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by Marc Imhotep Cray, M.D.

Basic Medical Sciences Professor

Companion Notes IVMS BASIC PHARMGeneral Principles, Pharmacokinetics and Pharmacodynamics Notes

Chemotherapy drugs in vials and an IV bottle. (Bill Branson Photographer; image courtesy of National Cancer Institute Visuals Online.)

Drug Elimination II
Topics: Drug Excretion continued Drug Interactions Pharmacogenetics

Hepatic or Biliary Excretion


Some organic acids and bases are actively secreted into the bile. Some drugs are secreted into the bile. Glucuronides of steroids and morphine are actively secreted.

The Enterohepatic Cycle

Prolongs drug half-life

Enterohepatic Cycle

Liver
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Portal vein
1

Common bile duct


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Small intestine
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Pulmonary Excretion

Factors:

Plasma solubility of drug Cardiac output Respiration

Gaseous Anesthetics
*Rate of pulmonary excretion is
proportional to alveolar tension of the gaseous drug and inversely proportional to its plasma solubility.

Gaseous Anesthetics: Rate of Rise in Alveolar Tension


Least plasma-soluble

N2 O Halothane
Alveolar tension (mm Hg)

Most plasma-soluble

Ether

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60 Time (min)

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Factors Affecting Drug Elimination


Clinical Relevance of Drug Metabolism

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 Metabolic Activity

Hepatic drug metabolic activity

Birth

Puberty

Adulthood

Old age

Age
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Renal Excretion Of Drugs


Clinical Importance of Renal Disease

The Following Conditions Should All Apply for Renal Disease to be of Clinical Importance in the Renal Excretion of Drugs
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 Liver Disease

Parenchymal liver disease. Hepatic perfusion: cardiac failure, cirrhosis.


Affects mainly those drugs with high extraction ratios.

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Drug Interactions:

Potential Sites of Interference Pharmacokinetic Interactions Pharmacodynamic Interactions

1. Pharmacokinetic Interactions

Interactions that result in an alteration in the concentration of the drug at its site of action.

Pharmacokinetic Interactions:
Gut Absorption

Anticholinergics motility and abs.

Plasma Protein Binding

Strongly bound drugs displace more weakly bound drugs.

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Drug Interactions Related to Protein Binding


Moderately bound drugs (e.g., tolbutamide, methotrexate, warfarin) are displaced by strongly bound drugs (salicylates, sulfonamides), which could lead to: hypoglycemia, blood dyscrasias, and hemorrhage, respectively, due to elevated free concentrations of the displaced drugs.

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Plasma protein binding

Metabolic enzyme induction or inhibition

GI absorption

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Pharmacokinetic Interactions:
Liver metabolism: Enhance via induction. *Phenobarbital, phenytoin, phenylbutazone.
Inhibit directly.

*Cimetidine, carbidopa, MAOI, disulfiram.

Renal tubular secretion: Inhibit secretion of weak *Penicillin, salicylates. acids. Inhibit secretion of weak *Cimetidine. bases.

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Phenobarbital Effects on Plasma Levels of the Anticoagulant Warfarin

Plasma Level of Warfarin


PB
60 120 Days 180

Time-toClot

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Grapefruit Juice: Interactions With Drugs


* Inhibits first-pass elimination of drugs
metabolized by certain CYP P450s (3A4, 1A2, 2A6), including: Dihydropyridine Ca2+ channel blockers. Cyclosporine Midazolam Estrogens Caffeine

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Competition for Active Transport in Renal Tubules

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2. Pharmacodynamic Interactions

Interactions that alter the ability of a drug to exert an effect at its site of action.

Pharmacodynamic Interactions

Target cell or Receptor

Tricyclic antidepressants block tissue uptake of the antihypertensive drug guanethidine.

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Pharmacogenetics or Pharmacogenomics

Definition: the use of genetic information to 1) explain interindividual differences in drug responses or to 2) individualize dosages for patients with known genetic polymorphisms. Idiosyncratic Reaction: genetically determined abnormal drug response.

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Genetic Basis For Abnormal Drug Reactions


SEX-LINKED AUTOSOMAL DOMINANT
Trait carried on X-chrom. Trait not carried on X-chrom.

Expressed in heterozygotes and homozygotes.


Expressed only in homozygotes. Alternative expressions of the trait are possible.

RECESSIVE CODOMINANT

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Monogenic Inheritance

Trait associated with a pair of genes (e.g., either rapid or slow acetylation).

Bimodal Distribution of Patients: Rapid and Slow Metabolizers of Isoniazid.


Rapid acetylators

Slow acetylators

Plasma [Isoniazid]
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*All major deficiencies in drugmetabolizing activity are inherited monogenically as autosomal recessive traits.

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Some Genetic Polymorphisms of Drug Metabolism


Isoniazid, caffeine (N-acetylation) Ethanol (alcohol dehydrogenase, aldehyde dehydrogenase) Debrisoquin (hydroxylation via CYP2D6)
Mephenytoin, omeprazole (hyroxylation via CYP2D19)

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Polygenic Inheritance

The trait is phenotypically expressed as a continuous variation with a normal distribution.

Frequency Distn Shows Normal Variability in Plasma Conc. After a Fixed Dose is Given to a Large Patient Population

Numberof Individuals

Some people display very low or high plasma levels, but most are in the middle.

Plasma level

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