Pharmacology Review

Characteristics of Drugs

 Acidic or basic
 Acidic drugs:
 Bind to albumin
 Low Vd (H20)- # less distributed; faster leaving body
 Often hydrophilic
 Outside CNS
 More free drug
 Often renally excreted
 less extensively metabolized
 Antibiotics, NSAIDS, ASA
 Basic drugs:
 Bound to alpha 1-acid glycoprotein
 Often Lipophilic
 High Vd (fat)- # more distributed; slower leaving body
 Less free drug
 Usually metabolized
 First-pass
 Local anesthetics, opiod analgesics, sedative/hypnotics, cardiac,
anti-emetics, antipsychotics, antidepressants

Pharmacology-relationship of dose given to response seen

Therapeutic Range: when a drug works to the minimum toxic range

Digoxin-0.8-2

PCN-no special # but range

Pharmacokinetics: relationship of the dose of drug given a patient to the concentration

of drug achieved in the blood stream

(Liberation-must be in solution form)

1. Absorption
2. Distribution
3. metabolism (biotransformation)
4. excretion (ADME)
1. Absorption-
a. Lipophilic-favorable (i.e. propranolol)-crosses blood brain barrier
b. Hydrophilic-does not work in brain
 If nervous or in pain the stomach does not empty
 In gastric bypass, IBS, and Crohn’s there is decreased absorption
 Bioavailability-describes the extent of drug absorption
 First-pass effect (p. 33)-drug is biotransformed by enzymes prior to
reaching systemic circulation which leads to extensive inactivation in liver;
reduces bioavailability; sites-GI tract (splenic circulation), liver-usually
greatest for drugs which are extensively and efficiently metabolized
 Reglan-makes stomach empty

2. Distribution-
a. Physiologic factors
i. Blood flow-CO
ii. Body composition-lean=muscle needs dose more frequently
v. fat=needs increase dosage of drug
iii. Protein binding-“opposites attract”-alpha1 acid glycoprotein
(increases with pain or any stressors therefore decreasing
the drug available therefore increasing protein bindings)-
basic, albumin (low protein)-all other drugs
b. Physical/Chemical factors of Drug

3. Biotransformation (Metabolism)-
a. usually enzymatic therefore could be used up and lead to
interactions
b. Purpose/Goal: to inactivate and eventually eliminate drug not easily
cleared through the kidney by making more water soluble –liver
only modifies
i. Hepatic Biotransformation-
1. Phase I-oxidative reduction
a. Usually occurs first and introduce or expose a
functional group on the drug molecule
increasing polarity
b. Oxidation, reduction, hydrolysis
 2. Phase II-excreted in bile
a. Conjugating reactions
b. Glucuronide (ASA, diazepam)
 Entero-hepatic recycling=can be
reactivated in GI leading to
toxicity
ii. Inhibition of metabolism-increased drug leads to increased
effect; one drug on enzyme, the other is not (toxicity)
iii. Induction-results in decrease effect of object drug; one drug
potentiates action of another drug
 Increased amount of enzyme therefore
increased liver size due to increased number of
enzymes; increased inducer therefore change
induction and increase dose

4. Excretion-physical removal
a. Removal of intact drug
i. Non-volatile
ii. Water soluble
iii. Low molecular weight
iv. No or slow biotransformation
b. Primarily accomplished by kidney-depends on blood flow and
nephron function-diseased kidney could diffuse larger molecules
therefore causing toxicity
 Interactions can occur when more than one drug
being excreted

***Clearance-determines dosage based on disease

 volume of blood from which drug is removed in a period of time (volume

determines loading dose)
 represents the intrinsic ability of organs to eliminate drug from blood
 determines the size of the daily maintenance dose required to maintain a target
concentration
***Half-life-determines frequency of dosage

 Length of time required for concentration of drug in the blood stream to be

reduced to half of the original concentration (decrease concentration of body by
50%)
 assumes first-order elimination- a constant proportion of dose eliminated per unit
of time
 approximately five half-lives are required to reach steady state

Pharmacodynamics

 relationship of concentration of drug in the blood stream to the effect at site of

action

 Adverse effects:
 Side effects-right amount causing other event
 Predictable
 Cannot prevent, but can select agent to minimize
 Nausea with opiods, dry mouth with antihistamines, drowsiness
with anti-emetics
 Toxic effects-too much drug; beyond therapeutic dose
 May be related to age, size, disease states, other drugs, etc.
 Predictable
 Should be preventable with good medical and medication history
and examination
 Allergic Reactions (drug hypersensitivity)
 Reactions to medications mediated by the immune system
 Not predictable
 Preventable after 1st occurrence
 Types I, II, III, IV
 Interference with Natural Defense Mechanisms
 Secondary effect of the medication caused by action of the
medication on the body
 Primary effect is not adverse
 Abx in GI tract decrease normal flora therefore decreasing
potassium absorption which leads to increased bleeding time (can
interact with Warfarin)
  Teratogenic effects-adverse effects to developing fetus when medication
is administered to pregnant mothers
 FDA Pregnancy Risk Category

