Principles of Clinical Pharmacology¶
Chapter 71 | Part 3: Pharmacology · Part 3 – Pharmacology · Chapter 71
Key Clinical Points¶
- Adherence is preferred over 'compliance' to remove the implication that patients are at fault.
- Pharmacokinetics (PK) describes drug concentration vs. time; Pharmacodynamics (PD) describes drug concentration vs. effect.
- Therapeutic index (ratio/window) defines the margin between effective doses and toxic doses.
- First-pass elimination reduces bioavailability of oral drugs via intestinal and hepatic metabolism.
- P-glycoprotein (P-gp) acts as an efflux pump limiting systemic availability and brain penetration.
- Type A ADRs are dose-dependent; Type B ADRs are dose-independent and often unexpected.
- Steady state is achieved after approximately 5 elimination half-lives.
- Loading doses are used to reach therapeutic concentrations more rapidly in urgent cases.
- Renal and liver disease can significantly alter drug levels due to changes in excretion or metabolism.
- Heart failure can lead to redistribution of cardiac output, increasing CNS or cardiac effects of drugs.
- Drug interactions can be pharmacokinetic (changes in concentration) or pharmacodynamic (changes in effect without concentration change).
1. DEFINITION & OVERVIEW¶
• Core Concepts: Drugs are the cornerstone of modern therapeutics; outcomes vary based on individual factors (genetics, disease, interactions).
• Goals of Clinical Pharmacology: 1. Provide a description of conditions under which drug actions vary among human subjects. 2. Determine mechanisms underlying this variability to improve therapy with available drugs.
• Evolution of Field: Shift from empirical descriptions of sensitivity/disease influence to understanding molecular mechanisms (pharmacogenomics) and systems biology. Systems biology involves complex computational models, gene editing, and multi-omic measurements (transcriptomics, metabolomics, proteomics).
• Adherence vs. Compliance: The term 'adherence' is preferred over 'compliance' because it removes the idea that the patient is at fault.
• Therapeutic Index: Defined as the margin between doses required for effect and those producing toxicity. Also known as therapeutic ratio or therapeutic window. Monitoring is useful when a clear relationship exists between plasma concentration and effect (e.g., anticonvulsants, antirejection agents, antiarrhythmics).
2. EPIDEMIOLOGY¶
• Adverse Drug Reactions (ADRs): Can be mistaken for signs of underlying disease because they involve every organ system.
• Failure of Efficacy: The most common 'adverse' drug effect; occurs in up to half of patients with conditions like psychiatric disease or hypertension.
• Statistics (UK): 6.5% of hospital admissions are due to ADRs → 2.3% of these result in death.
• Common Culprit Drugs: Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), diuretics, warfarin, ACE inhibitors, antidepressants, opiates, digoxin, steroids, and clopidogrel.
• US Data: ADRs were responsible for >100,000 in-hospital deaths (4th to 6th most common cause).
3. ETIOLOGY & PATHOPHYYSOLOGY¶
• Pharmacokinetics (PK): Relationship between drug concentration and time (delivery/removal).
• Bioavailability: Fraction of drug available to the systemic circulation. - <100% due to: 1. Incomplete absorption. 2. Metabolism or elimination prior to entering the systemic circulation (presystemic/first-pass effect).
• First-Pass Effect: Occurs in intestinal enterocytes and the liver before reaching systemic circulation. - Enterocyte barrier: Drug may be metabolized, excreted into the lumen, or transported via P-glycoprotein. - Hepatic barrier: Drug may be metabolized or excreted into the bile. - Clinical Examples: - Nitroglycerin: 0% bioavailability orally due to complete extraction; used sublingually, transdermally, or intravenously. - Verapamil: High first-pass metabolism requires much higher oral doses (40–120 mg) compared to IV (1–5 mg).
• Drug Transport: Combination of passive diffusion and active transport. - P-glycoprotein (ABCB1/MDR1): - Function: Efflux pump. - Locations: Apical enterocyte, canicular hepatocyte, cerebral capillaries. - Effect: Limits drug availability to systemic circulation and brain penetration; forms part of the blood-brain barrier.
• Drug Metabolism: Converts drugs into more polar compounds for easier excretion. - Phase I: Chemical modification (mostly oxidation via Cytochrome P450/CYP). - Phase II: Conjugation of endogenous compounds (glucuronyl-, acetyl-, sulfo-, and methyltransferases).
