes osmotic

imbalance.

✓ Has also growth promotional effect in cattle.

✓ Generally they act at the stage of sporozoites and merozoites-

✓ They are for prevention and Rx

✓ Has low therapeutic index

Compiled by Lishan A (Dr) 97

Cont. ... MOA
Ionophore
Na+, K+
Normal Na+
situation

Na+ - K+ -pump Na+ - K+ - pump

K+
Ionophore

Na+, K+ Na+, K+ Na+,K+

Destruction by Na+, K+ Na+, K+

Bursting Na+, K+

Osmotic Pressure H2O Osmosis

 Lasalocid
➢ It has a high degree of anticoccidials activity.
➢ It also increases weight gain, feed conversion and
reduces the lesion in severe coccidiosis
➢ It has different ionic affinities and accepts divalent
cations as well as monovalent ions.
❖It is effective at 0.005-0.0075% concentration.
❖Dose:- 75-125ppm
 Salinomycin
➢ It is more closely related to monensin than lasalocid.

➢ It has anticoccidials activity at 0.01 % in the feed and it

was as effective as 0.0121% monensin in controlling
coccidiosis poultry.

➢ The ionic affinity is similar to that of monensin i.e.

sodium and potassium ions.
 Maduramicin
➢ It is most potent among the polyether Ionophores.

➢ It is given at 5-6 ppm in feed and activity is similar to

that of other Ionophores

❖Problem of these Ionophores is that they may cause

severe cardiovascular defects in animal cells.
Ionophores Therapeutic conc. for Coccidiosis in Chicken
Withdrawal
Drug Use Level (% in feed)
Time (days)
Monensin 0.01–0.0121 0
Narasin 0.006–0.008 0
Narasin + Nicarbazin 0.003–0.005 (of the combination) 5
Salinomycin 0.0044–0.0066 0
Semduramicin 0.0025 0
Lasalocid 0.0075–0.0125 3
Maduramicin 0.0005–0.0006 5
 Synthetic Chemicals
❖ Clopidol: effective against sporozoites (early stage )
– Used in the first shuttle program.
– Effective for all spp of Eimeria
✓ MOA: Inhibition of parasite mitochondrial respiration
– Dose:- 125ppm in feed

❖ Decoquinate
✓ Highly effective for static envading sporozoite.
✓ Use next to clopidol
✓ MOA: Inhibition of parasite mitochondrial respiration
➢ It inhibit electron transport (additional MOA).
✓ Used in wide range of spp- chicken, lamb, cattle.
✓ Dose:- 20-40ppm - Cattle
• 100ppm - chicken Compiled by Lishan A (Dr) 103
 ❖ Nicarbazine
➢ It was the first product to have truly broad-spectrum activity.
➢ It is used as a prophylactic
➢ it has broad spectrum activity & effective against all Eimeria spp.
➢ Therapeutic dose lies near the toxic dose.

➢ This compound has coccidio-cidal activity

✓Mainly Act on schizonts appear after the 1 st generation.

➢Marked act on the second generation schizonts

❖ Halofuginones,
✓ Act at early developmental stage of second asexual generation.
✓ Dose 3ppm
 ❖ Sulfa drugs
❖ Sulfonamides: Are coccidiostats.

• Currently there are simple sulfas and potentiated sulfas.

❖ Simple sulphas: - include
– Sulfamethazine
– Sulfachlorpyridazine
– Sulfadimethoxine
– Sulfaquinoxaline

❖ The potentiated sulfas: - sulfa-dimethoxine with ormethoprim,

sulfadiazine with trimethoprim.

Compiled by Lishan A (Dr) 105

 Cont. …………Sulfa drugs
• MOA:- inhibition of follic acid synthesis

• Act at last stage of second schizonts. – after development

of clinical sign.

• Used in chicken, cattle, and also sheep

• Dose:- 125-150ppm – in feed – chicken

• 5mg/kg injection (iv, sc, im) – cattle and sheep

• Can be also given with feed/water.

Compiled by Lishan A (Dr) 106

 ❖Amprolium :-
➢ It is thiamine antagonist- inhibit DNA synthesis

✓ Act on early first generation schizonts.

✓ Usually in market in combination with sulfa drugs.

▪ Dose:- 125ppm- chicken – Sulfaquinoxaline +

Amprolium; for caecal coccidiosis.
✓10mg/kg - cattle

Compiled by Lishan A (Dr) 107

 Chemicals for Prevention of Coccidiosis in Chicken
Drug Use Level (% in feed) Withdrawal Time (days)

Amprolium 0.0125–0.025 0
Amprolium + ethopabate 0.0125–0.025 + 0.0004–0.004 0
Clopidol or meticlorpindol 0.0125–0.025 0
Decoquinate 0.003 0
Diclazuril 0.0001 0
Dinitolmide (zoalene) 0.004–0.0125 0
Halofuginone hydrobromide 0.0003 4–7
Robenidine hydrochloride 0.0033 5
Sulfadimethoxine + ormetoprim 0.0125 + 0.0075 5

Compiled by Lishan A (Dr) 108

 Resistance and Cross Resistance
Reduced sensitivity/resistance Cross-resistance

After some time of use If resistance to one product arises

The efficacy of anticoccidials Other similar products will also work

decreases less efficient
 Cross resistance
❖Chemicals:
➢ All have very different targets to kill parasite

➢ No occurrence of cross-resistance

❖Ionophores:
➢ Have a common mode of action

➢ Cross-resistance can be a problem

 Overcoming Resistance
• Two program to slow or stop selection of resistance.

1. Shuttle program:- two or more drugs which are

different in their MOA are given until marketable for the
batch, we can change with in the batch at different time.

2. Rotational program:- using one or two drugs with

different mode of action given for a given batch , for the
next batch change the drug- to avoid resistance.
 Antitheilerial Durg
• Used to treat theileriosis.

A. Buparvacone- drug of choice to treat T.annulata, T.lawrencei, and T. orientalis of

cattle. Cttle: - 2.5mg/kg Im

B. Chlortetracycline – used for therapy and prophylaxis of T.annulata of cattle. Cattle:

1.5mg/kg/d Po for 28 days.

C. Halofuqinone lactat: - used for the treatment of T. annulata, parva, lawrencei of

cattle. Cattle- 1.2mg/kg, po.

D. Oxyteteracycline: - used for prophylaxis and therapy of T. annulata. Cattle- 5-

15mg/kg 4-6 times daily Iv after initial exposure or early infection. 2mg of long
acting form/kg IM after initial exposure.

E. Parvaquinone: - used for the treatment of T. annulata, parva, Cattle: - 20mg/kg IM.

Compiled by Lishan A (Dr) 112

 Miscellaneous Antiprotozoals

❖Furazolidone, Gloxazone, Nitroimidazoles,

metronidazole, nitrothiazole, tetracyclines etc.

• Used for the control of Amebiasis, Anaplasmosis,

Balantodiosis, Giardiasis and Histoplasmosis etc.

Compiled by Lishan A (Dr) 113

2.2. Drugs Acting on CNS

Compiled By Dr Lishan A 1
 ❖Terms in CNS depression

❑ Sedation: Slight depression of the NS and the animal is awake

but drowsy/sleepy

❑ Hypnosis: Greater depression of the patient nervous system and

the patient is as dead but if we apply stimuli the animal will awake

❑ Narcosis: hypnosis + analgesia, the patient is as sleep and if a

stimulus is applied the animal will awake but return to asleep
again.

❑ Tranquilization: A state where there is some sedation, hypnosis

and altered behavior (reduced reaction to the environment)

Compiled By Dr Lishan A 2
 Cont. ……. Terms in CNS depression
❑ Pain: the perception of pain depends on central analysis of pain

(pricking /piercing/, burning, aching)

❑ Analgesia: Alleviation of pain.

❑ Amnesia: Loss of memory (unable to remember past history).

❑ General Anesthesia: it is a sate of unconsciousness, no

sensation at all ( Analgesia + Amnesia + Immobility)

✓The patient can’t be awakened whatever stimuli is applied

Compiled By Dr Lishan A 3
❖CNS Neurotransmitters
• ACh

• Monoamines: (Noraderenaline[NE], Dopamine [DA], 5-

hydroxy tryptamine (Serotonin)[5-HT]

• Others: Gamma amino butyric acid ( GABA), Glycine,

Glutamic acid, Histamine, Endorphin, Enkephalin
❖ GABA and Glycine are known to have inhibitory action on CNS

Compiled By Dr Lishan A 4
 CNS Receptors
1. Post junctional (postsynaptic) receptors. Two types

➢Alpha one (α1): NE is stimulatory agonist

➢Dopamine: DA is the stimulating agonist

2. Pre-junctional (presynaptic receptors) or α2

receptors:
• Xylazine is an agonist

Compiled By Dr Lishan A 5
 CNS Drugs
❖ Anticonvulsants:
• prevent seizures by suppressing the spread of abnormal electric
impulses from the seizure focus to other areas of the cerebral
cortex
o All anticonvulsants are CNS depressants
o S/E: may cause ataxia, drowsiness /sleepiness/ lethargy, and hepatotoxicity
➢ Examples:
• Phenobarbital (short-acting barbiturate)
• Primidone (structurally similar to phenobarbital)
• Diazepam (used IV to treat status epilepticus)
• Clorazepam (adjunct anticonvulsant)
• Potassium bromide (adjunct anticonvulsant)
Compiled By Dr Lishan A 6
Cont. ………..CNS Drugs
❖Tranquilizers, Sedatives or Anti-anxiety drugs:
➢ Used to calm animals (quiet excited animals)
➢ Reduce anxiety and aggression
➢ Decrease irritability and excitement
➢ Lessen-anxiousness (anxiety), but do not make animals drowsy/sleepy

❑Examples in these groups:

o Benzodiazepines
• Diazepam, Midazolam
o Butyrophenone: Azaperone
o Phenothiazines
• Acepromazine maleate, Chlorpromazine hydrochloride, Promazine
hydrochloride, Triflupromazine hydrochloride

o Alpha-2 agonists (xylazine, detomidine, medetomidine)

Compiled By Dr Lishan A 7
 CNS Stimulants:
– Reverse CNS depression caused by CNS depressants
– Doxapram:
• stimulates brainstem to increase respiration in animals with
apnea
• Commonly used when animals have C-sections

– Methylxanthines:
• Bronchodilators that have adverse effect of CNS stimulation.
• Include caffeine, theophylline, and aminophylline.
• Side effects include GIT irritation and bronchodilation

Compiled By Dr Lishan A 8
Cont. ………..CNS Drugs
❖Euthanizing agents:
– painless killing to relieve suffering

– Used to humanely end an animal’s life

❖Example:
• Injectables: usually contain pentobarbital

• Inhaled agents: CO2, CO, N2, anesthetics overdose

Compiled By Dr Lishan A 9
 Cont. ………..CNS Drugs
❖Anesthetics:
▪ Anesthesia means without sensation
▪ Interfere with generation and conduction/propagation of nerve impulses
▪ Produce loss of sensation and muscle relaxation, and may cause loss of
consciousness

➢ General anesthetics
▪ Affect the CNS, produce loss of sensation with partial or complete loss of
consciousness

➢ Local anesthetics
▪ Block nerve transmission in the area of application with no loss of
consciousness or alteration of CNS activity

Compiled By Dr Lishan A 10
❖Local Anesthetics
❑Local anesthetics are drugs that produce a reversible
block of nerve impulse conduction and generation

❑Have a local effect.

❑They block
✓motor and sensory nerves
✓reflexes but
✓cannot produce a cortical nerve block like
general anesthetics

Compiled By Dr Lishan A 11
 Based on chemistry local anesthetics are divided into two.

Aminoesters Aminoamides
• Contain ester linkage between • With an amide link between aromatic
amine and aromatic ends and amide ends

• Hydrolyzed by pseudo-cholin- • They are biotransformed in the liver.

esterase enzyme in plasma.
• E.g. Procaine, Chlorprocaine, Tetrcaine • E.g. Lidocaine, Mepivacaine, Bupivacaine

Compiled By Dr Lishan A 12
 ❖Cont………..Local Anesthetics
❖ Procaine is an irritant, short acting, poorly penetrate tissues → not
important for surface anesthesia.
❖ Lidocaine is less irritant, long acting and used for all types of local
anesthesia.
❖ Side effects of local anesthesia is if they are absorbed in to the
circulatory system.
❖ To avoid this problem we use a mixture of local anesthetics with
vasoconstrictor drugs.
❖Example: lidocaine (local anesthetic) + adrenaline (adrenergic agonist)

Compiled By Dr Lishan A 13
❖Techniques of local anesthesia
1. Topical / surface anesthesia
✓ The drug is applied to the skin or mucus membrane to cause loss of sensation by
paralyzing sensory nerve endings.

✓Mucus membranes of the eye, nose and mouth are most commonly used.

2. Infiltration anesthesia/regional
✓ It is the most common method and consists of making numerous subcutaneous
injections of small volumes of local anesthetic solutions in to tissues.

✓ The drug diffuses in to the surrounding tissues from the site of injection and
anesthetizes nerve fibers and endings.

➢ Ring type, square type, rectangular type and inverted ”L”

Compiled By Dr Lishan A 14
Cont …Techniques LA

3. Epidural anesthesia
✓Is injecting local anesthetic solution into the epidural space at the level of
✓The lumbo-sacral region (High)or
✓First or second inter-coccygeal space (high or low).

➢ Acts upon the posterior spinal nerves before they leave the vertebral
column
4. Para-vertebral anesthesia
• It is a special form of conduction anesthesia where in the local anesthetic
is applied to spinal nerves as they emerge from the inter-vertebral
foramina.

Compiled By Dr Lishan A 15
Cont …Techniques LA

5. Peripheral nerve block

✓It involves injection of a local anesthetic in the immediate vicinity
of individual peripheral nerves or nerve plexuses

➢E.g. : Cornual nerve block / dehorning procedure

: Retrobulbar nerve block, etc

6. Intravenous injection of local anesthetic into a limb, with
circulation briefly occluded by a tourniquet, has been employed in
animals and in humans.

Compiled By Dr Lishan A 16
 General Anesthesia
Is a state of unconsciousness with
absence of pain sensation over the entire body of the
animal with muscle relaxation.
• The fundamental pharmacological objectives of
anesthesia: (Balanced Anesthesia)
• Sensory block (analgesia)
• Mental block (Hypnosis and amnesia)
• Motor Block (relaxation of muscle)
• Blocking of reflex
Compiled By Dr Lishan A 17
❖The cardinal features of general anaesthesia are:

• Loss of all sensation, especially pain

• Sleep (unconsciousness) & amnesia

• Immobility & muscle relaxation

• Abolition of somatic & autonomic reflexes

Compiled By Dr Lishan A 18
❖Signs and Stages of GA
•The progressive changes resulting from administration of anaesthetic drugs are
classified into four stages
Stage I - Stage of voluntary movement / Stage of analgesia
Stage II - Stage of involuntary movement / Stage of delirium / Excitement
Stage III - Stage of surgical anaesthesia: 4 planes
I. Plane 1→ light anesthesia in which reflexes are present
II. Plane 2** → medium anesthesia. Sign of plane 1 is absent. Muscles are relaxed;
most surgeries can be conducted except abdominal surgery.
III. Plane 3**→ deep anesthesia. No corneal and pedal reflex, Relaxation of
abdominal muscles
IV. Plane 4→ too deep. All muscles including diaphragm and inter costal muscles
are paralyzed
Stage IV - Stage of medullary paralysis

2024/4/30 Compiled By Dr Lishan A 19

 Pharmacokinetics
Procedure for producing anaesthesia involves
smooth & rapid induction

Maintenance

Prompt recovery after discontinuation

Induction –
✓ “Time interval between the administration of anaesthetic drug
& development of stage of surgical anaesthesia”

✓ Fast & smooth induction desired to avoid dangerous

excitatory phase

❖ Thiopental or Propofol often used for rapid induction

➢ Unconsciousness results in few minutes after injection

➢ Lipophilicity is key factor governing pharmacokinetics of inducing agents

❖Maintenance
• Patient remains in sustained stage of surgical
anaesthesia (stage 3 plane 2)
• Depth of anaesthesia depends on concentration of
anesthetic in CNS
• Usually maintained by administration of gases or
volatile liquid anesthetics (offer good control over depth
of anaesthesia)
❖Recovery
• Recovery phase starts as anaesthetic drug is discontinued
(reverse of induction)
• In this phase, nitrous oxide moves out of blood into alveoli
at faster rate (causes diffusion hypoxia)
• Oxygen given in last few minutes of anaesthesia & early
post-anaesthetic period
• More common with gases relatively insoluble in blood
❖Classification GA

❖There are two types of anaesthetics :

1. Inhalational --- for maintenance

2. Intravenous --- for induction and short procedures

❖Inhalation anaesthetics:
✓ Inhalational anesthetics are unique among the anesthetic drugs. Why?

➢ because they are administered and in large part removed

from the body via the lungs.

Compiled By Dr Lishan A 24
INHALATIONAL ANAESTHETICS

❖Non-halogenated gas
➢ Nitrous oxide
❖Halogenated hydrocarbons
➢ Halothane
➢ Enflurane
➢ Isoflurane
➢ Desflurane
➢ Sevoflurane
➢ Methoxyflurane – nephrotoxicity.

Compiled By Dr Lishan A 25
Kinetic transfer of inhalational anesthetic
❑Inhalation in to the alveoli → a partial pressure/ tension will develop → absorbed
in to the arterial circulation→ reach the brain by crossing the BBB and induce
anesthesia → Finally they will return into the alveoli through the venous
system and be mostly exhaled unchanged

❖ Properties influencing kinetic transfer

1. Partial pressure of anesthetic in inspired gas (Pt)

2. Solubility in the blood (λ)(Blood : Gas partition co-efficient)

3. Solubility in the fat(o.g): (Oil : Gas partition co-efficient

4. Alveolar exchange

5. Potency of anesthetics

Compiled By Dr Lishan A 26
Blood : Gas Partition Co-efficient

 It is a measure of solubility in the blood.

 It determines the rate of induction and recovery of Inhalational

anesthetics.

 Lower the blood : gas co-efficient – faster the induction and

recovery – e.g., Nitrous oxide.

 Higher the blood : gas co-efficient – slower induction and

recovery – e.g., Halothane.

Compiled By Dr Lishan A 27
BLOOD GAS PARTITION CO-EFFICIENT

Compiled By Dr Lishan A 28
Oil: Gas Partition Co-efficient

• It is a measure of lipid solubility.

• Lipid solubility - correlates strongly with the

potency of the anesthetic.

• Higher the lipid solubility – potent anesthetic

e.g., halothane

Compiled By Dr Lishan A 29
 Cont. ……. Inhalational A
Parameters N20 Ether Enflurane Isoflurane Halothane Methoxyflurane

MAC% (Mean 188 3 2.2 1.5 0.8 0.2

Alveolar [])
λ 0.5 1.4 1.9 2.3 12 13
o.g 1.4 90 98 99 224 970
Flammability no yes no no no no

Irritation no emesis no no no no

Induction rapid slow medium medium slow slow

Analgesia mild strong mild - mild -

Muscle no strong little - little -
relaxation
Potency little potent potent potent very very potent
potent

Compiled By Dr Lishan A 30
 II. Parenteral Anaesthetics (Iv)
• These are used for induction of anesthesia.

• Rapid onset of action.

• Recovery is mainly by redistribution.

• Also reduce the amount of inhalation anesthetic for

maintenance.
➢ E.g., thiopental, midazolam propofol, etomidate, ketamine.