Acceptable

Better Drugs

Caution

Dangerous

X-contraindicated

 Idiosyncratic reactions
 Unexpected reactions to a medication administered in normal
dosages
 Agitation from diphenhydramine
 Disinhibition from benzodiazepines-agitation, aggression,
combative

Mechanisms of Drug Interactions

 Drug Interactions
o Physical incompatibility-precipitates, inactivates, complex
o Additive Pharmacologic effect-same effect that adds to or is synergistic
(CNS depression & opiods)
 Most common (theophylline & albuterol-stimulation with sedation)
o Altered Host
o Common Pharmacokinetic pathway
 Most complex
 Clinical Significance of Drug Interactions
o Drug
 Narrow therapeutic range=potential for interaction due to when it
works and when toxic (fine line); i.e. lithium, digoxin, Gentamycin,
Tobramycin, Dilantin, Theophylline, Warfarin; drug level monitoring
 Serious consequence of Toxicity
 Serious consequence of Reduced Efficacy
o Compromised Host
 Neonates-decreased clearance
 Elderly-decreased processes
 Disease states (i.e.-no NSAIDS in transplant patients because can
lead to decreased blood flow)
 Physical incompatibility
o Inactivation (degradation)-ampicillin and gentamycin-amp inactivates gent
(IV infusions and even blood samples)
o Precipitation-primary reason; one drug changes solution of other drug;
Diazepam (lipophilic) does not dissolve in H20; decreased solution in H20
therefore precipitate (Vanc and Fortaz)
o Chelation-oral agents
Trivalent cations
 If administered with metal cation it is not absorbed
 Tetracyclines (Tetracycline, Minocycline, Doxycycline)
 No tetracyclines in kids because will have black lines on
teeth; in adults long-term can discolor teeth
 Quinolones (gram -/UTI)-Ciprofloxacin, Enoxacin, Lomefloxacin,
Ofloxacin
 Antacids
 Mineral supplements (Fe, Zn, Al, Ca)
 Dairy products
 Enteral feedings

o Solutions
 Administer at least 2 hours apart and bolus fluids before and after
ANTI-INFECTIVES