• Table 1 Summary: - CYP3A: Substrates include CCBs, Antiarrhythmics (lidocaine, quinidine, mexiletine), HMG-CoA reductase inhibitors (statins), Cyclosporine, tacrolimus, Indinavir, saquinavir, ritonavir, Timolol, metoprolor, carvedilol, Propafenone, flecainide, Tricyclic antidepressants, Fluoxetine, paroxetine. Inhibitors: Amiodarone, Ketoconazole, Itraconazole, Erythromycin, Clarithromycin, Ritonavir, Gemfibrozil/fibrates. - CYP2C9: Substrates include Warfarin, Phenytoin, Glipizide, Losartan, Omeprazole, Mephenytoin, Clopidogrel. Inhibitors: Amiodarone, Fluconazole, Phenytoin. - CYP2B6: Substrates include Efavirenz, 6-Mercaptopurine, azathioprine. Inhibitor: Ticlopidine. - N-acetyltransferase: Isoniazid, Procainamide, Hydralazine, Sulfonamides, Irinotecan. - Pseudocholinesterase: Succinylcholine. - P-glycoprotein: Substrates include Digoxin, HIV protease inhibitors, many CYP3A substrates. Inhibitors: Quinidine, Amiodarone, Verapamil, Cyclosporine, Itraconazole, Erythromycin.
• Drug Elimination: Most processes are first-order (rate depends on amount present). - Half-life: Time for 50% of a first-order process to be completed. - Steady State: Achieved after approximately 5 elimination half-lives. - Distribution vs. Elimination: Initial rapid drop in concentration = distribution into tissues; Slower decline = elimination from system.
• Pharmacodynamics (PD): Relationship between drug concentration and effect (action). The linear framework of PK/PD is a first approximation for understanding drug effects.
4. CLINICAL FEATURES¶
• Adverse Drug Reactions (ADRs): Categorized by mechanism and predictability. - Type A: - Mechanism: Exaggeration of intended pharmacologic action. - Characteristics: Dose-dependent, predictable (e.g., bleeding with anticoagulants). - Type B: - Mechanism: Toxic effects unrelated to intended actions. - Characteristics: Dose-independent, often unanticipated; may result from toxic effects unrelated to intended actions.
5. DIFFERENTIAL DIAGNOSIS¶
• Drug Interactions: Must be considered in any unusual response during system-wide drug therapy. - Pharmacokinetic (PK) Interactions: - Result from changes in drug disposition (absorption, distribution, metabolism, excretion). - Pharmacodynamic (PD) Interactions: - Result from changes in drug response without changes in plasma concentration.
• Table 2 Summary: - Decreased Effect (PK): - Due to gut binding: Antacids/tetracyclines, Cholestyramine/digoxin. - Due to induction of metabolism/transport: Rifampin, Carbamazepine, Phenytoin, St. John's wort, Glutethimide, smoking, etc. - Increased Effect (PK): - Due to inhibited transport: Amiodarone (inhibits many CYPs and P-glycoprotein). - Due to reduced renal clearance: Probenecid, probenecid, salicylates (increases methotrexate toxicity). - Antagonistic (PD): - Example: Loss of antihypertensive drug effects with NSAIDs.
6. INVESTIGATIONS & DIAGNOSIS¶
• Monitoring Parameters: Identify drugs where plasma concentration correlates with effect to guide dosing. - Anticonvulsants. - Antirejection agents. - Antiarrhythmics.
7. MANAGEMENT & TREATMENT¶
• Dosing Strategies: 1. Loading Doses: - Used for urgent indications to reach therapeutic levels faster. - Note: Does not alter the final steady state, only the time required to achieve it. 2. Steady State Adjustments: - For first-order elimination: Doubling the dose results in a doubling of the steady-state concentration. - Timeframe: Steady state is reached after ~5 half-lives. 3. Route Selection based on Bioavailability: - Drugs with high first-pass metabolism (e.g., Nitroglycerin) → use sublingual, transdermal, or IV routes to bypass presystemic metabolism. - Drugs with high first-pass but usable oral doses (e.g., Verapamil) → require significantly higher oral doses than IV equivalents.
8. PROGNOSIS & COMPLICATIONS¶
• Clinical Implications of Drug Distribution: - Heart Failure: Decreased tissue perfusion redistributes cardiac output, increasing CNS or cardiac effects of drugs. - P-glycoprotein (P-gp) Dysfunction: - Reduced P-gp function (e.g., due to drug interactions) can increase penetration of substrate drugs into the brain even when plasma concentrations are unchanged.
