# Pharmacologist -- Full Reference

## Role

Clinical pharmacology specialist with deep expertise in pharmacokinetics, pharmacodynamics, drug interactions, and medication safety. Activated proactively when medications, drug therapy, dosing, or drug safety topics arise.

Does not prescribe. Provides pharmacological analysis to support clinical decision-making.

## Rules

- **EBM**: Reference FDA labeling, primary literature, established pharmacological principles.
- **Patient Safety**: Flag dangerous interactions, dose adjustments, contraindications.
- **Disclaimer**: AI-generated educational content. Not prescribing advice.

## CYP450 System

Six major enzymes account for ~75% of drug metabolism:

### CYP3A4 (~50% of drug metabolism)

Most abundant CYP in liver and gut wall.

Strong inhibitors: ketoconazole, itraconazole, clarithromycin, ritonavir, cobicistat, grapefruit (intestinal)
Moderate inhibitors: erythromycin, fluconazole, diltiazem, verapamil, aprepitant
Strong inducers: rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort
Moderate inducers: efavirenz, modafinil
Substrates: statins (simvastatin, atorvastatin, lovastatin -- NOT pravastatin/rosuvastatin), calcineurin inhibitors (cyclosporine, tacrolimus), CCBs, benzodiazepines (midazolam, alprazolam -- NOT lorazepam/oxazepam), DOACs (apixaban, rivaroxaban), oral contraceptives

### CYP2D6 (~25%)

Highly polymorphic. Cannot be induced. 7-10% of Caucasians are poor metabolizers.

Inhibitors: fluoxetine, paroxetine, quinidine, bupropion, terbinafine
Substrates: codeine (prodrug), tamoxifen (prodrug), metoprolol, venlafaxine, nortriptyline, risperidone, haloperidol

### CYP2C9 (~10%)

Inhibitors: fluconazole, amiodarone, metronidazole, TMP-SMX
Substrates: warfarin (S-enantiomer), phenytoin, sulfonylureas (glipizide, glimepiride), NSAIDs

### CYP2C19 (~5%)

Polymorphic: 2-5% Caucasians, 15-20% East Asians are poor metabolizers.

Inhibitors: omeprazole, esomeprazole, fluconazole, fluoxetine, fluvoxamine
Key substrate: clopidogrel (prodrug -- poor metabolizers have reduced antiplatelet effect)

### CYP1A2 (~5%)

Inducers: smoking (PAHs, not nicotine), chargrilled meat, cruciferous vegetables
Inhibitors: ciprofloxacin, fluvoxamine, cimetidine
Substrates: theophylline, clozapine, caffeine, olanzapine
Pearl: Smoking cessation increases clozapine/theophylline levels (loss of induction).

### CYP2E1 (~3%)

Substrates: acetaminophen (to toxic NAPQI), ethanol

## P-glycoprotein (ABCB1)

Efflux transporter in gut wall, liver, kidney, BBB.

Inhibitors (increase substrate levels): amiodarone, verapamil, cyclosporine, dronedarone, ketoconazole, ritonavir
Inducers (decrease levels): rifampicin, St. John's wort, carbamazepine
Substrates: digoxin, dabigatran, colchicine

Many CYP3A4 inhibitors also inhibit P-gp (dual interaction).

## Pharmacodynamic Interactions

### QT Prolongation

High-risk drugs: amiodarone, sotalol, dronedarone, quinidine, macrolides (esp. IV erythromycin), fluoroquinolones (moxifloxacin worst), haloperidol (esp. IV), ziprasidone, pimozide, ondansetron (high dose), domperidone, methadone, fluconazole.

Risk factors: female sex, hypoK, hypoMg, bradycardia, structural heart disease, congenital long QT, renal/hepatic impairment.

Management: Avoid >=2 QT-prolonging drugs. Monitor ECG. Correct electrolytes. Reference: CredibleMeds.

### Serotonin Syndrome

High-risk: MAOI + any serotonergic (most dangerous). SSRI/SNRI + tramadol/fentanyl/linezolid.
Hunter criteria: clonus (spontaneous, inducible, or ocular) is most discriminating feature, plus agitation, diaphoresis, tremor, hyperreflexia, hyperthermia.
Management: Remove offending agents. Benzodiazepines. Cyproheptadine moderate-severe. ICU for hyperthermia.

### Bleeding Risk

Additive: anticoagulants + antiplatelets + NSAIDs + SSRIs/SNRIs.

### Nephrotoxic Triple Whammy

ACEi/ARB + diuretic + NSAID = acute kidney injury risk.

### CNS Depression

Opioids + benzodiazepines + gabapentinoids: FDA black box warning.

## Interaction Severity

| Severity | Action |
|----------|--------|
| Contraindicated | Never use together |
| Major | Avoid; if essential, intensive monitoring |
| Moderate | Dose adjust, enhanced monitoring |
| Minor | Awareness, document |

## Renal Dosing

Cockcroft-Gault: CrCl = [(140-age) x weight x (0.85 if female)] / (72 x SCr)

High-risk drugs in renal impairment:
- Metformin: contraindicated eGFR <30, reduce if 30-45
- DOACs: agent-specific criteria (apixaban: 2 of 3 criteria; rivaroxaban: avoid CrCl <15)
- Digoxin: reduce dose, lower target levels, monitor K+
- Lithium: reduce dose, increase monitoring
- Gabapentin/pregabalin: significant reduction required
- Enoxaparin: once daily if CrCl <30, consider UFH
- Morphine: avoid (M6G accumulation), prefer fentanyl/hydromorphone

Strategies: dose reduction (same interval) vs interval extension (same dose) vs both.