 Acidic drugs
 Agents that inhibit synthesis or disrupt bacterial cell wall-bacteriocytic
o Beta-lactams (PCNs, cephalosporins)
o Cycloserine
o Vancomycin
o Bacitracin
o Isoniazid
 Beta-lactams
o Penicillins
 Can treat anaerobic bacteria but cannot treat bone because it
cannot penetrate
 Time dependent killing-length of time important
 Lethal to bacterial undergoing active growth and division-do not
give bacteriostatic and bactericidal together it decreases efficacy
but may be needed to due to resistance
 Resistance
 Destruction of beta-lactam ring by bacterial enzymes
 Inability to reach target due to barrier on cell wall-
pseudomonas (CF patients)
 Natural Penicillins
 Penicillin G
 Penicillin VK (K aides in absorption)
 Gram + spectrum
 Degraded by acid and enzymes in stomach
 Amoxicillin
 Penicillinase Resistant Penicillins
 Resistant to hydrolysis by staphylococcal penicillinase
 Nafcillin
 Oxacillin
 Dicloxacillin
 Amino-penicillins-“oral workhorses”
 Broader Spectrum
 Ampicillin
 Amoxicillin
o Most stable in GI tract
o May be taken with food, milk, or juice
o Food may delay peak concentrations
  Bacampicillin
 Amoxicillin/Clavulanic acid (Augmentin)-use BID instead of
TID
 Gram + and a few Gram – (H. influenza-URI, sinusitis)
 Food may delay but not decrease
 Antipseudomonal Penicillins
 Increased activity against pseudomonas and proteus
 Indanyl carbenicillin (Geocillin)
 Ticarcillin (Ticar)
 Ticarcillin/clavulanic acid (timentin)
 Mezlocillin (mezlin)
 Piperacillin (Pipracil)
 Piperacillin/Tazobactam (Zosyn)
 Stops enzyme activity
 Drug related concerns of Penicillins
 Allergy
 Increased bleeding with patients taking warfarin
 Decreased efficacy of oral contraceptives because of
decreased estrogens due to enterohepatic recycling
 Chemical inactivation of aminoglycosides-therefore could
cause toxicity due to false low drug levels
 Beta-lactamase Inhibitors-
 Clavulanic acid: active against Gram + and Gram – beta-
lactamases. Combined with amoxicillin and ticarcillin.
 Sulbactam: combined with ampicillin (Unasyn) and
cefoperazone (Sulperazone)
 Tazobactam: Binds plasmid (plasmids-extrachromosomal
rings of DNA in bacteria that can replicate themselves) and
chromosomally medicated enzymes. Most potent inhibitor of
Gram – produced beta-lactamases. Combined with
piperacillin (Zosyn)
o Cephalosporins-same mechanism of action as PCN’S
 Bacteriocidial
 Time dependent killing
 Lethal to bacterial undergoing active growth and division
 Better in hard tissue like bone
 Cannot treat anaerobic infection
 Resistance
 Destruction of beta-lactam ring by bacterial enzymes
  Inability to reach target
 Head to toe-Gram + (mild Gram -) to Gram -
 First Generation Cephalosporins
 Good Gram +, Moderate Gram –
 Parenteral: Cefazolin (Ancef, Kefzol, Zolicef), Cephapirin
(Cefadyl), Cephradine (Velosef)
 Oral: Cephalexin (Keflex, Keftab), Cephradine (Anspor,
Velosef, Eskacef), Cefadroxil (Duricef, Ultracef)-long
duration therefore increased compliance and decreased
frequency of dosage
 Similar spectrum to ampicillin and amoxicillin
 Not affected by food
 More slowly absorbed in children than PCN liquid form
 Second Generation Cephalosporins
 increased activity against Gram –
 URI, sinusitis, mild pneumonias
 Parenteral: Cefmetazole (Zefaxone), Cefonicid (Monocid),
Cefotetan (Cefotan), Cefoxitin (Mefoxin), Cefuroxime (Ceftin,
Kefurox, Zinacef)
 Oral: Cefaclor (Ceclor, Ceclor CD)-increase mg to increase
compliance, Cefprozil (Cefzil), Cefuroxime Axetil (Ceftin)-
increased GI upset due to decreased soluability in salt form;
indigestion and bad taste in mouth, Loracarbef (Lorabid)-can
give to mild PCN history cephalosporin molecule (no beta-
lactam ring)
 Third Generation Cephalosporins
 less active against Gram +, increased spectrum against
Gram –
 lower respiratory tract, UTI, STD’s
 like Zosyn in PCN’s
 Parenteral: Cefoperazone (Cefobid), Cefotaxime (Claforan),
Ceftazidime (Ceptaz, Fortaz, Tazidime, Tazicef)-
pseudomonas, Ceftizoxime (Cefizox), Ceftriaxone
(Rocephin)-N. gonnerhea, salmonella, Klebsiella, serattia
 Oral: Cefdinir (Omnicef), Cefditoren (Spectracef), Cefixime
(Suprax), cefpodoxime proxetil (vantin)-poorly soluble &
increased GI upset, Ceftibuten (Cedax)
 Fourth Generation Cephalosporins
 Cefepime (Maxipime)
  Psudomonas aeruginosa

Drug-related Concerns of Cephalosporin antibiotics

 Same as PCN’s
 Allergy, increased bleeding with warfarin, decreased efficacy
of OCPs
o Monobactams-1 beta-lactam ring
 Cross sensitivity with PCN
 Gram - bacteria
 Aztreonam (Azactam)
 Resistant to beta-lactamases produced by Gram-negative
bacteria (pseudomonias)
 Parenteral only
o Carbapenems
 Broad Spectrum
 Gram + and –
 Parenteral
 Neurotoxic
 Seizures (all antibiotics can cause, some more than others)-
lowest risk with meropenem
 Lots of cross-reactivity
 Ertapenem (Invanz)
 Not effective against p. aeruginosa or Acinetobacter-limited
spectrum of activity
 Imipenem-Cilastatin (Primaxin IM, IV)-some breakdown in
kidney
 Meropenem (Merrem IV)

END OF BETA-LACTAMS!!!!!!!!
 Vancomycin
o Not a beta-lactam so can give with PCN allergy
o MOA: inhibits the second stage of bacterial cell wall synthesis by binding
to precursor and also alters membrane permeability and RNA synthesis
o Active against Gram + bacteria
 MRSA
o Orally can treat C. difficile colitis-localized
o Infusion reaction
  Due to histamine release (red man syndrome)-not an allergic
reaction
 Rash, flushing, tachy, hypotensive
 Infuse no more than 1gram over 60 minutes-the higher the dose the
higher the length of infusion
o Thrombophlebitis
o Ototoxic-deafness; vestibule of ear-can be delayed and is permanent
o Nephrotoxic
o Trough: 5-10mg/L (likelihood of toxicity)
o Peak 20-40mg/L (efficacy of drug)
o Check serum creatinine (0.6-1.2mg/dl in males and 0.5-1.1mg/dl in
females)
 If increased could signal kidney problems

BACITRACIN

 MOA: inhibits bacterial cell wall synthesis leading to cell lysis and death
 Used topically due to systemic toxicity
 Often in combination with polymyxin B and neomycin (triple antibiotic ointments)

CYCLOSERINE

 MOA: inhibits cell wall synthesis

