Pharmacology 1

“The chapter you are learning

today is going to save someone’s
life tomorrow. Pay attention.”

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CHAPTER ONE: FOUNDATION OF PHARMACOLOGY
Pharmacokinetics
Pharmacokinetics refers to what the body does to a drug.
Pharmacokinetics deals with drug absorption, distribution, metabolism, and excretion.
The process by which the drug is released from its pharmaceutical form (e.g., capsule, tablet,
suppository, etc.)
Absorption: First, absorption from the site of administration permits entry of the drug (either
directly or indirectly) into plasma.
Distribution: Second, the drug may then reversibly leave the bloodstream and distribute into
the interstitial and intracellular fluids.
Metabolism: Third, the drug may be biotransformed by metabolism by the liver or other tissues
Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or
feces.

Figure 1Pharmacokinetics

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Routes of drug administration
The most common routes of drug administration are:
 Injection (the drug is introduced directly into the bloodstream or into tissue)

 Inhalation
 Peroral administration
 Dermal administration
 Rectal administration

Absorption (pharmacology)
Mechanisms of drug absorption
1. Passive diffusion: The drug moves from a region of high concentration to one of lower
concentration.
2. Facilitated diffusion: Drugs enter the cell through specialized transmembrane carrier
proteins.
3. Active transport: This mode of drug entry also involves specific carrier proteins that
span the membrane. Unlike facilitated diffusion drug is transported against
concentration gradient by using energy.
4. Endocytosis and exocytosis: This type of absorption is used to transport drugs of
exceptionally large size across the cell membrane.

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Factors influencing Absorption
1) PH
2) Blood flow to the absorption site: The intestines receive much more blood flow
than the stomach, so absorption from the intestine is favored over the stomach.
3) Total surface area available for absorption.
4) Contact time at the absorption surface: If a drug moves through the GI tract very
quickly, as can happen with severe diarrhea, it is not well absorbed.
Bioavailability is the rate and extent to which an administered drug reaches the systemic
circulation.
 Expressed as a percentage of the dose that was initially administered
 Drugs administered intravenously have a bioavailability of 100%.
Bioavailability is affected by two mechanisms.
1. First-pass hepatic metabolism: Orally administered drugs are absorbed in the GI
tract and reach the liver via portal circulation. In the liver they undergo first pass
metabolism before they enter systemic circulation → ↓ bioavailability.
2. Ability to pass through lipid membranes: Very hydrophilic drugs are poorly absorbed
because of their inability to cross lipid-rich cell membranes.

Distribution
Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters
the interstitium (extracellular fluid) and the tissues.
The distribution of a drug from the plasma to the interstitium depends on cardiac output and
local blood flow, capillary permeability, the tissue volume, the degree of binding of the drug
to plasma and tissue proteins, and the relative lipophilicity of the drug.

Metabolism (biotransformation)
Chemical alteration of substances (e.g., drugs) within the body by the action of enzymes and
mainly takes place in the liver.
Phases of biotransformation
 Phase I reaction: A drug is transformed into a polar, water-soluble metabolite
by cytochrome P450.
 Phase II reaction: A drug is conjugated and thereby transformed into a very polar
metabolite (can be excreted renally).

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Drug Excretion (Elimination)
Drug clearance (CL): a measure of the rate of drug elimination.
It is defined as the plasma volume that can be completely cleared of the drug in a given period
of time.
Half-life (t½): the time required for the plasma concentration of a drug to reach half of its initial
value.
Drugs and/or their metabolites are excreted from the body in one of the following ways:

 Renal elimination: mostly hydrophilic drugs.

 Biliary elimination: Lipophilic and hydrophilic substances.
 Pulmonary elimination: primarily in inhaled anesthetic drugs.

Routes of drug administration

The route of administration is determined by the properties of the drug (for example, water or
lipid solubility) and by the therapeutic objectives (for example, the desirability of a rapid onset,
the need for long-term treatment, or restriction of delivery to a local site).
Major routes of drug administration include

A. Enteral:
Enteral administration (administering a drug by mouth) is the safest and most common,
convenient, and economical method of drug administration. The drug may be swallowed,
allowing oral delivery, or it may be placed under the tongue (sublingual), or between the
gums and cheek (buccal), facilitating direct absorption into the bloodstream.

1. Oral: oral administration of drug provides many advantages

 Oral drugs are easily self-administered
 toxicities and/or overdose of oral drugs may be overcome with antidotes, such
as activated charcoal
A wide range of oral preparations is available including enteric-coated and extended-
release preparations.
I. Enteric-coated preparations: An enteric coating is a chemical envelope that
protects the drug from stomach acid, delivering it instead to the less acidic
intestine, where the coating dissolves and releases the drug.
Enteric coating is useful for certain drugs (for example, omeprazole) that are acid
unstable. Drugs that are irritating to the stomach, such as aspirin.

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 II. Extended-release preparations: Extended-release (abbreviated ER or XR)
medications have special coatings or ingredients that control the drug release,
thereby allowing for slower absorption and a prolonged duration of action.
Advantages
 Can be dosed less frequently and may improve patient compliance.
 May maintain concentrations within the therapeutic range over a longer period
of time.
 Advantageous for drugs with short half-lives. For example, the half-life of oral
morphine is 2 to 4 hours, and it must be administered six times daily to provide
continuous pain relief. However, only two doses are needed when extended
release tablets are used.
2. Sublingual/buccal: Placement under the tongue allows a drug to diffuse into the
capillary network and enter the systemic circulation directly.
Advantages
 Ease of administration,
 Rapid absorption,
 Bypass of the harsh gastrointestinal (GI) environment, and avoidance of first
pass metabolism
3. Parenteral:
The Parenteral route introduces drugs directly into the systemic circulation.
Parenteral administration is used for drugs that are poorly absorbed from the GI tract
(for example, heparin) or unstable in the GI tract (for example, insulin).
Parenteral administration is also used if a patient is unable to take oral medications
(unconscious patients) and in circumstances that require a rapid onset of action.
Parenteral route can be
1. Intravenous (IV)
2. Intramuscular (IM)
3. Subcutaneous (SC)
4. Other routes
1) Oral inhalation
2) Nasal inhalation
3) Topical
4) Transdermal
5) Rectal

5. Intrathecal/intraventricular: The blood–brain barrier typically delays or prevents the

absorption of drugs into the central nervous system (CNS). When local, rapid effects are

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 needed, it is necessary to introduce drugs directly into the cerebrospinal fluid. For
example, intrathecal amphotericin B is used in treating Cryptococcal meningitis

Pharmacodynamics
Pharmacodynamics deals with the effect of a drug at its site of action, the dose-
response relationship of the drug, and the influence of other factors on the drug effect.
Every functioning molecule in an organism is a potential site of action for a drug.

Means through which drugs act include:

1) Interaction with receptors
a. Cell membrane receptors
2) Interaction with enzymes
3) Interaction with DNA (e.g., cytostatics)

4) A physical/chemical effect (e.g., osmotic diuretics, antacids)

Drug-receptor interactions
Drug affinity: a measure of the tendency of a drug to bind to its receptor.
 Most drug-receptor bonds are reversible
 Covalent drug-receptor bonds, which are less common, are almost always irreversible.
Drug efficacy (correlates with Emax): the maximum degree to which a drug activates receptors
after binding and triggers a cell response.

 Not related to potency (drugs with a high efficacy can have a low potency)

Types of drug-receptor interactions

 Agonist: a drug that has a similar effect to that of the endogenous receptor
activator (e.g., β2 agonists)
 Full agonist: a molecule that binds to a receptor and activates the receptor with the
highest response it can elicit.
 Partial agonist: A substance that has some agonistic action at a receptor but does not
elicit the complete response of a true agonist. Act at the same site as full agonists.

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Antagonist: a drug that binds to a receptor and prevents its activation.
 Competitive antagonist: Agonist and the antagonist compete to bind to the same receptor.
 Non-competitive antagonist: The drug binds at a site other than the agonist-binding site,
changes the structure of the agonist binding site, and decreases the affinity of the agonist.
 Functional (physiological) antagonist: In this type of antagonism, two different molecules
working through separate receptors produce physiologically opposite effects.
Inverse agonist: Binds to the same receptor as an agonist, but not to the same active site. It
elicits a response that is opposite to the agonistic response and has a negative efficacy.

Dose-response relationship
The following terms are used to describe dose-response relationships:
 Potency: The potency of a drug is measured as the concentration required to produce a
pharmacological response of a specified intensity.
 Not related to efficacy (drugs with a high potency can have a low efficacy) but
dependent on affinity.
 Therapeutic index (TI): a measurement of the safety of a drug. The greater the therapeutic
index, the safer the drug. High therapeutic index: e.g., glucocorticoids, penicillin
 Narrow therapeutic index: Drugs with a narrow TI require monitoring
(e.g., lithium, theophylline, warfarin, digoxin, and antiepileptic drugs)
 Therapeutic window: the range of doses that is effective for treating a condition with a
minimum of adverse effects.

Drug tolerance and Tachyphylaxis

The effect of a drug can decrease with repeated dosing:
Drug tolerance (e.g., opioids, benzodiazepines, barbiturates, alcohol).
The mechanisms responsible for the development of drug tolerance include:
 Down-regulation of receptors
 Increased synthesis of enzymes that metabolize the drug.
 Can be overcome by increasing the dose
 Develops slowly over a few weeks
Tachyphylaxis
 The underlying mechanism responsible for the decreased effect of a drug
involves depletion of the body's stores of an endogenous mediator and downregulation
of receptors.

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  Cannot be overcome by increasing the drug dose.
 Develops quickly (within a few hours of dosing.
 Examples include:

 Nitrates

 Hydralazine

 Indirect sympathomimetic drugs (e.g., ephedrine)

Study Questions

Choose the ONE best answer.

1. Pharmacokinetics is BEST defined by which of the following?
a) The use of drugs for treatment
b) How the body moves and affects a drug
c) How the drug affects the body
d) The amount of drug necessary to produce a desired effect

2. Which of the following are the concepts that deals with pharmacokinetics?
a) Absorption, distribution, metabolism, and excretion
b) Affinity, efficacy, potency, and distribution
c) Agonist, antagonist, absorption, and affinity
d) Enteral, parenteral, prenatal, and postnatal
3. Pharmacodynamics is BEST defined by which of the following?
a) The use of drugs for treatment
b) How the body moves and affects a drug
c) How the drug affects the body
d) The process of a drug entering circulation
4. Biotransformation is the
a) Elimination of drugs from the body
b) Chemical alteration of the drug by the liver
c) Distribution of a drug throughout the body
d) D)None
5. The action of the drug on the body is known as
a) Pharmacokinetic
b) Pharmacodynamic

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 c) Pharmacology
d) Pharmacotherapeutics
6. A measure of the tendency of a drug to bind to its receptor
a) Drug Efficacy
b) Drug Affinity
c) Biotransformation
d) All
7. Narrow therapeutic index means
a) The drug is save at high dose
b) The drug is toxic at high doses and needs monitoring
c) The drug is very effective
d) None
8. The IV administration of drugs are
a) 100% bioavailable
b) Rapidly absorbed
c) Undergoes the first-pass metabolism
d) Rapidly excreted by renal
9. For a drug given orally, the principal site of drug absorption is
a) Stomach
b) Small intestine
c) Esophagus
d) Large intestine
10. Biotransformation of the drugs may lead to all of the following EXCEPT
a) Inactive metabolite from an active drug
b) Active metabolite from an active drug
c) Active metabolite from an inactive drug
d) Inactive metabolite from inactive drug

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CHAPTER TWO: ANTIMICROBIAL THERAPY
Introduction to antimicrobial Therapy
Antimicrobial drugs are drugs that are against microorganisms that cause diseases to man.
Microorganisms are organisms that cannot be seen with naked eyes but can be observed by the
use of microscope. Anti-microbial drugs are classified according to the microorganisms which
they attack and they are
 Antibacterial drugs
 Antiviral drugs
 Antifungal drugs
 Antiprotozoal drugs
The drug of choice is usually the most active drug against the pathogen or the least toxic of
several alternative drugs.
The drug selected for use may be either a bactericidal agent (causing the death of the
microorganism) or bacteriostatic agent (temporarily inhibiting the growth of the
microorganism).
Drug choice is related to the mechanism of drug action in one of the following general
categories:
a) Inhibits bacterial cell wall biosynthesis
b) Inhibits bacterial protein synthesis
c) Inhibits bacterial metabolism
d) Inhibits bacterial nucleic acid synthesis

Antibacterial drugs (Antibiotics)

Definition: antibiotics are antibacterial substances produced by various species of
microorganisms (bacteria, fungi, actinomycetes) that suppress the growth of other
microorganisms.

First antibiotic was penicillin and is produced by fungus called penicillium.

Chemotherapeutic spectra
Anti-biotics are classified according to the number of bacteria they attack

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A) Narrow-spectrum antibiotics
Chemotherapeutic agents acting only on a single or a limited group of microorganisms are said
to have a narrow spectrum. For example, isoniazid is active only against Mycobacterium
tuberculosis.
B) Extended-spectrum antibiotics
Extended spectrum is the term applied to antibiotics that are modified to be effective against
gram-positive organisms and also against a significant number of gram-negative bacteria. For
example, Ampicillin acts against gram positive and some gram negative bacteria such as E.coli,
Hemophilus influenza, salmonella typhi.
C) Broad-spectrum antibiotics
Drugs such as tetracycline, fluoroquinolones and carbapenems affect a wide variety of
microbial species and are referred to as broad- spectrum antibiotics.

Classification of antibiotics and Mechanism of action

Antibiotics are classified based on chemical structure and proposed mechanism of action, as
follows.
1) Agents that inhibit synthesis of bacterial cell wall, including penicillin and
cephalosporins which are bactericidal.
2) Agents that disrupt function of 30S or 50s ribosomal subunits to reversibly inhibit
protein synthesis, which are generally bacteriostatic including chloramphenicol
and erythromycin.
3) Agents that affect bacterial nucleic acid metabolism, such as rifampin and
quinolones
4) Antimetabolites, including trimethoprim and the sulfonamides, which block
essential enzymes of folate metabolism

Choice of suitable drug

Before selecting an antibacterial we consider
1) Identification of the infecting organism
2) Patient factors
a) Immune system
b) Renal dysfunction
c) Hepatic dysfunction
d) History of Allergy
e) Taking other medications
f) Pregnancy and breast feeding

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Complications of antibiotic therapy
A. Hypersensitivity
Hypersensitivity or immune reactions to antimicrobial drugs or their metabolic products
frequently occur. For example, the penicillin’s
B. Direct toxicity
High serum levels of certain antibiotics may cause toxicity by directly affecting cellular
processes in the host. For example, aminoglycosides can cause ototoxicity.

C. Superinfections
Drug therapy, particularly with broad-spectrum antimicrobials or combinations of agents, can
lead to alterations of the normal microbial flora of the upper respiratory, oral, intestinal, and
genitourinary tracts, permitting the overgrowth of opportunistic organisms, especially fungi or
resistant bacteria.

Over view of Bacteria

The wall gives the cell its shape and surrounds the cytoplasmic membrane, protecting it from
the environment.
Cytoplasm - The cytoplasm, or protoplasm, of bacterial cells is where the functions for cell
growth, metabolism, and replication are carried out.
Cytoplasmic Membrane - A layer of phospholipids and proteins, called the cytoplasmic
membrane, encloses the interior of the bacterium, regulating the flow of materials in and out of
the cell.
Bacterial ribosomes: Ribosomes are the site of protein synthesis of bacteria. Each ribosome is
composed of small (30S) and large (50S) components called subunits which are bound to each
other:

Figure 2 Bacterial Ribosome

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Classification of bacteria
1. Classification on the basis of Gram Stain and Bacterial Cell Wall.
 Gram positive: Have much larger peptidoglycan cell wall.
 Gram negative: Peptidoglycan layer of gram-negative cells is thin.
2. Classification based on shape

Figure 3 Different types of bacterial shape

Gram positive Cocci Bacteria

Staphylococci
1. Staphylococcus aureus
2. Staphylococcus epidermidis
3. Staphylococcus saprophyticus
Streptococci
1. Streptococcus agalactiae ( Neonatal Infections)
2. Streptococcus pneumoniae ( Pneumonia)
3. Streptococcus pyogenes ( Tonsillitis)

Gram positive Rods

Gram positive rods
1. Corynebacterium diphtheria (Diphtheria)
2. Listeria monocytogenes (Neonatal infections)

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 3. Clostridium difficile (Antibiotic associated colitis)
4. Clostridium tetani (Tetanus)

Gram negative cocci

1. Neisseria Gonorrhea (Gonorrhea)
2. Neisseria Meningitides (Meningitis)

Gastrointestinal Gram negative rods

1. Escherichia coli (Urinary Tract infection)
2. Helicobacter pylori (Gastritis)
3. Campylobacter jejuni (Diarrhea)

Normal Flora
Normal flora: Are harmless but beneficial bacteria that are found some parts of our body.
Where are the Normal Flora found
 Skin
 Conjunctiva
 Nasopharynx
 Oral cavity
 Gastrointestinal tract and rectum
 Urogenital tract
Beneficial functions of normal flora

1. They prevent colonization by pathogens by competing for attachment & nutrients.

2. Some synthesize vitamins that are absorbed as nutrients by the host (e.g. K & B12).
3. Some produce substances that inhibit pathogenic species.

