Drug Metabolism 101: A Med Student’s Crash Course

 

By a fellow student who survived the Pharm exam (barely) 

Hey future docs! Let’s talk about drug metabolism—the process that determines why some meds work, why others turn toxic, and why Grandma’s warfarin dose is a constant nightmare. This isn’t just textbook fluff; it’s high-yield for exams and wards. Let’s break it down like we’re cramming together at 3 AM.  

Why Should You Care?

Drugs don’t just disappear after they work. They get metabolized (chemically altered) and excreted (kicked out via pee/poop). But here’s the kicker:  

- Prodrugs need metabolism to become active (e.g., levodopa → dopamine for Parkinson’s).  

- Active drugs might turn inactive (e.g., diazepam → oxazepam) or stay active (looking at you, toxic metabolites!).  

Exam Hack: If a drug starts with “levo-” (levodopa) or ends with “-prodrug,” it’s probably a prodrug. Write that down.  

Phase I vs. Phase II: The Body’s Detox Duo  

Think of metabolism as a two-step detox plan for your liver.  

Phase I: The “Expose the Weakness” Phase  

- Goal: Slap a polar group (-OH, -NH₂) onto the drug so Phase II can finish it off.  

- Reactions: Oxidation (most common!), reduction, hydrolysis.  

- Key Players: Cytochrome P450 (CYP450) enzymes (microsomal).  

Real Talk: CYP3A4 is the Beyoncé of enzymes—it metabolizes 50% of drugs (statins, antidepressants, you name it).  

Phase II: The “Waterproofing” Phase  

- Goal: Glue a big polar molecule (like glucuronic acid) to the drug to make it water-soluble.  

- Reactions: Glucuronidation (MC), sulfation, acetylation.  

- Key Players: Non-microsomal enzymes (e.g., UDP-glucuronosyltransferases).  

Example: Paracetamol (Tylenol) gets glucuronidated. But overdose it, and Phase I makes a toxic metabolite that fries your liver. Yikes.  

Microsomal vs. Non-Microsomal Enzymes: Who’s Who?

Microsomal Enzymes  

- Where they live: Smooth endoplasmic reticulum (SER) of liver cells. Think of them as the lab rats working in a fancy, membrane-bound lab.  

- What they do:  

  - Phase I reactions: Oxidation (CYP450’s specialty!), reduction, hydrolysis.  

  - Phase II: Glucuronidation (the most common Phase II reaction).  

- Superpower: They can be induced (turned up) or inhibited (shut down) by drugs, herbs, or lifestyle (e.g., smoking).  

  - Example: Rifampicin (antibiotic) → induces CYP450 enzymes → metabolizes drugs faster (e.g., warfarin stops working).  

  - Example: Grapefruit juice → inhibits CYP3A4 → toxic levels of simvastatin.  

Non-Microsomal Enzymes  

- Where they live: Floating in the cytoplasm or mitochondria. These are the freelancers of the enzyme world.  

- What they do:  

  - Phase II reactions (except glucuronidation): Sulfation, acetylation, methylation, glutathione conjugation.  

- Personality: Chill and stubborn. They can’t be induced or inhibited easily. No drama here.  

  - Example: N-acetyltransferase (acetylates INH) → genetic variations explain why some people get INH toxicity.  

Why You Care 

- Drug interactions happen here: Microsomal enzymes (especially CYP450) are the reason grandma’s warfarin dose goes haywire when she starts antibiotics.  

- Phase I vs. II:  

  - Phase I = “Prep phase” (adds a handle to the drug).  

  - Phase II = “Tag-and-bag phase” (slaps on a water-soluble group for excretion).  

Why This Matters for Exams:  

- Enzyme inducers (e.g., rifampicin, carbamazepine) → Speed up metabolism → Lower drug levels (e.g., warfarin stops working).  

- Enzyme inhibitors (e.g., erythromycin, ciprofloxacin) → Slow metabolism → Toxicity risk (e.g., theophylline overdose → seizures).  

Mnemonics You’ll Actually Remember  

Enzyme Inducers

“GPRS Cell Phone” (because you’ll need to call a friend after memorizing this):  

- Griseofulvin  

- Phenytoin, Phenobarbitone  

- Rifampicin  

- Smoking (induces CYP1A2)  

- Carbamazepine  

Pro Tip: Most antiepileptics are inducers… except valproate (it’s an inhibitor—plot twist!).  

Enzyme Inhibitors  

“VK CCEI” (sounds like a bad radio station):  

- Vlproate  

- Ketoconazole  

- Cimetidine, Ciprofloxacin  

- Erythromycin  

- Isoniazid  

Fun Fact: Grapefruit juice inhibits CYP3A4 → ↑ levels of simvastatin, amlodipine, and half the drugs in First Aid.  