Compiled By Dr Lishan A 31
Cont. …..Parenteral anesthetics
o It is easy to inject an overdose; if this occurs, it cannot be readily
eliminated or detoxified
o They have short induction time.
o Safety margin is low b/c medullary paralysis comes very early
o No stimulation of respiratory and salivary secretions
o Unlike inhaled anesthetics, parenteral /intravenous agents do not
require specialized vaporizer equipment for their delivery or
expensive facilities for the recovery and disposal of exhaled
gases.

Compiled By Dr Lishan A 32
Types of parenteral anesthetics
1. Barbiturates

2. Cataleptic anesthetics/Dissociative anesthetics

3. Neuroleptic/Neurolept analgesia

4. Benzodiazepine

1. Barbiturates

➢Hygroscopic and will decompose on exposure to air, heat and light.

➢Should be stored in dark bottles

➢ Eg. Barbitural sodium and phenobarbital

Compiled By Dr Lishan A 33
 ❖Pharmacology of barbiturates
✓CNS depression is dose dependent
❖ Depending on the dose they can be sedatives, hypnotics, basal
anesthetics, general anesthetics or euthanasia
➢They are poorly analgesic(they don’t cause sensory block)
➢They depress respiratory center
➢ They have a hypotensive effect

❖Thiobarbiturates:
✓ Cause Cerebral metabolism and oxygen utilization
✓ Are arrhythmogenic e.g. fibrillations and are contraindicated for animals
with cardiovascular problems.
✓ Cause muscle paralysis Compiled By Dr Lishan A 34
Cont……………Thiobarbiturates …

❖ Thiobarbiturates are tissue irritants they should only be given

through IV.

❖ Barbiturates strictly forbidden for pregnant animals

❖ Phenobarbitol sodium and pentobarbital sodium can be given

through IM route.

Compiled By Dr Lishan A 35
❖Barbiturates: MOA
o Increase the GABA binding and decrease rate of
dissociation of GABA from its receptor.
➢ Decrease the nerve impulse transmission at the nictonic Ach
receptors in NMJ

❖Used mainly as anticonvulsants, anesthetics, and

euthanasia solutions

Compiled By Dr Lishan A 36
 Cont. …injctable…. Barbiturates

• Side effects:
➢potent cardiovascular and respiratory depression

• May be long-acting, short-acting, or ultra-short act

• May vary in structure and be classified as an oxybarbiturate or

thiobarbiturate

• Examples:
• Thiopental, Pentobarbital, Phenobarbital, Methohexital

Compiled By Dr Lishan A 37
 ❖Dissociative anesthetics/ Cataleptic anesthetics

• belong to the cyclohexamine family

• Cause:
– Muscle rigidity (catalepsy), amnesia, and mild analgesia

• Work by altering neurotransmitter activity.

– Binds to NMDA (n-methyl-D-aspartate) receptor and prevent the binding

of excitatory NT (glutamate)

➢ Effects on opioid, MAO, Muscarine and voltage sensitive Ca-channels

receptors

Compiled By Dr Lishan A 38
Cont. ……… Dissociative GA
• Use:

– restraint, diagnostic, and minor surgical procedures

• Side effects:
– cardiac stimulation, respiratory depression, and
exaggerated reflexes
• Examples include:

– Ketamine, Tiletamine

Compiled By Dr Lishan A 39
 Cont. ………Injectable Miscellaneous GA
• Propofol:
– short-acting injectable anesthetic agent that produces rapid and
smooth induction when given IV (lasts 2–5 minutes)
– Decreases the rate of GABA dissociation from its receptors, thus
increasing the opening of Cl channels
• Etomidate
– Agonist of GABA receptor producing hypnosis and depression by
enhancing effects of inhibitory NT (GABA)
• Others: Chloral hydrate, neurosteroids, urethane, propandid,
metomidate, tribromethanol,

Compiled By Dr Lishan A 40
 Pharmacologic Characteristics of Intravenous Anesthetics

Drug Induction and Recovery Comments

Etomidate Rapid onset and moderately fast Provides cardiovascular stability; causes decreased
recovery steroidogenesis and involuntary muscle movements

Ketamine Moderately rapid onset and Causes cardiovascular stimulation, increased cerebral blood
recovery flow, and emergence reactions that impair recovery

Midazolam Slow onset and recovery; Used in balanced anesthesia and conscious sedation;
flumazenil reversal available provides cardiovascular stability and marked amnesia

Propofol Rapid onset and rapid recovery Used in induction and for maintenance; can cause hypotension;
has useful antiemetic action

Thiopental -Rapid onset and rapid recovery Standard induction agent;

(bolus dose) causes cardiovascular depression;
-slow recovery following infusion avoid in porphyria

Fentanyl Slow onset and recovery; Opioid used in balanced anesthesia and conscious sedation;
naloxone reversal available produces marked analgesia

Compiled By Dr Lishan A 41
Monitoring the depth of general anesthesia
1. Frequent reflex testing Include:
➢ Corneal reflex (the stimuli is touch, the response is closer of the eye)
➢ Anal reflex: contraction of the anal sphinctor
➢ Pupillary reflex (the stimuli is light)
➢ Palpebral reflex (the stimuli is touch, the response is oscillatory
movement of the eye)
➢ Pedal reflex
➢ Ear twitching

➢ Scratch reflex, etc

Compiled By Dr Lishan A 42
Cont. ………..Monitoring GA
❖Respiratory Pattern - rate, depth and character of the
respirations.
❖Watch the pattern of respiration

Shallow, thoracic pattern = lightly anesthetized

Deep, abdominal pattern = deeply anesthetized
Pattern should be regular
❖Monitored by observing flow valves, re-breathing bag,
observing chest movement, in-line flow meter.
Compiled By Dr Lishan A 43
 Cont. ………..Monitoring GA
❖Mucous membrane color - The gums, lips, rectum/vulva
remain pink if the animal is receiving enough oxygen.
➢They turn blue if there is a lack of oxygen.
❖Capillary refill time - Measured by pressing on the gum
line until the color blanches and timing its return to normal
color when pressure is released.
➢Normal is 2 seconds or less.
➢Longer times indicate a perfusion problem from
lowered cardiac output, increased vascular resistance, or
hypovolemia.
Compiled By Dr Lishan A 44
 Cont. …….Monitoring GA
❖Pulse evaluation:- Done on the femoral or
mandibular artery or the heart itself. The strength
and character of the pulse vary with anesthetic depth
and blood pressure.
❖Blood pressure - Blood pressure can be measured
indirectly using a pressure cuff on the tail or leg and
an ultrasonic doppler flow detector. An arterial
catheter can be used for direct BP.

Compiled By Dr Lishan A 45
Cont. …….Monitoring GA
❖Body temperature - Anesthesia affects the brain’s heat
regulatory center, lowering the patient’s temperature.
➢Heat Loss is minimized by using a heating pad,
warm fluids, and a heat lamp during recovery.
➢Cooler temperatures slow the metabolism of the
anesthetic.
❖Eyes - Presence or absence of reflexes or nystagmus, and size of
the pupil indicate the level of anesthesia

Compiled By Dr Lishan A 46
Cont. …….Monitoring GA
❖Muscle tone - varies with type of anesthesia used.
Ketamine results in stiff, rigid muscles.
➢Most other anesthetics result in some degree of
relaxation which is easily observed in the larger species
using jaw tone.
❖Reflexes - most common is the pedal or withdrawal
reflex, anal reflex also used.
➢Both disappear as surgical plane reached.
➢Laryngeal reflex used to determine time to remove
endotracheal tube Compiled By Dr Lishan A 47
❖Some Consideration when we Choose GA

• Species & breed:

– There is variation in response to anesthesia, E.g.
• Equines are very aggressive in the first stage of anesthesia
(involuntary excitation).

• Ruminants: cattle because of the bulky nature of the four-

stomach general anesthesia is not usually recommended
because it leads to a problem of bloat, so local and regional
anesthesia are preferable.

Compiled By Dr Lishan A 48
 Cont. …. General consideration
• Susceptibility for anesthesia varies b/n d/t groups of
animals
– E.g. cats are highly excited by morphine, so the drug of choice
for this specie of animals is Ketamine.

• Drug interaction:
– E.g. the presence of chloramphenicol (CYP 450 inhibitor)
affects the biotransformation of barbiturates

• Ambient temperature should be taken in to consideration

during surgical practice under general anesthetics.
Compiled By Dr Lishan A 49
 Preanesthetics
❖ Preanesthetics include tranquilizers, analgesics, and
anticholinergics

• Tranquilizers - lower the animals apprehension /anxiety and aid

in restraint for anesthetic induction. E.g. Phenothiazines reduce
anxiety and cause muscular relaxation.

• Note: These agents cause peripheral vasodilation and

hypotension.

Compiled By Dr Lishan A 50
 cont. ……….Preanesthetics
• Analgesics – work with the tranquilizer to lower the amount of
general anesthetic needed, increasing the safety margin. Can
mask the anesthetic stages.
– E.g. Medetomidine, Xylazine provides some anesthesia as well as
analgesia and sedation. Often used with ketamine.

• Anticholinergics:- reduce secretions and raise heart rate

– E.g. Atropine blocks acetylcholine resulting in decreased secretions from
salivary and respiratory glands; blocks the vagal tone on the heart,
increasing the heart rate

Compiled By Dr Lishan A 51
 Post-anesthesia
and Emergency Care
❖ Drugs to keep on hand for – Epinephrine HCl - for
emergencies: asystole
– Apomorphine - induces – Heparin - dissolves blood
vomiting clots
– Lactated Ringer’s - increases
– Atropine sulfate - increases blood volume
heart rate
– Morphine HCl - analgesia
– Calcium gluconate - – Pentobarbital - anesthesia
strengthens myocardium
– Pitocin - stimulates uterus
contractions
– Sodium bicarbonate -
– Chlorpromazine - tranquilizer acidosis
– Dexamethasone - steroid for – Normal saline - increases
shock/anaphylaxis blood volume
– Doxapram - stimulates – Isoproterenol - stimulates
breathing heart

Compiled By Dr Lishan A 52
Ecto-parasiticides

Compiled by Lishan A(Dr) 1

 Introduction
• Arthropod parasites (ectoparasites) are:
✓ A major cause of production losses in livestock throughout the world.

✓ Many species act as vectors of disease for both animals and humans.

• Therefore treatment often required to maintain health and to prevent

economic loss in food animals.

• The choice and use of ectoparasiticides depends to a large extent on:

✓ Husbandry and management practices,

✓ The type of ectoparasite causing the infestation.

➢ Accurate identification of the parasite or correct diagnosis based on

clinical signs is necessary for selection of the appropriate drug.
Compiled by Lishan A(Dr) 2
 Cont. ...............Introduction
• Parasites that live permanently on the skin, e.g., lice, keds, and mites,
➢ Are controlled by directly treating the host.

• Some mange mites burrow into the skin

➢ more difficult to control with sprays or dips than are lice and keds

❖ However, once these obligate parasites are eradicated, re-infection

occurs only from contact with other infected animals.
❖ Non permanent parasites (ticks, flies, etc) are less/not easily controlled
because only a small proportion of the population can be treated at any
one time, and other hosts may maintain them.

Compiled by Lishan A(Dr) 3

Cont. ...............Introduction

• Larvae of other flies spend several months inside

animals, e. g,

✓Nasal bots in the nasal passages of sheep and goats,

✓Bots in the stomach of horses, and

✓Cattle grubs or warbles in the spinal canal, back, or

esophageal tissues.

Compiled by Lishan A(Dr) 4

 Chemotherapeutic Agents
• Most ectoparasiticides are neurotoxins, exerting their effect on the
nervous system of the target parasite.

• Those used in large animals can be grouped according to structure and

modes of action into the:
✓ Organochlorines, Organophosphates and Carbamates,

✓ Pyrethrins and pyrethroids,

✓ Avermectins and milbemycins,

✓ Formamidines, insect growth regulators, and a number of

miscellaneous compounds, including synergists (eg, piperonyl butoxide).

Compiled by Lishan A(Dr) 5

 Organochlorines:
• Have been withdrawn in many parts of the world due to concerns regarding
environmental persistence.
• However, γ-lindane (γ benzene hexachloride) and methoxychlor, are still used
for topical application
DDT
• Organo-chlorines fall into 3 main groups:
1. Chlorinated ethane derivatives : such as
➢ DDT (dichlorodiphenyltrichloroethane),
➢ DDE (dichlorodiphenyldichloroethane), and
➢ DDD (dicofol, methoxychlor);
❖ MOA: Chlorinated ethanes cause inhibition of sodium conductance along
sensory and motor nerve fibers by holding sodium channels open, resulting in
delayed repolarization of the axonal membrane.

Compiled by Lishan A(Dr) 6

Cont. ..................Organochlorines
2. Hexachlorocyclohexanes such as benzene hexachloride (BHC), which includes the γ-isomer,

lindane.

❖ MOA:- binds to GABA receptors, resulting in an inhibition of GABA-dependent Cl- flux into the

neuron.

❖ DDT and BHC were used extensively for fly strike control but were subsequently replaced in

many countries by more effective Cyclodiene compounds and Pyrethroids.

3. Cyclodienes, including chlordane, aldrin, dieldrin, hepatochlor, endrin, and tozaphene.

❖ MOA: The cyclodienes appear to have at least 2 component modes of action:-

➢ Inhibition of γ-amino butyric acid (GABA)-

➢ Stimulated Cl- flux and interference with Ca2+ flux.

❖ Both the development of resistance and environmental concerns led to their withdrawal. DDT and

lindane were widely used in dip formulations to control sheep scab, but they have mostly been

replaced by the organophosphates and subsequently the synthetic pyrethroids.

Compiled by Lishan A(Dr) 7
 Organophosphates and Carbamates:
• The organophosphates comprise a large group, available for:-

✓ Topical application

✓ Ear tags

✓ Premise control of parasites.

• Many products available worldwide, but only a few of them to be

used for on-animal treatment.

Compiled by Lishan A(Dr) 8

 MOA:
• Organophosphates inhibit the action of Acetylcholinesterase (AChE) at
cholinergic synapses and muscle endplates.
➢ Mimics the structure of acetylcholine (ACh) → When it binds to AChE it
causes transphosphorylation of the enzyme → The transphosphorylated
AChE is unable to break down → accumulating ACh at the postsynaptic
membrane, leading to neuromuscular paralysis.

❖ The degree of transphosphorylation of the enzyme helps to determine

the activity of the organophosphate.

❖ This is not an irreversible process; eventually the AChE is metabolized

by oxidative and hydrolytic enzyme systems.

Compiled by Lishan A(Dr) 9

 Toxicity:
• Organophosphates can be extremely toxic in animals and
humans, causing an inhibition of AChE.

• Cases of organophosphate toxicity are treated with oximes or

atropine.

• Example: Organophosphates used topically include:-

➢ Coumaphos, diazinon, dichlorvos, famphur, fenthion, malathion,
trichlorfon, stirofos, phosmet, and propetamphos.

➢ Ear tags containing fenthion, chlorpyrifos, and diazinon are

available in some countries.

Compiled by Lishan A(Dr) 10

 Activity:
❖ Are generally active against:-
➢ fly larvae, flies, lice, ticks, and mites on domestic livestock.

❖ Activity varies between compounds and differing formulations.

– Diazinon and pro-petamphos:- dip formulations for the control of psoroptic
mange in sheep.

– In cattle:- for the systemic control of warble fly grubs and lice
➢ As pour-on or hand sprays, or dips for tick control

❖ Products containing haloxon and metri-phonate:- used PO for the

control of stomach bot fly larvae and helminths in horses.

Compiled by Lishan A(Dr) 11

 Carbamate

• Carbamate insecticides:-
✓Are closely related to OP and are anticholinesterases.
✓Unlike organophosphates, they cause a spontaneously
reversible block on AChE without changing it.

• The 2 main carbamate compounds used are: carbaryl

and propoxur.
❖Carbaryl has low mammalian toxicity but may be
carcinogenic.
Compiled by Lishan A(Dr) 12
 Pyrethrins and Synthetic Pyrethroids
• Natural pyrethrins are derived from pyrethrum, a mixture of alkaloids from the
chrysanthemum plant.
• The pyrethrins and pyrethroids are lipophilic molecules that generally undergo
rapid absorption, distribution, and excretion.
• Pyrethrin and pyrethroids:- provide excellent knockdown (rapid kill) but
have poor residual activity due to instability.
• Pyrethroids are synthesized chemicals modeled on the natural pyrethrin
molecule. They are more stable, thus have longer residual activity, and have a
higher potency than natural pyrethrins.
• Pyrethroids:- available as pour-on, spot-on, spray, and dip formulations.
➢ Activity:- against biting and irritation flies, lice, and ticks on a domestic livestock.

➢ Flumethrin :- are also active against mites (Rx of psoroptic mange of sheep).
Compiled by Lishan A(Dr) 13
 MOA:
• Interference with sodium channels of the parasite
nerve axons, resulting in delayed repolarization
and eventual paralysis.
❖Example: Some of the more common pyrethroids
used include:-
➢Bioallethrin, Cypermethrin, Deltamethrin,
Fenvalerate, Flumethrin, Lambdacy-halothrin,
Phenothrin, and Permethrin.

Compiled by Lishan A(Dr) 14

❖Macrocyclic Lactones ( Avermectins and Milbemycins):

• It include:-
❖ The Avermectins:
➢ Sabamectin, Doramectin, Eprinomectin, Ivermectin, And Selamectin

❖ The Milbemycins:-
➢ Moxidectin and Milbemycin Oxime.

• These compounds are active against a wide range of nematodes and arthropods
and, as such, are often referred to as endectocides.

❖ The route of administration and product formulation influence the

➢ Rates of absorption, metabolism, excretion, and subsequent

bioavailability and pharmacokinetics of individual compounds.
Compiled by Lishan A(Dr) 15
 Cont. ................Macrocyclic Lactones

❖In cattle (endectocide):- Available & given PO,

injection, or topically using pour-on formulations.
➢ Pour-on more effective against lice (Linognathus, Haematopinus,
and to some extent Bovicola) and head fly (Haematobia/
Lyperosia) infestations, when compared with parenterally.

❖In sheep(endectocides):- PO has little effect against

psoroptic mite infestations ( Psoroptes ovis ), but parenteral
increases activity.

Compiled by Lishan A(Dr) 16

 MOA

➢ Macrocyclic lactones bind to glutamate receptors of glutamate-gated

chloride channels → triggering Cl– ion influx and hyperpolarization of
parasite neurons → leading to flaccid paralysis.

• OR

➢ Ivermectin is known to act on GABA neurotransmission at 2 or more

sites in nematodes, blocking inter-neuronal stimulation of excitatory
motor neurons, leading to flaccid paralysis. Or NMJ of arthropods.

❖ These molecules have low affinity for mammalian ligand-gated chloride

channels and do not readily cross the blood-brain barrier.

Compiled by Lishan A(Dr) 17

 Formamidines
❖ Amitraz is the only formamidine used as an
ectoparasiticide.
✓ It appears to act by inhibition of the enzyme monoamine
oxidase(MAO) and as an agonist at octopamine receptors.

✓ Has a relatively wide safety margin in mammals.

✓ Available as a spray or dip for use against mites, lice, and

ticks in domestic livestock.

✓ It is contraindicated in horses.

Compiled by Lishan A(Dr) 18

 Reading assignment
• Chloro-nicotinyls and Spinosyns
• Insect Growth Regulators:

Compiled by Lishan A(Dr) 19

 Ectoparasiticides Used in Small Animals
❖ Flea and tick infestation of dogs and cats is a major health problem to the
animals and an economic burden to their owners.

❖Avermectins:
❑ Selamectin: the only avermectin control internal and external parasites in dogs
and cats.