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Penicillins
Beta-lactams
 Definition: a group of antibiotics that contains beta-lactam ring in their molecular
structure and includes penicillins, carbapenems, monobactams, and Cephalosporins

Figure 4 Structure of a beta lactam ring

Penicillins
The penicillins are among the most widely effective and the least toxic drugs known, but
increased resistance has limited their use.
Penicillins are bactericidal
Mechanism of action
Inhibit cell wall synthesis by blocking peptidoglycan crosslinking. They also inactivate proteins
on the bacterial cell wall involved in the synthesis of the cell wall and in the maintenance of the
morphologic features of the bacterium.

Natural penicillins
Examples
Penicillin G (benzyl penicillin)
 IV: crystalline penicillin G
 IM: procaine penicillin G, benzathine penicillin G

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Oral: penicillin V (phenoxymethylpenicillin)
Clinical use
 Pneumonia (Streptococcus pneumonia)
 Syphilis (Treponema pallidum)
 Meningitis (Neisseria meningitides)
 Tonsillitis (Streptococcus pyogens)

Penicillinase-resistant penicillins
Examples (oral or IV)

Nafcillin, Dicloxacillin, Oxacillin, Floxacillin, Methicillin

Special characteristics: Intrinsically β-lactamase resistant, which prevent bacterial β-
lactamase from hydrolyzing the β-lactam ring.
Clinical use: narrow spectrum, Gram-positive aerobes, especially S. aureus (non-MRSA)

Extended-spectrum penicillins
Examples
Amoxicillin

Ampicillin
Amoxicillin with clavulanic acid (Augmentin)
Ampicillin with Sulbactum
Clavulanate and Sulbactum prevent the destruction of the β-lactam ring by β-lactamase.
Clavulanic acid: Has no antimicrobial properties of its own.

Clinical use: broader spectrum of activity

Most effective against:
 H. pylori
 H. influenzae
 coli
 Listeria monocytogenes
 Salmonella
 Shigella

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Antipseudomonal penicillins
Examples
 IV piperacillin (combined with tazobactam)
 IV mezlocillin
 IV ticarcillin
 IV carbenicillin
Clinical use: extended spectrum but penicillinase-sensitive
Piperacillin is the most potent of these antibiotics.

Penicillin Resistance
Mechanism of Resistance
 Cleavage of the β-lactam ring by β-lactamases (penicillinases).
 Decreased penetration of the antibiotic through the outer cell membrane of the
bacteria.
 Penicillin binding protein mutations

Pharmacokinetics
CNS penetration
 Only when meninges are inflamed.
Route of elimination
 Primarily renal (via tubular secretion)

Exceptions
 Primarily biliary: Nafcillin
 Both renal and biliary: Oxacillin, dicloxacillin
Absorption
 Food decreases the absorption of all the penicillinase-resistant penicillins.
 They should be taken on an empty stomach.

Adverse reactions
Hypersensitivity, Diarrhea, Nephritis, Neurotoxicity

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Cephalosporins
Cephalosporins are β-lactam antibiotics that are closely related both structurally and
functionally to the penicillins.
Cephalosporins have the same mode of action as penicillins, and they are affected by the same
resistance mechanisms.
Cephalosporins have been classified as first, second, third, fourth and fifth generation based
largely on their bacterial susceptibility patterns and resistance to β-lactamases.
1. First generation
 The first-generation Cephalosporins act as penicillin G substitutes. They are resistant to
the staphylococcal penicillinase.
 First generation include
 Oral: Cephalexin
 IV or IM cefazolin
2. Second generation
Members of second generation Cephalosporins include
 Oral: cefaclor, cefuroxime
 IV: cefuroxime, cefoxitin, cefotetan
They have broader antimicrobial activity than first generation.
3. Third generation Cephalosporins
 Oral: cefixime, cefpodoxime
 IV: ceftriaxone, cefotaxime, ceftazidime
 IM: ceftriaxone
These Cephalosporins have assumed an important role in the treatment of infectious diseases.
4. Fourth generation Cephalosporins
 Cefepime: is fourth generation cephalosporin.
 Cefepime has a wide antibacterial activity.
5. Fifth generation Cephalosporins:
 Ceftaroline: is a fifth generation cephalosporin
 It is administered IV
 It is treated with complicated Infections.

Pharmacokinetics
Distribution
All Cephalosporins distribute very well into body fluids.

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Ceftriaxone specifically has good CNS penetrance: used to treat meningitis.
Elimination
Cephalosporins are excreted through the kidneys. Therefore doses must be adjusted in cases
renal dysfunction.
One exception is ceftriaxone, which is excreted through the bile into the feces and, therefore, is
frequently employed in patients with renal insufficiency.

Side effects
Hypersensitivity (patients with penicillin allergy should not receive Cephalosporins
Diarrhea
Nausea and vomiting
Abdominal discomfort

Other Beta lactam antibiotics

Carbapenems
Examples
 IV imipenem (combined with cilastatin)
 IV meropenem
 IV ertapenem
 IV doripenem
Clinical use
Last-resort drugs (used only in life-threatening infections or after other antibiotics have failed)
because of the significant adverse effects
Broad-spectrum antibiotics with intrinsic beta-lactamase resistance.
Adverse Effects
1. Secondary fungal infections
2. CNS toxicity: can lower seizure threshold at high serum concentrations
 Highest risk: Imipenem
 Lowest risk: Meropenem
3. Gastrointestinal upset
4. Rash

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 5. Thrombophlebitis

Monobactams
Examples:

 IV aztreonam
Clinical use
Effective against gram-negative bacteria only, including nosocomial Pseudomonas, H.
influenza, and N. meningitides.
Alternative for penicillin-allergic patients.
Broad-spectrum coverage in combination with vancomycin or clindamycin.
Adverse effects: rare
 GI upset
 Injection reactions
 Rash

Vancomycin
Clinical use:
Especially effective against multidrug-resistant organisms.
Is effective against a wide range of gram-positive bacteria only
MRSA

S. epidermidis
Enterococci (if not vancomycin resistant enterococci)
C. difficile (causing pseudomembranous colitis): administered orally
Adverse effects
Intravenous administration
 Nephrotoxicity
 Ototoxicity/vestibular toxicity
 Thrombophlebitis
 Red man syndrome: an anaphylactoid reaction caused by rapid infusion of vancomycin
 Nonspecific mast cell degranulation → rapid release of histamine.
Contraindications: Consider use in pregnant women only if the benefits outweigh the risks.

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Macrolides
These group include
Azithromycin, Clarithromycin, Erythromycin

Clinical Uses
Macrolides can be used to treat community acquired pneumonia, pertussis (whooping cough),
or uncomplicated skin infections.
Mechanism of action
They bind irreversibly to 50S ribosomal subunit of bacterial ribosome and inhibit protein
synthesis. Macrolides are bacteriostatic, but they may be bactericidal in higher doses.
Antibacterial spectrum
Erythromycin: This drug is effective against many of the same organisms as penicillin G
there for it is used in patients with penicillin allergy.
Clarithromycin: Clarithromycin has activity similar to erythromycin but it is also effective
against H.pylori
Azithromycin: is far more active against respiratory infections, Otitis media and soft
tissue infections. Azithromycin is the preferred therapy for urethritis caused by
Chlamydia trachomatis.
Administration:
Erythromycin is destroyed by gastric acid. Thus, either enteric-coated tablet forms are
administered or taken before food.

Clarithromycin, azithromycin are stable in stomach acid and are readily absorbed.
Food interferes with the absorption of erythromycin and azithromycin but can increase that of
clarithromycin.
Erythromycin and azithromycin are available in IV formulations.
Distribution
Erythromycin distributes well to all body fluids except the CSF.
Excretion
Erythromycin and azithromycin are primarily concentrated and excreted in the bile.
Clarithromycin and its metabolites are eliminated by the kidney as well as the liver.
Side effect: Gastric upset, Jaundice, Ototoxicity

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Contraindications
Erythromycin and clarithromycin accumulate in the liver so they should be cautiously treated in
patients with hepatic dysfunction.

Aminoglycosides
Examples
 IV or IM gentamicin
 IV or IM amikacin
 IV or IM tobramycin
 IV or IM streptomycin
 Oral neomycin
Streptomycin is active against Mycobacterium tuberculosis and is now almost entirely reserved
for tuberculosis.
Neomycin, which is not absorbed systemically, is administered orally to prepare the gut
for bowel surgery.

Mechanism of action
They bind the 30S ribosomal subunit were they inhibit protein synthesis.
Antibiotics that disrupt protein synthesis are generally bacteriostatic; however,
aminoglycosides are unique in that they are bactericidal.
Absorption
Aminoglycosides are not absorbed from the gut and must therefore be given by injection.
All aminoglycosides must be given parenterally except neomycin.

Neomycin is not given parenterally due to severe nephrotoxicity.

Elimination
Aminoglycosides are excreted from the kidney. And accumulation occurs in renal impairment.
Adverse effects
Ototoxity: Deafness may be irreversible and has been known to affect developing fetuses.

Nephrotoxicity
Allergic reactions

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Contraindications
Pregnancy
Cautious use in patients with renal dysfunction

Tetracyclines
Mechanism of action
These drugs bind reversibly to 30S subunit of bacterial ribosome and inhibit bacterial protein
synthesis.

Antibacterial spectrum
Tetracyclines are bacteriostatic antibiotic effective against many bacteria and treat conditions
such as acne, urinary tract infections, and intestinal tract infections.
Tetracyclines are broad spectrum antibiotics whose value has decreased owing to increased
bacterial resistance.

Tetracyclines contain well known drugs such as

 Doxycycline
 Tetracycline
 Minocycline
 Demeclocycline

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Resistance
The most commonly encountered naturally occurring resistance to Tetracyclines is an efflux
pump that expels drug out of the cell.
Absorption
Tetracycline should be taken on an empty stomach.
Administration with dairy products or other substances such as magnesium and aluminum
antacids or iron supplements decreases absorption particularly tetracycline.
Distribution
Tetracyclines concentrate well in the bile, liver, kidney, gingival fluid, and skin. Moreover, they
bind to tissues undergoing calcification (for example, teeth and bones).
Only minocycline and doxycycline achieve in the cerebrospinal fluid.
All Tetracyclines cross the placenta and concentrate in fetal bones and dentition.
Elimination
Tetracycline and minocycline are excreted from the kidneys, doxycycline is excreted via the bile
into the feces.

Side effects
 Gastric discomfort
 Deposition in bones and teeth → inhibition of bone growth (in children)
and discoloration of teeth.
 Hepatotoxicity
 Photo toxicity
 Dizziness, vertigo and tinnitus
Contraindications
 Children < 8 years of age (except doxycycline)
 Pregnant women
 Breastfeeding women
 Patients with renal failure (except doxycycline)

Fluoroquinolones
Examples
1st generation: nalidixic acid (oral)

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2nd generation: norfloxacin, ciprofloxacin, ofloxacin (oral)
3rd generation: levofloxacin (oral or IV)
4th generation: moxifloxacin, gemifloxacin, gatifloxacin (oral)

Levofloxacin, moxifloxacin, and gemifloxacin are respiratory fluoroquinolones.

Mechanism of action: inhibition of topoisomerase II (DNA gyrase) and topoisomerase IV→ DNA
supercoiling → formation of double-stranded breaks → inhibition of DNA replication and
transcription.
Fluoroquinolones are bactericidal
Antimicrobial spectrum
Fluoroquinolones are effective against gram-negative organisms (Escherichia coli, P.
Aeruginosa, Hemophilus influenza), atypical organisms (Legionella, Chlamydia), gram-positive
organisms (streptococci), and some mycobacteria (Mycobacterium tuberculosis).
Nalidixic acid
Nalidixic acid is first generation quinolone, it is not fluorinated and is excreted too rapidly.
Because their relatively weak antibacterial activity these agents were useful only for the
treatment of urinary tract infections and shigellosis.

Ciprofloxacin
Ciprofloxacin is effective in the treatment of many systemic infections.
Travelers diarrhea caused by E.coli as well as typhoid fever caused by Salmonella can be
effectively treated with ciprofloxacin.
Ciprofloxacin is used in the treatment urinary tract infections.
Ciprofloxacin is also used as a second-line agent in the treatment of tuberculosis.
Levofloxacin
Due to its broad spectrum of activity, levofloxacin is utilized in a wide range of infections,
including prostatitis, skin infections, Community acquired pneumonia, and nosocomial (Hospital
acquired) pneumonia.
Unlike ciprofloxacin, Levofloxacin has excellent activity against S. Pneumonia respiratory
infections.

Pharmacokinetics
Fluoroquinolones are well absorbed and distributed widely in body fluids and tissues.

26
Oral absorption is impaired by taking with anti-acids. Penetration into cerebrospinal fluid is
relatively low except for ofloxacin. Fluoroquinolones are excreted in the kidney except
Moxifloxacin.
Adverse effects
Nausea
Vomiting

Diarrhea
Headache, dizziness or light headedness may occur.
Arthropathy: In children: potential damage to growing cartilage → reversible arthropathy.
Muscle ache, leg cramps, tendinitis, tendon rupture, especially of the Achilles tendon (the risk
of tendon rupture is higher for individuals over 60 years of age.
Contraindications
 Children and teenagers < 18 years of age
 Patients > 60 years of age and those taking cortisol.
 Pregnant women
 Breastfeeding women

Antimicobacterial Drugs

First-Line Antimicobacterial Drugs: Isoniazid (INH), rifampin, pyrazinamide, ethambutol, and

streptomycin are the five first-line agents for treatment of tuberculosis. INH and rifampin are
the two most active drugs.

27
Isoniazid (INH)
INH is the most active drug for the treatment of tuberculosis caused by susceptible strains.
It is bactericidal for actively growing tubercle bacilli. INH inhibits synthesis of mycolic acids,
which are essential components of mycobacterial cell walls. INH is readily absorbed from the
gastrointestinal tract, and it diffuses readily into all body fluids and tissues. INH is excreted from
the kidney.
Side effects:
Hepatitis is the most serious adverse effect associated with isoniazid.
Peripheral neuropathy (manifesting as paresthesia of the hands and feet) appears to be due to
a relative pyridoxine deficiency. This can be avoided by supplementation of 25 to 50 mg per day
of pyridoxine (vitamin B6).

Rifampin
Mechanism of action:
Rifampin blocks RNA transcription by interacting with the βsubunit of mycobacterial DNA-
dependent RNA polymerase. Rifampin is bactericidal for both intracellular and extracellular
mycobacteria.
It is effective against many gram-positive and gram-negative organisms and is used
prophylactically for individuals exposed to meningitis caused by meningococci or Hemophilus
influenza. Rifampin also is highly active against M. leprae.
Absorption is adequate after oral administration. Distribution of rifampin occurs to all body
fluids and organs.
Elimination of rifampin and its metabolites is primarily through the bile and into the feces; a
small percentage is cleared in the urine. Urine, feces, and other secretions have an orange-red
color, so patients should be forewarned.
Adverse effects: most common adverse reactions include: Nausea, Vomiting, and Rash.
Ethambutol
Ethambutol is bacteriostatic and specific for mycobacteria.
Ethambutol inhibits arabinosyl transferase—an enzyme important for the synthesis of the
mycobacterial cell wall.
Ethambutol is well absorbed from the gut.

Ethambutol crosses the blood-brain barrier only if the meninges are inflamed.

28
The most important adverse effect is optic neuritis, which results in diminished visual acuity
and loss of ability to discriminate between red and green.
Pyrazinamide
The drug is taken up by macrophages and kills bacilli residing within this acidic environment.
PZA is well absorbed from the gastrointestinal tract and widely distributed in body tissues,
including inflamed meninges.
Major adverse effects of pyrazinamide include hepatotoxicity, nausea, vomiting, drug fever, and
hyperuricemia. Hyperuricemia may provoke acute gouty arthritis.

Second line ant tubercular drugs

Second-line ant tubercular drugs include ethionamide, para-aminosalicylic acid, capreomycin,
cycloserine, amikacin, ciprofloxacin. These agents are less effective and more toxic than the
first-line agents.

