Pharmacokinetics Review – Absorption, Distribution, Metabolism, Excretion

These flashcards cover key principles and examples from the lecture on pharmacokinetics, including absorption, distribution, metabolism (Phase I & II, enzyme modulation), and renal excretion strategies.

Four major pharmacokinetic processes

Absorption, Distribution, Metabolism, Excretion (ADME).

Drug absorption

The movement of a drug into the bloodstream after administration.

Physicochemical properties favoring membrane permeation during absorption

Unionized, non-polar, lipophilic characteristics.

Primary absorption site for acidic drugs

The stomach.

Reason for acidic drug absorption in the stomach

They are protonated (AH), unionized, non-polar, and lipophilic in an acidic environment.

Primary absorption site for basic drugs

The intestine (small intestine).

Reason for basic drug absorption in the intestine

At higher pH they are deprotonated (B), unionized, non-polar, and lipophilic.

Characteristics of ionized drugs

Polar and water-soluble.

Characteristics of unionized drugs

Non-polar and lipid-soluble (water-insoluble).

Protonation

The addition of a proton (H⁺) to a molecule.

Drug form when pH < pKa

Protonated form (AH or BH⁺).

Drug form when pH > pKa

Deprotonated form (A⁻ or B).

Absorbable form of an acidic drug

The protonated unionized form (AH).

Absorbable form of a basic drug

The deprotonated unionized form (B).

Benzyl penicillin (pKa 2.76) form at gastric pH 1.5

Protonated acid (AH).

Absorption of benzyl penicillin in the stomach

Yes, because it is an acidic drug in its unionized form.

Tetracycline (pKa 7.8) form and absorption at gastric pH 1.5

Protonated base (BH⁺); not absorbed.

Tetracycline (pKa 7.8) form and absorption at intestinal pH 9.5

Deprotonated base (B); yes, it is absorbed.

Benzyl penicillin (pKa 2.76) form and absorption at intestinal pH 9.5

Deprotonated acid (A⁻); no, because it is ionized.

Drug distribution

The process of delivering a drug from the bloodstream to body tissues.

Drug form that readily crosses capillary fenestrations

Free (unbound) drug.

Properties increasing drug distribution ability (besides being free)

Small molecular size and lipophilicity.

Characteristic required for hydrophilic drugs to pass fenestrations

Small size.

Formula for Volume of Distribution (Vd)

Vd = \frac{\text{Dose}}{\text{Plasma concentration (C₀)}}

Indication of high plasma drug concentration regarding Vd

Low Vd.

Indication of low plasma drug concentration regarding Vd

High Vd.

Implication of high Vd regarding tissue binding

Extensive distribution into tissues.

Drug metabolism

The biochemical breakdown or biotransformation of drugs in the body.

Primary goal of drug metabolism

To produce water-soluble metabolites for easier excretion.

Alternative name for Phase I metabolism

Functionalization.

Main Phase I reactions

Oxidation, Reduction, Hydrolysis.

Functional groups introduced or exposed by Phase I metabolism

Functional groups such as -OH, -NH₂, -SH.

General characteristics of Phase I metabolites

Often still active and more polar.

Alternative name for Phase II metabolism

Conjugation.

Purpose of Phase II (conjugation) metabolism

Attach hydrophilic groups to further increase water solubility or detoxify the metabolite.

Common Phase II reactions

Glucuronidation, Sulfation, Methylation, Acetylation (plus GSH and glycine conjugation).

Phase II reactions that may not increase polarity

Methylation and Acetylation.

Mnemonic for enzyme inducers

CRAP GPS.

Examples of enzyme inducers

Carbamazepine, Rifampicin, Phenytoin (also Phenobarbital, Alcohol, Griseofulvin, Sulfonylureas).

Mnemonic for enzyme inhibitors

SICKFACES.COM.

Examples of enzyme inhibitors

Cimetidine, Ketoconazole, Erythromycin (also Isoniazid, Ciprofloxacin, Chloramphenicol, etc.).

Effect of an enzyme inducer on active drug metabolism and therapeutic effect

Increases metabolism; may decrease therapeutic effect.

Effect of an enzyme inhibitor on active drug metabolism and therapeutic effect/toxicity

Decreases metabolism; may increase therapeutic effect/toxicity.

Effect of inducers/inhibitors on prodrugs

Induction increases activation (\uparrow effect); inhibition decreases activation (\downarrow effect).

Phenytoin classification as an enzyme modulator

Inducer.

Effect of Phenytoin on active Drug C: metabolism and effect

Metabolism will increase; Drug C effect will decrease.

Ketoconazole classification as an enzyme modulator

Inhibitor.

Effect of Ketoconazole on active Drug D: metabolism and effect

Metabolism will decrease; Drug D effect will increase.

Ideal characteristics of metabolites for renal excretion

Small, ionized (charged), and polar.

Three renal elimination mechanisms

Glomerular filtration, Active tubular secretion, Passive tubular reabsorption.

Metabolites readily passively reabsorbed

Non-polar (unionized) metabolites.

Urine pH for enhanced excretion of an acidic drug

Basic (alkaline).

Urine pH for enhanced excretion of a basic drug

Acidic.

Examples of urinary acidifiers

Ammonium chloride, Ascorbic acid (also Citric acid, Methenamine).

Examples of urinary alkinizers

Sodium bicarbonate, Acetazolamide (also Sodium citrate, Potassium citrate).