❖ MOA:- Believed that selamectin:-

➢ Binds to glutamate-gated chloride channels in the parasites’ nervous system →
Increasing their permeability → Allowing for the rapid and continued influx of
chloride ions into the nerve cell → Inhibits nerve activity and causes paralysis.

• Applied topically → rapidly absorbed through the skin → distributed via the
blood.
Compiled by Lishan A(Dr) 20
 Cholinesterase Inhibitors:
❖ Organophosphates for small animal therapy include:-
➢ Chlorpyrifos, dichlorvos, malathion, diazinon, phosmet, fenthion,
chlorfenvinphos, and cythioate.

❖ Carbamates include carbaryl and propoxur.

❖ Chlorinated Hydrocarbons:
✓ Lindane and methoxychlor are still occasionally used.

❖ Chloro-nicotinyls:
✓ The nicotinoids are a new class of insecticides.

✓ Two compounds for veterinary use;- Imidacloprid and Nitenpyram.

Compiled by Lishan A(Dr) 21
 ❖Imidacloprid:- (a class of Chloro-nicotinyls)
➢ MOA:- binding to postsynaptic nicotinic acetylcholine receptors in
insects → inhibits cholinergic transmission → paralysis and death.
✓ Applied as a 10% spot-on topical product

✓ Used primarily to control fleas on both dogs and cats.

✓ It also has excellent activity against lice.

❖Nitenpyram is administered PO in pill form to kill fleas in both

dogs and cats.

➢ MOA:- While imidaclopridis described as a paralytic, nitenpyram

produces hyper-excitability in fleas prior to death.

Compiled by Lishan A(Dr) 22

 Formamidines:
❖Amitrazis:- used primarily as an acaricide to control
ticks and mites.

• Available as a dip for canine demodicosis and scabies.

• An amitraz-impregnated collar - for the control of ticks

on dogs.

• Amitraz is not approved for use on cats.

Compiled by Lishan A(Dr) 23

 Pyrethrins and Pyrethroids:

• Is notable for its rapid but brief/short action and relative

lack of toxicity in dogs and cats.

• Synthetic pyrethroid (E.g. permethrin) become less

well tolerated in cats, can be highly toxic.

Compiled by Lishan A(Dr) 24

 ❖Repellents: DEET(N,N-diethyl-meta-tolu-amide)
• It is a broad-spectrum → effective against mosquitos, biting flies,
chiggers(Tunga penetrans; harvest mite), fleas, and ticks.

• The effectiveness of DEET(N,N-diethyl-meta-tolu-amide)

formulations for dogs and cats has not been proved.

• The synthetic pyrethroid-permethrin, while not a true repellant, is a

rapidly acting contact insecticide that affects arthropod nervous
systems.

• This leads to death or “knockdown,” thereby producing a repellent-like

activity against fleas, ticks, and mosquitos.

• S/E:- weakness, paralysis, liver disease, and seizures in pets.

Compiled by Lishan A(Dr) 25
Compiled by Lishan A (Dr) 26
Compiled by Lishan A (Dr) 27
Compiled by Lishan A (Dr) 28
Compiled by Lishan A (Dr) 29
Compiled by Lishan A (Dr) 30
Compiled by Lishan A (Dr) 31
Veterinary Pharmacology and
Therapeutics II

Course Code: Vetm4112

Credit Hour: 3 (5 ECTS)
By
Mr. Takele Beyene
(B. Pharm, MSc; Assoc. Professor)
Department of BMS

Course outlines

© 2023 by Takele B. Tufa, AAU-CVMA

 Course evaluation Methods

• Quiz #4 =20%
• Test (Mid term) =20%
• Assignment /report individual =10%
• Final exam =50%

Assignment /report individual

❑ Visit veterinary clinic and document all drugs used to
manage diseases of cattle, small ruminants, equines, pets
and chicken [VTH, SPANA, DONKEY Sactuary)

© 2023 by Takele B. Tufa, AAU-CVMA

Chemotherapeutic Agents
/Antimicrobial Drugs/

General principles of antimicrobial

therapy
 Learning objectives
❑ At the end of this chapter students should be able
to:
– Define different terms associated with antimicrobial
agents (AMAs)
– Understand the general principles of AM therapy
– Differentiate antiseptics and disinfectants with their
mode of application
– Describe how antibacterials disrupt cell function
– List commonly used antifungals and their sites of action
– State how antiviral agents work
– Explain the MoA of antiparasitic agents

© 2023 by Takele B. Tufa, AAU-CVMA

 Antimicrobial Drugs (AMDs)

• Is a chemical substance that has the capacity, in

diluted solutions, to kill or inhibit the growth of
microbes
– Chemicals used to treat microbial infections

• The goal of antimicrobial treatment

– is to render the microbe helpless (either by killing them
or inhibiting their replication) and not to hurt the animal
being treated

© 2023 by Takele B. Tufa, AAU-CVMA

 AMs
• Antimicrobials can be classified as:
– Antibacterials/Antibiotics
– Antifungals
– Antivirals
– Antiprotozoals
– Antiparasitics

Chemotherapeutic agent= Antimicrobial drug?

© 2023 by Takele B. Tufa, AAU-CVMA

Terms related to Antimicrobial medications

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles of Antimicrobial
Therapy (AMT)

❑ Overview
• Takes the advantage of the biochemical
differences that exist between MOs and
animals/humans

• AMAs are effective in the t/t of infections because

of selective toxicity
– The ability to injure/kill an invading MOs without
harming the cells of the hosts
– Controlling the drug concentration is very important

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles…cont’d

➢ Selective Toxicity
– Cause greater harm to microorganisms than
to host
❑ Chemotherapeutic index
▪ lowest dose toxic to patient divided by
dose typically used for therapy

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles…cont’d

❑ Selection of AMAs
– Selection of the most appropriate AMAs
requires knowing
A. The organism’s identity
B. Organism’s susceptibility to a particular
agent
C. The site of infection
D. Patient factors
E. Safety of the AMAs
F. Cost of therapy

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles…cont’d
A. Identification of the infecting organisms
– Rapid assessment: Gram stain
– Conclusive Dx: Culture
– Definitive: Laboratory techniques
– Detecting microbial antigens, DNA, RNA
– Detection of host immune response to the Mos
B. Empiric therapy prior to identification of the Mos
▪ Ideally, the AMA is used to treat infections after the Mos
identified and drug susceptibility established
▪ Timing
▪ Therapy initiated after specimen for lab analysis has
been obtained but before culture result
▪ Selecting a drug
▪ Broad spectrum therapy may be indicated initially

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles…cont’d
C. Determining the AM Susceptibility testing
✓ A guide to select AMT
❑ Antimicrobial Action
• Bacteriostatic: inhibit the growth and
replication of MOs at serum/urine
levels achievable in the patient
– Thus, limiting the spread of
infection until the body’s immune
system attacks, immobilizes and
eliminates the pathogens
– E.g. Sulphonamides,
tetracyclines, erythromycin,
chloramphenicol
• Bactericidal: Kill microorganisms
– E.g. Fluoroquinolones, B-
lactams, Aminoglycosides
Fig. Effect of bactericidal and bacteriostatic drugs on the growth
of bacteria in-vitro
© 2023 by Takele B. Tufa, AAU-CVMA
 General Principles…cont’d

C. Determining the AM Susceptibility…(cont’d)

❑ MIC (Minimum inhibitory

concentration)
➢ The lowest conc. of
antibiotic that inhibits
growth

❑ MBC (Minimum
bactericidal concentration)
• The lowest conc. of
antibiotic that kills 99.9% of
bacteria

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles…cont’d
D. Effect of the site of infection on therapy
e.g. BBB
• Factors that affect the conc. of drugs in the brain:
– Lipid solubility
• E.g. CAF, Metronidazole - lipid soluble
– Molecular weight
• E.g. vancomycin-poorly
– Protein binding affinity
• Unbound/free drug has high conc in the brain
F. Patient factors
✓ immune system,
✓ Renal & hepatic dysfunction
✓ Poor perfusion
✓ Age
✓ Pregnancy: category A, B, C, D & X (refer from books)
✓ Lactation
© 2023 by Takele B. Tufa, AAU-CVMA
 General Principles…cont’d
G. Safety of the agent
✓ Penicillins are, among the least toxic of all
drugs
✓ Chloramphenicol is less MOs specific &
reserved for life threating infections in
humans, but CI in food animals

H. Cost of therapy
✓ Often several drugs may show similar
efficacy in treating an infection, but vary
widely in cost

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles…cont’d
❑ Route of Administration
➢ Oral –for mild infections & favorable conditions

➢ Parenteral
e.g. Amphotericin B, aminoglycosides, vancomycin
✓Poorly absorbed from GIT- have low
oral bioavailability
✓Used to treat GIT mucosal infections

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles…cont’d
❑ Spectrum of Activity
• Antimicrobial medications vary with respect to the range of
microorganisms they kill or inhibit
• Narrow-spectrum antimicrobial
– kill single or only limited range MOs
• Extended/ Broad-spectrum antimicrobial
– kill wide range of microorganisms
– E.g. Gram +ve & -ve bacteria

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles…cont’d
❑ Effects of Combining Drugs
• Advantage
– Combinations are sometimes used to fight mixed
infections, but the drugs must be chosen with care.
– Synergistic:
• action of one drug enhances the activity of another or
more effective than either of the drugs used separately
• E.g. Penicillin + Streptomycin
• Disadvantage
– Antagonistic:
o activity of one drug interferes with the action of
another
• E.g. bacteriostatic + bactericidal
• Inhibit multiplication + are active mainly against multiplying
ones
© 2023 by Takele B. Tufa, AAU-CVMA
 General Principles…cont’d
❑ Complications of antibiotic therapy:
1. Allergic Reactions:
✓ some animal develop hypersensitivities to
antimicrobials or their metabolic products
✓ E.g. penicillins
2. Direct toxicity:
– some antimicrobials are toxic at high concentrations or
cause adverse effects
– E.g. ototoxicity of aminoglycosides
3. Superinfection:
– Due to Suppression of normal flora by broad spectrum
antibiotics- the death of normal flora permits overgrowth of
other pathogens (opportunistic- fungi or resistant)

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles…cont’d

❑ Antimicrobials Resistance (AMR)

– Means the MOs survive and continue to multiply after
administration of the drug
– Occurs when the MOs change in some way that
reduces or eliminates the effectiveness of the agent
used to cure or prevent the infection
– Some MOs inherently resistant to effects of a particular
drug
E.g. G-ve bacteria to vancomycin
– Other previously sensitive microorganisms can develop
resistance through:
• Spontaneous mutations or
• Acquisition of new genes that code for resistance

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles…cont’d
❑ AMR…(cont’d)
❖ Genetic alterations
– The ability of DNA to undergo spontaneous mutation or to
move from one organism to another
A. Spontaneous mutation of DNA
✓ Chromosomal alteration by insertion, deletion, or
substitution of one or more nucleotides within the
genome
B. DNA transfer of drug resistance
• Resistance properties usually encoded
extrachromosomal R factors, i.e. Resistance plasmids
• Most resistance genes are plasmid mediated
• Plasmids enter cells by process of
– Transduction (phage mediated)
– Transformation, or
– Bacterial conjugation
© 2023 by Takele B. Tufa, AAU-CVMA
 General Principles…cont’d

❑ AMR…(cont’d)
❖ Altered expression of proteins in drug
resistant organisms
– Lack of or modification of target sites
– Lowered penetrability of the drug due to decreased
permeability
– Decreased accumulation/ increased efflux
– Enzymatic inactivation

© 2023 by Takele B. Tufa, AAU-CVMA

General Principles…cont’d

© 2023 by Takele B. Tufa, AAU-CVMA

 General Principles…cont’d
❑ Antimicrobial residue

• Is the presence of a chemical or its metabolites in

animal tissue or food products:
– Antibiotic residues can cause allergic reactions
in people or can produce resistant bacteria that
can be transferred to people who consume
these products

– Withdrawal times for antibiotics are aimed at

eliminating antibiotic residues in food-
producing animals

© 2023 by Takele B. Tufa, AAU-CVMA

 AAU
CVMA
Dept of Vet BMS
General Veterinary Pharmacology &
Therapeutics (For VLT BSC Students)

Compiled By Dr Lishan A 1
 Introduction
❖Historical development
• Knowledge of drugs and their use in disease is as old as
history of mankind, but as a science Pharmacology is
quite a young one.
• The birth date of pharmacology is not as clear-cut.
• Primitive men gathered the knowledge of healing and medicine
by:-
➢Observing the nature,
➢Noticing animals while ill and
➢Personal experiences after consuming certain herbs and
berries as remedies.

Compiled By Dr Lishan A 2
Cont……… History:

• Ancient civilizations discovered that extracts

from plants, animals, and minerals had
medicinal effects on body tissue.

• These discoveries became the foundation of

pharmacology.

Compiled By Dr Lishan A 3
 Cont. …………History

•The field of pharmacology grew rapidly in the 20th and 21st

centuries, increasing in the number of new drugs that would
improve the human condition tremendously.

• Many drugs, from lifesaving antibiotics, vaccines, to important

hormonal compounds like insulin (to treat diabetes) were
developed.
• Likewise, there has been great progress in the treatment of
chronic conditions like diabetes, hypertension, and depression.

Compiled By Dr Lishan A 4
 Definition of terms
** Pharmacology: is an experimental science of drugs.
Greek: Pharmakon = medicine/Drug; Logos = Science/study

▪ The study of drugs and their properties, effects on / interactions with

living systems

❖ Wide term which includes:

- The investigation of the biochemical and physiological effects of drugs

- The study of drug absorption; distribution; metabolism and excretion

- The knowledge about the history; sources; physical and chemical

properties and therapeutic uses of drugs

Compiled By Dr Lishan A 5
• ** Drug: French: Drogue – a dry herb:
➢ A single active chemical entity present in a medicine that is used for
diagnosis, mitigation, prevention and treatment of diseases.
✓ Articles other than food intended to affect the structure or function of the
body.

- A chemical substance that is primarily used to reverse a

pathophysiological defect = disease
= Virtually all chemicals may be drugs
= All drugs are toxins but not all toxins are drugs

Compiled By Dr Lishan A 6
• Chemical nature of drugs
- Acidic: Aspirin, barbiturates...etc

- Basic or alkaline: Morphine, Atropine,

Alkaloids...etc

- Neutral: Steroids

Compiled By Dr Lishan A 7
 Human Pathophysiological
/ Animal Process=Disease

Management
Drugs

Compiled By Dr Lishan A 8
Drug and Medicine
• Drug:- a chemical substance of known structure, other than a
nutrient or an essential dietary ingredient, when administered
to living organism, produce a biological effect
• Medicine:- a chemical preparation which usually but not
necessary contain one or more drugs
➢ Substance that have medical importance or therapeutic values
➢ Mostly, Drug + additives

Compiled By Dr Lishan A 9
 Cont. ….. Defn of terms
• Xenobiotic : is a compound foreign to the body
✓ Not produced within the body

✓ Physiologically, endocrinologically, or pharmacologically active

• Dose: quantity of medication to be administered at one time.

• Dosage regimen: is the Manner in which a drug is taken.

• Dosing frequency – The time interval between Doses.

• Pharmaceutics: large-scale manufacture of drugs.

• Steady state: is achieved when the Rate of administration =
Rate of elimination.
Compiled By Dr Lishan A 10
 Cont. ….. Defn of terms

• Drug therapy:- the proper administration of drugs used

to treat disease.

• Indication – the use of that drug for treating a particular

disease.
✓ Example: insulin is indicated for the treatment of diabetes.

❖ Placebo: Drug dosage form such as a tablet/capsule that has no

pharmacologic activity because the dosage form has no active
ingredients

Compiled By Dr Lishan A 11
Cont. ….. Defn of terms
• Contraindication: Are factors in a patient condition
that make the use of a drug dangerous. e.g.
✓ Renal failure, pregnancy, hypertension, diabetes.

✓ Camels do not tolerate the trypanocidal drugs diminazine

aceturate and isometamidium chloride, at doses harmless to
other ruminants.

Compiled By Dr Lishan A 12
 Sub Fields Of Pharmacology
• Pharmacokinetics: It deals with Absorption, Distribution, Metabolism
and Excretion (ADME) of drugs.
➢ What our body does to a drug.

❖ Pharmacodynamics: is the study of the :

✓ Biochemical and physiological effect of the drugs on our body,
parasites and micro-organisms,
➢ what a drug does to our body.

✓ Mechanism of action.

✓ Relation between drug concentration and its therapeutic effect.

Compiled By Dr Lishan A 13
 Cont. ……..Sub Fields

• Pharmacotherapeutics: study the use of drug in the

treatment and prevention of disease.
✓Use of drugs and clinical indications of drugs to prevent
and treat disease (clinical management of diseases)

✓which among the drugs would be most effective or

appropriate for a specific disorder or what dose would be
required.
• Toxicology:- Study of the harmful effect of drugs and
chemicals.
Compiled By Dr Lishan A 14
 Cont. ……..Sub Fields

• Chemotherapy: A branch of pharmacology dealing with

drugs that selectively inhibit or destroy specific agents of

diseases such as bacteria, viruses, fungi and other parasites.

➢ It also includes the drugs used in malignancy/ neoplastic diseases.

• Pharmacognosy: is the study of identification/source of

drugs.

Compiled By Dr Lishan A 15
 Cont. ……..Sub Fields

❖Pharmacopoeia: It is an official code containing a

selected list of the established drugs and medicinal
preparations with descriptions of their physical
properties and tests for their identity, purity and
potency.
➢Define the standards of preparations. Examples- BP, USP,
IP an EP

Compiled By Dr Lishan A 16
 Sources of Drugs
• Drugs are obtained from many sources.
1. Natural sources

❖ Plants = Roots, bark, sap, leaves, flowers, seeds were sources for
drugs. E.g. Morphine, digoxin, atropine, castor oil, etc
❖ Minerals = acids, bases, iron, kaolin , liquid paraffin, salts like
Epsom salt, etc
❖ Microorganisms = Natural penicillin from mold, streptomycin and
many other antibiotics.
❖ Animals = Insulin from the pancreases of pigs and cattle, thyroid
extract, heparin and antitoxin sera, etc..

Compiled By Dr Lishan A 17
 Cont. …….Sources of Drugs
2. Synthetic / Semi-synthetic
➢ Synthetic drugs: are created artificially. E.g. aspirin
➢ Semi-synthetic: contain both natural and synthetic components.
E.g. ampicillin, diacetylmorphine etc.

3.Radiopharmaceuticals: are diagnostic or therapeutic drugs

containing radioactive isotopes.

Compiled By Dr Lishan A 18
 Dosage Forms Of Drug
• Dosage form of drug is medicated product specially designed
/preparations of drugs compounded/ for administration depending
upon the routes to the patient for diagnosis and treatment of disease.

