AIM STEP 10
Student Memory Support
Drug Distribution, Biotransformation and Pharmacogenetic Variation
3rd Year MBBS · Foundation Module · High-yield memory reinforcement and last-minute revision
1. High-Yield Flashcards
Tap each question to reveal the answer.
What is drug distribution?
Reversible transfer of a drug from systemic circulation into body fluids and tissues.
What is redistribution of a drug?
Movement of drug from a highly perfused tissue to other tissues such as muscle and fat.
Which fraction of a plasma protein-bound drug readily crosses membranes and acts on receptors?
The free or unbound drug fraction.
Which major factors determine drug distribution?
Blood flow, capillary permeability, lipid solubility, ionization, plasma protein binding and tissue binding.
How is apparent volume of distribution calculated?
Vd = Amount of drug in the body ÷ Plasma drug concentration.
What does a large apparent volume of distribution suggest?
Extensive distribution or binding of the drug within tissues.
What is the purpose of a loading dose?
To achieve the desired plasma concentration rapidly.
How is loading dose related to volume of distribution and bioavailability?
Loading dose = Target plasma concentration × Vd ÷ Bioavailability.
Why do many polar drugs enter the brain poorly?
Tight junctions of cerebral capillary endothelial cells restrict their passage across the blood-brain barrier.
Is the placenta an absolute barrier to drugs?
No. Many drugs can cross the placenta and reach the fetal circulation.
What is biotransformation?
Enzymatic chemical modification of a drug or other xenobiotic within the body.
What is the major organ of drug biotransformation?
The liver.
Which reactions belong to Phase I metabolism?
Oxidation, reduction and hydrolysis.
What is the main principle of Phase II metabolism?
Conjugation, which generally increases drug polarity and facilitates elimination.
Where are microsomal CYP450 enzymes mainly located?
In the smooth endoplasmic reticulum, especially in hepatocytes.
What is the usual effect of enzyme induction on an active substrate drug?
Faster metabolism, lower parent-drug concentration and potentially reduced effect.
What is the usual effect of enzyme inhibition on an active substrate drug?
Reduced metabolism, increased drug concentration and increased risk of toxicity.
How can inherited enzyme variation alter drug response?
It can produce slow or rapid metabolism, altering therapeutic effect and toxicity.
What inherited abnormality can cause prolonged paralysis after succinylcholine?
Deficiency or abnormality of plasma pseudocholinesterase.
What is mechanism-based or suicide inhibition?
The enzyme converts a substance into a reactive product that then inactivates the same enzyme.
2. Mnemonics
Mnemonic Title:
Phase I Reactions
Mnemonic Word:
ORH
Meaning:
Oxidation · Reduction · Hydrolysis
Mnemonic Title:
Major Factors Affecting Distribution
Mnemonic Word:
BLIP-T
Meaning:
Blood flow · Lipid solubility · Ionization · Plasma protein binding · Tissue binding, with capillary permeability also determining access to tissues.
Mnemonic Title:
Important Enzyme Inducers
Mnemonic Word:
RiP-C
Meaning:
Rifampicin · Phenytoin/Phenobarbital · Carbamazepine
3. Memory Tables
Phase I vs Phase II Biotransformation
| Feature | Phase I | Phase II |
|---|---|---|
| Main process | Functionalization | Conjugation |
| Typical reactions | Oxidation, reduction, hydrolysis | Glucuronidation, sulfation, acetylation |
| CYP450 | Major role in many oxidations | Not the main conjugating system |
| Usual result | Drug may be activated, inactivated or modified | Usually increases polarity |
Enzyme Induction vs Enzyme Inhibition
| Feature | Induction | Inhibition |
|---|---|---|
| Enzyme activity | Increases | Decreases |
| Active parent drug | Usually decreases | Usually increases |
| Main risk | Reduced therapeutic effect | Excess effect or toxicity |
| Prodrug effect | May increase activation | May reduce activation |
4. Rapid Revision Points — Last-Minute Revision
Must Remember:
- Only the free fraction of a protein-bound drug readily distributes and produces pharmacological effects.
- Highly perfused organs receive drugs earlier than poorly perfused tissues.
- Large apparent Vd indicates extensive tissue distribution or tissue binding.
- Loading dose increases as Vd increases for the same target concentration.
- Incomplete bioavailability requires a larger loading dose than complete bioavailability.
- The blood-brain barrier restricts many polar and ionized drugs.
- The placenta is not an absolute barrier; fetal exposure to maternal drugs can occur.
- Phase I includes oxidation, reduction and hydrolysis; Phase II mainly involves conjugation.
- CYP450 enzymes are important microsomal enzymes associated with smooth endoplasmic reticulum.
- Enzyme induction may reduce an active parent drug but may increase activation of a prodrug.
- Mechanism-based inhibition persists because the enzyme itself becomes inactivated.
KMU Exam Trap: Drug metabolism does not necessarily mean drug inactivation. It may produce an active metabolite, activate a prodrug or generate a toxic metabolite.
5. Clinical Memory Hooks
Chronic liver disease with low albumin
→
increased free fraction of a highly protein-bound drug
→
exaggerated drug effect.
→
increased free fraction of a highly protein-bound drug
→
exaggerated drug effect.
Short action of a lipid-soluble IV anesthetic despite little metabolism
→
redistribution from brain to muscle and fat.
→
redistribution from brain to muscle and fat.
Rifampicin added to an active substrate drug
→
enzyme induction
→
faster metabolism and reduced drug effect.
→
enzyme induction
→
faster metabolism and reduced drug effect.
Erythromycin added to a CYP-metabolized active drug
→
enzyme inhibition
→
drug accumulation and toxicity risk.
→
enzyme inhibition
→
drug accumulation and toxicity risk.
Prolonged paralysis after succinylcholine
→
inherited abnormal plasma pseudocholinesterase
→
idiosyncratic drug response.
→
inherited abnormal plasma pseudocholinesterase
→
idiosyncratic drug response.
6. High-Yield Exam Points
- ⭐ A low plasma concentration with substantial drug in tissues produces a large apparent volume of distribution.
- ⭐ Loading dose = Target plasma concentration × Vd ÷ Bioavailability.
- ⭐ Only free drug readily crosses membranes, reaches receptors and undergoes filtration.
- ⭐ Phase I = oxidation, reduction and hydrolysis; Phase II = conjugation.
- ⭐ Enzyme induction lowers concentrations of many active parent drugs but may increase activation of prodrugs.
- ⭐ Enzyme inhibition can increase active parent-drug concentrations and toxicity, but may reduce prodrug activation.
- ⭐ Succinylcholine-associated prolonged paralysis due to inherited pseudocholinesterase abnormality is a classic pharmacogenetic idiosyncratic response.