How Drugs Get To Where They're Going (Pharmacokinetics)

27.2.06

Why do you need to know?
• Duration of drug action.
• Impact of disease on drug levels.
• Basis of many drug interactions.
• Management of overdoses.

Routes of drug administration
• Systemic.
-Oral.
-Parenteral (subcutaneous, intra-muscular, intra-venous).
-Rectal and transcutaneous.
• Topical.
-Skin preparations.
-Inhaled medications.
-Rectal and vaginal formulations.

Processes relevant to systemic use of drugs
• Absorption (not relevant to IV use).
• Distribution.
• Metabolism (biotransformation).
• Excretion.

Absorption
Lipid solubility
• Most drugs weak acids/bases.
• Drugs cross membranes when unionised.
• Look up Henderson-Hasselbach equation.

Other major factors
• Surface area: small bowel >> stomach (surface area).
• Blood flow: relevant to IM route.

Bioavailability = Proportion of a dose that gets from point of delivery unaltered to systemic circulation (metabolites reduce bioavailbility).

Benzyl penicillin falls apart in extremes of pH.
Amino glycosines are lipid insoluble - not absorbed.
Lygeryl trinitrate metabolised by liver - sublingual administration.

FIRST-PASS METABOLISM.

Distribution
Plasma protein binding
• α-1 acid glycoprotein - plasma protein to which drugs bind (+ albumin, ionically).
• Less albumin, drug more potent.
• Common cause of nephritic syndrome (kidney loses albumin) is diabetes mellitus → drop in plasma albumin concentration → toxic drug may cause adverse effects; extreme effects, both therapeutic and toxic.
• Acute phase reactant - group of proteins - concentration increases in inflammation, infection eg. α-1 acid glycoprotein.
• Drugs bound to α-1 acid glycoprotein less potent.
• Diffusion down concentration gradients.
• Changes in plasma protein concentration affects distribution.

Tissue distribution
• Blood-brain barrier junctions, active pumping (ability to keep things out of brain water), increased water solubility (polar eg. penicillin), decreased lipid solubility.
• Muscle - leaky junctions.
• Thiopentone - anaesthetic induction agent.

Metabolism - biotransformation
Principles of hepatic drug metabolism
• Most drugs relatively lipid-soluble.
• Readily absorbed, but more difficult to eliminate.
• Metabolism converts lipid-soluble drug to more water-soluble molecule.
• Usually terminates biologic activity.
• …But sometimes, the reverse.

Hepatic drug metabolism
• Phase I (decreasing weight).
-Oxidation, reduction, deamination, hydrolysis.
-Can be INDUCED and INHIBITED (look up - p. 450 of Walley/Winstanley).
-Metabolite may retain biologic activity.
• Phase II (increasing weight).
-Conjugation.
-Usually with glucoronate, acetate or sulphate.
-Metabolite lacks biologic activity.
• Pro-drug - no effect, needs Phase I to produce metabolite that has desired effect.

Excretion
• Mostly via kidney.
• Entereohepatic circulation - oestrogens.

Irreversible elimination
• Mainly kidney.
• Glomerular filtration.
• Tubular secretion.
• Tubular re-absorption.

LOOK UP ASPIRIN OVERDOSE.

Pharmacokinetic parameters
• Essentially, use of maths to describe drug disposition.
• Half-life.

Volume of distribution
• Measure of degree to which drug in circulation or tissues.
• Drugs with high VD mainly in tissues.
• Practical implication: such drugs cannot be easily removed from body (eg. by dialysis) after overdose.

Clearance
• Volume of blood completely cleared of compound per unit time.
• Units = L hr-1.
• Clinical relevance includes effect of liver/renal disease of drug elimination.

Reading
• Henderson-Hasselbach ~ p.8.
• Aspirin ~ p.200.
• p. 10, p. 231.