9. SPECIAL CONSIDERATIONS¶
• Renal and Liver Disease: - Metabolism/Excretion: - Drugs with predominant renal excretion (e.g., digoxin, dofetilide) require dose reduction in renal disease. - In liver disease, oral bioavailability of high first-pass drugs (e.g., morphine, nifedipine) is almost doubled.
• Drug Interaction Risks: - Amiodarone: Potent inhibitor of many CYPs and P-glycoprotein; can significantly increase levels of warfarin, digoxin, and dabigatran.
10. KEY PEARLS & CLINICAL TRAPS¶
• P-glycoprotein (P-gp): Acts as a critical gatekeeper at the blood-brain barrier; its inhibition can lead to CNS toxicity even if plasma levels are stable. • First-Pass Effect: Crucial for determining oral vs. parenteral dosing requirements; determines bioavailability of drugs like Nitroglycerin and Verapamil. • Type A vs. Type B: Distinguishing between dose-dependent (A) and dose-independent/unexpected (B) reactions is vital for safety monitoring. • Steady State Rule: Always remember the 5 half-lives rule for reaching steady state after any change in dosing or initiation of therapy.
Reference Tables¶
TABLE 71-1 Molecular Pathways Mediating Drug Disposition¶
Harrison's 22e, p.485
| ENZYME | SUBSTRATESa | INHIBITORSa |
|---|---|---|
| CYP3A | Calcium channel blockers | Amiodarone |
| Antiarrhythmics (lidocaine, quinidine, mexiletine) |
Ketoconazole, itraconazole |
|
| HMG-CoA reductase inhibitors (“statins”; see text) |
Erythromycin, clarithromycin |
|
| Cyclosporine, tacrolimus | Ritonavir | |
| Indinavir, saquinavir, ritonavir |
Gemfibrozil and other fibrates |
|
| Timolol, metoprolol, carvedilol Propafenone, flecainide Tricyclic antidepressants Fluoxetine, paroxetine |
||
| CYP2C9b | Warfarin | Amiodarone |
| Phenytoin | Fluconazole | |
| Glipizide | Phenytoin | |
| Losartan | ||
| Omeprazole Mephenytoin Clopidogrel |
||
| CYP2B6b | Efavirenz | Ticlopidine |
| 6-Mercaptopurine, azathioprine |
||
| N-acetyltransferaseb | Isoniazid | |
| Procainamide | ||
| Hydralazine | ||
| Some sulfonamides | ||
| Irinotecan | ||
| Pseudocholinesteraseb | Succinylcholine | |
| TRANSPORTER | SUBSTRATESa | INHIBITORSa |
| P-glycoprotein | Digoxin | Quinidine |
| HIV protease inhibitors | Amiodarone | |
| Many CYP3A substrates | Verapamil | |
| Cyclosporine | ||
| Itraconazole | ||
| Erythromycin | ||
| Simvastatin and some other statins |
TABLE 71-2 Drug Interactions MECHANISM Pharmacokinetic Interactions Causing Decreased Drug Effect Decreased absorption…¶
Harrison's 22e, p.489
| MECHANISM | EXAMPLE |
|---|---|
| Pharmacokinetic Interactions Causing Decreased Drug Effect | |
| Decreased absorption due to drug binding in the gut |
Antacids or bile acid sequestrants decrease the absorption of many drugs: Antacids/tetracyclines Cholestyramine/digoxin |
| Induction of drug metabolism and/ or drug transport: Rifampin Carbamazepine Phenytoin St. John’s wort Glutethimide (also smoking, exposure to chlorinated insecticides, and chronic alcohol ingestion) |
Decreased concentrations and effects of: Warfarin Quinidine Cyclosporine Losartan Oral contraceptives Methadone Dabigatran |
| Reduced delivery of drug to active sites of action |
Tricyclics prevent clonidine uptake into adrenergic neurons, preventing antihypertensive effects |
| Pharmacokinetic Interactions Causing Increased Drug Effect | |
| Inhibited drug transport | Amiodarone (inhibits many CYPs and P-glycoprotein): Warfarin Digoxin Dabigatran |
| Decreased elimination due to altered renal function |
Inhibitors of renal tubular transport (phenylbutazone, probenecid, salicylates) increase methotrexate toxicity |
| Pharmacodynamic Drug Interactions | |
| Antagonistic effects on the same biologic process |
Loss of antihypertensive drug effects with NSAIDs |