❖ The dosage form is broadly divided into:

• Solid dosage (Bolus, Tablets. Powder, capsule etc )

• Semi-solid dosage (Cream, Ont, gel) which are, used both

• Liquid dosage (Solutions, suspension) internally as well as,
externally
• Inhalations

Compiled By Dr Lishan A 19
 Storage and Handling of Cytotoxic and
Hazardous Drugs
• Storage??
✓Pharmacological
✓Alphabetical
✓Dosage forms

❖Utilization of stored chemicals

✓Based on expiration date (LIFO/FIFO Method)

Compiled By Dr Lishan A 20
 Safe Handling of Hazardous Drugs
❖What Are Hazardous Medications?
• Medications that are known or suspected to cause
adverse health effects from exposures in the
workplace.
• They include:
✓Antiviral medications, hormones, antibacterial, & other
miscellaneous medications.
✓Chemicals for ecto-parasites

Compiled By Dr Lishan A 21
 Potential Risks to Health Care Workers
• Working with or near hazardous medications in health
care settings can potentially cause:
✓Skin rashes
✓Infertility
✓Miscarriage
✓Birth defects
✓Organ toxicities
✓Leukemia or other cancers

Compiled By Dr Lishan A 22
Adverse Health Effects of Occupational
Exposure to Hazardous Drugs on specific system
• Integumenary/Mucosal • Reproductive
– Skin irritation or contact
dermatitis – Infertility
– Mouth and nasal sores – Prolonged time to conception
– Partial alopecia*; hair thinning – Premature delivery/low birth weight
• Neurologic
– Ectopic pregnancy
– Headaches
– Dizziness – Spontaneous abortions/miscarriages
• Respiratory – Stillbirths
– Dyspnea
– Learning disabilities in offspring
• Gastrointestinal
– Nausea and vomiting • Malignancies
– Abdominal pain – Leukemia
• Hypersensitivity – Non-Hodgkin’s lymphoma
– Allergic asthma
– Bladder cancer
– Eye irritation
–
Compiled By Dr Lishan A
Liver cancer 23
 How Do Staff Come in Contact With Hazardous
Medications?
Direct contact Indirect Contact

• Primary physical contact with • Secondary contact with a

a hazardous medication hazardous medication from
during: body fluids, bed linens,
✓ Preparation or medical equipment, etc.
✓ Administration or

✓ When managing a hazardous

medication spill/fall.

Compiled By Dr Lishan A 24
 Exposure Risks
Studies show:
• Chronic (repeated exposure during preparation or
administration of chemotherapy drugs without the use of
protective gloves) low-level exposure to HDs can lead to
absorption.
➢ Chronic low-level absorption may cause significant long-term
side effects.
❖ The use of personal protective equipment (PPE) reduces
the risk of absorption.

Compiled By Dr Lishan A 25
Types of Exposure

• Absorption (through skin, eyes, or mucous

membranes)

• Injection (accidental needle sticks)

• Ingestion

• Inhalation (sprays, aerosolization, drug dust, spills)

Compiled By Dr Lishan A 26
 Controls to Exposure
• Work Practice Controls (procedures performed to
reduce exposure)
─ Prime IV tubing in the Biologic safety cabinets (BSC) , with
saline/locking connections

• Administrative Controls
– Provide clear policy/procedure, education, training, and
evaluation.*

• Personal Controls
─ Personal Protective Equipment – known as “PPE”

Compiled By Dr Lishan A 27
Guidelines for PPE

Compiled By Dr Lishan A 28
 When Should PPE Be Used?
• Introducing or withdrawing needles from vials
• Transferring drugs from vials to other containers using needles or syringes

• Opening ampoules
• Expelling air from a drug-filled syringe
• Administering HDs by any route

• Spiking IV bags containing HDs and changing IV tubing

• Disposing of HDs and items contaminated by HDs
• Handling the body fluids of a patient who received HDs in the past 48 hours

• Cleaning HD spills/fall/leak

Compiled By Dr Lishan A 29
 Disposal of HDs
• Place in leak-proof container.
• Label as hazardous. Put sharps in a puncture-proof
container.
• Seal containers when full.
• Decontaminate reusable equipment (IV poles).
• Keep HDs away from pets and children.
• Follow local regulations regarding disposal.*

Compiled By Dr Lishan A 30
 Spill Management
• Prevent spills as much as possible!

• Be prepared for one if it happens (spill kit).

• Post signs where spill is located; evacuate area.

• If clothes or skin are contaminated, remove clothes; wash

skin with soap and water; get medical attention.

• Wear full PPE, including respirator mask and shoe covers,

before attempting to control spill.

Compiled By Dr Lishan A 31
Mgt of Acute Accidental Cytotoxic Exposure:

❖Skin ❖Inhalation
– Remove contaminated – Move away from area of
garments. exposure.
– Immediately wash skin – Seek emergency treatment.
with soap and water. – Refer to emergency department.
– Refer to emergency
department.
❖Ingestion
– Do not induce vomiting.
❖Eye – Seek emergency treatment.
– Immediately flush eye(s). – Refer to emergency department.
– Seek emergency treatment.
– Refer to emergency
department.

Compiled By Dr Lishan A 32
 Prescription writing and Drug order
❖ Definition: A written order issued by a physician/veterinarian
or other qualified practitioner that authorizes a pharmacist to
supply a specific medication for a patient, with instructions on
its use. (written order for medicine)

❖ It bears:
1. The date of writing the prescription

2. Patient/owner Information (patient’s full name, age, and current

address.)

3. Detail info of the prescribed drug and sign

Compiled By Dr Lishan A 33
Cont. ……prescription

• Names of drugs to be included in the prescription

✓Should not be abbreviated but
✓ Written out in full to avoid possible errors
✓ Chemical formulas must not be used
✓Written in generic name
❖Dose calculation:- usually using units of mg, ml,
and IU per kg of live body weight.

Compiled By Dr Lishan A 34
 QUIZE 1 (VBSCs) (10pts)
1. Write at least 3 units to express dose.(1pt)

2. If the recommended dose of Albendazole to treat liver fluke is 15mg/kg Bwt, how
many mg of the Albendazole is administered once for the animal weighing 100kg?
(2pts)

3. A procaine penicillin is a drug of choice to treat anthrax at a dose rate of 30,000IU/Kg

Bwt, IM, BID for 3 days. If the diseased animal weight is 300kg (4pts)
A. Calculate the volume of the drug in ml given at once

B. How many vials of the drug are used for the total course of treatment?

4. As an antiseptic purpose, 2% iodine working solution is needed. But at your hand you
have 10% iodine stock solution. You want to prepare 1000ml of the working solution
of iodine.(3pts)
A. How many ml of the stock solution you use to prepare the required working solution?

B. How many ml of diluents (water) you use to prepare the needed amount of solution?
Compiled By Dr Lishan A 35
 Routes of drug administration
• Drugs can be administered by various routes.

• Most Commonly used routs:

1. Topical Routes: to produce local effects, drugs are applied

topically to skin or mucous membranes.

✓ Skin: the dosage forms applied locally to skin are powders,

paste, lotions, ointments, creams, plasters and jellies.

✓ Mucous membranes: nose, throat, eye, ear, bronchi, rectum,

urethra, vagina and rectum

Compiled By Dr Lishan A 36
 Routes. ……cont’d
2. Systemic routes: to produce systemic effects
➢ Drugs are administered orally, rectally, parentally or by
inhalation route.

➢ The drug administered through systemic route is absorbed into

the blood, distributed along through the circulation and
produces their desired effects.

Compiled By Dr Lishan A 37
Routes. ……cont’d

✓ Inhalation route: the volatile liquids and gasses are given by

inhalation route.

❖ Drugs given by this route are quickly absorbed, which takes

place from the vast surface of alveoli and produce rapid action.

Compiled By Dr Lishan A 38
Summary and other route of drug administration

Compiled By Dr Lishan A 39
Compiled By Dr Lishan A 40
Compiled By Dr Lishan A 41
 Fate of Administered Drug
• Most drugs after administered to the body they undergo 2
major process
❑ Pharmacokinetics process:- process that involve
absorption, distribution, metabolism, excretion.
❑ Pharmacodynamics process:- process that involve
receptor – drug interaction which determines types and
selectivity of the drug effect and quantitative
determination of drug effect

Compiled By Dr Lishan A 42
 1.2. PHARMACOKINETICS

• Pharmacokinetics is derived from ancient

Greek. Pharmakon means 'drug' and kinetikos means
'moving or putting in motion.'
• Pharmacokinetics is the effects of the body on drug delivery
to its site of action.
➢ “The journey of medication through the body”
• Pharmacokinetic aspects are determined by general
processes, such as absorption, distribution, metabolism and
renal elimination (ADME).

Compiled By Dr Lishan A 43
 1.2.1. Absorption
• Absorption is the transfer of the drug from the site of administration to
the general circulation
❖ Mechanism
• The main mechanisms by which drugs can cross cell membranes are:
❖Diffusion :-
✓Simple / Passive diffusion

❖Transport Mediated By Membrane Proteins

✓Facilitated diffusion /Carrier-mediated processes/
✓Active Transport

❖ Through pores or ion channels

❖ By Endocytosis (phagocytosis and pinocytosis) and exocytosis

Compiled By Dr Lishan A 44
 Factors affecting absorption of a drug
❖ A number of factors can affect the rate and extent to which a drug is
absorbed and into the general circulation.
❖ Drug structure (PH and Ionization)
❖ Drug Formulation (Dosage form)
❖ Administration route
❖ Gastric emptying
❖ Total surface area for absorption
❖ Blood flow to absorbing site
❖ Solubility of the drug
❖ Barriers of the body
❖ Time of arrival and contact time at absorption site
❖ Chemical stability (Will it break down readily?)
❖ Lipid to water partition coefficient (Is it more fat soluble than
water soluble?)
Compiled By Dr Lishan A 45
 1.2.2. Bioavailability
• The fraction of the administered dose of the unchanged drug that
reaches the systemic circulation available to have an effect.

• Any factor that affects drug absorption influence drug bioavailability.

❖ Example: Affected by:

✓ Drug food interaction

✓ Drug-Drug interaction concomitantly in absorption

❖ Route:- drug administered IV bioavailability is 100%.
➢ Administered via other routes (such as orally), bioavailability decreases (due
to incomplete absorption and first-pass metabolism).
➢ Drugs administered by IM or SC have greater bioavailability than those given
orally.
Compiled By Dr Lishan A 46
 1.2.3. Distribution of drug
• Following absorption or systemic administration into the
bloodstream, a drug distributes into interstitial and
intracellular fluids.

• Goal: is for the drug to reach the target tissue or

intended site of action.

Compiled By Dr Lishan A 47
 Drug administered
(oral, Iv, rectal…)

Absorption
Storage in tissue
Site of action (eg- body fat)
( receptors…)
distribution
distribution Plasma compartment

Free drug bound drug

distribution

Metabolism
(eg- liver, GI. Lung…)
Unwanted site distribution
( side effect..)

Excretion
( eg- kidney, lung,
sweat…)
Compiled By Dr Lishan A 48
 1.2.4. Metabolism/Biotransformation
• Drug metabolism also known as xenobiotic
metabolism is the biochemical modification of
pharmaceutical substances by living organisms, usually
through specialized enzymatic systems.

• purpose of biotransformation is to facilitate renal or

biliary excretion of drugs by rendering it more polar.

Compiled By Dr Lishan A 49
 …con’t
• Drug metabolism helps to:
✓Reduce the drug effect

✓Often inactivates the drug

✓Usually makes the drug more polar → converts lipophilic chemical

compounds into more readily excreted hydrophilic products.

• The enzymes responsible for drug biotransformation are

primarily found in the smooth endoplasmic reticulum of
liver and to limited extent, in GIT, kidneys, and lung.

Compiled By Dr Lishan A 50
 ❖Enzyme Inducing Drugs

✓ Enhance the (production of) liver enzymes which break down drugs
✓ Faster rate of drug breakdown
✓ Larger dose of affected drug needed to get the same clinical effect
❖ Enzyme Inhibiting Drugs
✓ Inhibit the enzymes which break down drugs
✓ Decreased rate of drug breakdown
✓ Smaller dose of affected drug needed to produce the same clinical
effect

Compiled By Dr Lishan A 51
 1.2.5. Drug excretion
❖ Excretion: elimination of drugs or its chemical
byproducts
➢ Bile, feces, lungs, saliva, sweat, breast milk, tear,
genital secretion

➢ Primary organ responsible for excretion is the

kidney, most common mechanism for the
elimination of polar drugs or their metabolites.

Compiled By Dr Lishan A 52
 Renal drug elimination depends on:

✓ Blood flow to kidney

✓ Glomerular filtration rate
✓ Urine flow rate and pH which indirectly alter
➢Passive reabsorption
➢Active tubular secretion

❖Patients with poor renal function will not eliminate

renally excreted drugs very well

Compiled By Dr Lishan A 53
…cont
• Other routes of drug elimination include biliary and
fecal excretion.
• Drugs excreted in bile enters the intestine, where they
are either excreted in the feces or passively reabsorbed.
• Species difference in the extent of biliary excretion exist.
Dogs, cats, and humans are considered good, fair, and
poor biliary excrators, respectively.

Compiled By Dr Lishan A 54
Compiled By Dr Lishan A 55
 Dose of drug
administered

ABSORPITION

Drug concentration DISTRIBUTION Drug in PHARMACOKINETICS

in systemic tissue of
circulation distribution
ELIMINATION
Drug metabolized
Drug
or excreted
concentration at
the site of action

Pharmacologic effect
PHARMACODYNAMICS
Clinical response
Toxicity Efficacy
Compiled By Dr Lishan A 56
 Pharmacodynamics (PD) :
• Is the study of the biochemical and physiological effects of
drug and their mechanism of action.
➢ Study how the drug affects the body
• Pharmacodynamics places particular emphasis on the
study of dose–response relationships.
➢The relationships between drug concentration and
effect.
➢ Provides the basis for –
➢ Rational/Normal therapeutic use of a drug and,

➢ Design of new and superior therapeutic agents.

Compiled By Dr Lishan A 57
 Receptors and theories of occupation
❖ Receptors: area usually (but not always) a protein molecule with
which the appropriate ligand can interact or bind.

❖ Ligands: a substance that attaches and interacts with a receptor.

▪ The ligand is thought of as a “key” fitting into the “lock” which is

the receptor.

▪ The ligand usually fits the receptor as its 3D molecular structure

corresponds to the 3D structure of the receptor.
▪ Ligands: can refer to an endogenous substance.
▪ e.g. Acetylcholine is a ligand that binds to nicotinic or muscarinic receptors.
▪ Also refers to exogenous substance; e.g. drug.

Compiled By Dr Lishan A 58
 Location of receptors
❖Receptors can be found
❖ On / In ion channels,
❖ Adjacent to ion channel,
❖ On enzymes,
❖ Associated with carrier molecules,
❖ Within the cell cytoplasm or
❖ Within the cell nucleus.
➢ Receptors are not only found in animal host, they can also be
found in parasites, bacteria, viruses, and fungi etc.
➢ Not all drugs exert their pharmacological action via receptor-
mediated mechanisms.
Compiled By Dr Lishan A 59
❖Non- receptor based mechanism of action
✓Osmotic diuretics,

✓Purgatives,

✓Antiseptics,

✓Antacids,

✓Chelating agents

✓Urinary acidifying and alkalinizing agent- is

attributed to the physiochemical properties.
Compiled By Dr Lishan A 60
 Terms Define Drug Receptor mediated activity:-
• Affinity: is a measure of the attraction of the ligand for the receptor.

• Selectivity: a drug's ability to preferentially produce a particular effect.

➢ It is related to the structural specificity of drug binding to receptors.

• Efficacy
➢ Degree to which a drug is able to produce the desired response
✓ “The greater the magnitude of the response, the greater the agent’s
efficacy”.
✓ measure thee effectiveness of drug (potency, agonist & antagonist)

Compiled By Dr Lishan A 61
• Potency: is a measure of concentration
– Used to compare compounds within classes of drugs.

– A potent drug requires a lesser concentration to exert an effect.

– Potency of an agent varies inversely with the dose; “the lower

the dose required the more potent the drug”.

• Agonists: Drugs that bind to physiological

receptors and mimic the regulatory effects of the
endogenous signaling compounds.

Compiled By Dr Lishan A 62
• Partial agonists: Agents that are only partly as effective
as agonists no matter the dose employed.

• Inverse agonists: Those that stabilize the receptor in its

inactive conformation.

• Antagonists:
➢A chemical that binds to a receptor but elicits no
response and blocks access to the receptor by an
agonist.
Compiled By Dr Lishan A 63
Cont. ……… Drug-Receptor Interactions
✓ Mimic actions of neurotransmitter at same site (agonist)

✓ Bind to nearby site and facilitate neurotransmitter binding (agonist)

✓ Block actions of neurotransmitter at same site (antagonist)

Compiled By Dr Lishan A 64
 Signal Transduction Mechanisms
❖ Signal Transduction = Cellular Communication
➢ Cells must communicate with one another at either a distance or nearby
➢ Communication is determined by chemical signals and cellular receptors

❖A signal transduction pathway is a series of steps by

which a signal on a cell’s surface is converted into a
specific cellular response.

• Activated by the binding of ligands

65
 Cont. …………Signal Transduction
• According to the source of the ligand and the location of its
receptors three general modes of signaling, can be distinguished.

➢ Autocrine: signals act on cells that secreted it

➢ Paracrine: signals released locally, acting on nearby tissues.

➢ Endocrine: signals produced at a great distance from the target

tissue hormones.

66
67
 Cont. …………Signal Transduction
• Key Steps In Signal Transduction

✓Release of the primary messenger

✓Reception of the primary messenger

✓Delivery of the message inside the cell by the second

messenger →Transduction → Response
• Drugs act as signals, and their receptors act as signal detectors.
➢ Many receptors signal their recognition of a bound drug by initiating a
series of reactions that ultimately result in a specific intracellular response.

68
 Generic/General
Pathway
✓ Reception – Chemical message
(ligand) docks at receptor on
cell membrane and changes its
shape

✓ Transduction – switching
message from chemical signal
received on cell outside to
chemical messages on interior
of cell

✓ Response – Signal transduction

cascade occurs until end result
is reached
EXTRACELLULAR CYTOPLASM
FLUID
Plasma membrane

1 Reception 2 Transduction 3 Response

Receptor

Activation
of cellular
response
Relay molecules in a signal transduction pathway

Reception
Signaling
molecule Transduction
Response
Figure: Overview of cell signaling
 Example: Endogenous vasodilators

FIG 19–2 Regulation of vasorelaxation by endothelial-derived nitric oxide (NO).

71
 Dose response relationships and curves
• Pharmacodynamics= concentration of a drug + response.

• Individual patients may respond to smaller concentrations, or

• Require concentrations that are much greater to obtain a

therapeutic effect.

• Thus, we start by plotting a drug response curve where the

concentration of the drug is along the X-axis and the magnitude of
the effect is along the Y-axis.

Compiled By Dr Lishan A 72
(excited)

Dose response relationships curves

Compiled By Dr Lishan A 73
• The therapeutic index(TI):

➢ It is the ratio of the dose that results in an undesired

effect to that which results in a desired effect.

❖Lethal dose 50 (LD50): is a dose that kills 50% of the animals/subject.

❖Effective dose 50 (ED 50): a dose that produce the desired effect in 50% of the

subject.
❖Margin of Safety

Margin between the therapeutic and lethal doses of a drug

Compiled By Dr Lishan A 74
 1.4. Drug Interaction
✓ Drug could have an interaction with other agents that
administered to body concomitantly

✓ Drug interaction could be significantly important or harmful

❖ Type of interaction: based on type of agents that

interact

➢ Drug –drug interaction(DDI):-

✓ E.g. Antacid Vs Ketoconazole --- ketoconazole needs an acidic
environment for better absorption—antacid alkalinize the
media --- so ↓absorption
Compiled By Dr Lishan A 75
➢Drug-food interaction

✓E.g. grape fruit juice Vs phenytoin ---- grape fruite

juice inhibits cyp3A4 enzyme → ↓ metabolism of
phenytoin → toxicity

➢Drug – beverage interaction

✓E.g. MAOI Vs wine → wine have tyramin which
have sympathetic effect → increase the synthesis
of NE + MAOI inhibit the metabolism of NE →
have excess NE → hypertensive crises

Compiled By Dr Lishan A 76
❖Based on level of interaction: drug-
interaction classified as:-

I. Pharmaceutical Interaction:-

✓ Interaction happen to drug during the process

of manufacturing, packaging and storage
condition.