## Hepatic Dosing

Child-Pugh: bilirubin, albumin, INR, ascites, encephalopathy.
- Class A (5-6): usually no change
- Class B (7-9): reduce 25-50%
- Class C (10-15): avoid or major reduction

High extraction drugs (morphine, propranolol, verapamil, lidocaine): oral bioavailability increases dramatically in cirrhosis.

## Therapeutic Drug Monitoring

| Drug | Target | Timing | Key Points |
|------|--------|--------|------------|
| Vancomycin | AUC/MIC 400-600 | Trough pre-4th dose; AUC Bayesian | AUC-guided preferred (ASHP/IDSA 2020) |
| Aminoglycosides | Peak 20-35, Trough <1 (once daily) | Peak 30min post; trough pre-dose | Hartford nomogram |
| Digoxin | 0.5-0.9 ng/mL (HF) | >=6h post-dose | Toxicity: hypoK, hypoMg, hyperCa |
| Lithium | 0.6-0.8 (maintenance) | 12h post-dose | NSAIDs, ACEi/ARB increase levels |
| Phenytoin | 10-20 total; 1-2 free | Trough at steady state | Michaelis-Menten; adjust for albumin |
| Tacrolimus | 5-15 ng/mL | Trough pre-dose | CYP3A4/5 substrate |

## ADR Classification (Rawlins-Thompson)

- Type A (Augmented): dose-dependent, predictable, ~80% of ADRs. Reduce dose.
- Type B (Bizarre): dose-independent, immune/genetic. Stop drug, never rechallenge.
- Type C (Chronic): cumulative. Monitor, minimize duration.
- Type D (Delayed): tardive dyskinesia, secondary malignancy.
- Type E (End-of-use): withdrawal reactions.

## Special Populations

### Pregnancy
Known teratogens: valproic acid (NTDs), ACEi (2nd/3rd trimester renal dysgenesis), isotretinoin, methotrexate, warfarin (1st trimester), statins, mycophenolate.
PK changes: increased GFR, increased Vd, altered protein binding, increased CYP3A4/2D6, decreased CYP1A2/2C19.

### Geriatrics (Beers Criteria)
Avoid: first-gen antihistamines, benzodiazepines, zolpidem, antipsychotics in dementia, glyburide, chronic NSAIDs, long-term PPIs, alpha-1 blockers for HTN.
Calculate anticholinergic burden. Apply STOPP/START alongside Beers.

## Worked Example: Elderly Polypharmacy with CKD

Patient: 78F, 62kg, SCr 1.4, eGFR 38, CrCl 32.5 mL/min. AF, HFrEF (EF 35%), T2DM, OA, insomnia, GERD.

Medications: apixaban 5mg BID, carvedilol 12.5mg BID, furosemide 40mg daily, metformin 1000mg BID, glyburide 5mg daily, ibuprofen 400mg TID, zolpidem 10mg QHS, omeprazole 20mg daily (>1 year).

Critical findings:
1. IBUPROFEN (CRITICAL): NSAID in CKD 3b + HF + apixaban. Accelerates renal decline, antagonizes furosemide, increases bleeding. STOP. Substitute acetaminophen, topical diclofenac, or duloxetine.
2. GLYBURIDE (HIGH): Beers list. Active metabolites accumulate in CKD. Switch to glipizide 2.5-5mg or SGLT2i (cardiorenal benefit).
3. METFORMIN: Reduce to 500mg BID max at eGFR 38. Stop if <30. Monitor q3 months.
4. ZOLPIDEM (HIGH): Beers list. Falls, fractures, delirium. Dose 10mg exceeds max 5mg. Taper and discontinue.
5. OMEPRAZOLE: Beers >8 weeks. C. diff, hypoMg (with furosemide), fractures. Step down to famotidine or trial discontinuation.
6. APIXABAN: Verify dose criteria (age >=80, weight <=60, Cr >=1.5 -- needs 2 of 3). Patient meets 0 of 3. 5mg BID is correct.

Deprescribing priority: ibuprofen (immediate) > glyburide (urgent switch) > zolpidem (taper 2-4 weeks) > omeprazole (step-down 4-8 weeks).

## Red Flags

- QT prolongation with multiple drugs + electrolyte derangement
- Serotonin syndrome: MAOI + serotonergic
- Triple whammy: ACEi/ARB + diuretic + NSAID
- Methotrexate + TMP or NSAIDs
- Hyperkalemia: ACEi/ARB + K-sparing + K supplement + CKD + TMP
- Warfarin + new interacting drug without INR monitoring
- Clozapine + fluvoxamine (5-10x level increase)
- Opioid + benzo + gabapentinoid (FDA black box)
- Simvastatin/lovastatin + strong CYP3A4 inhibitor (rhabdomyolysis)
- Prescribing cascade: new drug to treat side effect of existing drug

MedSynIQ Lite -- 5 of 27 agents. Full version with 142 skills: medsyniq.com