Drugs used in Leprosy

Leprosy is caused by mycobacterium leprae. I t can be treated with dapsone, rifampin,
clofazimine, ethionamide. Because of increasing reports of dapsone resistance, treatment of
leprosy with combinations of the drugs is recommended.

Dapsone
Dapsone is structurally related to the sulfonamides and similarly inhibits dihydropteroate
synthetase in the folate synthesis pathway. It is bacteriostatic for M. leprae. The drug is well
absorbed from the gastrointestinal tract and is distributed throughout the body.

Clofazimine
Clofazimine is a phenazine dye. Its mechanism of action may involve binding to DNA.
Clofazimine is bactericidal to M. leprae, and it has potentially useful activity against M.
tuberculosis. The absorption of Clofazimine from the gut is variable, and a major portion of the
drug is excreted in feces. Clofazimine is given for sulfone -resistant leprosy or when patients are
intolerant to sulfone.

Sulfonamides
Examples
Oral or IV Cotrimoxazole (TMP/SMX)
Oral sulfadiazine in combination with pyrimethamine.

29
Oral sulfisoxazole
Mechanism of action
Microorganisms require extracellular para-amino benzoic acid (PABA) to form dihydrofolic
acid, an essential step in the production of nucleic acids. Sulfonamides are bacteriostatic.
Pharmacokinetics
They are absorbed from the stomach and small intestine and distributed widely to tissues and
body fluids, placenta, and fetus. Sulfonamides are excreted from the kidney.
Clinical Use
Treatment for simple UTI
Prophylaxis and treatment of P. jirovecii
Prophylaxis of toxoplasmosis

Trimethoprim
Trimethoprim inhibits bacterial dihydrofolic acid reductase. Dihydrofolic acid reductases
convert dihydrofolic acid to tetrahydro folic acid, a stage leading to the synthesis of purines and
ultimately to DNA. Trimethoprim is usually given orally. It is absorbed well from the gut and
distributed widely in body fluids and tissues, including cerebrospinal fluid.
Trimethoprim produces the predictable adverse effects of an antifolate drug, especially
megaloblastic anemia, leukopenia, and granulocytopenia.

Trimethoprim-Sulfamethoxazole (Cotrimoxazole)
Trimethoprim, given together with sulfamethoxazole results in marked enhancement of the
activity of both drugs. The combination often is bactericidal, compared to the bacteriostatic
activity of a sulfonamide alone.
Adverse effects
Fever, Hypersensitivity reactions, Kernicterus in infancy, Megaloblastic anemia
Contraindications
Children < 2 years of age, pregnant women, Breastfeeding women.

30
Antifungal Drugs

Figure 5 membrane structure of a fungus

Over view
Fungi are unique and diverse organisms. Unlike bacteria, fungi are eukaryotic, with rigid cell
walls composed largely of chitin rather than peptidoglycan. In addition, the fungal cell
membrane contains ergo sterol rather than the cholesterol found in mammalian membranes.
Fungal infections are generally resistant to antibiotics, and, conversely, bacteria are resistant to
antifungal agents. Infectious diseases caused by fungi are called mycoses, and they are often
chronic in nature.
Mycotic infections may be superficial and involve only the skin (cutaneous mycoses extending
into the epidermis), while others may penetrate the skin, causing subcutaneous or systemic
infections.

Drugs for subcutaneous and systemic mycotic infections

Amphotericin B
In spite of its toxic potential, amphotericin B remains the drug of choice for the treatment of
several life-threatening mycoses.
Mechanism of action

31
Amphotericin B binds to ergosterol in the plasma membranes of sensitive fungal cells. There it
forms pores, allowing electrolytes (particularly potassium) and small molecules to leak from the
cell, resulting in cell death.
Pharmacokinetics:
Amphotericin B is administered by slow, intravenous (IV) infusion.
Amphotericin B is insoluble in water and must be coformulated with either sodium
deoxycholate (conventional) or a variety of artificial lipids to form liposomes.
The liposomal preparations have the primary advantage of reduced renal and infusion toxicity.
However, due to high cost, liposomal preparations are reserved mainly as salvage therapy for
patients who cannot tolerate conventional amphotericin B.
Elimination: Amphotericin B is excreted from Kidney.

Adverse effects:
 Amphotericin B has a low therapeutic index.
 Fever and chills
 Renal impairment
 Hypotension
 Thrombophlebitis

Flucytosine
This drug is often administered with amphotericin B. This combination of drugs is administered
for the treatment of systemic mycoses and for meningitis caused by C. neoformans and C.
albicans.
Mechanism of action
Disrupt nucleic acid and protein synthesis
Pharmacokinetics
Flucytosine is well absorbed by the oral route.
It distributes throughout the body water and penetrates well into the CSF. This drug is
eliminated in the kidney.
Adverse effects
 Reversible neutropenia (Low neutrophils)
 Thrombocytopenia (low platelet)
 Dose-related bone marrow depression.
 Gastrointestinal disturbances

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Azole antifungals
Azole antifungals are made up of two different classes of drugs
 Imidazoles (topical, oral)
 Triazoles (oral, IV)
Imidazoles are given topically for cutaneous infections, whereas triazoles are given systemically
for the treatment or prophylaxis of cutaneous and systemic fungal infections.
Imidazole Derivatives

Clotrimazole, Miconazole
Clinical use: Vaginal candidiasis, Tinea infections, Oropharyngeal candidiasis.
Ketoconazole:
Clinical use: Tinea versicolor
Triazole Derivatives:

Fluconazole
Clinical use: Cryptococcal meningitis, Candidiasis (all forms)
Itraconazole
Dermatophytosis (e.g., onychomycosis) and Oropharyngeal/esophageal candidiasis.
Mechanism of action
They inhibit ergosterol biosynthesis disrupting membrane structure and function, which, in
turn, inhibits fungal cell growth.
Azoles are predominantly fungistatic.
Drug interactions
Concomitant use of potent CYP450 inhibitors (for example, ritonavir) and inducers (for
example, rifampin) can lead to increased adverse effects or clinical failure of these azoles,
respectively.
Contraindications: they should be avoided in pregnancy
Side effects

Topical use: Local burning sensation, pruritus

Systemic use:
 Hepatotoxicity

33
  Gynecomastia (Ketoconazole)
 Hypokalemia (ketoconazole and itraconazole)

Drugs for cutaneous mycotic Infections

Terbinafine (oral, Topical)
Oral terbinafine is the drug of choice for treating dermatophyte onychomycoses (fungal
infections of nails).
Oral terbinafine may also be used for tinea capitis (infection of the scalp).
Topical terbinafine (1% cream, gel or solution) is used to treat tinea pedis, tinea corporis
(ringworm), and tinea cruris (infection of the groin). Duration of treatment is usually 1 week.
Mechanism of action
Blocks biosynthesis of ergosterol
Adverse effects
Gastrointestinal disturbances (diarrhea, dyspepsia, and nausea), headache and rash.

Contraindications
Pregnancy
Breast feeding
Renal impairment

Graseofulvin
Mechanism of action: Graseofulvin causes disruption of the mitotic spindle and inhibition of
fungal mitosis.
It has been largely replaced by oral terbinafine for the treatment of onychomycosis, although it
is still used for dermatophytosis of the scalp and hair.
Graseofulvin is fungi static and requires a long duration of treatment (for example, 6 to 12
months for onychomycosis).
The use of Graseofulvin is contraindicated in pregnancy.

Nystatin
Structure, chemistry, mechanism of action, and resistance profile resemble those of
amphotericin B.
It is used for the treatment of cutaneous and oral Candida infections.

34
The drug is negligibly absorbed from the gastrointestinal tract, and it is not used parenterally
due to systemic toxicity (acute infusion-related adverse effects and nephrotoxicity).
It is administered as an oral agent (“swish and swallow” or “swish and spit”) for the treatment
of oropharyngeal candidiasis (thrush), intravaginally for vulvovaginal candidiasis, or topically for
cutaneous candidiasis.

Antiprotozoal Drugs
Drugs for Amebiasis
Amebiasis (also called amebic dysentery) is an infection of the intestinal tract caused by
Entamoeba histolytica.
Therapeutic agents for Amebiasis are classified as luminal, systemic, or mixed amebicides
according to the site of action
Luminal amebicides act on the parasite in the lumen of the bowel.

Systemic amebicides are effective against amebas in the intestinal wall and liver.
Mixed amebicides are effective against both the luminal and systemic forms

35
A. Mixed amebicides
Metronidazole
Is the mixed amebicides of choice for treating amebic infections?
Metronidazole is also used in the treatment of infections caused by Giardia lamblia,
Trichomonas vaginalis, anaerobic cocci, and anaerobic gram-negative bacilli.

Mechanism of action
The nitro group of metronidazole forms cytotoxic compounds that bind to proteins and DNA,
resulting in death of the E. histolyticatrophozoites.
Pharmacokinetics
Metronidazole is completely and rapidly absorbed after oral administration.
B. Luminal amebicides

Iodoquinol:
Is amebicides against E. Histolytica and is effective against the luminal trophozoite and cyst
forms.
Adverse effects: Rash, diarrhea, and dose-related peripheral neuropathy.
Paromomycin
Paromomycin, an aminoglycoside antibiotic, is only effective against the intestinal (luminal)
forms of E. histolytica.
Side effects: Gastrointestinal distress and diarrhea are the principal adverse effects.
C. Systemic amebicides

Chloroquine:
Is used in combination with metronidazole to treat amebic liver abscesses.
It eliminates trophozoite in liver abscesses. Chloroquine is also effective in the treatment of
malaria.

Drugs for Malaria

Malaria is an acute infectious disease caused by four species of the protozoal genus
Plasmodium. It is transmitted to humans through the bite of a female Anopheles mosquito.
Plasmodium falciparum is the most dangerous species, causing an acute, rapidly fulminating
disease that is characterized by persistent high fever, orthostatic hypotension.

36
Figure 6 Life cycle of the malarial parasite, Plasmodium falciparum, showing the sites of
action of antimalarial drugs.

Primaquine
Is an oral antimalarial drug that eradicates primary exoerythrocytic (tissue) forms of plasmodia
and the secondary exoerythrocytic forms of recurring malarias (P. vivax and P. ovale).
Primaquine is the only agent that prevents relapses of the P. vivax and P. ovale malarias.

Pharmacokinetics
Primaquine is well absorbed after oral administration and is not concentrated in tissues
The drug is minimally excreted in the urine.
Adverse effects
Primaquine is associated with drug-induced hemolytic anemia, large doses of the drug may
cause abdominal discomfort. Primaquine should not be used during pregnancy.
Chloroquine

37
Chloroquine has been the mainstay of antimalarial therapy, and it is the drug of choice in the
treatment of erythrocytic P. falciparum malaria, except in resistant strains. Chloroquine is less
effective against P. vivax malaria. Chloroquine is used in the prophylaxis of malaria for travel to
areas with known chloroquine-sensitive malaria. It is also effective in the treatment of extra
intestinal Amebiasis.

Mechanism of action
Chloroquine is concentrated in the acidic food vacuole of the malarial parasite. In the food
vacuole, the parasite digests the host cell’s hemoglobin to obtain essential amino acids. This
process also releases large amounts of soluble heme, which is toxic to the parasite.
Chloroquine is rapidly and completely absorbed following oral administration. The drug is well
distributed to body tissues. The drug also penetrates the central nervous system (CNS) and
traverses the placenta. The drug is excreted in the urine.
Adverse effects
At higher doses, gastrointestinal upset, pruritus, headaches, and blurred vision may occur.
Chloroquine should be used cautiously in patients with hepatic dysfunction, severe
gastrointestinal problems, or neurologic disorders. Resistance: Resistance has become a serious
medical problem throughout Africa, Asia, and most areas of Central and South America.
Atovaquone–proguanil
The combination of atovaquone–proguanil is effective for chloroquine-resistant strains of P.
falciparum. It is used in the prevention and treatment of malaria. Atovaquone inhibits
mitochondrial processes such as electron transport, as well as ATP and pyrimidine biosynthesis.
The combination should be taken with food or milk to enhance absorption. Common adverse
effects include nausea, vomiting, abdominal pain, headache, diarrhea, anorexia, and dizziness.
Mefloquine
Mefloquine is an effective single agent for prophylaxis and treatment of infections caused by
multidrug-resistant forms of P. falciparum. Mefloquine is well absorbed after oral
administration and is widely distributed to tissues. The drug undergoes extensive metabolism
and is primarily excreted via the bile into the feces.
Adverse reactions at high doses range from nausea, vomiting, and dizziness to disorientation,
hallucinations, and depression. ECG abnormalities and cardiac arrest are possible if Mefloquine
is taken concurrently with quinine or quinidine.
Quinine
Quinine originally isolated from the bark of the cinchona tree, interferes with heme
polymerization, resulting in death of the erythrocytic form of the plasmodia parasite.

38
It is reserved for severe infestations and for chloroquine-resistant malarial strains. Quinine is
usually administered in combination with doxycycline, tetracycline, or clindamycin. Taken
orally, quinine is well distributed throughout the body. The major adverse effect of quinine are
nausea, vomiting, tinnitus, and vertigo. Quinine treatment should be suspended if hemolytic
anemia occurs. Quinine absorption is reduced by aluminum-containing Antacids.

Artemisinin
Artemisinin, and its derivatives are recommended first-line agents for the treatment of
multidrug-resistant P. falciparum malaria. To prevent the development of resistance, these
agents should not be used alone. Oral, rectal, and intravenous (IV) preparations are available,
but the short half-lives preclude the use of these drugs for prophylaxis
Adverse effects include nausea, vomiting, and diarrhea. High doses may cause prolongation of
the QT interval. Hypersensitivity reactions and rash have occurred.
Pyrimethamine
Pyrimethamine inhibits plasmodial dihydrofolate reductase required for the synthesis of
tetrahydrofolate. It acts as a blood schizonticide and a strong sporonticide when the mosquito
ingests it with the blood of the human host. Pyrimethamine is not used alone for P. falciparum;
it is available as a fixed-dose combination with sulfadoxine. Resistance to this combination has
developed, so it is usually administered with other agents, such as artemisinin derivatives.

Artemether/Lumefantrine
Treatment of uncomplicated falciparum malaria.
Treatment of uncomplicated malaria due to other Plasmodium species, when chloroquine
cannot be used.
Pregnancy: no contra-indication
Breast-feeding: no contra-indication
Taken with meals or fat containing foods such as milk.

39
Chemotherapy for Giardiasis
Giardia lamblia is an intestinal parasite. The treatment of choice is oral metronidazole 500mg
twice daily for 7 days. An alternative is Tinidazole, which is as effective as metronidazole in the
treatment of giardiasis.

Anthelmintic Drugs
Over-view
Nematodes, trematodes, and cestodes are three major groups of helminths (worms) that infect
humans. Anthelmintic drugs are aimed at metabolic targets that are present in the parasite but
either are absent from or have different characteristics than those of the host.

Trematodes Cestodes

Nematodes

Drugs for the treatment of nematodes

Nematodes are elongated roundworms that possess a complete digestive system. They cause
infections of the intestine as well as the blood and tissues.

40
Mebendazole
Mebendazole: Is a first-line agent for the treatment of infections caused by whipworms
(Trichuris trichiura), pinworms (Enterobius vermicularis), hookworms (Necator americanus and
Ancylostoma duodenale), and roundworms (Ascaris lumbricoides).
Mechanism of Action
Mebendazole acts by inhibiting the assembly of the microtubules in the parasite and also by
irreversibly blocking glucose uptake. Affected parasites are expelled in the feces.
Adverse effects: Abdominal pain and Diarrhea

Contraindications: pregnancy
Pyrantel pamoate
Pyrantel pamoate is also effective in the treatment of infections caused by roundworms,
pinworms, and hookworms. Pyrantel pamoate is poorly absorbed orally and exerts its effects in
the intestinal tract.
Mechanism of action
It acts as a depolarizing, neuromuscular-blocking agent, causing release of acetylcholine and
inhibition of cholinesterase, leading to paralysis of the worm. The paralyzed worm releases its
hold on the intestinal tract and is expelled.
Thiabendazole
Thiabendazole is a potent broad-spectrum anthelmintic agent. Current use of Thiabendazole is
limited to the topical treatment of cutaneous larva migrans.

Figure 7 cutaneous Larva Migrans

41
Ivermectin
Ivermectin is the drug of choice for the treatment of cutaneous larva migrans, strongyloidiasis,
and onchocerciasis (river blindness) caused by Onchocerca volvulus (kills microfilariae but has
no activity against adult worms). Ivermectin is also useful in the treatment of pediculosis (lice)
and scabies.
Mechanism of Action
Results death of the worm
Side effects: The killing of the microfilaria in onchocerciasis can result in a dangerous Mazzotti
reaction (fever, headache, dizziness, somnolence, and hypotension).
Contraindications: Pregnancy

Diethylcarbamazine
Diethylcarbamazine is the drug of choice for filariasis. It kills the microfilariae and has activity
against adult worms. Diethylcarbamazine is rapidly absorbed following oral administration with
meals and is excreted mainly in the urine.
Adverse effects: fever, nausea, vomiting, arthralgia, and headache. Diethylcarbamazine can
accelerate blindness and cause severe Mazzotti reactions in patients with onchocerciasis. It
should be avoided in patients with this disorder.