Compiled By Dr Lishan A 77
Cont. ……………Drug interaction

II. Pharmacokinetic level interaction

❖ Absorption:
 E.g. Tetracycline + antacid :
✓ Antacid contains heavy metals like Ca2+, Mg2+ since
TTC is chelating agent ----form chelation ----- ↓
absorption (complexetion)

Compiled By Dr Lishan A 78
 III. Distribution level interaction
✓ Main factor for this interaction is:

– high plasma protein binding capacity +

– Low excretion rate

✓ So displacement of these drugs by other highly plasma protein

binding drug → ↑plasma level → toxicity
➢ Eg: Warfarin + phenylbutazone

➢ both are highly plasma protein binding, so taking of phenylbutazone while

in Warfarin therapy → Warfarin displaced from albumin by
phenylbutazone → Warfarin in plasma → bleeding

Compiled By Dr Lishan A 79
Cont. …………Distribution level interaction
• A drug administered may induce or inhibit the liver
microsomal enzyme as a result there may be drug interaction
in concomitant use of more than 2 drugs

 Commonly they are:

➢ Eg : Cimetidine + Warfarin ----- bleeding …??

Phenobarbital + OCT-----pregnancy….??
❖ Enzyme inducer ❖ Enzyme inhibitor
✓Phenobarbital ✓Cimetidine
✓Carbamazepine ✓Ketoconazole
✓Phenytoin ✓Erythromycin
✓Rifampin ✓Isoniazide
✓NVP &EFV ✓CAF
✓Gresofulvin ✓Omeprazole
Compiled By Dr Lishan A ✓Grape fruit juice 80
IV.Excretion level interaction
 Mostly occur at two level:
 Tubular secretion :- since there is carrier case
▪ Eg – probencide + pencillin : since pencillin have short
duration of action ---- ↑duration ---by ↓excretion
 Tubular re-absorption: since there is PH based ionization
of drug and further degree of re-absorption
▪ Eg – weak acid drug + bicarbonate ----- ↑ excretion

Compiled By Dr Lishan A 81
V. Pharmacodynamics Level of Interaction

I. Agonizing interaction
A. Additive/ summative : 1+1=2 ; Eg- carbachole + metanichole
B. Potentiation : 1+ 0 > 1, Eg -caffeine + ergotamine
C. Synergistic : 1+1 >2, Eg- adrenaline + cardiac glycoside

II. Antagonizing interaction:

➢Concomitant administration of drugs, one may

suppress or inhibit/ abolish the effect of the other
or aggravate toxicity.
Compiled By Dr Lishan A 82
1.5. Adverse drug reactions (ADRs) [reading assignment]

✓The drugs that produce useful therapeutic effect may also

produce unwanted or toxic effects

❖Adverse drug reaction (ADR, or adverse drug effect)

➢is a noxious or unintended response to a drug that

occurs at appropriate doses used for prophylaxis,
diagnosis, or therapy.

• Serious systemic drug toxicity may result from overdoses.

Compiled By Dr Lishan A 83
• It is always an exaggeration of its pharmacological
actions and some times it is predictable. e.g.
✓ Hypotension following antihypertensive drugs.

✓ Hypoglycaemia following insulin.

❖Occurrence:
➢May occur following a single dose or prolonged
administration of a drug.

➢Result from the combination of two or more drugs.

Compiled By Dr Lishan A 84
 Causes Of Adverse Reactions
• The basic causes of adverse drug reactions are excessive
drug use and failure to establish a therapeutic end point.

• Can be:

• Drug factors: this is intrinsic to the drug (use of drug and

interaction between drugs) or

• Non-drug factors: this is intrinsic to the patient (age, sex

and genetics).

Compiled By Dr Lishan A 85
• Use of human –
✓ Label drug in animal patient for which drug safety and
efficacy data may be lacking.

✓ Use of drug with low therapeutic indices/index.

✓ Inappropriate or unimportant drug use.

✓ Failure to set therapeutic goals or end points.

✓ Use of multiple drugs simultaneously in a patient or fixed dose

combinations.

✓ Failure to weigh the benefits versus the risks of drug therapy.

Compiled By Dr Lishan A 86
 Management of ADRs
❖Provide life support

• A patient with acute renal tubular necrosis provided by

drugs will be treated in much the same manner as
animals with end-stage renal disease.

• Similarly, drug-induced bronchoconstriction would be

managed as one could approach the patient with
asthma.

Compiled By Dr Lishan A 87
❖Stop medication with the drug
✓In less urgent situations, stop therapy and allow time
for the processes biotransformation and exertion to
remove the drug from the body.

✓Most doses related effects will abate/decrease as the

drug is eliminated from the body.

Compiled By Dr Lishan A 88
• Enhance elimination of the drug,
✓ Enhance elimination of the drug after an over dose.
✓ E.g., salicylism in cats, increase renal clearance of salicilate by
maintaining a brisk alkaline diuresis with IV infusion of Mannitol
and sodium bicarbonate solutions.

• Administer drug antagonists or antidotes if available,

✓ Excessive muscarinic effects of cholinergic drugs can be

controlled with atropine, and naloxone will reverse the

gastrointestinal and central nervous system effects of opiate

Compiled By Dr Lishan A 89
 Prevention
• Avoid all inappropriate use of drugs in the context of
patient’s clinical condition.
• Using appropriate dose, route and frequency of drug
administration based on patient’s specific variable.
• Taking into consideration previous history of drug
reaction including allergic diseases.
• Ruling out possibility of drug is prescribed.
• Carrying out appropriate laboratory monitoring.
Compiled By Dr Lishan A 90
 Assignment
❖Dosage Forms Of Drug
✓ Solid Dosage Forms
✓ Semi-solid Dosage Form
✓ Liquid dosage forms
✓ Aerosol Dosage Forms
❖Naming /Nomenclature of drugs
❖First pass effect

Compiled By Dr Lishan A 91
 AAU, CVMA, Dept of BMS

o Course Title: Veterinary Toxicology (Vetm-3121)

o Program: Year 4th DVM, Semester: II; A/Year: 2016 E.C.
o Contents
✓Pesticides
✓Mineral toxicities in Animals (metals and non-metals)

❖Individual/Group Assignment
➢non-metals
Pesticides

2
 Definition of a Pesticide

➢ Pesticide –any s/b or mixture of s/bs (physical,

chemical, or biological agent) used to prevent, destroy
(kill), repel, or mitigate any an undesirable plant or
animal pest.
❖The term pest includes harmful, destructive, or
troublesome animals, plants, or microorganisms

3
 ❖ Veterinary importance of Pesticides:
✓ Control vector borne diseases like malaria/Tryps (How?)
✓ Promotion of agricultural production
✓ Control domestic pests (e.g. house hold and garden pests)
❖Individuals may be exposed to pesticides:
✓Occupational
eg. from working in a pesticide formulating plant or
from commercial pesticide application
✓Environmentally
eg. from food products such as fruits & vegetables
treated for pests
✓At their residence
eg. from use as home or garden insecticides.
4
Cont. ……. pesticides

Pesticides are grouped

based on their target of Insecticides
action as:
Herbicides

Rodenticides

Fungicides ,etc
5
 I. Insecticides
➢ S/bs that destroy , repel or prevent harmful insects
➢ All chemical insecticides in use today poison the nervous systems
of the target organisms
➢ Not selective
➢ Affect non target species as readily as target organisms

➢ Mechanism(s) of action may be similar in all species

➢ Only the dosage (level of exposure & duration) will dictate
the intensity of biological effect.

6
 MOAs
1. Interference with membrane transport of Na, K, Ca,
& Cl ions.
2. Selectively Inhibit enzymatic activities; and
3. Contribution to the release and/or persistence of NTs at
nerve endings
❖ Classes of insecticides:
✓Organochlorine insecticides
✓Organophosphate & Carbamate insecticides (AchEIs)
✓Insecticides of biological origin

7
1. Organochlorine(chlorinated HCs) insecticides

➢ The organochlorine (Chlorinated HCs) insecticides

are belongs to three distinct chemical classes:
✓ Dichlorodiphenylethanes
• eg.DDT ,diclofol, methoxychlor ,etc
✓ Chlorinated cyclodiene & benzene (Hexachlorocyclohexanes)
• eg aldrin , dieldrin ,heptachlor ,chlordane, etc
✓ Cyclohexane-related structures
• E.g. lindane

8
 Cont. ……………..Organochlorine
❖ Mechanism of Toxic Actions:
❖ Four mechanisms for DDT-type insecticides (Dichlorodiphenylethanes):

1) Reduce K+ transport across the membrane

2) Alters Na+ channel opening and closing rate
3) Inhibit neuronal ATPase (Na+, K+, Ca2+, Mg 2+) which play
vital roles in neuronal repolarization
4) Inhibits calmodulin
➢ w/c transport calcium ions that are essential for the release of NTs

9
 Cont. …………….. Organochlorine MOA

❖ The Chlorinated Cyclodiene-, Benzene-, and Cyclohexane-type:

✓ The cyclodiene cpds (aldrin, dieldrin) : has at least 2 MOA
➢ Inhibition of GABA Receptors by acting on GABAAR

➢ The neurotransmitter can no longer close the chloride channel.

➢ Stimulated Cl- flux and interference with Ca2+ flux.

✓ Cyclohexane-relatedcpds (Hexachlorocyclohexanes)(lindane):
✓ E.g. Gamma-hexa chlorocyclohexane (γ-HCH) & lindane
✓ Binds to GABA receptors, resulting in an inhibition of GABA-dependent
Cl- flux into the neuron.

10
 ❖Kinetics of Organochlorine Insecticides:
➢ Properties that contribute to organochlorine insecticides:-
➢ Persistence in the environment,
➢ Has ability to accumulate in living tissue.
✓ Bio-concentration and Bio-magnification in food chains.

❖ The biologically active body burdens at higher levels is due to:

▪ Low volatility
▪ Chemical stability
▪ High lipid solubility, and
▪ Slow rates of degradation

11
❖ Slow biotranformation (poorly degraded) due to:
✓ The complex aromatic ring structure
✓ The number of the chlorine substituent's
➢ Exhibit environmental persistence & accumulates

❖ Its Slow biotransformation + highly lipophilic nature cause

➢ Sequestered in body tissue having a high lipid content.
❖ Organochlorins has been banned in many countries since 1974
because of its toxicity & above effects; but used (DDT &
Lindane)in developing tropical countries since they are
➢ Effective,
➢ cheap, and
➢ Essential chemicals in agriculture, forestry, and public health

12
❖ Bioconcentration (Bioaccumulation) & Biomagnification:-

➢ Bioaccumulation: if the intake of a long-lasting contaminants by

an organism exceeds the ability to metabolize or excrete the
substance, the chemical accumulates within the tissue of the
organism.

➢ Biomagnification: although the concentration of a contaminant

may be virtually/practically undetectable in water, it may be
magnified hundreds or thousands of time as the contaminant
passes up the food chain.

13
14
 Clinical signs
➢ Symptoms of life-threatening OCl insecticide poisoning :
➢ Tremor, motor seizure, &
➢ Interference with respiratory function (hypoxia & resulting
acidosis ) arising from repetitive stimulation of CNS

➢ Treatment
➢ General decontamination &
➢ Supportive treatment,
➢ Diazepam or Phenobarbital –to control the convulsions

15
2. Organophosphate (OP) & Carbamate Insecticides
(Anti-cholinesterase Agents)
➢ OP are used as substitution for organochlorine insecticides

➢ OP don’t bioaccumulates in tissue or organisms or

accumulate in the environments as do the organochlorines.

➢They are not considered to be persistent pesticides

➢Relatively unstable & break down in the environment.

16
❖However, b/c of the acute toxicity of the OP
compounds, another class of pesticide-pyrethrins-are
becoming more widely used

✓ Organophosphate ✓ Carbamates insecticides

▪ Aldicarb
insecticides ▪ Carbaryl etc
▪ Malathion
▪ Parathion
▪ Diazinon
▪ Chlorpyrifos etc

➢These two types of insecticides have similar MOA

17
 Mechanism of Toxic Action
❖ OP + AChE

➢leaving a stable, phosphorylated, and largely

unreactive inhibited enzyme –reactivated only at a
very slow rate
➢ Inhibition of AchE
➢ accumulation of Ach –continued stimulation of cholinergic
synapses.

18
➢ OP are grouped into two depending on whether or not they
require metabolic activation before they inhibit AchE:

➢ Direct inhibitors (OP those containing =O) –no need of

metabolic activation

➢produce local toxic effect at site of exposure ;

✓Sweating(dermal),

✓Miosis or pinpoint pupils (eye contact),

✓Broncho-spasm(inhalation)

19
➢ Indirect OP inhibitors (those containing =S)
➢ must undergo metabolic bioactivation to become biologically active
(with=O)

➢ Reaction is oxidative desulfuration (replace =S by =O) results in the

formation of the ‘’oxon’’ of parent drug-which is more toxic.

✓ Parathion......paraoxon

✓ Malathion…..malaoxon

✓ Diazinon……diazonon

✓ Chlorpyrifos..chlorpyrifosoxon

❖ Carbamate esters don’t require metabolic activation, AchE

inhibition is readily reversible.

20
➢ Once AchE activity has been inhibited by OP, the recovery of
that compound is dependent on
✓ The reversal of inhibition
✓ Aging
✓ The rate of regeneration of a new enzyme
➢ Aging: is caused by an enzyme that fix an extra charge to the
protein, causing some disturbance to the active site and thus
preventing de-phosphorylation

21
 ❑Cpds that used for recovery of AchE depend on the
occurrence or absence of aging.

➢ If given before aging has occurred, strong

nucleophiles (pralidoxime) are able to break the
phosphorus-enzyme bond and can be used as
“Cholinesterase regenerator’’

➢ Once aging has occurred ,the only way to restore the

enzyme activity is through synthesis of new enzyme.

22
 Toxic Effect of OP

➢ chronic effect—deleyed neurotoxicity

➢ OP induced delayed neuropathy (OPIDN)
➢ Don’t occurs due to carbamate esters
Treatment of poisoning;
➢ OP intoxication is treated by atropine and pralidoxime (2-PAM)
✓ Atropine doesn’t prevent nicotinic effect, & regenerate AchE.
✓ 2-PAM is not effective in aged enzyme
➢ The oximes are not effective in antagonizing the toxicity of the
carbamoyl ester inhibitor-even aggravates the toxicity.

23
 Cont….

➢ General suportive measures-also important;

✓Decontamination,or gastric lavage

✓Artificial respiration

✓Treatment of convulsions with diazepam (5 to 10 mg ,IV).

✓Treatment of shock

24
 3. Insecticides of biological origin
➢ Used as household insecticide and pet products (e.g. flea & tick
dips & sprays)

➢ E.g. Pyrethrum :- extracts from the chrysanthemum flower.

➢a mixture of six insecticidal esters (pyrethrins I & II,

cinerins I & II, and jasmolins I & II)

➢Pyrethroids:- are synthetic derivatives of pyrethrin

❖ Retenone:- extracts from leguminacae genera

25
 Cont.……..Pyrethrum and pyrethrins
❖ Mechanism of action
✓ Voltage-gated sodium, calcium (Increase [Ca]i), and chlorine channels
(Decrease Cl- flow to the cell), as well as benzodiazepine receptor (GABA
antagonist action ) are possible targets.
✓ They keep Na channel open for long time, causing flow of Na which
results in persistence depolarization
❖ Pyrethroids elicit little toxicity in either animals or humans due to:
▪ Little storage or accumulation
▪ An efficient detoxification of the chemicals and
▪ Differences in Na channel—more toxic to insects

26
❖ Rotenone
✓ Acute poisoning in animals is characterized by an initial
respiratory stimulation followed by respiratory depression,
ataxia, convulsion and death by respiratory arrest.

▪ It is respiratory toxicant

✓ The anesthetic-like action—block electron transport in

mitochondria by inhibiting oxidation linked to NADH2 (inhibit
NADH2 to NAD)

➢ This resulting in nerve conduction blockade

▪ Human intoxications are rare

27
 II. Herbicide
➢ Any compound that is capable of either killing or severely injuring plants
➢ Used to eliminate plant growth or kill plant parts
❑ Chlorophenoxy compounds:
✓ 2,4-Dichorophenoxyacetic acid (2,4-D),
✓ 2,4,5-trichlorophenoxyacetic acid (2,4,5-T),and

❖ Their salts and esters are used for the destruction of broad leaf
weeds
✓ 2,4-D + 2,4,5-T used in combination called Agent orange
✓ In plants, these chemical mimic the action of auxins, hormones that
stimulates growth
➢ They acts as growth in plants and by uncoupling oxidative
phosphorylation and decreasing oxygen consumption
▪ Less effect in non target organ. 28
❑ Bipyridyl derivatives

▪ Paraquat (1,1’-dimethyl-4,4’-bipyridylium dichloride,) and

▪ Diquat (1,1’-ethylene-2,2’-bipyridylium dibromide)

❖Paraquat: a non-selective contact herbicide,

✓ It is one of the most specific pulmonary toxicants
✓ Its toxicity is due to formation of ROs.

29
❖ Mechanism of toxicity of paraquat
➢ After oral ingestion → taken up in to the lung via polyamine
transport system in alveolar cells.

➢ Then accumulate in the lung undergoing a NADPH-

dependent one electron reduction to a free radical that
reacts with molecular oxygen to regenerate the paraquat
cation plus a reactive superoxide anion (O2.-), which is
converted into H2O2 by the enzyme superoxide dismutase.

30
Cont…………. Paraquat MOA

➢ Both O2.- and H2O2 can attack polyunsaturated lipids,

forming lipid hydroperoxides that in turn, react with
unsaturated lipids to form more lipid-free radicals,
perpetuating the destruction reaction.
➢ Diquat is less toxic to respiratory system b/c not
accumulate in alveolar cells
✓It is poor substrate for polyamine transporters
✓It has wide margin of safety

31
III. Fumigants

➢ Are agents used to kill

➢ Insects,
➢ Nematodes,
➢ Weed seeds, and
➢ Fungi in soil and to prevent stored food staffs e.g. HCN,CS2,
phosphine(PH3) etc
➢ They are gaseous formulation (could be insecticide, fungicide,
herbicide)

32
➢ May be liquid e.g. Formaldehyde that readily vaporize at ambient
temperature; Or

➢ Solids that can release a toxic gas on reacting with

➢ Water (Zn2P3, AlP) or
➢ Acid [NaCN, Ca(CN)2];or
➢ Gases (Methylbromide, Hydrogen cyanide, ethylene oxide)
➢ These chemicals are nonselective, highly reactive , and
cytotoxic.

33
❑ Cyanide (hydrocyanic acid , HCN-prussic acid)
➢ Cyanide has very high affinity to ferric(Fe3+) state
➢ Reacts readily with Fe3+ of Cytochrome oxidase
➢Inhibit cellular respiration
➢Resulting in lactic acidosis and cytotoxic hypoxia
➢Death due to respiratory arrest
❖ Treatment:
➢ Diagnosis aided by the toxic odor of cyanide
➢ Treatment is aimed at prevention or reversal of binding of cyanide to
cytochrome oxidase by providing a large pool of ferric iron to compete for
cyanide.