CYP450: The Enzyme Family That Never Sleeps ( CYP enzymes)

Cytochrome P450 enzymes are crucial for drug metabolism, especially in the liver. They get their name from their ability to absorb light at 450 nm.

Understanding CYP Nomenclature

Example: CYP3A4

3 → Family

A → Subfamily

4 → Isoform

Here’s the breakdown you need for exams (with mnemonics and clinical pearls!):  

CYP3A4: The "Big Boss" Enzyme

Mnemonic: CT SCAN 

- Cyclosporine  

- Tacrolimus  

- Statins (e.g., simvastatin, atorvastatin)  

- CAT drugs:  

  - Cisapride (withdrawn)  

  - Astemizole (withdrawn)  

  - Terfenadine (withdrawn)  

- NNRTIs/Navirs (HIV protease inhibitors: ritonavir, saquinavir)  

Why the "CAT" drugs were withdrawn: They cause QT prolongation (→ torsades de pointes) because CYP3A4 inhibition (e.g., by grapefruit juice, erythromycin) → toxic levels → fatal arrhythmias.  

CYP2C9: The "Clotting & Brain" Enzyme  

Mnemonic: "Clotting = C" 

- Warfarin (anticoagulant): Most important!

  - Polymorphisms in CYP2C9 → unpredictable warfarin metabolism.  

  - Drugs like sulfamethoxazole (Bactrim) inhibit CYP2C9 → ↑ warfarin levels → bleeding risk.  

- Phenytoin (antiepileptic):  

  - Mirror trick: "9" flipped looks like "P" for Phenytoin.  

CYP2C19: The "Clopidogrel Drama" Enzyme

Mnemonic: "Clopidogrel’s Problem Child"  

- Clopidogrel (antiplatelet): Needs CYP2C19 to activate.  

- Ticlopidine (older antiplatelet): Also metabolized here.  

Clinical Bomb:  

- PPIs (e.g., omeprazole) inhibit CYP2C19 → ↓ clopidogrel activation → ↑ risk of stent thrombosis.  

- Solution: Use PPIs that don’t inhibit CYP2C19 (e.g., pantoprazole) or avoid PPIs if possible.  

Key Exam Scenarios

1. Grapefruit juice + statins: Inhibits CYP3A4 → ↑ statin levels → myopathy/rhabdo.  

2. Fluconazole + warfarin: Inhibits CYP2C9 → ↑ INR → bleeding.  

3. Clopidogrel + omeprazole: ↓ antiplatelet effect → stent thrombosis.  

Why This Matters 

- Drug interactions: CYP enzymes explain why certain combos are deadly (e.g., erythromycin + simvastatin).  

- Genetics: Poor metabolizers (e.g., CYP2C19) need alternative drugs (ticagrelor instead of clopidogrel).  

- Real-world: Always check for enzyme inhibitors/inducers when prescribing!  

Now go impress your attending with this knowledge! 💊

Most Important CYP Enzymes

- CYP3A4: Metabolizes the most drugs. If you forget everything else, remember this.  

- CYP2D6: Handles beta-blockers, antidepressants, and codeine. Fun fact: 10% of people are “poor metabolizers” (thanks, genetics!).  

- CYP2C9/19: Warfarin’s BFFs. Polymorphisms here explain why your grandma’s warfarin dose is a nightmare to adjust.  

Clinical Pearl: Always ask about herbal supplements! St. John’s Wort induces CYP3A4 (→ ↓ drug levels), and turmeric can inhibit it.  

High-Yield Clinical Scenarios 

1. Rifampicin + Warfarin: Rifampicin induces warfarin metabolism → INR drops → patient clots. Solution: ↑ Warfarin dose.  

2. Erythromycin + Theophylline: Erythromycin inhibits theophylline metabolism → toxicity (tachycardia, seizures).  

3. Clopidogrel + CYP2C19 Poor Metabolizers: Clopidogrel won’t activate → stent thrombosis. Switch to ticagrelor.  

How to Not Fail Your Pharm Exam

1. Focus on the exceptions: Valproate (only antiepileptic that’s an inhibitor), rifampicin (only antibiotic that’s an inducer).  

2. Memorize the CYP450 chart in First Aid. Trust me, it’s worth it.  

3. Practice drug interaction questions: They’re free points if you know the inducer/inhibitor game.  

Final Takeaway  

Drug metabolism isn’t just rote memorization—it’s about predicting how drugs interact and why patients crash. Nail this, and you’ll look like a genius on rounds. Now go crush that exam (and maybe drink some grapefruit juice ironically).  

Need more mnemonics or panic-induced study tips? Hit me up. We’re all in this together. 😅  

P.S.: If you see a typo, no you didn’t. I wrote this between coffee IVs.

Thank you