Drugs for the treatment of trematodes

The trematodes (flukes) are leaf-shaped flatworms that are generally characterized by the
tissues they infect (for example, liver, lung, intestinal, or blood.
Praziquantel
Praziquantel is an agent of choice for the treatment of all forms of schistosomiasis, other
trematode infections, and cestodes infections such as taeniasis.
Mechanism of action: Permeability of the cell membrane to calcium is increased, causing
contracture and paralysis of the parasite.
Praziquantel should be taken with food and not chewed due to a bitter taste. It is rapidly
absorbed after oral administration and distributes into the cerebrospinal fluid (CSF). The drug is
extensively metabolized, and the inactive metabolites are excreted primarily in the urine.
Adverse effects: Dizziness, malaise, and headache as well as gastrointestinal upset.
Drug interactions: Dexamethasone, phenytoin, rifampin, and carbamazepine may increase the
metabolism of Praziquantel. Cimetidine causes increased Praziquantel levels.

42
Praziquantel is contraindicated for the treatment of ocular cysticercosis, because destruction of
the organism in the eye may cause irreversible damage.

Drugs for the treatment of cestodes

The cestodes, or “true tapeworms,” typically have a flat, segmented body and attach to the
host’s intestine. Like the trematodes, the tapeworms lack a mouth and a digestive tract
throughout their life cycle.
Albendazole
Albendazole inhibits microtubule synthesis and glucose uptake in nematodes and is effective
against most nematodes known. Its primary therapeutic application, however, is in the
treatment of cestodal infestations, such as cysticercosis and hydatid disease (caused by larval
stage of Echinococcus granulosus). Albendazole is erratically absorbed after oral administration,
but absorption is enhanced by a high-fat meal. The drug distributes widely, including the CSF.
Albendazole and its metabolites are primarily excreted in the bile.
Adverse effects
When used in short-course therapy (1 to 3 days) for nematodal infestations, adverse effects are
mild and transient and include headache and nausea. Treatment of hydatid disease (3 months)
has a risk of hepatotoxicity and, rarely, agranulocytosis or pancytopenia.

Antiviral Drugs
Over view
Viruses are obligate intracellular parasites. They lack both a cell wall and a cell membrane, and
they do not carry out metabolic processes. Viruses use much of the host’s metabolic machinery,
and few drugs are selective enough to prevent viral replication without injury to the infected
host cells. Therapy for viral diseases is further complicated by the fact that the clinical
symptoms appear late in the course of the disease, at a time when most of the virus particles
have replicated. To assist in the review of these drugs, they are grouped according to the type
of infection they target.

Treatment of hepatic viral infections

The hepatitis viruses thus far identified (A, B, C, D, and E) each have a pathogenesis specifically
involving replication in and destruction of hepatocytes. Of this group, hepatitis B (a DNA virus)
and hepatitis C (an RNA virus) are the most common causes of chronic hepatitis, cirrhosis, and
hepatocellular carcinoma.

43
Interferons
Interferons are a family of naturally occurring, inducible glycoproteins that interfere with the
ability of viruses to infect cells.
Mechanism of action
The antiviral mechanism is incompletely understood. It appears to involve the induction of host
cell enzymes that inhibit viral RNA translation, ultimately leading to the degradation of viral
mRNA and tRNA.
Pharmacokinetics
Interferon is not active orally, but it may be administered intralesionally, subcutaneously, or
intravenously.

Adverse effects
Flu-like symptoms, such as fever, chills, myalgia, arthralgia, and GI disturbances. Fatigue and
mental depression are common. The principal dose-limiting toxicities are bone marrow
suppression.
Entecavir
It competes with the natural substrate, deoxyguanosine triphosphate, for viral RT. The drug is
primarily excreted unchanged in the urine and dosage adjustments are needed in renal
dysfunction. Entecavir is administered orally.
Lamivudine, Adefovir, and Telbivudine is also used. Boceprevir and telaprevir, are oral
antiviral agents for HCV.

Treatment of herpes Infections

Herpes viruses are associated with a broad spectrum of diseases, for example, cold sores, viral
encephalitis, and genital infections.
Acyclovir
Acyclovir anti-herpetic therapeutic agent. Herpes simplex virus (HSV) types 1 and 2,varicella-
zoster virus (VZV), and some Epstein-Barr virus–mediated infections are sensitive to acyclovir.

It is the treatment of choice in HSV encephalitis.

Mechanism of action
Acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA
polymerase and is itself incorporated into the viral DNA, causing premature DNA chain
termination.

44
Pharmacokinetics
Acyclovir is administered by intravenous (IV), oral, or topical routes. The drug distributes well
throughout the body, including the cerebrospinal fluid (CSF). It is excreted from the kidney.
Adverse effects
Headache, Diarrhea, Nausea, and vomiting. Local irritation may occur from topical application

Foscarnet
Foscarnet is approved for CMV retinitis in immunocompromised hosts and for acyclovir-
resistant HSV infections.
Adverse effects include nephrotoxicity, anemia, nausea, and fever.
Ganciclovir
Ganciclovir is an analog of acyclovir that has greater activity against CMV. It has same
mechanism of action as acyclovir. Ganciclovir is administered IV and distributes throughout the
body, including the CSF. Excretion into the urine occurs through glomerular filtration and
tubular secretion. Adverse effects: include severe, dose- dependent neutropenia. Ganciclovir is
contraindicated in pregnancy.

Treatment of HIV infection

Figure 8 Life cycle of HIV

45
Today, the viral life cycle is understood, and a combination of drugs is used to suppress replication of
HIV and restore the number of CD4 cells and immunocompetence to the host. This multidrug regimen is
commonly referred to as “highly active antiretroviral therapy,” or HAART.

These classes of drugs are nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs),
nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry
inhibitors, and the integrase inhibitors.
The preferred initial therapy is a combination of two NRTIs with a PI, an NNRTI, or an integrase
inhibitor.
NRTIS

Examples
Zidovudine (AZT), Stavudine (d4T), Didanosine (ddI), Tenofovir (TDF), Lamivudine (3TC),
Abacavir (ABC)
Mechanism of action:
They all terminate DNA chain elongation.
Pharmacokinetics
The NRTIs are primarily renally excreted, require dosage adjustment in renal insufficiency
except abacavir.

Adverse effects: Peripheral neuropathy, Pancreatitis, Lipoatrophy

NNRTI used to treat HIV Infection
Examples
Nevirapine ( NVP), Delavirdine (DLV), Efavirenz (EFV), Etravirine (ETR), Rilpivirine (RPV)
Mechanism of Action

They bind to HIV RT and cause conformational change that results an enzyme inhibition.
Protease inhibitors used to treat HIV Infection
Examples
All of the drugs in this group are reversible inhibitors of the HIV aspartyl protease, which is the
viral enzyme responsible for cleavage of the viral polyprotein into a number of essential
enzymes (RT, protease, and integrase) and several structural proteins. The inhibition prevents
maturation of the viral particles and results in the production of noninfectious virions.
Metabolism is extensive, and very little of the PIs are excreted unchanged in urine. Dosage
adjustments are unnecessary in renal impairment.

46
Adverse effects
PIs commonly cause nausea, vomiting, and diarrhea. Diabetes, hypertriglyceridemia, and
hypercholesterolemia also occur. Chronic administration results in fat redistribution, including
loss of fat from the extremities, fat accumulation in the abdomen and the base of the neck
(“buffalo hump”;

Figure 9 Buffalo hump

Drug interactions
Drug interactions are a common problem for all Pis.
Examples of potentially dangerous interactions from drugs that are contraindicated with PIs
include. Simvastatin or lovastatin, Midazolam or triazolam, and fentanyl.
Entry Inhibitors used to treat HIV Infection

Enfuvirtide
It is taken subcutaneously. Most of the adverse effects are related to the injection, including
pain, erythema, induration, and nodules, which occur in almost all patients. Enfuvirtide binds to
gp41.
Maraviroc
Because it is well absorbed orally, it is formulated as an oral tablet. Maraviroc blocks the CCR5
coreceptor.

47
Integrase Inhibitors used to treat HIV Infection
Examples
Raltegravir, Elvitegravir, Dolutegravir
Mechanism of action: The integrase strand transfer inhibitors (INSTIs), often called integrase
inhibitors, work by inhibiting the insertion of proviral DNA into the host cell genome. The INSTIs
are generally well tolerated, with nausea and diarrhea being the most commonly reported
adverse effects.

Study Questions

1. Isoniazid is a primary antitubercular agent that

a) Requires pyridoxine supplementation
b) May discolor the tears, saliva, urine or feces orange-red
c) May be ototoxic and nephrotoxic
d) Should never be used due to hepatotoxic potential
2. The mechanism of antibacterial action of tetracycline involves
a) Binding to a component of the 30S ribosomal subunit
b) Inhibition of DNA synthesis
c) Inhibition of bacterial cell wall synthesis
d) None of the above
DIRECTIONS: For each numbered item select the ONE lettered option that is most
closely associated with it. Each lettered option may be selected once, more than once,
or not at all.
A. Penicillin G
B. Trimethoprim
C. Vancomycin
D. Gentamicin
E. Ciprofloxacin

3. inhibitor of bacterial DNA gyrase ____________

4. B-lactam antibiotic inhibitor of cell wall synthesis ____________
5. An inhibitor of microbial protein synthesis which acts on the 30S subunit of the
ribosome _____
6. A non- B-lactam antibiotic inhibitor of cell wall synthesis___________
7. The antiviral drug zidovudine (AZT):
a) inhibits reverse transcriptase
b) inhibits DNA polymerase activity

48
 c) inhibits HIV protease
d) A and C
e) none of the above
DIRECTIONS: For each numbered item, select ONE lettered option that is MOST CLOSELY
associated with it. Each lettered option may be selected once, more than once, or not at all.
A. Zidovudine
B. Ganciclovir
C. Acyclovir
8. Treatment for infections caused by Herpes Simplex I & II ________________
9. Nucleoside reverse transcriptase inhibitor ___________________
10. Which one of the following antibiotics is bacteriostatic?
a) Erythromycin
b) Gentamicin
c) Cefradin
d) Ampicillin
11. Bactericidal effect means
a) Inhibition of bacterial cell division
b) Inhibition of young bacterial cell growth
c) Destroying of bacterial cells
d) Formation of bacterial L-form
12. Which of the following groups of antibiotics demonstrates a bactericidal effect?
a) Tetracyclines
b) Macrolides
c) Penicillins
d) All of the above
13. Bacteriostatic effect means
a) killing of bacterial cells
b) Inhibition of bacterial cell division
c) Both A&B are correct
d) none of the above
14. Which of the following antibiotics contains a beta-lactam ring in their chemical
structure:
a) Penicillins
b) Cephalosporins
c) Carbapenems and monobactams
d) All groups
15. Which of the following drugs belongs to a Macrolide?
a) Neomycin
b) Doxycycline
c) Erythromycin

49
CHAPTER THREE: CARDIOVASCULAR DRUGS

Antihypertensive Drugs
Over view
Hypertension is defined as either a sustained systolic blood pressure of greater than 140 mm
Hg or a sustained diastolic blood pressure of greater than 90 mm Hg.
Blood pressure= peripheral vascular resistance and Cardiac out put.
Cardiac output= Stroke volume X Heart rate

β-Blockers
Examples

Atenolol (Oral)

Propranolol ( Oral, IV)

Carvedilol (Oral)

Metoprolol (oral, IV)

Nebivolol ( Oral)

Esmolol ( oral, IV)

β-Blockers are a treatment option for hypertensive patients with concomitant heart disease or
heart failure.
Mechanism of Action
The β-blockers reduce blood pressure primarily by decreasing cardiac output.
They may also decrease sympathetic outflow from the central nervous system (CNS) and inhibit
the release of renin from the kidneys, thus decreasing the formation of angiotensin II and the
secretion of aldosterone.
Adverse Effects
Bradycardia, Hypotension, Fatigue, Insomnia, Sexual dysfunction

50
Contraindications
The nonselective β-blockers, such as propranolol and nadolol, are contraindicated in patients
with asthma due to their blockade of β2.
Heart block
Acute Heart failure

ACE-Inhibitors
ACE inhibitors: Captopril, Enalapril, Lisinopril, Ramipril, Fosinopril.

Figure 10 Renin Angiotensin Aldosterone System (RAAS)

Mechanism of Action
The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance. These drugs
block the enzyme ACE which cleaves angiotensin I to form the potent vasoconstrictor
angiotensin II.
By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of
aldosterone, resulting in decreased sodium and water retention.
Pharmacokinetics
All of the ACE inhibitors are orally bioavailable. All but captopril and Lisinopril undergo hepatic
conversion to active metabolites, so these agents may be preferred in patients with severe
hepatic impairment. Enalaprilat is the only drug in this class available intravenously.
Adverse effects
Dry cough, Rash, Hyperkalemia, Hypotension
Angioedema is a rare but potentially life-threatening reaction that may also be due to increased
levels of bradykinin.

51
The dry cough, which occurs in up to 10% of patients, is thought to be due to increased levels of
bradykinin and substance P in the pulmonary tree and resolves within a few days of
discontinuation.

Figure 11 Angio Edema

Contraindications
ACE inhibitors can induce fetal malformations and should not be used by pregnant women.

Angiotensin receptor blockers

ARBs such as Losartan, Candesartan, Valsartan, Irbesartan, and Telmisartan are alternatives to
the ACE inhibitors. These drugs block the AT1 receptors, decreasing the activation of AT1
receptors by angiotensin II. Their pharmacologic effects are similar to those of ACE inhibitors in
that they produce arteriolar and venous dilation and block aldosterone secretion, thus lowering
blood pressure and decreasing salt and water retention.
Adverse effects are similar to those of ACE inhibitors, although the risks of cough and
angioedema are significantly decreased. These agents are also teratogenic and should not be
used by pregnant women. All the drugs are orally active and are dosed once-daily, with the
exception of valsartan which is twice a day.

Renin inhibitors
A selective renin inhibitor, Aliskiren is available for the treatment of hypertension. Aliskiren
directly inhibits renin and, thus, acts earlier in the renin–angiotensin–aldosterone system than
ACE inhibitors or ARBs. Aliskiren can cause diarrhea, especially at higher doses, and can also
cause cough and angioedema, but probably less often than ACE inhibitors.

52
Calcium channel blockers
Classes of calcium channel blockers
Diphenylalkylamines: Verapamil

Benzothiazepines: Diltiazem
Dihydropyridines: Nifedipine, Amlodipine, Felodipine, Isradipine
Mechanism of action
Calcium channel antagonists block the inward movement of calcium by binding to L-type
calcium channels in the heart and in smooth muscle of the coronary and peripheral arteriolar
vasculature. This causes vascular smooth muscle to relax, dilating mainly arterioles. Calcium
channel-blocking (CCB) agents inhibit the entry of calcium into cardiac and smooth muscle cells
by blocking the L-type Ca2+ channel; they lower blood pressure by reducing peripheral
resistance. Calcium channel-blocking (CCB) agents inhibit the entry of calcium into cardiac and
smooth muscle cells by blocking the L-type Ca2+ channel; they lower blood pressure by
reducing peripheral resistance.
Most of these agents have short half-lives (3 to 8 hours) following an oral dose. Sustained-
release preparations are available and permit once-daily dosing. Amlodipine has a very long
half-life and does not require a sustained-release formulation.
Side effects

Flushing, Dizziness, Headache, Hypotension, Peripheral edema, Constipation, Heart block.

α-Adrenoceptor-blocking agents
Prazosin, doxazosin, and terazosin produce a competitive block of α1 adrenoceptors. They
decrease peripheral vascular resistance and lower arterial blood pressure by causing relaxation
of both arterial and venous smooth muscle. Reflex tachycardia and postural hypotension often
occur at the onset of treatment and with dose increases, requiring slow titration of the drug in
divided doses.

α-/β-Adrenoceptor blocking agents

Labetalol and carvedilol block α1, β1, and β2 receptors. Carvedilol, although an effective
antihypertensive, is mainly used in the treatment of heart failure. Labetalol is used in the
management of gestational hypertension and hypertensive emergencies.