34
 ❖ Nitrite that oxidize hemoglobin (Fe2+) to Methemoglobin (Fe3+)
▪ Methemoglobin (Fe3+) competes with Cytochrome oxidase for
cyanide ion; the rxn favours metHgb whereby cyanometHgb is
formed & cytochrome oxidase is restored

❖ Hydroxycobalamine-combines with CN- to form

cyanocobalamine (vit B12) which is non toxic
❖ Rhodanase (tran-salfurase)-converts CN- to SCN-, which is less
toxic
❖ To accelerate detoxification, Na thiosulfate (Na2S2O3) is given IV and the
SCN- formed is readily excreted in the urine
Na2S2O3 + CN- → SCN- + Na2SO3

35
 ❖ Methylbromide (Gas):

❑ has high affinity for ligands that contain-SH group

➢ Thus (-SH) chelating agents used as an antidote during
poisoning.

❖ So toxic, chloropicrin (CCl3NO2), a power stimulator of

lacrimation is added to the methyl bromide preparation as
a warning of methyl bromide intoxication.

36
iv. Rodenticides

37
 Rodenticides

➢ Many vertebrates:
➢rates, mice, squirrels, bats, rabbits, skunks, monkey &
even elephants-on occasional can be considered to be
pests
➢ The black rat (Rattus rattus), the brown or Norway rat
(R. norvegicus), and the house mouse (Mus musculus)
pose particularly serious problems because they act as
vectors for several human diseases.
38
 Cont. …………Rodenticides
➢ Common rodenticides are:

✓ Zinc phosphide

✓ Flouro-acetic acid and derivatives

✓ -Naphthyl -thio-urea

✓ Anticoagulants

➢ Accidental or intentional ingestion of most rodenticides poses a

serious, acute toxicologic problem,

➢ Rodenticide poisoning is seen more frequently in children.

39
 Zinc Phosphide
✓ Widely used in developing nations, b/s it is cheap and effective

✓ hydrolyzes with water, producing PH3

✓ Cause cellular toxicity with necrosis of the gut, liver and

kidneys.

❖ Signs of intoxication or poisonings include

➢ Vomiting, diarrhea, cyanosis, tachycardia, restlessness, fever,

albuminuria several hours after exposure, hypertension,
pulmonary edema, dysrhythmias, and convulsions.

40
 Fluoro-acetic Acid and its Derivatives
✓ Na fluoro-acetate & fluoro-acetamide have extreme toxicity
➢ Readily absorbed from the GIT

❖MOAs
✓ Fluoroacetate:- inhibits the enzyme aconitase and prevents
the conversion of citrate to isocitrate in TCA cycle
➢ Decreases glucose metabolism, cellular respiration, and tissue
energy stores.
✓ There are no known antidotes to fluoro-acetate intoxication

41
❖-Naphthyl-thio-urea (ANTU)

✓ Is relatively selective rodenticide

❖MOA:- is not exactly known, but it biotransformed

into a reactive intermdiate; which act on the
pulmonary capillaries → Causes pleural effusion &
extensive pulmonary edema.

42
 Anticoagulants
❖ Coumadin (Warfarin):- antagonizes the actions of vitamin K in
the synthesis of clotting factors II, VII, IX, and X.
➢ The Superwarfarins (brodifacoum, coumachlor, diphencoumarin) &

➢ The Indanediones (diphacinone, chlorophacinone, pindone) differ from one

another in terms of :

✓ Acute toxicity/Rapidity of action, and

✓ Acceptance by the rodent

43
 Clinical signs
❖Bleeding of the:-
✓ Gingiva and nose,
✓ Gastrointestinal bleeding with dark tarry stools,
✓ Hematuria,
✓ Epistaxis,
➢ The signs and symptoms persist for many days after the
cessation of exposure owing to the prolonged biological half-
lives of the Warfarins.

44
❖Management of Anticoagulant Rodenticide Poisoning

✓ Induce emesis
✓ Give activated charcoal
✓ Vit K1 (up to 1 month) check PT times off the medication
✓ Blood Transfusions
✓ Oxygen Therapy
✓ Preventing Trauma for several days while on the antidote

45
Metals Toxicity In Animals
 Heavy Metals Toxicity In Animals
• All living creatures
requires minerals
• Naturally metals are
distributed in environment
during earth's origin.
• Heavy metals contaminate
the environment due to
– Rapid industrialization
– Overgrowing
urbanization
– Environmental
manipulation

47
 Sources Of Heavy Metals:- 1o and 2ry
Primary/main Sources of Heavy Metals
• Pb: Battery plant, Refinery, Smelter, Fuel combustion, Leaded
gasoline, Lead-based paints, Lead-soldered food cans, Lead
plumbing pipes & automobile exhaust (Tetraethyl lead)
• Hg: Refinery, Plastic, Paints, Antiseptic, Scientific instruments,
Photography, Fuel combustion
• Cd: Tannery, smelter, battery crushing unit, mining,
Electroplating, Pigments (Cd yellow) and plastics
• As: Pesticides, Wood preservative, Glass/Copper smelters, Coal
combustion & Uranium mining.
48
 ❖Secondary/minor sources of heavy metals
✓ Most of the animals affected
✓ Industrial & Domestic wastage directly/indirectly release in
water (Pb, Hg, Cd, As)
❖ Agriculture soil contaminated by Heavy metals through…
– Long-term use of phosphatic fertilizers (Cd)
– Sewage /sludge application (Hg, Cd)
– Dust from smelters, industrial waste (Pb, Hg, Cd, As)
– Bad watering practices in agricultural lands (Pb, Hg, Cd, As)

49
❖Plants are contaminated by Heavy metals through…

– Excessive use of fertilizers /pesticides/ insecticides

– Plants growing in soil contaminated area
– Irrigation of crop by contaminated water

50
 Pb Toxicity
• One of the most common causes of metallic poisoning in dogs and cattle.

❖ Factors affecting lead toxicity:

• Age: Young animals are considerably more sensitive than old ones.

• Species and individual variation: Goats, swine and chicken are more
resistant.

• General health state: Poorly nourished and debilitated and parasitized

animals are more susceptible.

• Reproductive state Pregnant ewes are reported to be more susceptible than

non-pregnant ewes.

51
 Cont. ……….Pb Toxicity
• Route of entry: Only 1-2 % of the ingested lead may be
absorbed.
➢ The organic forms of (tetra methyl lead and tetraethyl lead) can also
penetrate the intact skin

• Form of lead: Soluble salts are more readily absorbed.

➢ Forms : Pb-acetate, Pb-oxide, Pb-carbonate; equipment

• Condition of the gastrointestinal tract: Presence of ingesta may

delay or reduce the absorption of lead.
 Animals exposed to lead toxicity via
o Drinking contaminated water
o Exposed to toxicological cpds (Discarded containers) when
➢Animals ingest lead -based paints
➢Used engine oil and battery disposal is handled improperly, it
becomes a major source of lead poisoning.
o Vegetation grown in lead smelter areas
➢Grazing in contaminated areas
➢Crops growing in contaminated soil
o Use of some drugs that predispose metal toxicity.(e.g. dipping)
❖ Pb is ubiquitous environmental contaminant.
➢ Cattle, Horse, Dog more susceptible
➢ Chicken, Goat, Pig & Cat rare (more resistance)
53
 Toxico-kinetics
• The absorption of lead from GIT is very limited (1-2 %) → about 98%
of it is eliminated in the faeces.

• After absorption, a large proportion of lead in blood is carried to

erythrocytes membranes.

• Portal circulation carries lead to liver, much of it is excreted in bile

then reabsorbed (enterohepatic biliary cycle).

❖ Mechanism of toxicity:

❖ Lead appears to inhibit haeme synthetase, a thiol containing enzyme

which is required to incorporate iron in the haeme molecule.
55
56
 Mercury (Hg)

✓ Liquid forms at room temp

✓ Mercury exists in a variety of organic and inorganic forms.

• Young ruminants more susceptible than Horse & Pig

• Elemental-Hg –
– Non toxic (orally),

– Highly toxic (inhalation)

• Inorganic-Hg – less toxic (insoluble < soluble)

• Organic-Hg – more toxic

❖ Se & Vitamin E protects against toxicity →anti-dot

Sources of Hg poisoning: Organic & inorganic
• Inorganic mercurial poisoning include
➢ Elemental mercury and
➢ Salts such as
✓ Mercuric chloride (corrosive sublimate),
✓ Mercurous chloride (calomel),
✓ Yellow mercuric oxide, red mercuric iodide, and mercuric nitrate.

• Organic mercurial toxicity include

➢ Fungicides (ethyl mercuric chloride and hydroxide) and
➢ Methyl mercuric dicyan-di-amide & methoxy-ethyl mercuric
silicate used as seed dressing agents in agriculture.
 Toxico-kinetics of Hg
• Once absorbed, mercury gets distributed throughout the body and
is stored mainly in the liver and kidneys.

• It eliminated very slowly, chiefly in the urine.

• Organic mercurials have the tendency to readily bio accumulate

in the brain.
❖Mechanism of Toxicities:
➢ Methyl mercury may interact with DNA and RNA and binds with-SH
groups resulting in changes in the secondary structure of DNA and RNA.
60
61
62
63
64
 CADMIUM (Cd)
• Regulatory limit in agricultural soil is 100 mg/kg soil.
• > 5ppm toxic effect
• Most common in Ruminants
• Cd involved in Metal interaction
• Antagonistic activity against Cu, Zn, Se & Fe (chemical
similarities & competition for binding )
• Oxidative stress
✓ Destroy the superoxide dismutase (SOD) (Cd replaces Zn2+ )
➢(Zn maintain the structure of superoxide dismutase (SOD)
that scavenges the Free Radical)
➢ Inhibits the GSHB-Peroxidase (catalyzed the destruction of H2O2 &
protects the lipids membrane from peroxide damage)
65
Affected organ/system

66
Clinical Signs
▪ Anemia
▪ Retarded growth
▪ Proteinuria
▪ Glycosuria,
▪ Hyperphosphatemia
▪ Testicular degeneration and necrosis
▪ Arthropathy and osteoporosis
▪ Vomition and diarrhoea in acute cases.

67
 Arsenic
• Arsenic poisoning is caused by different commercial forms of inorganic
and organic arsenical compounds.

❖ Inorganic arsenic

• Sources of poisoning:
➢ Arsenic trioxide(arsenite, H3AsO3),

➢ Arsenic pentoxide (arsenate, H3AsO4 ) ,

➢ Sodium and potassium (arsenate and arsinite)

➢ Lead or calcium arsenate.

• Trivalent arsenicals are more soluble, and therefore, more toxic (5-10
times) than pentavalent cpds
 Cont. …………….ARSENIC

❖Forms of Inorganic arsenic formerly used as arsenic

trioxide, a herbicide and insecticide.
❖ Insecticides: Paris green (copper aceto-arsenite) & lead arsenate
❖ Herbicides: Monosodium Methane-arsonate (MSMA) & Disodium
Methane-arsonate (DSMA)

❖ Animals Exposure to arsenic /Sources of poisoning/:

❖ Organic Arsenicals:
➢ Persistence of MSMA or DSMA in soil and their tendency to accumulate in
plants is a potential for arsenic poisoning, especially in grazing animals.

69
 Cont. ….. Animals Exposure to arsenic:
➢ Accidental exposure to old pesticides such as
✓ Lead arsenate & arsenic trioxide improperly discarded or stored.

➢ Wood products treated with arsenic cpds such as

✓ Copper, chromium, and arsenic (CCA) can cause toxicosis when they are
burned and generate ashes.

❖ Arsine (ASH3) is the hydride industrial gas or gaseous product

of arsenic from the charging of storage batteries.
❖ Drinking water:.
➢ Drinking water can contaminated in mining areas.

70
 Mechanism of Toxicity
❖After absorption, arsenic is tends to accumulate in
the liver and kidneys.
• Trivalent arsenicals inhibit cellular respiration.
→ Bind to sulfhydryl compounds, especially lipoic acid and α-keto-
oxidases.

• Lipoic acid, a tissue respiratory enzyme cofactor, plays an

important role in the tricarboxylic acid (TCA) cycle.
• Trivalent arsenic also affects capillary integrity by an unknown mechanism

• The hydride gas of arsenic, ASH3 , can combine with

hemoglobin and oxidized to a hemolytic metabolite.

71
 Clinical Signs.
• Arsenic Cpds cause severe effects in the gastrointestinal system.
❖ Organic or inorganic trivalent arsenicals cause acute or per-acute poisoning.
• Common signs include:
✓ Vomiting, intense abdominal pain,

✓ Weakness, staggering, ataxia, recumbency, and weak,

✓ Rapid pulse with signs of shock.

• Others may occur and include
✓ Rapid onset of watery diarrheal or

✓ Rumen and gastrointestinal atony.

❖ Damage to the kidneys → result in oliguria and proteinuria follow the initial
toxicosis.
• The resulting dehydration, acidosis, and azotemia may cause death.
• Chronic poisoning is rarely seen in domestic animals but has been observed
frequently in humans. 72
• Organic pentavalent arsenical feed additives (usually in
swine) can cause signs within 2 to 4 days of an overdose.

• Clinical signs include

✓ Ataxia, incoordination, torticollis, and blindness.

✓ Affected animals assume a dog-sitting position and eventually

become paralyzed in lateral recumbency.

✓ Appetites remain normal and affected animals are cognizant,

except for some with blindness.

73
 Management of Heavy Metal Toxicity
• Basic principles of metal toxicity management
1) Prevention of further metal absorption into the system
2) Elimination of metal from the circulation
3) Inactivation of metal bioavailable in the system

1. Decontamination
➢ Removal of the patient from the source → Critical to limiting dose.
❖If ingestion is recent: Emetics, activated charcoal, gastric
lavage,.
• Charcoal administered @1-4 mg/kg PO.

74
 Cont. …..Heavy Metal Toxicity Mgt

2. Resuscitation / Recovery
✓ Good supportive care is critical.

3. Chelation= Holding with a strong grip

• They suggested the term for the caliper-like groups
which function as two associating units and fasten to
a central atom so as to produce heterocyclic rings.

➢Hence, facilitate removal of toxins from the body

75
 Chelating agents
❖ EDTA- Calcium Disodium (CaNa2EDTA): It reacts with metals.
❖ Use: food preservative, anticoagulant, treatment of lead poisoning.
✓ Treatment of poisoning by metals that have higher affinity for the chelating
agent Ca2+. C10H16N2O8 (Ethylene Diamine Tetra-Acetate).
✓ EDTA is charged at physiological pH, it does not significantly penetrate
cells;
✓ Lead Poisoning.
✓ Bone provides the primary source of lead that is chelated by CaNa2EDTA
✓ After such chelation, lead is redistributed from soft tissues to the skeleton.

76
 Cont. ………….Chelating agents

❖ Like EDTA, a polycarboxylic acid chelator, but it has somewhat

greater affinity for most heavy metals.

• Limited access to intracellular sites of metal storage

❖ Disadvantage: depleting Zn from the system; that may be

overcome by supplementation or using the zinc salt of the drug.

➢ Teratogenic like CaNa2EDTA due to its Zn and Mn depletion

effect

77
 Dimercaprol (2,3dimercaptopropanol)

• Instable in aqueous solutions & the solvent employed is peanut oil.

• Arsenicals form a very stable and relatively nontoxic chelate ring
with the dimercaprol
• MOA: Formation of chelation complex between its cellular
sulfhydryl groups and metals
• Antagonizes: principally arsenic, gold, and mercury.

78
Cont. …………..Dimercaprol

• Used in combination with CaNa2EDTA to treat lead poisoning,

especially when evidence of lead encephalopathy exists.
❖ Dimercaprol Route:- not given orally; deep IM, at dose of 100
mg/ml solution in peanut oil,
• Toxicity: rise in systolic and diastolic arterial pressures,
accompanied by tachycardia
• Arsenic toxicity: BAL(British Anti-lewisite)/ Dimercaprol:@4-
7mg/kg IM t.i.d x3days.

79
80
81
 Ideal Chelater

✓ Greater Affinity, Low Toxicity

✓ Ability to compete with natural chelators
✓ Ability to penetrate cell membranes
✓ Rapid elimination of the toxic metal
✓ High water solubility
✓ Capacity to form non-toxic complexes
✓ Same distribution as the metal

82
 Chelation
Benefits Drawbacks
• Effective against acute • Redistribution of toxic metal
poisoning • Essential metal loss
• No removal of metal from
• Form non-toxic complexes
intracellular sites
• Remove metal from soft tissues • Hepatotoxicity and
• Oral therapy is available nephrotoxicity
• Poor clinical recovery
• Headache, nausea, increased
• blood pressure

83
 TOXICITY of NON-METALS
• Assignment (submission date14/05/2024)
❖Nitrates And Nitrites
Individual
❖ UREA And AMMONIA
✓Phosphorus
✓Chlorates
✓Fluorine
✓Common salts (Sodium chloride)
NEUROPHARMACOLOGY
rd
(For 3 Year DVM)

Compiled By Lishan A(Dr) 1

Introduction

Controls all the major functions of the body.

2
Compiled By Lishan A(Dr)
 Cont. …. Introduction

v ANS: Controls & regulate the function of heart,

respiratory system, GI tract, bladder, eyes & glands
(Happens in glands, smooth and cardiac muscle)
Ø control involuntary functions or the vegetative functions of the body
which include functions like circulation, respiration, digestion and the
maintenance of body temperature.

v Somatic
Ø Happens in skeletal muscle
Ø control voluntary functions

Compiled By Lishan A(Dr) 3

 NEUROTRANSMISSION

• Conduction- is the passage of an impulse along

an axon or muscle fiber;
• Transmission- the passage of an impulse across a
synaptic or neuro-effector junction.
• Very few drugs (Local anesthetics) modify axonal
conduction in the doses employed
therapeutically.
Compiled By Lishan A(Dr) 4
 Receptors:
v Adrenergic: α - α1, α2
β – β1, β2

v Cholinergic: M (M1-M-3)
N
• Receptors that respond to adrenergic nerve transmitter are
termed adrenergic receptors.
• These receptors are subdivided into alpha and beta
adrenoreceptor types on the basis of both agonist and
antagonist selectivity.

Compiled By Lishan A(Dr) 5

Compiled By Lishan A(Dr) 6
 Neuro-pharmacology
• Study of drugs that alter processes controlled by the nervous system

• Regulation of Neurons Physiology

– Transmission of impulse down axon

– Release of neurotransmitter from axon terminal

– Binding of neurotransmitter to receptor on post-synaptic cell

– Post-synaptic cell changes action

• Muscle relaxes or contracts

• Glands secrete or stop secreting

• Neurons fire more often or less often

Compiled By Lishan A(Dr) 7

Steps of Transmitter Synthesis & Synaptic Transmission

– Transmitter synthesis
– Transmitter Storage (vesicles)
– Release of Transmitter
• Only small number of vesicles release
– Receptor Binding (reversible)
– Termination of Transmission
• Reuptake
• Enzymatic degradation
• Diffusion

Compiled By Lishan A(Dr) 8

 Drugs Can Interfere/ Act
o Alter axonal conduction
– Local anesthetics
o Alter synaptic Transmission
o Affect receptors, If drug
Ø Causes same effect as natural process: receptor activation
Ø If drug reduces or causes opposite: receptor deactivation.
o Drug can:
– Increase transmitter synthesis
– Decrease transmitter synthesis
o Storage: drugs can interfere with storage
– Less transmitter stored  less released
o Transmitter release: drugs can
– Promote release
– Inhibit release

Compiled By Lishan A(Dr) 9

Cholinergic transmission

Compiled By Lishan A(Dr) 10

 Receptor Binding
v Drug can
– Bind directly to receptors and activate them
• Agonists
– Bind to receptors and block them
• Antagonists
– Bind to receptor and enhance activation by natural transmitter
v Termination of Transmitter
• Block Reuptake
– Reuptake inhibitors
• Inhibition of enzymatic degradation
• Both cause more increased transmitter action

Compiled By Lishan A(Dr) 11

 Synthesis of Ach

Lambert-Eaton
Myasthenic Syndrome

Compiled By Lishan A(Dr) 12

 Drugs Affecting the
Autonomic Nervous System
(Drugs Affecting PSNS and SNS)

Compiled By Lishan A(Dr) 13

 AUTONOMIC DRUGS

Drugs acting on the SNS Drugs acting on PSNS

A. Sympathomimetic or A. Parasympathomimetics or
adrenergic drugs: are cholinergic drugs: are drugs
which mimic acetylcholine or the
drugs that mimic the effects effects of parasympathetic nerve
of sympathetic nerve stimulation
stimulation. B. Parasympatholytics: are drugs
B. Sympatholytics: are drugs that inhibit parasympathetic
that inhibit the activity of nervous system activity or that of
cholinergic drugs.
sympathetic nerve or that of
sympathomimetics.
Compiled By Lishan A(Dr) 14
 Cholinergic receptors
Nicotinic receptors Muscarinic receptors
(Central) (peripheral )
Types Two types:- M1, M2 (cardiac), M3
üGanglionic (glandular & smooth muscle) M4
üNeuromuscular (brain). M5,M6 and M7.
Stimulatd Nicotine in small doses, Muscarine, Ach,
by Ach, metacholine carbancholine
Blocked Nicoitin in large doses, Atropine
by hexamethonium, pentamethonium, Scopolamine
d-tubocurarine.
site Autonomic ganglia (ganglia of Ø Parasympathetic (post-ganglionic,
both the PSNS and SNS), cardiac, nerve terminal, glands,
skeletal muscle, Adrenal smooth muscles)
medulla, Pre-ganglionic neuron, Ø Sympathetic postganglionic nerve
M.E.P (Motor end plate) endings (sweat glands, Effector organs
of cholinergic sympathetic fibers).

