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by Marc Imhotep Cray, M.D.Basic Medical Sciences Professor
Chemotherapy drugs in vials and an IV bottle. (Bill Branson Photographer;image courtesy of National Cancer Institute Visuals Online .)
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Companion NotesIVMS BASIC PHARM-General Principles,
Pharmacokinetics andPharmacodynamics Notes
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Drug Elimination IITopics:
Drug Excretion continued Drug Interactions
Pharmacogenetics
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Hepatic or Biliary Excretion
Some organic acids and bases are activelysecreted into the bile.
Some drugs are secreted into the bile.
Glucuronides of steroids and morphine are
actively secreted.
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The Enterohepatic Cycle
Prolongs drug half-life
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Enterohepatic Cycle
Liver
Common bile duct
Small intestine
Portal vein
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4 1
2
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Pulmonary Excretion
Factors:
Plasma solubility of drug Cardiac output Respiration
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Gaseous Anesthetics
*Rate of pulmonary excretion isproportional to alveolar tension of thegaseous drug and inversely
proportional to its plasma solubility.
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Gaseous Anesthetics: Rate of Rise inAlveolar Tension
1203 30 60
Alveolartension(mm Hg)
Time (min)
N2O
Halothane Ether
Least plasma-soluble
Most plasma-soluble
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Factors Affecting Drug Elimination
Clinical Relevance of Drug Metabolism
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Normal Dose Regimen May Lead to
Toxicity or Decreased Effectiveness
Age: Renal and Hepatic Metabolism Renal Disease Liver Disease
Drug Interactions
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Age and Hepatic MetabolicActivity
Hepatic drugmetabolic activity
Age
AdulthoodPubertyBirth Old age
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Renal Excretion Of Drugs
Clinical Importance of Renal Disease
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The Following Conditions Should AllApply for Renal Disease to be of ClinicalImportance in the Renal Excretion ofDrugs
Renal excretion of active drug is 50%. Renal function drops below 50% of normal
adult value.
Drug has low therapeutic index.
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Clinical Importance Of LiverDisease
Parenchymal liver disease.
Hepatic perfusion: cardiac failure, cirrhosis.
Affects mainly those drugs with high extractionratios.
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Drug Interactions:
Potential Sites of Interference Pharmacokinetic Interactions Pharmacodynamic Interactions
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1. Pharmacokinetic Interactions
Interactions that result in an alteration inthe concentration of the drug at its site of
action.
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Pharmacokinetic Interactions:
Gut Absorption Anticholinergicsmotility and abs.
Plasma Protein Binding Strongly bounddrugs displacemore weaklybound drugs.
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Drug Interactions Related to ProteinBinding
Moderately bound drugs (e.g., tolbutamide,
methotrexate, warfarin) are displaced by stronglybound drugs (salicylates, sulfonamides), whichcould lead to: hypoglycemia, blood dyscrasias,and hemorrhage, respectively, due to elevatedfree concentrations of the displaced drugs.
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Plasma proteinbinding
Metabolicenzymeinduction orinhibition
GI absorption
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Pharmacokinetic Interactions:
Liver metabolism:Enhance via induction.
Inhibit directly.
Renal tubular secretion:Inhibit secretion of weakacids.
Inhibit secretion of weakbases.
*Phenobarbital, phenytoin,phenylbutazone.
*Cimetidine, carbidopa,
MAOI, disulfiram.
*Penicillin, salicylates.
*Cimetidine.
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Phenobarbital Effects on PlasmaLevels of the Anticoagulant Warfarin
PB
PlasmaLevel of Warfarin
Time-to-Clot
Days12060 180
Days
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Grapefruit Juice: Interactions WithDrugs
* Inhibits first-pass elimination of drugsmetabolized by certain CYP P450s (3A4, 1A2,2A6), including:
Dihydropyridine Ca 2+ channel blockers. Cyclosporine Midazolam
Estrogens Caffeine
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Competition for Active Transportin Renal Tubules
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2. Pharmacodynamic Interactions
Interactions that alter the ability of a drugto exert an effect at its site of action.
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Pharmacodynamic Interactions
Target cell Tricyclic antidepressants
or Receptor block tissue uptake of theantihypertensive drugguanethidine.
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Pharmacogenetics or Pharmacogenomics
Definition: the use of genetic information to 1)explain interindividual differences in drugresponses or to 2) individualize dosages forpatients with known genetic polymorphisms.
Idiosyncratic Reaction: genetically determinedabnormal drug response.
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Genetic Basis For Abnormal DrugReactions
SEX-LINKED Trait carried on X-chrom. AUTOSOMAL Trait not carried on X-chrom. DOMINANT Expressed in heterozygotes
and homozygotes. RECESSIVE Expressed only in
homozygotes. CODOMINANT Alternative expressions of the
trait are possible.
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Monogenic Inheritance
Trait associated with a pair of genes(e.g., either rapid or slow acetylation).
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Bimodal Distribution of Patients:
Rapid and Slow Metabolizers ofIsoniazid.
Plasma [Isoniazid]
Rapid acetylators
Slow acetylators
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*All major deficiencies in drug-metabolizing activity are inherited
monogenically as autosomalrecessive traits.
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Some Genetic Polymorphisms ofDrug Metabolism
Isoniazid, caffeine (N-acetylation)
Ethanol (alcohol dehydrogenase, aldehydedehydrogenase) Debrisoquin (hydroxylation via CYP2D6)
Mephenytoin, omeprazole (hyroxylation viaCYP2D19)
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Polygenic Inheritance
The trait is phenotypically expressed as acontinuous variation with a normal
distribution.
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Frequency Distn Shows Normal Variability inPlasma Conc. After a Fixed Dose is Given to a
Large Patient Population
Plasma level
N
u m
b e r o f
I n d i v i d
u a l s
Some people display very lowor high plasma levels, but mostare in the middle.
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