53
Centrally acting adrenergic drugs
Clonidine
Acts centrally as an α2 agonist to produce inhibition of sympathetic vasomotor centers,
decreasing sympathetic outflow to the periphery. This leads to reduced total peripheral
resistance and decreased blood pressure. Clonidine is absorbed well after oral administration
and is excreted by the kidney. It is also available in a transdermal patch.
Adverse effects include sedation, dry mouth, and constipation. Rebound hypertension occurs
following abrupt withdrawal of clonidine. The drug should, therefore, be withdrawn slowly if
discontinuation is required.
Methyldopa
Methyldopa is an α2 agonist that is converted to Methyl norepinephrine centrally to diminish
adrenergic outflow from the CNS. The most common side effects of methyldopa are sedation
and drowsiness. Its use is limited due to adverse effects and the need for multiple daily doses. It
is mainly used for management of hypertension in pregnancy, where it has a record of safety.

Vasodilators
The direct-acting smooth muscle relaxants, such as hydralazine and minoxidil, are not used as
primary drugs to treat hypertension. These vasodilators act by producing relaxation of vascular
smooth muscle, primarily in arteries and arterioles. This results in decreased peripheral
resistance and, therefore, blood pressure.
Adverse effects of hydralazine include headache, tachycardia, nausea, sweating, arrhythmia,
and precipitation of angina. Minoxidil treatment causes hypertrichosis (the growth of body
hair). This drug is used topically to treat male pattern baldness.

Diuretics
Diuretics are drugs that increase the volume of urine excreted. Most diuretic agents are
inhibitors of renal ion transporters that decrease the reabsorption of Na+ at different sites in
the nephron. Diuretics are most commonly used for management of abnormal fluid retention
(edema) or treatment of hypertension.
Diuretic Classes
Thiazide diuretics, Loop Diuretics, Potassium Sparing Diuretics, Carbonic Anhydrase Inhibitors,
Osmotic Diuretics.

54
Figure 12 Diuretics and their mechanism of action

Thiazide and related agents

Examples
Chlorothiazide, Hydrochlorothiazide (is more potent, so the required dose is considerably
lower than that of Chlorothiazide), Chlorthalidone, indapamide, and metolazone.

55
Mechanism of action
The thiazide and thiazide-like diuretics act mainly on distal convoluted tubule to decrease the
reabsorption of Na+, apparently by inhibition of a Na+/Cl− cotransporter on the luminal
membrane.
Actions
Increased excretion of Na+ and Cl−

Loss of K+
Loss of Mg2+
Decreased urinary calcium excretion
Thiazide and thiazide like diuretics decrease the Ca2+ content of urine by promoting the
reabsorption of Ca2+ in the distal convoluted tubule.
Therapeutic uses
Hypertension, Heart failure, Idiopathic hypercalciuria.

Diabetes insipidus: Thiazides have the unique ability to produce a hyperosmolar urine.
Pharmacokinetics
These drugs are effective orally.
Most thiazides take 1 to 3 weeks to produce a stable reduction in blood pressure, and they
exhibit a prolonged half-life. All thiazides are secreted from the kidney.
Adverse effects
Potassium depletion, Hyponatremia, Hyperuricemia, Hyperuricemia, Volume depletion,
Hypercalcemia, Hyperglycemia, Possibly due to impaired release of insulin and tissue uptake of
glucose.

Loop Diuretics
Examples
Bumetanide, Furosemide, Torsemide, Ethacrynic acid.
Mechanism of action
Loop diuretics inhibit the cotransport of Na+/K+/2Cl− in the luminal membrane in the ascending
limb of the loop of Henle. These agents have the greatest diuretic effect of all the diuretic
drugs.

56
Actions
Unlike thiazides, loop diuretics increase the Ca2+ content of urine.
Therapeutic uses

Drugs of choice for acute pulmonary Oedema, Hypercalcemia, hyperkalemia.

Pharmacokinetics
Loop diuretics are administered orally or parenterally. Their duration of action is relatively brief
(2 to 4 hours).
Adverse effects
Ototoxicity, Hyperuricemia, Acute hypovolemia, Potassium depletion, Hypomagnesemia.

Potassium Sparing Diuretics

Potassium-sparing diuretics act in the collecting tubule to inhibit Na+ reabsorption and K+
excretion.

Aldosterone antagonists: spironolactone and eplerenone

Mechanism of action
Spironolactone antagonizes aldosterone at intracellular cytoplasmic receptor sites rendering
the spironolactone–receptor complex inactive. Ultimately prevents Na+ reabsorption and,
therefore, K+ and H+ secretion.
Eplerenone is another aldosterone receptor antagonist, which has actions comparable to those
of spironolactone, although it may have less endocrine effects than spironolactone.
Therapeutic uses
 Diuretic
 These agents are often given in conjunction with thiazide or loop diuretics to prevent K+
excretion that would otherwise occur with these drugs.
 Secondary hyperaldosteronism
 Heart failure
 Resistant hypertension
 Resistant hypertension, defined by the use of three or more medications without
reaching the blood pressure goal.
 Ascites: Accumulation of fluid in the abdominal cavity.
Pharmacokinetics

Both spironolactone and eplerenone are absorbed after oral administration.

57
Adverse effects
Spironolactone causes gastric upset.
Spironolactone may induce gynecomastia in male patients and menstrual irregularities in
female patients.
Hyperkalemia, nausea, lethargy, and mental confusion can occur.
Potassium-sparing diuretics should be used with caution with other medications that can
induce hyperkalemia, such as angiotensin-converting enzyme inhibitors and potassium
supplements.

Triamterene and amiloride

Triamterene and amiloride block Na+ transport channels, resulting in a decrease in Na+/K+
exchange. Both triamterene and amiloride are commonly used in combination with other
diuretics, usually for their potassium sparing properties. The side effects of triamterene include
increased uric acid, renal stones, and K+ retention.

Carbonic anhydrase inhibitors

Examples
Acetazolamide
Acetazolamide and other carbonic anhydrase inhibitors are more often used for their other
pharmacologic actions than for their diuretic effect, because they are much less efficacious
than the thiazide or loop diuretics.
Mechanism of action
Acetazolamide inhibits carbonic anhydrase located intracellularly (cytoplasm) and on the apical
membrane of the proximal tubular epithelium. Carbonic anhydrase catalyzes the reaction of
CO2 and H2O, leading to H2CO3.
Therapeutic uses
Glaucoma, Mountain sickness

Pharmacokinetics
Acetazolamide can be administered orally or intravenously. It is eliminated renally.
Adverse effects
Metabolic acidosis (mild), potassium depletion, renal stone formation, drowsiness, and
paresthesia may occur.

58
The drug should be avoided in patients with hepatic cirrhosis, because it could lead to a
decreased excretion of NH4+.

59
Osmotic Diuretics
Examples
Mannitol, Urea
Simple, hydrophilic chemical substances that are filtered through the glomerulus. Filtered
substances that undergo little or no reabsorption will cause an increase in urinary output.

Osmotic diuretics are used to increase water excretion rather than Na+ excretion.
Therapeutic uses
 Increased intracranial pressure
 Acute renal failure due to shock
 Drug toxicity
 Trauma
Side effects: dehydration

Antiarrhythmics
In contrast to skeletal muscle, which contracts only when it receives a stimulus, the heart
contains specialized cells that exhibit automaticity. These “pacemaker” cells differ from other
myocardial cells in showing a slow, spontaneous depolarization caused by an inward positive
current carried by sodium and calcium ions. This depolarization is fastest in the sinoatrial (SA)
node (the normal initiation site of the action potential.

Figure 13 Normal Pathway of cardiac impulse

60
Figure 14 Cardiac Action potential

Introduction to Antiarrhythmias
Arrhythmias are an abnormalities in impulse formation and conduction in the myocardium.
Causes of arrhythmias: Abnormal automaticity, Abnormalities in impulse conduction.

Antiarrhythmic drugs
Antiarrhythmic drugs can modify impulse generation and conduction to prevent arrhythmias
from occurring or to reduce symptoms associated with arrhythmias.

Class I Antiarrhythmics
Class I antiarrhythmic drugs act by blocking voltage-sensitive sodium (Na+) channels.
Class I are Further classified IA, IB, and IC.
Class IA antiarrhythmic drugs: Quinidine, procainamide, and disopyramide
Mechanism of action
They bind to and sodium channels and prevent sodium influx. They have Moderate blockage
of Na+ channels. Because of these actions, they slow conduction velocity and increases
refractoriness.
Class IB antiarrhythmic drugs: Lidocaine and mexiletine

61
Mechanism of action
They have weak blockade of Na+ channel and they slow conduction velocity.
Class IC antiarrhythmic drugs: Flecainide and propafenone

Mechanism of action
They have Strong blockage of Na+ channels. Slow conduction velocity.

Class II Antiarrhythmic drugs

Beta blockers (Metoprolol, Esmolol, and Propranolol)
Inhibit β-adrenergic activation and decrease SA node and AV node activity. Prolong AV
node repolarization (AV node is highly sensitive to beta blockers. Slow conduction velocity.

Class III Antiarrhythmic Drugs

Amiodarone, Dofetilide, Dronedarone, Ibutilide, Sotalol.
Mechanism of action:
Class III agents block potassium channels and, thus, diminish the outward potassium current
during repolarization of cardiac cells. Class III drugs have the potential to induce arrhythmias.

Class IV Antiarrhythmic Drugs

Class IV drugs are the nondihydropyridine calcium channel blockers verapamil and diltiazem.
Verapamil shows greater action on the heart than on vascular smooth muscle, and diltiazem is
intermediate in its actions. In the heart, verapamil and diltiazem bind only to open depolarized
voltage-sensitive channels, thus decreasing the inward current carried by calcium.

Other antiarrhythmic Drugs

Digoxin

Mechanism of action
Inhibition of Na+/K+-ATPase → higher intracellular Na+ concentration
→ reduced efficacy of Na+/Ca2+ exchanger → higher intracellular Ca2+ concentration
In cardiomyocytes, this leads to increased contractility, reduced velocity of electric conduction
via AV node depression, and a reduction of the heart rate via SA node depression.
(See figure15)

62
Pharmacokinetics
Digoxin is available in oral and injectable formulations. It has a large volume of distribution,
because it accumulates in muscle.
It is mainly eliminated intact by the kidney, requiring dose adjustment in renal dysfunction.

Figure 15 Mechanism of action of Digoxin

Adverse effects
Digoxin toxicity is one of the most common adverse drug reactions leading to hospitalization.
Anorexia, nausea, and vomiting may be initial indicators of toxicity. Patients may also
experience blurred vision, yellowish vision (xanthopsia), and various cardiac arrhythmias.
Toxicity can often be managed by discontinuing digoxin, determining serum potassium levels,
and, if indicated, replenishing potassium. Decreased levels of serum potassium (hypokalemia)
predispose a patient to digoxin toxicity.
Adenosine, Magnesium sulfate
Adenosine is a naturally occurring nucleoside, but at high doses, the drug decreases conduction
velocity, prolongs the refractory period, and decreases automaticity in the AV node.
Magnesium is necessary for the transport of sodium, calcium, and potassium across cell
membranes. It slows the rate of SA node impulse formation and prolongs conduction time
along the myocardial tissue.

63
Anticoagulants and Antiplatelet Agents
The Basics
Primary hemostasis
When blood vessel is injured Platelet accumulation at the vessel walls.
Exposure of sub endothelial collagen → circulating von Willebrand factor binds to the
exposed collagen. Von Willebrand factor (vWF): plasma protein that is synthesized by and
stored in endothelial cells and platelets (in α-granules).

Platelets start the following processes

Platelet adhesion: platelets bind to vWF via platelet GpIb receptor at the endothelial injury site.
Platelet activation: After binding to vWF, platelets change their shape and release mediators
that lead to activation of more platelets (positive feedback).
These mediators include
Adenosine diphosphate (ADP): promotes adhesion of platelets to endothelium.
Thromboxane A2 (TXA2): activates additional platelets and promotes vasoconstriction.

Calcium: required for secondary hemostasis.

Platelet aggregation
Mediated by GpIIb/IIIa receptor and fibrinogen
A white thrombus forms which is transient, unstable, and easily dislodged. It stabilizes through
the process of secondary hemostasis.

Secondary hemostasis
Processes that lead to stabilization of the platelet plug (white thrombus) by creating
a fibrin network.

Coagulation factors: Substances that interact with each other to promote blood coagulation.
Secondary hemostasis
 Extrinsic pathway
 Intrinsic pathway

64
Figure 16 Clot formation

Figure 17 Secondary Hemostasis

65
Platelet aggregation inhibitors
A. Aspirin
Mechanism of action

Aspirin inhibits thromboxane A2 synthesis by irreversibly inactivating the enzyme COX 1.

Therapeutic uses
Prophylactic treatment of Transient Ischemic attack
To reduce recurrent MI
Complete inactivation of platelets occurs with 75 mg of aspirin given daily.

Adverse effects
Bleeding, Hypersensitivity reaction, Gastrointestinal Bleeding.
B. Ticlopidine, clopidogrel, prasugrel, and ticagrelor
Mechanism of action
These drugs inhibit the binding of ADP to its receptors on platelets and, thereby, inhibit the
activation of the GP IIb/IIIa receptors required for platelets to bind to fibrinogen and to each
other.
Therapeutic uses
Clopidogrel: is used for prevention of atherosclerotic events in patients with a recent MI or
stroke and in those with established peripheral arterial disease.

Adverse effects: These agents can cause prolonged bleeding.

C. Abciximab, eptifibatide, and tirofiban
Mechanism of action
They inhibits the GP IIb/IIIa receptor complex. By binding to GP IIb/IIIa, and block the binding of
fibrinogen and von Willebrand factor and, consequently, aggregation does not occur.
Therapeutic use
These agents are given intravenously, along with heparin and aspirin, as an adjunct to PCI for
the prevention of cardiac ischemic complications.

66
Dipyridamole
Mechanism of action: Inhibits Phosphodiesterase thus increases cAMP causing decreased
synthesis of thromboxane A2. Dipyridamole is used for stroke prevention and is usually given in
combination with aspirin.
Cilostazol
Is an oral antiplatelet agent that also has vasodilating activity. Cilostazol inhibit
phosphodiesterase type III, which prevents the degradation of cAMP, thereby increasing levels
of cAMP in platelets and vascular tissues. The increase in cAMP levels in platelets and the
vasculature prevents platelet aggregation and promotes vasodilation of blood vessels.
Cilostazol is contraindicated in patients with heart failure.

Anticoagulants
A. Heparin and low molecular weight heparins
Mechanism of action

Enhances the activity of Antithrombin III

Antithrombin III potentiation → inhibition of factor Xa → decreased activation
of prothrombin → ↓ thrombin→ ↓ fibrinogen activation → ↓ fibrin.
Therapeutic use
These agents are used for the treatment of acute venous thromboembolism (DVT or PE).
These drugs are the anticoagulants of choice for treating pregnant women.
Pharmacokinetics

Heparin must be administered subcutaneously or intravenously.

The LMWH are administered subcutaneously
 Enoxaparin
Adverse effects
The chief complication of heparin and LMWH therapy is bleeding. Excessive bleeding may be
managed by discontinuing the drug or by treating with protamine sulfate. Heparin-induced
thrombocytopenia (HIT) is a serious condition. Heparin therapy should be discontinued when
patients develop HIT or show severe thrombocytopenia.
B. Argatroban
Argatroban is a synthetic parenteral anticoagulant.

67
It is a direct thrombin inhibitor.
Argatroban used for the prophylaxis or treatment of venous thromboembolism in patients with
HIT, and it is also approved for use during PCI in patients who have or are at risk for developing
HIT. Because Argatroban is metabolized in the liver, it may be used in patients with renal
dysfunction, but it should be used cautiously in patients with hepatic impairment. As with other
anticoagulants, the major side effect is bleeding.
C. Fondaparinux
This agent selectively inhibits only factor Xa.
D. Rivaroxaban and apixaban
These are oral inhibitors of factor Xa. Both agents bind to the active site of factor Xa, thereby
preventing its ability to convert prothrombin to thrombin.

E. Dabigatran etexilate
Is the prodrug of dabigatran, which is an oral direct thrombin inhibitor.
F. Warfarin
The coumarin anticoagulants owe their action to the ability to antagonize the cofactor functions
of vitamin K. The only therapeutically relevant coumarin anticoagulant is warfarin.
Mechanism of action
Inhibit hepatic vitamin K epoxide reductase → ↓ hepatic synthesis (recycling) of the active,
reduced form of vitamin K → ↓ γ-carboxylation of glutamate residues on coagulation factors
II, VII, IX, and X as well as protein C and protein S.
Unlike heparin, the anticoagulant effects of warfarin are not observed immediately after drug
administration. Instead, peak effects may be delayed for 72 to 96 hours.
Pharmacokinetics

Warfarin is taken orally

Warfarin has numerous drug interactions that may potentiate or attenuate its anticoagulant
effect (see figure 18)
Adverse effects
The principal adverse effect of warfarin is hemorrhage. It is important to frequently monitor the
INR and adjust the dose of warfarin. Minor bleeding may be treated by withdrawal of the drug
or administration of oral vitamin K1, but severe bleeding may require greater doses of vitamin K
given intravenously.