Compiled By Lishan A(Dr) 15

Effects of Cholinergic NT (Ach) on muscarinic receptor
Cardiovascular effets (M2):
 cardiac slowing and (reduced automaticity)
 decreased force of contraction (mainly in atria)
 inhibition of AV conduction
Smooth muscle (except vascular smooth muscle
 contracts in response to muscarinic agonists
 peristaltic activity of GIT increase
 bladder and bronchial smooth muscle also contract
Vascular smooth muscle
 acetylcholine produces vasodilatation - mediator is NO
Exocrinne glands
 stimulation of gastric acid secretion (M1)
 sweating, lacrimation, salivation, bronchial secretion (M3)
Effects on eye
 lower the intraocular pressure, myosis
Compiled By Lishan A(Dr) 16
 A. Cholinergic Drugs
v Also called Parasympathomimetic drugs
v Drugs that stimulate the parasympathetic nervous system (PSNS).
Ø Drugs that mimic the effects of the PSNS neurotransmitter Acetylcholine (ACh)
v Ach is NT released at S & PS ganglia & at most PS neuro-effector junction.

v 2 types of cholinergic receptors

A. muscarinic - stimulates smooth muscle & slows HR
B. nicotinic - affect skeletal muscle

ü Many are nonselective & affect both receptors

ü Some affect only the muscarinic receptors and not the nicotinic
receptors
Compiled By Lishan A(Dr) 17
 Cholinergic drugs

Direct-acting Indirect-acting

Esters of choline Cholinergic alkaloids Reversible Irreversible

•Acetylcholine •Pilocarpine, Neostigmine, •Organophosphate Cpds.

•Methacholine, • Muscarine, Physostigmine, •Echothiophate

•Carbachol, •Arecoline, Edrophonium

•Betanechol • Nicotine • Inhibit the action of

acetylcholinesterase enzyme
•Bind to and activate muscarinic or
nicotinic receptors (mostly both)
Compiled By Lishan A(Dr) 18
 Esters of Choline
• Acetylcholine is the prototypical cholinergic agent.
• It functions as a NT at all cholinergic sites in the body.
• Pharmacokinetics
v Acetylcholine is poorly absorbed from the gastric mucosa; therefore it is
ineffective if given orally,  administration is parenteral.

Ø In the blood it is rapidly hydrolyzed by the enzyme cholinesterase into

acetic acid and choline

Ø This makes its duration of action very short and unreliable for therapeutic
purposes.

Ø Nonselective effect (M and N)

Compiled By Lishan A(Dr) 19

v Pharmacodynamics
• The actions of Ach may be divided into two main groups: -

1. Nicotinic actions- those produced by stimulation of all

autonomic ganglia and the neuromuscular junction

2. Muscarinic actions- those produced at postganglionic cholinergic

nerve endings

Compiled By Lishan A(Dr) 20

vThe muscarinic actions (Effect of cholinomimetics)
SYSTEM CHANGE (EFFECT)
Heart, CVS slow heart rate
Blood vessels, vasodilator
Blood Pressure falls because of the effect on the heart and blood vessels
Gastrointestinal It stimulates the tone and motility of the GlT but the
tract sphincters will be relaxed
Urinary tract It stimulates the detrusor muscle and relaxes the internal
urethral sphincter resulting in evacuation of bladder
Bronchioles It increase bronchial secretion and brings about broncho-
constriction
Eye It has two effects- myosis and ciliary muscles contraction.
Exocrine glands it stimulates salivary, gastric, bronchial, lachrymal and sweat
gland secretions.

Compiled By Lishan A(Dr) 21

 Synthetic Choline Esters
• These are synthetic derivatives of choline and include
Ø E.g. Metacholine, Carbachol (Non-selective) And Betanechol (M-selective).

• These drugs have the following advantages over

acetylcholine:
– They have longer duration of action,

– They are effective orally as well as parenterally, and

– They are relatively more selective in their actions.

Compiled By Lishan A(Dr) 22

 Uses of Choline-esteres
Bethanechol Carbachol Methacholine:

Used post-operatively after Wide-angle glaucoma, only Produces cardiovascular

when other cholinomimetics effects primary at m-
abdominal surgery & are no longer effective receptors.
postpartum to reduce Flaccid type of colic More active on the CVS than
Rumen atony and impaction; on the GI or urinary tracts.
bladder distention;
It is only given through SC Intravenous administration,
Urinary bladder atony in route (because it is highly like ACh, produces a
toxic); depressor response and
cats;
Not use for Intestinal slowing of heart rate by
Alternative to pilocarpine obstruction or rupture activation of m-receptors
located on blood vessels and
for promotion of salivation in the heart.

Compiled By Lishan A(Dr) 23

 Contraindications to the use of choline esters
1. Bronchial asthma because they may induce bronchial
constriction and increase bronchial secretions

2. Hyperthyroidism because of the danger of inducing atrial

fibrillation

3. Peptic ulcer disease b/se it increase in gastric acid secretion

4. Coronary insufficiency because the hypotension produced will

further compromise coronary blood flow

5. Mechanical intestinal and urinary outlet obstruction

Compiled By Lishan A(Dr) 24

 Cholinergic Alkaloids
A. Those with chiefly nicotinic actions include
nicotine, lobeline etc.

B. Those with chiefly muscarinic actions include

muscarine, pilocarpine, arecoline etc.
Ø These are plant alkaloids exerted primarily at muscarinic
sites with minimal nicotinic effects.

Compiled By Lishan A(Dr) 25

 Pilocarpine
• It is particularly effective in stimulating flow of secretions
from exocrine glands, including; salivary, mucous, gastric,
digestive and pancreatic secretions.
• It causes contraction of GI smooth muscle, thereby increasing
smooth muscle tone and peristaltic activity.
v It has a considerable importance and potent constrictor effect
on the pupil.
ü The drug directly stimulates the muscarinic receptors to bring
about all the muscarinic effects of acetylcholine.

Compiled By Lishan A(Dr) 26

Cont. ………Pilocarpine
v Indications:
ü Pilocarpine hydrochloride is available as a 1%, 2%, and 4% ophthalmic
solution.
ü Topical pilocarpine causes miosis/myosis (constriction of pupil) and lowers
the intraocular pressure.
Ø For the treatment of Glaucoma

v Arecoline
ü Activates muscarinic receptors located at numerous targets including; glands, smooth
muscles, and myocardium, and produces the usual para-sympathomimetic effects.
ü It is similar to pilocarpine in scope of activity.

Compiled By Lishan A(Dr) 27

 Indirect acting cholinergic agonists
v Drugs that inhibit the cholinesterase enzyme/ Anti-cholinesterase
Ø These drugs preserve the action of Ach by preventing the action of
cholinesterase enzyme and they are two types:-
q Reversible AChE Inhibitors

ØCarbamates: Neostigmine, Physostigmine, Rivastigmine,

q Irreversible AChE Inhibitors
ØOrganophosphates: Malathion, parathion, Echothiophate,
Isoflurophate

Compiled By Lishan A(Dr) 28

 Physostigmine
• Completely absorbed from the GIT and it can pass the blood brain barrier.
• Inhibits the enzyme cholinesterase; therefore, it increases and prolongs the
effect of endogenous acetylcholine at different sites.
• It has no direct effect on cholinergic receptors.

v Indications
– Glaucoma
– Atropine over dosage

Compiled By Lishan A(Dr) 29

 Neostigmine
• Poorly absorbed from the GIT and is poorly distributed; it cannot pass the BBB.

• Just like physostigmine, it inhibits cholinesterase enzyme; but unlike

physostigmine, it has a direct nicotinic action on skeletal muscles.

v Indications
– Paralytic Ileus

– Reversal of effect of muscle relaxants, e.g. tubocurarine

– Post operative urine retention

– Myasthenia gravis

Compiled By Lishan A(Dr) 30

 Organophosphate
Ø Combine with cholinesterase irreversibly and thus hydrolysis is
very slow. E.g. echothiophate, isofluorophate, etc.

vIndication:
ü They may be used in glaucoma.

ü Other organophosphates like parathion and malathion are used as

insecticides.

vAnticholinesterase poisoning is reversed by

ØAtropine- counteract the muscarinic action and
ØPralidoxime (2-PAM) is a mechanism-based antidote for poisoning
ØReactivate AChE

Compiled By Lishan A(Dr) 31

 B. ANTICHOLINERGICS
• Also called Muscarnic like action blockers

• Anticholinergics block the effects of acetylcholine and other

cholinergic drugs at cholinergic receptors (m & N-receptors) of
effector cells.

Compiled By Lishan A(Dr) 32

vAnticholinergics fall into two major families:

ANTICHOLINERGICS

Antinicotinics Antimuscarinics

Ganglion blockers Neuromuscular blockers Tertiary amines Quaternary amines

•Hexamethonium, •Gallamine, •Propantheline,

•Trimethaphan •Tubocurarine, •Atropine,
•Ipratropium,
•Pancuronium •Scopolamine,
•Benztropine
•Tropicamide

Compiled By Lishan A(Dr) 33

 Cont. ………Anticholinergics
• MOA: Competitive inhibition
• Pharmacologic effects opposite of the muscarinic agonists

• Antagonistic responses include:

• Decreased contraction of GI and urinary tract smooth
muscles,

• Dilation of pupils,

• Decreased saliva, gastric & bronchial secretion.

Compiled By Lishan A(Dr) 34

 ATROPINE
Ø Atropine is found in the plant Atropa belladonna and it is the
prototype of muscarinic antagonists.
ü Absorbed completely from all sites except from the skin wall,
ü It has good distribution.

Ø Atropine antagonizes the effect of acetylcholine by competing for

the muscarinic receptors peripherally and in the CNS; therefore
the effect of atropine is opposite to the acetylcholine effect.

Compiled By Lishan A(Dr) 35

 Organ-system Effects By Atropine
Organ-system Effects
CNS - lower doses produce sedation
- higher doses produce excitation, agitation and hallucination
Eyes -relaxation of constrictor pupillae (mydriasis)
- relaxation or weakening of ciliary muscle (cycloplegia-loss of
the ability to accommodate)
CVS: - blocks vagal parasympathetic stimulation (tachycardia)
- vasoconstriction
Respiratory - bronchodilatation and reduction of secretion

GIT: - decreased motility and secretions

Sweat Glands: - suppresses sweating
GUS(Genitourinary- Relaxes smooth muscle of ureter and bladder wall; voiding is
ry system) slowed.

Compiled By Lishan A(Dr) 36

v Clinical Indications
ü Pre anesthetic medication -to reduce the amount of secretion and to prevent excessive vagal
tone due to anesthesia.

ü As antispasmodic in cases of intestinal, biliary, and renal colic

ü Heart block

ü Organophosphate poisonings

v Side effects
ü Dryness of the mouth, tachycardia and blurred vision

ü Retention of urine

v Contraindications
ü Glaucoma

ü Bladder outlet obstruction.

Compiled By Lishan A(Dr) 37

 Hyoscine (Scopolamine)
ü This drug has the same effect as atropine except for some differences
which includes:-
Ø It has shorter duration of action

Ø It is more depressant to the CNS.

ü All other properties are similar to atropine.

v It has certain advantage over atropine. These include:

Ø Better for pre-anesthetic medication because of strong anti-secretory and
antiemetic action and also brings about amnesia.

Ø Can be used for short- travel motion sickness

Compiled By Lishan A(Dr) 38

 Nicotinic Antagonists
Two subclasses:
1. Skeletal neuromuscular blocking agents/Myorelaxants
2. Ganglionic blocking agents.

Compiled By Lishan A(Dr) 39

 Classification of myorelaxants

I. Drugs that act presynaptically

v By inhibiting ACH synthesis: hemicholinium
v By inhibiting ACH release: botulinum toxin, bungarotoxin
(venom of various snakes (cobra family)
v By inhibiting calcium entry (magnesium ion, aminoglycoside
ATB),
Ø Produces flaccid paralysis of skeletal muscle
v Therapeutic Uses:
ü Administered locally, via im or intradermal injections, to control muscle
spasms/contraction and to facilitate muscle relaxation (eye; face; neck etc.)

Compiled By Lishan A(Dr) 40

 II. Drugs that act postsynaptically
• Interfering with the postsynaptic action of ACH:
• Classified as: Non-depolarising & Depolarising agents
A. Non-depolarising agents /stabilizing= competitive blocking agents/
§ E.g. tubocurarine, pancuronium, gallamine
v Plant alkaloid from Chondodendron tomentosum.
ü Causes muscle paralysis (arrow poison).
ü Rapid onset of action
v MOA:- Competitively displace Ach and prevent depolarization of
the endplate.

Compiled By Lishan A(Dr) 41

 Cont. …..Non-depolarising agents - tubocurarine
vEffects
• Paralysis
ü small muscles of the face and eye are paralyzed first,
 limb, neck and trunk  then intercostal muscles are affected  diaphragm
muscles.
• Other effects
Ø release of histamine  vasodilatation  fall in blood pressure,
Ø bronchospasm consequence of histamine release  asthma,
vTherapeutic uses
ü Are used therapeutically as adjuvant in surgical anesthesia,
ü Tetanus and Strychnine intoxication,
ü Adjunct relaxation during maximal electroshock therapy.

Compiled By Lishan A(Dr) 42

 Tubocurarine derivatives
Ø Metocurine is a semi-synthetic analog of tubocurarine.
• More potent than the parent compound.

• Therapeutic Use:

• As a muscle relaxant in various surgical

procedures.

Compiled By Lishan A(Dr) 43

 B. Depolarising agents

v Succinylcholine/ suxamethonium, Decamethonium

• Initially depolarizes like Ach but persistent depolarization of nicotinic
receptors at NMJ leads to repolarization

– Decrease Ach release

– muscle relaxation

• Concurrent use of AChE inhibitors aggravate it

• Toxicity is not reversed by use of AChE inhibitors to increase Ach

• Action is terminated by plasma cholinesterase

Compiled By Lishan A(Dr) 44

Cont. …..Depolarizing agents - succinylcholine

vEffects
ü Does not produce ganglionic block,
ü Has weak histamine-releasing action,

vUnwanted effects
Ø Bradycardia
Ø Increased intraocular pressure
Ø Prolonged paralysis by genetic differences of cholinesterase activity

ØMalignat hyperthermia - sudden rise in body temperature

 usually treated by dantrolene (prevention of calcium release from sarcoplasmatic
reticulum) + rapid cooling
Compiled By Lishan A(Dr) 45
 2. Ganglionic blocking agents
A. Nicotine
Ø At low dose Stimulate ganglia like Ach by depolarizing the excitatory
postsynaptic membranes.
Ø At high dose, block the ganglia b/c of persistent depolarization
B. Hexamethonium, Trimethaphan, Mecamylamine
• Impair transmission
§ Compete with Ach for nicotinic receptor
§ Trimethaphan
§ Block the channel after it opens
– Hexamethonium

Compiled By Lishan A(Dr) 46

Drugs affecting
Sympathetic NS

Compiled By Lishan A(Dr) 47

 Sympathetic NS /"Fight or Flight" Response/
• EP/ NEP are major elements in the "fight or flight" response
• Epinephrine:
Ø Rapidly mobilizes fatty acids as the primary fuel for muscle action
Ø Increases muscle glycogenolysis
Ø Mobilizes glucose for the brain by ↑ hepatic glycogenolysis/ gluconeogenesis
Ø Preserves glucose for CNS by ↓ insulin release leading to reduced glucose uptake by muscle/
adipose.
Ø Increases cardiac output
• Norepinephrine :
Ø Elicits responses of the CV system - ↑ blood flow and ↓ insulin secretion.

Adrenergic Transmission/ Biosynthesis of catecholamines

Compiled By Lishan A(Dr) 48

 ADRENERGIC DRUGS

• As their name suggests, these drugs resemble

sympathetic nerve stimulation in their effects

• They may be divided into two groups on the basics

of their chemical structure.

1. Catecholamines: Cpds with the catechol nucleus.

2. Noncatecholmines: lack the catechol nucleus.

Compiled By Lishan A(Dr) 49

 Non-catecholmines

vMOA: They may directly act on the

receptors or may indirectly release the
physiologic catecholamines
üE.g. Ephedrine, amphetamine, phenylephrine

Compiled By Lishan A(Dr) 50

 Catecholamines
• Catecholamine’s have a direct action on sympathetic

effectors cells through interactions with receptor sites on

the cell membrane.

• They activate receptors of effector cells; therefore,

adrenergic nerves are not required for their effects.

vE. g.:- Adrenaline, noradrenaline, dopamine, isoprenaline, and dobutamine.

Compiled By Lishan A(Dr) 51

v Adrenergic drugs, like cholinergic drugs, can be grouped by mode
of action and spectrum of receptors that they affect.

A. Directly acting: directly interact with and activate

adrenoreceptors, e.g., adrenaline and noradrenaline

B. Indirectly acting: their actions are dependent on the release of

endogenous catecholamines. This may be;
I. Displacement of stored catecholamines from the adrenergic nerve endings,
e.g., amphetamine, tyramine

II. Inhibition of reuptake of catecholamines already released, e.g. cocaine,

tricyclic antidepressants.

III. Enzyme(MAO & COMT) inhibitors. E.g. Entacapone

Compiled By Lishan A(Dr) 52
vDegradation of EP, NEP and dopamine are via monoamine oxidase (MAO)
and catechol‑O‑methylt ransferase (COMT)

vNeuronal re-uptake and degradation of catecholamines quickly

terminates hormonal or neurotransmitter activity.
vCocaine binds to dopamine receptor to block re-uptake of
dopamine;
ØDopamine continues to stimulate receptors of the postsynaptic
nerve.

