55933033 ivms pharmacokinetics drug elimination 2

8/3/2019 55933033 IVMS Pharmacokinetics Drug Elimination 2

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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

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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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55933033 ivms pharmacokinetics drug elimination 2

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