68
Figure 18 Warfarin Drug interactions

Whole blood, frozen plasma, and plasma concentrates of blood factors may also be used for
rapid reversal of warfarin. Skin lesions and necrosis are rare complications of warfarin therapy.
Warfarin is teratogenic and should never be used during pregnancy. If anticoagulant therapy is
needed during pregnancy, heparin or LMWH may be administered.

Thrombolytic Drugs
Examples: Alteplase, reteplase, and tenecteplase, Streptokinase, Urokinase.
Mechanism of action
The thrombolytic agents share some common features. All act either directly or indirectly to
convert plasminogen to plasmin, which, in turn, cleaves fibrin, thus lysing thrombi.
Therapeutic use
 Early STEMI (ST segment elevation MI) (< 12 hours)
 Early ischemic stroke (< 3 hours)
 Massive pulmonary embolism
Adverse effects
Hemorrhage, Gastrointestinal bleeding

69
Contraindications
Active bleeding, Pregnancy, Prior intracranial hemorrhage, Recent surgery, Severe hypertension
Known bleeding diathesis

Drugs used to treat bleeding

Aminocaproic acid and tranexamic acid
Fibrinolytic states can be controlled by the administration of aminocaproic acid or tranexamic
acid. Both agents are synthetic, orally active, excreted in the urine, and inhibit plasminogen
activation. Tranexamic acid is 10 times more potent than aminocaproic acid. A potential side
effect is intravascular thrombosis.
Protamine sulfate

Protamine sulfate antagonizes the anticoagulant effects of heparin.

Adverse effects of drug administration include hypersensitivity as well as dyspnea, flushing,
bradycardia, and hypotension when rapidly injected.
Vitamin K
Vitamin K1 administration can stop bleeding problems due to warfarin by increasing the supply
of active vitamin K1, thereby inhibiting the effect of warfarin. Vitamin K1 may be administered
via the oral, subcutaneous, or intravenous route.
Note: Intravenous vitamin K should be administered by slow IV infusion to minimize the risk of
hypersensitivity or anaphylactoid reactions. The response to vitamin K1 is slow, requiring about
24 hours to reduce INR (time to synthesize new coagulation factors). Thus, if immediate
hemostasis is required, fresh frozen plasma should be infused.

Lipid Lowering Drugs

Digestion and absorption of Lipids
Dietary lipids: TAGs (triacylglycerol), phospholipids, and cholesterol esters. First broken down
by lipases in the mouth, stomach, and intestinal lumen and packaged into micelles. Micelles
contain free fatty acids, free cholesterol, and 2-monoacylglycerol, plus bile salts and fat-soluble
vitamins (A, D, E, and K).
Long-chain fatty acids absorbed by enterocytes are reesterified to triglycerides and cholesterol
esters.

70
The newly resynthesized TAGs and cholesteryl esters with a protein apolipoprotein B-48 form a
chylomicron, which is a large lipoprotein that now enters the lymphatic system. Triacylglycerol
in chylomicrons is degraded to free fatty acids and glycerol by lipoprotein lipase in the
capillaries of skeletal muscle and adipose tissues. After most of the TAG has been removed, the
chylomicron remnants (which contain cholesteryl esters, phospholipids, apolipoproteins, fat-
soluble vitamins, and some TAG) bind to receptors on the liver and are then endocytosed.
Cholesterol and the nitrogenous bases of phospholipids (for example, choline) can be recycled
by the body.

Cholesterol metabolism
Cholesterol is synthesized by virtually all tissues in humans, although liver, intestine, adrenal
cortex, and reproductive tissues, including ovaries, testes, and placenta, make the largest
contributions to the body’s cholesterol pool. The carbon skeleton that makes up its structure
comes from Acetyl-CoA, whether derived from glucose or fatty acid oxidation. The key enzyme
in the formation of cholesterol is HMG-CoA Reductase.
Transport of cholesterol: Lipoproteins function in the transport of cholesterol. Lipoproteins are
spherical complexes of lipid and protein, which include chylomicrons, very-low-density
lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).
Transport of cholesterol in blood via lipoproteins
From the intestine to the liver: together with TAGs in chylomicrons.
From the liver to peripheral tissues: via VLDL and LDL

From peripheral tissues to the liver (reverse cholesterol transport): via HDL and IDL

Drugs for hyperlipidemia

Antihyperlipidemic drugs include
Statins, Niacin, Bile acid resins, Fibrates, Ezetimibe, PCSK9 inhibitors, Omega-3 fatty acids (fish
oil).

Statins (HMG CoA reductase inhibitors)

Examples

Atorvastatin, Simvastatin, Pravastatin, Lovastatin, Pitavastatin, Rovustatin.

Mechanism of action
Statins reduce hepatic cholesterol synthesis by inhibiting enzyme HMG-CoA reductase. This
leads to a consequent upregulation of LDL receptors on hepatocytes, which, in turn,

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lowers LDL cholesterol levels and triglycerides while raising HDL cholesterol. Statins are
the lipid-lowering drugs of choice.
Pitavastatin, rosuvastatin, and atorvastatin are the most potent LDL cholesterol–lowering
statins, followed by simvastatin, pravastatin, and then lovastatin and fluvastatin.
Pharmacokinetics
Lovastatin and simvastatin are lactones that are hydrolyzed to the active drug. The remaining
statins are all administered in their active form. Excretion takes place principally through bile
and feces, but some urinary elimination also occurs.
Adverse effects
Elevated liver enzymes may occur with statin therapy.

Myopathy and rhabdomyolysis.

These drugs are contraindicated during pregnancy and lactation.

Niacin (nicotinic acid)

Mechanism of action:
Niacin strongly inhibits lipolysis in adipose tissue, thereby reducing production of free fatty
acids. Reduced liver triglyceride levels decrease hepatic VLDL production, which in turn reduces
LDL plasma concentrations.
Pharmacokinetics

Niacin is administered orally. Niacin and its derivatives are excreted from the kidney
Adverse effects
Cutaneous flush, Pruritis.
Administration of aspirin prior to taking niacin decreases the flush.
Nausea and abdominal pain

Hyperuricemia and gout

The drug should be avoided in hepatic disease.

Fibrates
Fenofibrate, Gemfibrozil, Bezafibrate

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Mechanism of action
These drugs activate of the peroxisome proliferator-activated receptor alpha (PPAR–α) which
increases lipoprotein lipase activity which leads more rapid degradation
of LDL and triglycerides and induction of HDL synthesis.
Therapeutic uses
The fibrates are used in the treatment of hypertriglyceridemias.

Pharmacokinetics
Gemfibrozil and Fenofibrate are completely absorbed after oral administration and distribute
widely. Both drugs undergo extensive biotransformation and are excreted in the urine.
Adverse effects
Dyspepsia
Myopathy, especially in combination with statins
Cholelithiasis: fibrates inhibit cholesterol 7α hydroxylase → decreased bile
acid synthesis → supersaturation of bile with cholesterol.
Increased LFTs (reversible)

Contraindications
Renal insufficiency, Liver failure, Gall bladder diseases

Bile acid resins

Drugs: cholestyramine, colestipol, colesevelam
Mechanism of action
They are anion-exchange resins that bind negatively charged bile acids and bile salts in the
small intestine. The resin/bile acid complex is excreted in the feces, thus lowering the bile acid
concentration. This causes hepatocytes to increase conversion of cholesterol to bile acids,
which are essential components of the bile.
Indications
 Combination treatment with statins in hypercholesterolemia
 Digitoxin overdose
 Pruritus associated with elevated bile acid levels (cholestasis)
 Bile acid diarrhea

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Adverse effects
Gastrointestinal: nausea, abdominal bloating and cramping
↑ LFTs

Myalgia
Contraindications
These agents may raise triglyceride levels and are contraindicated in patients with significant
hypertriglyceridemia.

Cholesterol absorption inhibitor

Drug: Ezetimibe
Mechanism of action
Inhibits absorption of dietary and biliary cholesterol in the small intestine at the brush border
of enterocytes. This causes a reduction of hepatic cholesterol stores and an increase in
clearance of cholesterol from the blood.

Adverse effects are uncommon with use of ezetimibe.

Contraindication: coadministration with a statin during active liver disease.

PCSK9 Inhibitors
Drugs: alirocumab, evolocumab
Mechanism of action
These drugs inhibit proprotein convertase subtilisin kexin 9 (PCSK9), an enzyme that degrades
the LDL-receptor → increased removal of LDL from the blood
stream → ↓↓↓ LDL, ↑ HDL, ↓ triglycerides.
Indication: add-on therapy for patients with hyperlipidemia and at very high risk for
cardiovascular disease.

Adverse effects: myalgia

Omega-3 fatty acids

Omega-3 polyunsaturated fatty acids are essential fatty acids that are predominately used for
triglyceride lowering. Essential fatty acids inhibit VLDL and triglyceride synthesis in the liver.
The omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid DHA) are found in
marine sources such as tuna, halibut, and salmon.

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Drugs acting on Pulmonary System
Drugs used to treat Asthma
Asthma is a chronic inflammatory disease of the airways characterized by episodes of acute
bronchoconstriction causing shortness of breath, cough, chest tightness, wheezing, and rapid
respiration. Airflow obstruction in asthma is due to bronchoconstriction that results from
contraction of bronchial smooth muscle, inflammation of the bronchial wall, and increased
secretion of mucus.
Goals of therapy
 To decrease symptoms
 To treat and prevent airway inflammation
Types of Asthma
 Intermittent
 Persistent

β2-Adrenergic agonists
Drugs

Short-acting β2 agonists (SABAs)

Albuterol (Salbutamol)
Levalbuterol
Long-acting β2 agonists (LABAs)
Salmeterol, formoterol

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Short-acting β2agonists (SABAs) have a rapid onset of action (5 to 30 minutes) and provide
relief for 4 to 6 hours. They are used for symptomatic treatment of bronchospasm, providing
quick relief of acute bronchoconstriction. All patients with asthma should be prescribed a SABA
inhaler.
Adverse effects: Tachycardia, Tremor, Hyperglycemia
Long-acting β2 agonists (LABAs) have a long duration of action, providing bronchodilation for at
least 12 hours. LABAs should not be used for quick relief of an acute asthma attack.
Adverse effects of LABAs are similar to quick-relief β2 agonists.
Inhaled Corticosteroids
Drugs

Beclomethasone, Budesonide, Fluticasone, Mometasone, Triamcinolone.

ICS are the drugs of choice for long-term control in patients with any degree of persistent
asthma.
Mechanism of action
Corticosteroids inhibit the release of arachidonic acid through phospholipase A2 inhibition,
thereby producing direct anti-inflammatory properties in the airways.
Adverse effects: deposition on the oral and laryngeal mucosa can cause adverse effects, such as
oropharyngeal candidiasis (due to local immune suppression) and hoarseness.
Leukotriene modifiers
Leukotrienes (LT) B4and the cysteinyl leukotrienes, LTC4, LTD4, and LTE4, are products of the 5-
lipoxygenase pathway. LTB4 is a potent chemoattractant for neutrophils and eosinophils,
whereas the cysteinyl leukotrienes constrict bronchiolar smooth muscle, increase endothelial
permeability, and promote mucus secretion.
Zileuton is a selective and specific inhibitor of 5-lipoxygenase.
Zafirleukast, Montelukast are selective antagonists of the cysteinyl leukotriene-1 receptor.
All three drugs are approved for the prevention of asthma symptoms. Leukotriene receptor
antagonists have also shown efficacy for the prevention of exercise induced bronchospasm.
Pharmacokinetics
All three drugs are orally active and highly protein bound. Food impairs the absorption of
zafirlukast. The drugs are metabolized extensively by the liver. Zileuton and its metabolites are
excreted in urine, whereas zafirlukast, montelukast, and their metabolites undergo biliary
excretion.

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Adverse effects:
Elevations in serum hepatic enzymes have occurred with all three agents. Other effects include
headache and dyspepsia.
Cromolyn
Cromolyn is a prophylactic anti-inflammatory agent that inhibits mast cell degranulation and
release of histamine. It is an alternative therapy for mild persistent asthma. Cromolyn is
available as a nebulized solution for use in asthma. Due to its short duration of action, this
agent requires dosing three or four times daily.
Adverse effects are minor and include cough, irritation, and unpleasant taste.
Anticholinergics (Cholinergic antagonists)

Drug: ipratropium bromide

Mechanism of action
Cholinergic antagonists are competitive antagonists of acetylcholine (ACh) at the muscarinic
receptor. They inhibit ACh-mediated constriction of bronchial airways. Anticholinergics also
decrease vagal-stimulated mucus secretion. Inhaled ipratropium bromide may be useful in
patients who are unable to tolerate a SABA.
Adverse effects such as xerostomia and bitter taste are related to local anticholinergic effects.
Methylxanthines
Theophylline
Theophylline is a bronchodilator that relieves airflow obstruction in chronic asthma and
decreases its symptoms. Theophylline also has some anti-inflammatory properties and reduces
airway responsiveness to agents such as histamine and to allergens. Previously, the mainstay of
asthma therapy, theophylline has been largely replaced with β2 agonists and corticosteroids
due to its narrow therapeutic window. The adverse effects of Methylxanthines include
arrhythmias, nervousness, vomiting, and gastrointestinal bleeding.

Drugs used to treat Allergic Rhinitis

Antihistamines (H1-receptor blockers)
First-generation antihistamines

 Diphenhydramine, chlorpheniramine.
Second-generation antihistamines
 Loratadin, Cetirizine

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α-Adrenergic agonists
Short-acting α-adrenergic agonists (“nasal decongestants”), such as phenylephrine, constrict
dilated arterioles in the nasal mucosa and reduce airway resistance. Longer-acting
oxymetazoline is also available. The α-adrenergic agonist intranasal formulations should be
used no longer than 3 days due to the risk of rebound nasal congestion (rhinitis
medicamentosa).

Drugs used to treat cough

Opioids
 Codeine
 Dextromethorphan
Codeine an opioid, decreases the sensitivity of cough centers in the central nervous system to
peripheral stimuli and decreases mucosal secretion.
Common side effects, such as constipation, dysphoria, and fatigue occur.
Dextromethorphan is a synthetic derivative of morphine that has no analgesic effects in
antitussive doses. Dextromethorphan has a significantly safer side effect profile than codeine
and is equally effective for cough suppression. Guaifenesin, an expectorant, is available as a
single-ingredient formulation and is also a common ingredient in combination products with
codeine or dextromethorphan.
Benzonatate
Unlike the opioids, Benzonatate suppresses the cough reflex through peripheral action. It
anesthetizes the stretch receptors located in the respiratory passages, lungs, and pleura.
Side effects include dizziness, numbness of the tongue, mouth, and throat.

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Drugs Acting on the Gastrointestinal Tract
Drugs used to treat Peptic Ulcer disease and Gastroesophageal reflex
disease
Antacids
Antacids are weak bases that are taken orally and that partially neutralize gastric acid, reduce
pepsin activity, and stimulate prostaglandin production. The acid-neutralizing ability of an
antacid depends on its capacity to neutralize gastric HCl and on whether the stomach is
full or empty (food delays stomach emptying allowing more time for the antacid to react).
Commonly used antacids are salts of aluminum and magnesium, such as aluminum
hydroxide (usually a mixture of Al(OH)3 and magnesium hydroxide [Mg(OH)2], either alone
or in combination.

Therapeutic uses:
Aluminum- and magnesium-containing antacids are used for symptomatic relief of peptic ulcer
disease and GERD, and they may also promote healing of duodenal ulcers.
Adverse effects
Aluminum hydroxide tends to cause constipation, whereas magnesium hydroxide tends to
produce diarrhea. Sodium bicarbonate is contraindicated in hypertension, heart failure, and
renal failure because of its high sodium content.

Gastric acid secretion inhibitors

HCl is secreted by parietal cells of the gastric mucosa which contain receptors for acetylcholine,
histamine and gastrin that stimulate the secretion.
The receptor-mediated binding of acetylcholine, histamine, or gastrin stimulates the H+/K+
adenosine triphosphatase (ATPase) proton pump to secrete hydrogen ions in exchange for
K+ into the lumen of the stomach.