Compiled By Lishan A(Dr) 53

 Summery of Adrenergic Drugs Action
ØAct or bind to the receptor (isoproterenol [on β], phenylepherine [on α])
ØReleasing agents ( amphetamine)
ØUptake inhibitors (cocaine)
ØMAO & COMT inhibitors (Entacapone) (↑[ EP, NEP, D])
ØMixed acting : Ephedrine

Compiled By Lishan A(Dr) 54

• Both types of sympathomimetics, direct and
indirect, ultimately cause activation of
adrenoreceptors leading to some or all
characteristic effects of the catecholamines.

vBasically there are two types of adrenoceptors.

Øα- adrenoceptors

Øβ- adrenoceptors

Compiled By Lishan A(Dr) 55

Table: Metabolic and muscle contraction responses to
catecholamine binding to various adrenergic receptors.
Type Tissue Actions
Most vascular smooth muscles Contraction,
Genitourinary muscles Impotence
α1
Radial muscle of pupil Mydriasis/ Relxation (pupil dilation)
Heart Increase force of contraction
Adrenergic nerve terminals Inhibition of transmitter release
α2
Platelets Aggregation
Heart Increase rate and force of contraction
β1
Urinary bladder Relaxation
Smooth muscle of: Bronchial,
genitourinary, GI tract and blood Relaxation
β2 vessels
↑liver /muscle Glycogenolysis, ↑liver
Liver (CHO Metabolism)
Gluconeogenesis; ↓ Glycogenesis
β3 Fat cells Lipolysis
56
Compiled By Lishan A(Dr)
• Epinephrine ≥ Norepinephrine >> Isoproterenol
when compare the potency in α- adrenoceptors

• Isoproterenol > Epinephrine > Norepinephrine

when compare the potency in β- adrenoceptors

vEpinephrine is a potent catecholeamine as

compared to the others.

Compiled By Lishan A(Dr) 57

 Drugs Acting on the Adrenergic Receptor Subtypes

α1 α2 β1 β2
Agonist

Phenylephrine Clonidine Dobutamine Salbutamol

Methoxamine Oxymetazoline Isoproterenol Terbutaline
Terbutaline Isoetharine

Prazosin Yohimbine Propranolol Timolol

Phentolamine Phentolamine Pindolol Propranolol
Antagonist

Phenoxybenzamine Phenoxybenzamine Atenolol Pindolol

Metoprolol Butoxamine
Timolol

Compiled By Lishan A(Dr) 58

• Adrenaline stimulates all the four receptor subtypes.

• Noradrenaline stimulates both alpha receptors and

β-1but has very poor affinity for β-2 receptors.

• Labetalol blocks all β-receptors as well as some α-

receptors.

Compiled By Lishan A(Dr) 59

 ADRENALINE
• This is the prototype of adrenergic drugs and is produced in the
body by the cells of the Adrenal medulla and by chromaffin
tissues.
ü Adrenaline is rapidly destroyed in the GIT, conjugated, and oxidized in the liver.

Ø Ineffective when given orally and should be given IM or SC.

ü IV injection is highly dangerous and is likely to precipitate ventricular fibrillation.

• Can be relaxing effect on the bronchi or

• It may be applied topically to mucus membranes to produce vasoconstriction.

v Adrenaline directly stimulates all the adrenergic receptors and brings

about effects of sympathetic nerve stimulation.

Compiled By Lishan A(Dr) 60

Cont. ………………. ADRENALINE

v Its action may be divided in to two, depending on the type of

receptor stimulated.
A. The α effects: consist of vasoconstriction in skin and viscera, mydriasis,

platelet aggregation and some increase in blood glucose.

B. The ß effects: consists of:-

ü Increased contractility and rate of heart with a decreased refractory period (ß1),

ü Vasodilatation in muscles and coronary vessels (ß2),

ü Bronchial relaxation (ß2) uterine relaxation (ß2),

ü Hyperglycemia, lactic acidemia and increased circulating free fatty acids.

Compiled By Lishan A(Dr) 61

 Cont. ……….Adrenaline
vIndications vAdverse reactions

ü Acute bronchial asthma ü Anxiety, restlessness, headache tremor

ü Anaphylaxis ü Anginal pain

ü Local haemostatic to stop bleeding ü Cardiac arrhythmias and palpitations

in epistaxis ü Sharp rise in blood pressure
ü With local anesthesia to prolong the ü Sever vasoconstriction resulting in
action gangrene of extremities
ü Cardiac arrest ü Tearing, conjunctival hyperemia

Compiled By Lishan A(Dr) 62

vContra indications
üCoronary diseases

üHyperthyroidism

üHypertension

üDigitalis therapy

üInjection around end arteries n g

i nt
d
a me
e
R gn
s si
A
Compiled By Lishan A(Dr) 63
 Isoprenaline, Dopamine, Dobutamine
• These are the other catecholamines which have similar properties to
adrenaline and noradrenaline.

• Dopamine is naturally occurring and is a precursor of noradrenaline.

• The other two-isoprenaline and dobutamine- are synthetic.

Ø These drugs have advantage over the others because they are more
selective in their action so that they have fewer side effects than
adrenaline and noradrenaline.

v Dopamine and dobutamine are very useful drugs for the treatment of
shock.

Compiled By Lishan A(Dr) 64

 NON- CATECHOLAMINES
• Most of the non- catecholamines function by releasing the
physiologic catecholamines from the postganglionic nerve
endings. E.g.
v EPHEDRINE
ü Ephedrine is absorbed from the GIT & from all parenteral sites.

ü It has a good distribution through out the body

ü Has resistant to hydrolysis by the liver enzymes.

ü Major proportion is excreted unchanged in the urine.

ü Because of its stability to metabolism it has long duration of

action than the catecholamine's.
Compiled By Lishan A(Dr) 65
vPharmacodynamics

ü Ephedrine stimulates both α and β receptors.

v This effect is partly by a direct action on the receptors and partly indirectly by
releasing noradrenaline from its tissue stores.
ü The effect of the drug to various organs and systems is similar to that of adrenaline.
ü It is also a mild CNS stimulant.

vIndications:
üBronchial asthma: - usually as a prophylactic for prevention of attacks
üNasal decongestion
üMydriasis
üHeart block
üNocturnal enuresis

Compiled By Lishan A(Dr) 66

vSide effects
• The side effects are similar to those of adrenaline; but

in addition it may produce insomnia and retention of

urine.

vContraindications

• The same as Adrenaline.

Compiled By Lishan A(Dr) 67

Alpha -1 adrenergic receptor agonists

1. Phenylephrine

2. Methoxamine

3. Midodrine

Compiled By Lishan A(Dr) 68

 Phenylephrine
v Direct acting non-catecholamine  powerful alpha 1 agonist/CNS
v MOA : activation of alpha1 adrenoceptors vascular smooth M = VC
(vasoconstriction)

ü peripheral VC =↑ systolic & diastolic BP

ü blood supply ↓renal, splanchnic & skin but ↑coronary blood flow

ü ↓Intra Ocular pressure  mydriasis

• Clinical indications
• Critical care unit  spinal/epidural anesthesia
• Elevates BP (reflux bradycardia negligable) = beneficial tachycardic
condition/ cardiomyopathy = Rx of hypotension
– As pressor agent  maintenance of blood pressure
• As midriatic agent  pupil dilation
Compiled By Lishan A(Dr) 69
 Doses

• Press or agent = reverse dropped BP

ü Dogs @ 1-3 microgram/kg/min

ü Cats @ 0.1mg/kg SC

ü Horses @ 5mg (total) IV

• 2.5% ophthalmic solution

• as mydriatic agent 10% solution

Compiled By Lishan A(Dr) 70

Alpha -2 adrenergic receptor agonists

1. Clonidine

2. Xylazine

3. Guanfacine & guanabenz

Compiled By Lishan A(Dr) 71

 Xylazine
• Alpha 2 adrenoceptor agonist structurally similar to clonidine
• Used as Central sedative, analgesic + muscle relaxant property
• MOA : stimulation action on central alpha 2 receptors 
sedation + analgesia
v On CVS  peripheral alpha2 action
 initial ↑peripheral resistance + ↑BP followed by long
duration of lowered BP(central action)

Compiled By Lishan A(Dr) 72

 Clinical indications
• Sedation in dogs, cats & horses.
• Pre-anesthetic sedative prior to inhalant anesthesia, injectable.
• As sedative prior to local, regional & epidural anesthesia.
• As general anesthesia with ketamine (KX =
Ketamine-Xylazine).

Compiled By Lishan A(Dr) 73

vDoses

• dogs & cats @ 1-3 mg/kg IM

• horses @ 0.6 -1 mg/kg IV

• pigs @ 0.5 – 3 mg/kg IM

• Sheep & goats @ 0.1 – 0.2 mg/kg IM

• Cattle @ 0.05-0.03 mg/kg IM

Compiled By Lishan A(Dr) 74

 Beta -1 adrenoceptor agonists
1. Dobutamine
2. Denopamine
3. Xamoterol
4. Prenalterol

↑ BP

Compiled By Lishan A(Dr) 75

 Beta-2 adrenoceptor agonists
1. Terbutaline
2. Clenbuterol
3. Salbutamol
4. Salmeterol
5. Pirbuterol
6. Isoetarine
7. Orciprinaline

Compiled By Lishan A(Dr) 76

 Terbutaline

• selective beta 2 adrenoceptor agonist found in

bronchial, vascular & uterine smooth M 
Relaxation.

• effective when taken orally, S/C, inhalation.

• horse  poor oral absorption  resorcinol ring

(not substrate MAO)

Compiled By Lishan A(Dr) 77

 MOA + CLINICAL INDICATION
Ø stimulates production of cAMP  activation of adenylate cyclase
Ø inhibit release of inflammatory mediators  mast cells
Ø stimulation of beta2 receptors  bronchodilation  bronchial
secretion increases + bronchial clearance by ciliary action.
Ø mucolytic activity applied therapeutically as a fast acting
bronchodilator & relief from profuse nasal secretion.

Ø cats  limited use Bcoz cardiac stimulant action

Ø Horses  after parenteral inj = sweating & CNS excitation.

Compiled By Lishan A(Dr) 78

 Doses

• Dogs @ 1.25 – 5 mg/kg, PO, TID.

• Cats @ 0.1 mg/kg PO BID

• Horses @ 0.002 -0.005 mg/kg IV dose may be

adjusted as required

• @ 2-4 mg/kg by inhalation using nebulizer

Compiled By Lishan A(Dr) 79

 Salbutamol
• highly selective beta 2 adrenergic agonist B2 >>B1
• pharmacological + therapeutic indication similar to
terbutaline
• bronchodilator effect with minimal cardiac stimulation

• Used principally in Dogs & Cats bronchial Smooth M 

to alleviate bronchospasm / cough
• Dogs @ 0.02 – 0.05 mg/kg PO 3-4 times daily

Compiled By Lishan A(Dr) 80

Compiled By Lishan A(Dr) 81
 Salmeterol
Ø Long acting selective beta2 adrenergic agonist

Ø Higher lipophilicity  prolonged pulmonary residence time

Ø Salmeterol 10 folds potent than salbutamol

Ø Horses  improves pulmonary function 55% with in 60

min of aerosol administration + long duration of action = 8
hours
Ø horses @ 0.5 – 1 microgram/kg by aerosol inhalation.

Compiled By Lishan A(Dr) 82

Compiled By Lishan A(Dr) 83
 D. Adrenergic Blockers/Sympatholytic
• Block the effects of the adrenergic neurotransmitters

• The drugs may be considered in two groups:

1. Drugs blocking the α Adrenergic receptor :

Ø e.g. phenoxybenzamine, prazosin, and yohimbine

3. Drugs blocking the β Adrenergic receptor

Ø E.g. propranolol, metoprolol, and timolol

Compiled By Lishan A(Dr) 84

• These drugs prevent the response of effectors organs to adrenaline,
noradrenaline and other sympathomimetic amines whether
released in the body or injected.

• Circulating catecholamines are antagonized more readily than are

the effects of sympathetic nerve stimulation.

• The drugs act by competing with the catechoamines for α or β

receptors on the effectors organs.

• They don’t alter the production or release of the substances.

Compiled By Lishan A(Dr) 85

Anti-adrenergic
Drug/Sympatholytics

Compiled By Lishan A(Dr) 86

 α- Adrenergic blockers
v Alpha adrenergic receptor antagonists may be reversible or
irreversible.

Ø Reversible antagonists dissociate from the receptors e.g.

phentolamine, tolazoline, prazosin, yohimbine, etc.

Ø Irreversible antagonists tightly bind to the receptor so that

their effects may persist long after the drug has been cleared
from the plasma e.g. phenoxybenzamine

Compiled By Lishan A(Dr) 87

vPharmacologic Effects:
üAlpha receptor antagonist drugs lower peripheral
vascular resistance and blood pressure.

üHence, postural hypotension and reflex tachycardia

are common during the use of these drugs.

üOther minor effects include miosis, nasal stuffiness,

etc.

Compiled By Lishan A(Dr) 88

Cont. ….Alpha receptor antagonists.
vCan be grouped as:-
Ø Non selective
üEg: phenoxybenzamine, phentolamine, dibenamine,
tolazoline, ergotamine , dihydroxyergotamine .
Ø Alpha-1 selective
üEg: prazocin, terazocin, urapidil etc.
Ø Alpha-2 selective
üEg: yohimbine.

Compiled By Lishan A(Dr) 89

 TOLAZOLINE
ü Imidazole derivative, non selective α-blocker.

ü Direct vasodilator & cardiac stimulant action

ü Also blocks 5HT receptors + histamine like action

ü In veterinary medicine used primarily as Antidote to

xylazine overdose in dogs & cats @ 4 mg/kg slow IV

Compiled By Lishan A(Dr) 90

 Ergot Alkaloids
st
ØAre the 1 adrenergic blocking drugs discovered
 vasomotor reversal phenomenon.

ØTherapeutic use  mainly to stimulate

contraction of uterus post – partum & to relieve
the pain of migraine in human medicine. E.g.
ergotamine/ Cafergot@

Compiled By Lishan A(Dr) 91

Compiled By Lishan A(Dr) 92
Compiled By Lishan A(Dr) 93
Selective Alpha-1 Adrenergic Receptor Antagonists

1. Quinalzoline Derivatives – prazosin, terazocin

2. Indole Derivatives – indoramin

3. Miscellaneous – urapidil, ketanserin

Compiled By Lishan A(Dr) 94

 Prazocin Hcl
Ø Prototype of selective Alpha-1 adrenergic R antagonists
Ø Extremly potent & highly selective alph-1 receptor blocking drug

ü Thus, it lowers BP, reduces venous return and cardiac output.

ü It also reduces the tone of internal sphincter of urinary bladder.
Ø Alpha-1 Receptor (1000folds) >>>> Alpha-2 Receptor

Ø Pharmacological effect ↓peripheral vascular resistance, ↓BP & indicated for Benign
prostatic hyperplasia
Ø In dogs for Rx systemic hypertension/pulmonary hypertension
Ø < 15 kg BW @ 1 mg total dose, PO, TID
Ø > 15 kg BW @ 2 mg total dose, PO, TID

Compiled By Lishan A(Dr) 95

vSelective α-2 Adrenrgic Receptor Antagonists
vYohimbine

• Indole-alkyl-amine alkaloid obtained

naturally from west African evergreen tree =
Pausinystalia yohimbe
• Rx of xylazine & medetomedine reversal
ü Dogs & Cats @ 0.1 mg/kg, slow IV.

• Rx of xylazine induced emesis

ü Dogs & Cats @ 0.25 – 0.5 mg/kg IM SC BID

Compiled By Lishan A(Dr) 96

 Atipamezole
v Synthetic selective alpha-2 adrenoceptor blocking drug primarily used
as a reversal drug for Medetomidine & dexmedetomidine induced
adverse effects.
v Acts by competitively blocking alpha2 receptors in CNS & periphery.
Clinical indications:
I. For Amitraz poisoning all species @ dose rate 0.05mg/kg, IV
II. For medetomidine & other alpha2 agonist reversal
– Dogs @ 5 times the previous asministered dose of medetomidine,IM.
– Cats @ 2.5 times the previously administered dose of medetomididne , IM.

Compiled By Lishan A(Dr) 97

Beta Adrenergic Receptor Antagonists
v Non Selective
ü {1st Generation} propranolol, nadolol, pindolol, timolol,
sotalol
ü {3rd Generation} carvedilol, carteolol, labetalol, bucindolol

v Selective
– {2nd Generation}beta 1 : metoprolol, atenolol, esmolol,
acebutolol
– {3rd Generation}beta 2 : betaxolol, celiprolol, nebivolol

Compiled By Lishan A(Dr) 98

Non-selective beta adrenergic receptor
antagonists

Compiled By Lishan A(Dr) 99

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 Propranolol

Ø Prototype of nonselective β receptor blockers.

Ø Interacts with both β-1 & β-2 receptors.

Ø Lacks sympathomimetic activity.

Ø Powerful local anesthetic action.

Ø Partial agonist @ serotonin 5HT1B receptors.

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 Clinical indication + doses
• Negative inotropic & negative chronotropic effects.

• Peripheral vasoconstriction.

• Bronchoconstriction.
– Used as Antiarrhythmic drug

– Dogs @ 0.1 mg/kg IM TID

– Horses @ 175 mg/kg total dose PO

– Cats @ 2.5 mg/kg total dose PO

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 METAPROLOL
• prototype of selective β-1 adrenergic receptor (cardioselective)

• Potency to block cardiac stimulation action >>> propranolol.

• Effectively used for supraventricular Tachycardia, pre-mature

ventricular contraction & V. hypertrophy.
ü Dogs @ 5-50 mg total dose PO BID/TID

ü Cats @ 2 – 15 mg total dose PO TID

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 LABETALOL
• Mixed alpha & beta adrenoceptor blocker
• Primarily used in Human medicine for Rx of
hypertension
• In veterinary medicine pheochromocytoma &
clonidine withdrawal hypertension
üDogs @ 0.2 – 0.4 mg/kg PO once daily following
titrating dose to twice daily.
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 Atenolol
• Devoid of intrinsic sympathomimetic & membrane
stabilizing activity.
• It is used mainly as anti-arrhythmic drug.
• Clinical indication:
• I. For cardiac conditions:-
ü Dogs @ 6.5-25mg total dose, PO, BID/TID
ü Cats @ 6.5-12.5mg total dose, PO, SID

• II. For hypertension:- Dogs & Cats @ 2 mg/kg, PO, SID

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 Esmolol
• An ultra short acting cardioselective β-1 adrenoceptor blocker.

• It is devoid of intrinsic sympathomimetic & membrane stabilizing

action.
• Esmolol is very useful for immediate therapy for tachycardias.

• It is particularly useful in critical ill patients where adverse effects

of bradycardia, heart failure/hypotension which may require rapid

withdrawl of drug.

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Dogs & Cats @ 0.5-1 mg/kg, slow IV as loading dose
followed by 0.05 -0.2 mg/kg/min IV infusion.

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Alpha & Beta Adrenergic Receptor Antagonists.

Ø Mixed alpha & beta adrenoceptor antagonist.

I. LABETALOL

II. CARVEDILOL

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 LABETALOL
ü Mixed alpha & beta adrenoceptor blocker.

ü Primarily used in human beings for Rx hypertension &

clonidine withdrawl hypertension in geriatric patients.

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 Carvedilol
• Blocks B1, B2 & A1 receptors.
• Therapeutic indication:
ü Hypertension (α1 antagonism)
ü Tachyarrhythmias ( B1 antagonism)
ü MI & CHF (antioxidant/antiproliferative effect).
– Dogs @ 0.2-0.4 mg/kg, PO, once daily, followed by titrating dose to twice
daily.

• Contraindicated in dehydrated/hypotensive/asthmatic animals.

• Adverse effect in dogs  bradycardia, hypotension, bronchoconstriction.

D
EN
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