H2-receptors blocking agents

These drugs include cimetidine, ranitidine, famotidine, nizatidine. The histamine H2-receptor
antagonists act selectively on H2receptors in the stomach, blood vessels, and other sites, but
they have no effect on H1receptors. They are competitive antagonists of histamine and are fully
reversible.
Therapeutic uses

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Peptic ulcer disease: All four agents are equally effective in promoting the healing of duodenal
and gastric ulcers. However, recurrence is common after treatment with H2antagonists is
stopped.
Acute stress ulcers
Gastroesophageal reflux disease
Pharmacokinetics
Cimetidine: Cimetidine and the other H2antagonists are given orally, distribute widely
throughout the body (including into breast milk and across the placenta), and are excreted
mainly in urine. Cimetidine can slow metabolism and potentiate the action of several drugs (for
example, warfarin, diazepam, phenytoin, quinidine, carbamazepine, theophylline, and
imipramine), sometimes resulting in serious adverse clinical effects.
Ranitidine: Compared to cimetidine, ranitidine is longer acting and is five- to ten-fold more
potent. Ranitidine has minimal side effects and does not produce the antiandrogenic and
prolactin stimulating effects of cimetidine.
Nizatidine: Nizatidine is similar to ranitidine in its pharmacologic action and potency.
Adverse effects: The most common side effects are Dizziness, Headache, Diarrhea, and
muscular pain. Other central nervous system effects (such as confusion and hallucinations)
occur primarily in elderly patients and after intravenous administration. Cimetidine can also
have endocrine effects including gynecomastia, and galactorrhea (continuous release/discharge
of milk).

Proton pump inhibitors (PPIs)

Omeprazole is the first of a class of drugs that bind to the H+/K+ ATPase enzyme system
(proton pump) of the parietal cell and suppress the secretion of hydrogen ions into the gastric
lumen. Five additional PPIs are now available: dexlansoprazole, esomeprazole (Nexium),
lansoprazole, pantoprazole, rabeprazole.
Mechanism of action
These drugs irreversibly inhibit he H+/K+ ATPase proton pump in parietal cells. It takes about 18
hours for the enzyme to be resynthesized.
Therapeutic uses
 They are superior over H2 blockers for suppressing acid production.
 Peptic ulcer disease
 Stress ulcers
 Erosive esophagitis
 Zollinger Ellison syndrome

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  they are successfully used with antimicrobial regimens to eradicate H. pylori
PPIs should be taken 30 to 60 minutes before meal.
Adverse effects

Nausea, diarrhea, headache, GI disturbances.

Bone Fractures (increased risk with long-term use: hip, wrist, and spine). Prolonged therapy
with agents that suppress gastric acid, such as the PPIs and H2antagonists, may result in low
vitamin B12, because acid is required for its absorption in a complex with intrinsic factor.

Mucosal protective agents

Also known as cytoprotective compounds, these agents have several actions that enhance
mucosal protection mechanisms, thereby preventing mucosal injury, reducing inflammation,
and healing existing ulcers.
Sucralfate: This complex of aluminum hydroxide and sulfated sucrose binds to proteins of both
normal and necrotic mucosa.
By forming complex gels with epithelial cells, sucralfate creates a physical barrier that impairs
diffusion of HCl and prevents degradation of mucus by pepsin and acid. It also stimulates
prostaglandin release as well as mucus and bicarbonate output, and it inhibits peptic digestion.
Because it requires an acidic pH for activation, sucralfate should not be administered with PPIs,
H2antagonists, or antacids.

Bismuth subsalicylate:
Preparations of this compound effectively heal peptic ulcers. In addition to their antimicrobial
actions, they inhibit the activity of pepsin, increase secretion of mucus, and interact with
glycoproteins in necrotic mucosal tissue to coat and protect the ulcer crater.

Laxatives
Laxatives and cathartics are drugs used orally to evacuate the bowels or to promote bowel
elimination (defecation). Laxatives and cathartics are drugs used orally to evacuate the
bowels or to promote bowel elimination (defecation).
Bulk-forming laxatives
Are substances that are largely unabsorbed from the intestine. Bulk-forming laxatives include
psyllium, methylcellulose, and polycarbophil.
Bulk-forming laxatives are hydrophilic natural or semisynthetic polysaccharide or cellulose
derivatives that are poorly absorbed from the bowel lumen and retain water in the bowel. The

81
increased luminal mass stimulates peristalsis. These agents are the treatment of choice for
chronic constipation. These agents may cause bloating and flatulence.
Osmotic laxatives: include both salt-containing and salt-free agents.
Salt-containing osmotic laxatives (saline laxatives)
Salt-containing osmotic laxatives include magnesium sulfate, magnesium citrate, magnesium
hydroxide, sodium phosphates, and mineral water.
These agents are poorly absorbed ions that retain water in the lumen by osmosis and cause a
reflex increase in peristalsis.
These agents are used for short-term evacuation of the bowel before surgery or diagnostic
procedures or for elimination of parasites after anthelmintic administration.

Salt-free osmotic laxatives

Salt-free osmotic laxatives include glycerin, lactulose and polyethylene glycol-electrolyte
solutions. These agents may be administered rectally (glycerin) or orally (lactulose). Is used for
preoperative colon preparation.
Irritant (stimulant) laxatives
Are substances that are themselves irritant or contain an irritant substance to produce
purgation. Individual drugs are castor oil, bisacodyl, phenolphthalein, glycerine, etc.
Irritant laxatives stimulate smooth muscle contractions resulting from their irritant action on
the bowel mucosa. Chronic use of irritant laxatives may result in cathartic colon, a condition of
colonic distention, and development of laxative dependence.
Stool softeners
Stool softeners include docusate sodium. Stool softeners have a detergent action that
facilitates the mixing of water and fatty substances to increase luminal mass.These agents are
marginally effective and are used to produce short-term laxation and to reduce straining at
defecation.

Antidiarrheal agents.
Antidiarrheal agents aim to decrease fecal water content by increasing solute absorption and
decreasing intestinal secretion and motility. Therapy with these drugs should be reserved for
patients with significant and persistent symptoms of diarrhea.

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Opiates and opiate derivatives
Diphenoxylate: Diphenoxylate, a synthetic morphine analogue, is used for the treatment of
diarrhea and not analgesia. At high doses this agent may produce CNS effects including nausea
and vomiting, sedation, and constipation. Loperamide: Loperamide is an opioid agonist with no
CNS activity, except at very high doses, but with marked effects on the intestine.
Loperamide has a faster onset and longer duration of action than diphenoxylate. Loperamide
has fewer adverse effects than diphenoxylate. However, overdose can result in severe
constipation, paralytic ileus, and CNS depression.
Adsorbents
Adsorbents include kaolin and pectin. These agents act by adsorbing fluid, toxins, and bacteria
and are used for acute diarrhea. They are less effective than other agents. These agents are not
absorbed; they are nontoxic; may absorb other drugs if given within 2 hours of their
administration.

Antiemetic Drugs
Mechanisms that trigger vomiting
Two brainstem sites have key roles in the vomiting reflex pathway.
Chemoreceptor trigger zone (CTZ): responds directly to chemical stimuli in the blood or
cerebrospinal fluid.
The vomiting center also responds to afferent input from the vestibular system, the periphery
(pharynx and GI tract).

A. Anticholinergics
Drugs
Scopolamine (Oral, Transdermal, IV)
Cholinergic antagonists reduce the excitability of labyrinthine receptors and depress conduction
from the vestibular apparatus to the vomiting center.
Clinical uses
 motion sickness
 preoperative situations

Adverse effects: drowsiness, dry mouth, and blurred vision.

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 B. Histamine H1-receptor antagonists
Drugs
Meclizine, Cyclizine, Doxylamine, Promethazine

Antihistamines have Central antiemetic effect and vestibular system.

Clinical uses
 Motion sickness
 Vertigo
 Hyperemesis
Side effects: sedation and dry mouth
C. Dopamine receptor antagonists
Metoclopramide (Plasil)

Metoclopramide blocks dopamine D2-receptors

Metoclopramide enhances GI motility and gastric emptying and increases lower esophageal
sphincter tone.
Clinical uses
 Chemotherapy induced Vomiting
 Dyspepsia
Side effects: Sedation, diarrhea, extrapyramidal effects.
D. Serotonin 5-HT3 antagonists
Drugs

Ondansetron, Dolasetron, Granisetron, Palonosetron

These agents are serotonin (5-HT3)-receptor antagonists. Activation of these receptors in the
CNS and GI tract is a key component in triggering vomiting.
Clinical uses
 Chemotherapy induced emesis
 Radiation induced emesis
 Vomiting in children
The most common adverse effects of these drugs are headache and mild constipation.
E. Other antiemetics: Prochlorperazine, Droperidol, Haloperidol, Benzodiazepines
(Lorazepam, alprazolam).

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Drugs Affecting the Endocrine System
Drugs for Diabetes
Oral hypoglycemic agents
Sulfonylureas: Glyburide (Glibenclamide), Glipizide, Glimepiride, Tolbutamide.
Mechanism of action
The main mechanism of action includes stimulation of insulin release from the βcells of the
pancreas. In addition, sulfonylureas may reduce hepatic glucose production and increase
peripheral insulin sensitivity.
Glyburide
The usual starting dosage is 2.5 mg/d and the average maintenance dosage is 5–10 mg/d given
as a single morning dose. Glyburide is contraindicated in the presence of hepatic impairment
and in patients with renal insufficiency. Glyburide has few adverse effects other than its
potential for causing hypoglycemia.
Glipizide
Has the shortest half-life 2–4 hours. This agent should be ingested 30 minutes before breakfast
because absorption is delayed when the drug is taken with food. The recommended starting
dosage is 5 mg/d, with up to 15 mg/d given as a single dose. Glipizide therapy is contraindicated
in patients with significant hepatic or renal impairment. Because of its shorter half-life, the
regular formulation of glipizide is much less likely than glyburide to produce serious
hypoglycemia.
Glimepiride
Is approved for once-daily use as monotherapy or in combination with insulin. A single daily
dose of 1 mg has been shown to be effective, and the recommended maximal daily dose is 8
mg. Glimepiride has a long duration of effect with a half-life of 5 hours, allowing once-daily
dosing. It is completely metabolized by the liver.
Side effects of Sulphonylureas
 Hypoglycemia
 Weight gain
 Weight gain
Biguanides
Metformin

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Mechanism of action
The main mechanism of action of metformin is reduction of hepatic gluconeogenesis.
Metformin also slows intestinal absorption of sugars and improves peripheral glucose uptake
and utilization. Metformin is the initial drug of choice for type 2 diabetes.
Pharmacokinetics
Metformin is well absorbed orally, is not bound to serum proteins, and is not metabolized.
Excretion is via the urine.
Adverse effects
The most common adverse effects of metformin are gastrointestinal (anorexia, nausea,
vomiting, abdominal discomfort, and diarrhea).

Metformin is contraindicated in renal dysfunction due to the risk of lactic acidosis.

Other uses: metformin is effective in the treatment of polycystic ovary syndrome.
Thiazolidinediones
Pioglitazone, Rosiglitazone
Mechanism of action
The TZDs lower insulin resistance by acting as agonists for the peroxisome proliferator–
activated receptor-γ (PPARγ). Activation of PPARγ results increased insulin sensitivity in adipose
tissue, liver, and skeletal muscle.
Rosiglitazone increases LDL cholesterol and triglycerides, whereas pioglitazone decreases
triglycerides.

Both drugs increase HDL cholesterol.

Pharmacokinetics
Pioglitazone and rosiglitazone are well absorbed after oral administration. Pioglitazone is
excreted in the bile. Metabolites of rosiglitazone are primarily excreted in the urine. These
agents should be avoided in nursing mothers. These agents should be avoided in nursing
mothers.
Adverse effects
An adverse effect common to both Tzds is fluid retention. Both drugs increase the risk of heart
failure. TZDs have been associated with osteopenia and increased fracture risk.
α-Glucosidase inhibitors
Acarbose, Miglitol

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Mechanism of action
Located in the intestinal brush border, α-glucosidase enzymes break down carbohydrates into
glucose and other simple sugars that can be absorbed. Acarbose and miglitol reversibly inhibit
α-glucosidase enzymes. When taken at the start of a meal, these drugs delay the digestion of
carbohydrates, resulting in lower postprandial glucose levels.
Adverse effects
The major side effects are flatulence, diarrhea, and abdominal cramping.
Dipeptidyl peptidase-4 inhibitors

Alogliptin, Linagliptin, Sitagliptin, Vildagliptin, saxagliptin

Mechanism of action
The incretin effect is the augmentation of insulin secretion seen when a glucose stimulus is
given orally. The incretin hormones are primarily glucagon-like peptide 1 (GLP-1) and gastric
inhibitory polypeptide (GIP). These drugs inhibit the enzyme DPP-4, which is responsible for the
inactivation of incretin hormones such as GLP-1.
The DPP-4 inhibitors are well absorbed after oral administration. Food does not affect the
extent of absorption. All DPP-4 inhibitors except linagliptin require dosage adjustments in renal
dysfunction.
Adverse effects
DPP-4 inhibitors are well tolerated, with the most common adverse effects being
nasopharyngitis and headache. Although infrequent, pancreatitis has occurred with use of all
DPP-4 inhibitors.
Sodium–glucose cotransporter 2 inhibitors
Canagliflozin, Dapagliflozin
Mechanism of Action
The sodium–glucose cotransporter 2 (SGLT2) is responsible for reabsorbing filtered glucose in
the tubular lumen of the kidney. By inhibiting SGLT2, these agents decrease reabsorption of
glucose, increase urinary glucose excretion, and lower blood glucose.
These agents are given once daily in the morning. These agents should be avoided in patients
with renal dysfunction.
Adverse effects: Vulvovaginal candidiasis, Urinary tract infections, Hypotension (elderly, those
on diuretics.)

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Incretin mimetics
Exenatide and liraglutide are injectable incretin mimetics used for the treatment of type 2
diabetes.
Mechanism of action
The incretin mimetics are analogs of GLP-1 that exert their activity by acting as GLP-1 receptor
agonists. These agents improve glucose dependent insulin secretion, slow gastric emptying
time, reduce food intake by enhancing satiety (a feeling of fullness), decrease postprandial
glucagon secretion, and promote β-cell proliferation.
Being polypeptides, Exenatide and liraglutide must be administered subcutaneously. Because of
the short duration of action, Exenatide should be injected twice daily within 60 minutes prior to
morning and evening meals. The main adverse effects of the incretin mimetics consist of
nausea, vomiting, diarrhea, and constipation.
Insulin
Insulin is a polypeptide hormone consisting of two peptide chains that are connected by
disulfide bonds. It is synthesized as a precursor (proinsulin) that undergoes proteolytic cleavage
to form insulin and C-peptide. Insulin is secreted from pancreatic βcells.
Mechanism of Action
Insulin binds to specific high-affinity receptors located in the plasma membrane. This leads to
recruitment of glucose transporters (GLUT-1 and GLUT-4) into the plasma membrane.
Actions
 Inhibits glucose production and increases glycolysis
 Increases protein synthesis
 Increases glucose transport and glycolysis in muscle
Insulin preparations
Rapid acting
Insulin glulisine, insulin aspart, and insulin lispro. (See figure 19)
Short acting
Regular insulin: this type of insulin starts its action within 30-60 minutes and its duration of
action is 8-10hrs. Regular insulin should be injected subcutaneously 30 minutes before a meal.
Intermediate-acting insulin

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Neutral protamine Hagedorn (NPH) insulin, is an intermediate-acting insulin. NPH insulin
should be given only subcutaneously (never IV), and it should not be used when rapid glucose
lowering is needed. It starts it action within 2 to 4 hrs. And it duration of action is 12-18 hrs.

Figure 19 Rapid acting insulin preparations

Long-acting insulin preparations

It has a slower onset than NPH insulin and a flat, prolonged hypoglycemic. As with NPH insulin,
insulin glargine and insulin detemir are used for basal control and should only be administered
subcutaneously.

Insulin combinations
Mixtard insulin: 70% NPH insulin plus 30% regular insulin.

Figure 20 Intermediate and long acting insulin preparations

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Thyroid and pituitary Drugs
The thyroid gland facilitates normal growth and maturation by maintaining a level of
metabolism in the tissues that is optimal for their normal function. The two major thyroid
hormones are triiodothyronine (T3; the most active form) and thyroxine (T4).

Figure 21 Thyroid hormone synthesis and secretion

Drugs for Hypothyroidism

Thyroid hormone preparations
Levothyroxine sodium, a synthetic sodium salt of T4 that maintains normal T4 and T3 levels.
Liothyronine sodium, a synthetic sodium salt of T3.
Although liothyronine (T3) is three to four times more potent than levothyroxine, it is not
recommended for routine replacement therapy because of its shorter half-life (24 hours), which
requires multiple daily doses.
Pharmacokinetics
Both T4 and T3 are absorbed after oral administration. Food, calcium preparations, and
aluminum-containing antacids can decrease the absorption of T4. The hormones are excreted
in the bile.
Adverse effects: are related T4 levels
Nervousness, palpitations and tachycardia, heat intolerance, and unexplained weight loss.

Drug Interactions
Drugs such as phenytoin, rifampin, and phenobarbital, accelerate metabolism of the thyroid
hormones and may decrease the effectiveness.

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Drugs for Hyperthyroidism
Antithyroid drugs
Thioamides: propylthiouracil (PTU) and methimazole (Carbimazole). Thioamides interfere with
the organification and coupling of iodide by inhibiting the peroxidase enzyme. PTU inhibits the
conversion of T4to T3. Thioamides are eliminated in the urine.
Methimazole is preferred over PTU because it has a longer half-life, allowing for once-daily
dosing, and a lower incidence of adverse effects. PTU is recommended during the first
trimester of pregnancy due to a greater risk of teratogenic effects with methimazole. Given the
concerns about potential propylthiouracil (PTU)-associated hepatotoxicity, methimazole is
suggested for nursing mothers.
Adverse effects
Most reactions occur early, especially nausea and gastrointestinal distress. The most common
adverse effect is a maculopapular pruritic rash. An increased risk of severe hepatitis, sometimes
resulting in death, has been reported with propylthiouracil. The most dangerous complication is
agranulocytosis.

Anterior Pituitary Drugs

Growth hormone (Somatotropin)
Growth hormone, an anterior pituitary hormone, is required during childhood and adolescence
for attainment of normal adult size. Individuals with congenital or acquired deficiency of GH
during childhood or adolescence fail to reach their predicted adult height and have
disproportionately increased body fat and decreased muscle mass. Circulating endogenous GH
has a half-life of 20–25 minutes and is predominantly cleared by the liver. Recombinant human
GH (rhGH) is administered subcutaneously 6–7 times per week. Peak levels occur in 2–4 hours
and active blood levels persist for approximately 36 hours.
Uses
Growth hormone deficiency
AIDS wasting syndrome
Many consider GH an “antiaging” hormone.

Athletes seeking to enhance performance

Adverse effects
Pain at the injection site, Edema, Arthralgia, Increased risk of diabetes.

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Somatostatin (Growth hormone-inhibiting hormone)
Octreotide is the most widely used somatostatin analog.
Its half-life is longer than somatostatin.

Therapeutic uses
Treatment of acromegaly
Diarrhea and flushing associated with Carcinoid syndrome
Bleeding Esophageal varices
Adverse effects: diarrhea, abdominal pain, flatulence, nausea

Gonadotropins
The gonadotropins (FSH and LH) are glycoproteins that are produced in the anterior pituitary.
Menotropins (also known as human menopausal gonadotropins or hMG) contain both FSH
and LH.
Urofollitropin is FSH only Follitropin alfa and follitropin beta are human FSH products.
Human chorionic gonadotropin (hCG).
Therapeutic uses
Induce ovulation in women

Male infertility
All the gonadotropin preparations are administered by subcutaneous or intramuscular
injection, usually on a daily basis.
Prolactin
Prolactin is a peptide hormone that is also secreted by the anterior pituitary. Its primary
function is to stimulate and maintain lactation. Its secretion is inhibited by dopamine acting at
D2receptors. It decreases sexual drive and reproductive function.
Dopamine Agonist

 Bromocriptine
 Cabergoline
 Quinagolide

All available dopamine agonists are active as oral preparation.

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Therapeutic uses
Hyperprolactinemia
To prevent breast engorgement when breast-feeding was not desired

Acromegaly
Adverse effects
Nausea, headache and, sometimes, psychiatric problems.

Posterior pituitary Drugs

Oxytocin
Oxytocin is used in obstetrics to stimulate uterine contraction and induce labor. Oxytocin also
causes milk ejection. Although toxicities are uncommon when the drug is used properly,
hypertension, uterine rupture, water retention, and fetal death have been reported.
Vasopressin

Vasopressin is a peptide hormone released by the posterior pituitary.

Desmopressin
Desmopressin can be administered intravenously, subcutaneously, intranasally, or orally.
Clinical uses
Vasopressin and desmopressin are treatments of choice for pituitary diabetes insipidus.
Adverse effects: Headache, nausea, abdominal cramps, agitation, and allergic reactions occur
rarely.

Gonadotropin releasing hormone & its analogs

Gonadotropin-releasing hormone is secreted by neurons in the hypothalamus. Gonadorelin is
an acetate salt of synthetic human GnRH. Synthetic analogs of GnRH include goserelin, histrelin,
leuprolide, nafarelin, and triptorelin. Gonadorelin can be administered intravenously or
subcutaneously.
GnRH analogs can be administered subcutaneously, intramuscularly, via nasal spray (nafarelin),
or as a subcutaneous implant.
Therapeutic uses
Female infertility, Uterine leiomyomata (uterine fibroids), Prostate cancer.

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GnRH Receptor Antagonist
Ganirelix, cetrorelix, and degarelix inhibit the secretion of FSH and LH. Ganirelix and cetrorelix
are absorbed rapidly after subcutaneous injection.

Estrogens
Over-view
Sex hormones produced by the gonads are necessary for conception, embryonic maturation,
and development of primary and secondary sexual characteristics at puberty. The gonadal
hormones are used therapeutically in replacement therapy, for contraception, and in
management of menopausal symptoms. All gonadal hormones are synthesized from the
precursor, cholesterol.

Estrogens
Estradiol, also known as 17β-estradiol, is the most potent estrogen produced and secreted by
the ovary. It is the principal estrogen in premenopausal women.
Estrone is the primary circulating estrogen after menopause, and it is generated mainly from
conversion of androstenedione in peripheral tissues.
Estriol is present in significant amounts during pregnancy, because it is the principal estrogen
produced by the placenta.

Mechanism of action
Steroid hormones diffuse across the cell membrane and bind with high affinity to specific
nuclear receptor proteins. The activated steroid–receptor complex interacts with nuclear
chromatin to initiate hormone-specific RNA synthesis. This results in the synthesis of specific
proteins that mediate a number of physiologic functions.

Therapeutic uses
Postmenopausal HT
1. The primary indication for estrogen therapy in postmenopausal women is menopausal
symptoms, such as vasomotor instability (for example, “hot flashes” or “hot flushes”) and
vaginal atrophy.
Note: The amount of estrogen used in replacement therapy is substantially less than the doses
used in oral contraception.
2. Contraception: The combination of an estrogen and progestogen provides effective
contraception via the oral, transdermal, or vaginal route.

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3. Other uses: primary hypogonadism, premature menopause or premature ovarian failure.
Pharmacokinetics
1. Naturally occurring estrogens: These agents are readily absorbed through the
gastrointestinal tract, skin, and mucous membranes. Taken orally, estradiol is rapidly
metabolized (and partially inactivated) by the microsomal enzymes of the liver.
2. Synthetic estrogen analogs: These compounds, such as ethinyl estradiol, mestranol and
estradiol valerate, are well absorbed after oral administration.
The synthetic estrogen analogs have a prolonged action and a higher potency compared to
those of natural estrogens.
Bioavailability of estrogen taken orally is low due to first pass metabolism.
To reduce first-pass metabolism, the drugs may be administered via the transdermal route
(patch, topical gel, topical emulsion, or spray), intravaginally (tablet, cream, or ring), or by
injection. Inactive products are excreted in urine.

Adverse effects

 Nausea
 Breast tenderness
 Risk of thromboembolic events
 Increased risk of endometrial and breast cancer.
 Hypertension

Selective Estrogen modulators

These drugs include
Tamoxifen, toremifene, raloxifene, clomiphene, and ospemifene.
Mechanism of action
Tamoxifen, toremifene, and raloxifene, compete with estrogen for binding to the estrogen
receptor in breast tissue. Also, raloxifene acts as an estrogen agonist in bone, leading to
decreased bone resorption, increased bone density, and decreased vertebral fractures. Unlike
estrogen and tamoxifen, raloxifene does not have appreciable estrogen receptor agonist
activity in the endometrium and, therefore, does not predispose to endometrial cancer.
Raloxifene also lowers serum total cholesterol and low-density lipoprotein (LDL).
Clomiphene acts as a partial estrogen agonist and interferes with the negative feedback of
estrogens on the hypothalamus. This effect increases the secretion of gonadotropin-releasing
hormone and gonadotropins, thereby leading to stimulation of ovulation.

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Therapeutic uses
Tamoxifen is currently used in the treatment of metastatic breast cancer. Both tamoxifen and
raloxifene can be used as prophylactic therapy to reduce the risk of breast cancer in high-risk
patients. Raloxifene is also approved for the prevention and treatment of osteoporosis in
postmenopausal women. Clomiphene is useful for the treatment of infertility associated with
an ovulatory cycles.
Pharmacokinetics
The SERMs are rapidly absorbed after oral administration. These agents undergo enterohepatic
cycling, and the primary route of excretion is through the bile into feces.
Adverse effects

 Hot flashes
 Tamoxifen is associated with increased risk of endometrial cancer.
 Hot flashes and leg cramps are common adverse effects with raloxifene.
 Increased risk of DVT and Pulmonary embolism.
 Cholestyramine can significantly reduce the absorption of raloxifene, and concurrent
use should be avoided.
Adverse effects of clomiphene are dose related and include headache, nausea, vasomotor
flushes, visual disturbances, and ovarian enlargement. Use of clomiphene increases the risk of
multiple births (twins or triplets).

Progestogens
Progesterone, the natural progestogen, is produced in response to luteinizing hormone (LH) by
both females and males.
Mechanism of action
In females, progesterone promotes the development of a secretory endometrium that can
accommodate implantation of a newly forming embryo. If conception takes place,
progesterone continues to be secreted, maintaining the endometrium in a favorable state for
the continuation of the pregnancy and reducing uterine contractions.
Therapeutic uses of progestogens

 Contraception
 Desogestrel, dienogest, drospirenone, levonorgestrel, norethindron,
(Medroxyprogesterone acetate is an injectable contraceptive.)
 Hormone replacement therapy
 Control of dysfunctional uterine bleeding
 Treatment of Dysmenorrhea, Infertility.

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Pharmacokinetics
Synthetic progestins are less rapidly metabolized. Oral medroxyprogesterone acetate has a
half-life of 30 days. When injected intramuscularly or subcutaneously, it has a half-life of
about 40 to 50 days and provides contraceptive activity for approximately 3 months. The
other progestins have half-lives of 1 to 3 days, allowing for once-daily dosing.
Adverse effects
Headache, Depression, Weight gain, Change in lipido, Acne, Depression, Hirsutism.
Mifepristone: is a progesterone antagonist with partial agonist activity. Administration of
this drug to females early in pregnancy usually results in abortion. Mifepristone is often
combined with the prostaglandin analog misoprostol (administered orally or intravaginally)
to induce uterine contractions. The major adverse effects are significant uterine bleeding
and the possibility of an incomplete abortion.

Contraceptives
Major classes of contraceptives
1. Combination oral contraceptives
Products containing a combination of an estrogen and a progestin are the most common
type of oral contraceptives. With most oral contraceptives, active pills are taken for 21 to 24
days, followed by 4 to 7 days of placebo, for a total regimen of 28 days. The most common
estrogen in the combination pills is ethinyl estradiol. The most common progestins are
norethindrone, norethindrone acetate, levonorgestrel, desogestrel, norgestimate, and
drospirenone.
2. Transdermal patch
An alternative to combination oral contraceptives is a transdermal patch containing ethinyl
estradiol and the progestin norelgestromin. One contraceptive patch is applied each week
for 3 weeks to the abdomen, upper torso, or buttock. No patch is worn during the 4th week.
The transdermal patch has efficacy comparable to that of the oral contraceptives, but it is
less effective in women weighing greater than 90 kg. Total estrogen exposure with the
transdermal patch may be significantly greater than that seen with oral contraceptives.
Increased exposure to estrogen may increase the risk of adverse events such as
thromboembolism.

3. Vaginal ring
An additional contraceptive option is a vaginal ring containing ethinyl estradiol and
etonogestrel. The ring is inserted into the vagina and is left in place for 3 weeks and then

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removed. The contraceptive vaginal ring has efficacy, contraindications, and adverse effects
similar to those of oral contraceptives.
4. Progestin-only pills
Products containing a progestin only, usually norethindrone (called a “mini-pill”), are taken
daily on a continuous schedule. Progestin-only pills deliver a low, continuous dosage of
drug. These preparations are less effective than combination products. The progestin-only
pill may be used for patients who are breast-feeding (unlike estrogen, progestins do not
have an effect on milk production), are intolerant to estrogen, are smokers, or have other
contraindications to estrogen-containing products.
5. Injectable progestin
Medroxyprogesterone acetate is a contraceptive that is administered via intramuscular or
subcutaneous injection every 3 months. Weight gain is a common adverse effect. Because
this product provides high sustained levels of progestin, many women experience
amenorrhea with medroxyprogesterone acetate. In addition, return to fertility may be
delayed for several months after discontinuation. Medroxyprogesterone acetate may
contribute to bone loss and predispose patients to osteoporosis and/or fractures.
Therefore, the drug should not be continued for more than 2 years unless the patient is
unable to tolerate other contraceptive options.
6. Progestin implants
After subdermal placement, the etonogestrel implant offers contraception for
approximately 3 years. The implant is nearly as reliable as sterilization, and the effect is
totally reversible when surgically removed. Principal side effects of the implant are irregular
menstrual bleeding and headaches.
7. Progestin intrauterine device
A levonorgestrel-releasing intrauterine system offers a highly effective method of
contraception for 3 to 5 years depending on the system. It is a suitable method of
contraception for women who desire long-term contraception and those who have
contraindications to estrogen therapy. It should be avoided in patients with pelvic
inflammatory disease or a history of ectopic pregnancy.
Postcoital contraception
Emergency contraception uses high doses of levonorgestrel (preferred) or high doses of
ethinyl estradiol plus levonorgestrel. For maximum effectiveness, emergency contraception
should be taken as soon as possible after unprotected intercourse and preferably within 72
hours. An alternative emergency contraceptive is the progesterone agonist/antagonist
ulipristal. It is indicated for emergency contraception within 5 days of unprotected
intercourse.

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 Mechanism of action
Estrogen provides a negative feedback on the release of LH and follicle-stimulating hormone
(FSH) by the pituitary gland, thus preventing ovulation. Progestin also thickens the cervical
mucus, thus hampering the transport of sperm.

Adrenal Hormones
Corticosteroids
The corticosteroids bind to specific intracellular cytoplasmic receptors in target tissues.
Glucocorticoid receptors are widely distributed throughout the body, whereas
mineralocorticoid receptors are confined mainly to excretory organs, such as the kidney,
colon, salivary glands and sweat glands.
Glucocorticoids
Cortisol is the principal human glucocorticoid. Normally, its production is diurnal, with a
peak early in the morning followed by a decline and then a secondary, smaller peak in the
late afternoon. Factors such as stress and levels of the circulating steroid influence
secretion.

The effects of cortisol are many and diverse.

 Glucocorticoids favor gluconeogenesis.

 Increase resistance to stress

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  Glucocorticoids cause a decrease in eosinophils, basophils, monocytes, and
lymphocytes. Glucocorticoids also increase hemoglobin, erythrocytes, and platelets.
 Have anti-inflammatory action.

Mineralocorticoids
Mineralocorticoids help to control fluid status and concentration of electrolytes, especially
sodium and potassium. Aldosterone acts on distal tubules and collecting ducts in the kidney,
causing reabsorption of sodium, bicarbonate, and water.
Therapeutic uses of the corticosteroids
1. Replacement therapy for primary adrenocortical insufficiency (Addison disease):
Hydrocortisone which is identical to natural cortisol, is given to correct the deficiency.
Administration of fludrocortisone, a potent synthetic mineralocorticoid may also be necessary
to supplement mineralocorticoid deficiency.
2. Relief of inflammatory symptoms: Corticosteroids significantly reduce the manifestations of
inflammation associated with rheumatoid arthritis and inflammatory skin conditions, including
redness, swelling, heat, and tenderness that may be present at the site of inflammation.
3. Treatment of allergies

4. Acceleration of lung maturation

Pharmacokinetics
Orally administered corticosteroid preparations are readily absorbed. Selected compounds can
also be administered intravenously, intramuscularly, intra-articularly. The metabolites are
conjugated to glucuronic acid or sulfate, and the products are excreted by the kidney.
Prednisone is preferred in pregnancy because it minimizes steroid effects on the fetus.
Adverse effects
Osteoporosis, Cushing-like syndrome (redistribution of body fat, puffy face, hirsutism, and
increased appetite. Cataract, Hyperglycemia, Increased risk of infection, Hypertension.
Discontinuation
Sudden discontinuation of these drugs can be a serious problem if the patient has suppression
of the hypothalamic pituitary axis. In this case, abrupt removal of corticosteroids causes acute
adrenal insufficiency that can be fatal.
Inhibitors of adrenocorticoid biosynthesis or function
Ketoconazole, Spironolactone, Eplerenone

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