Pharmacokinetic Interactions (ADME Breakdown); Pharmacodynamic Interactions

Absorption Interactions

_{^{Alterations in GI solubility, transit time, or active efflux transporters reduce or accelerate bioavailability.}}

Gastric pH Alteration

Chelation & Complexation

GI Motility Shifts

P-Glycoprotein (P-gp) Inhibition

Gastric pH Alteration

Weakly acidic drugs require an acidic gastric pH to remain non-ionized and soluble for absorption. Antacids, H2 blockers, and PPIs raise pH, stopping dissolution.

Chelation & Complexation

Polyvalent cations bind drugs, forming an insoluble ring structure that cannot cross the intestinal wall.

P-Glycoprotein (P-gp) Inhibition

Prokinetic agents speed gastric emptying (delivering drugs to the small intestine faster); anticholinergics slow transit time

P-Glycoprotein (P-gp) Inhibition

P-gp is an efflux pump in intestinal enterocytes that pumps drugs back into the lumen. Inhibiting P-gp dramatically increases oral absorption.

Gastric pH Alteration: example

Omeprazole + Ketoconazole / Itraconazole

_{^{Result: Decreased antifungal absorption and treatment failure.}}

Chelation & Complexation: Example

Antacids / Milk + Tetracyclines or Ciprofloxacin

_{^{Result: Over 80% reduction in antibiotic absorption.}}

GI Motility Shifts: Example

Metoclopramide + Acetaminophen (accelerates absorption) vs. Atropine + Morphine (delays absorption).

P-Glycoprotein (P-gp) Inhibition: Example

Verapamil / Amiodarone / Clarithromycin + Digoxin

_{^{Result: Increased Digoxin absorption → Digoxin Toxicity.}}

Plasma Protein Displacement

Only unbound (free) drug is pharmacologically active and capable of causing toxicity. Displacing 1–2% of a highly bound drug can double its active free concentration.

Kernicterus

Other Displacements: Sulfonamides displace Bilirubin from albumin in neonates → ‘blank’ (encephalopathy).

Excretion Interactions

_{^{Occur primarily in the renal tubules through competition for active secretion transporters or alteration of urinary pH.}}

Renal Tubular Competition

Renal Hemodynamics & Lithium Toxicity

Urinary Ion Trapping

Renal Tubular Competition

Probenecid blocks the Organic Anion Transporter (OAT) in the proximal tubule.

_{^{Application: Given with Penicillin to prolong penicillin's half-life; causes toxicity when co-administered with Methotrexate.}}

Renal Hemodynamics & Lithium Toxicity

Lithium is handled like Sodium in the proximal tubule.

Sodium depletion

Thiazide Diuretics, NSAIDs, or ACE inhibitors cause ‘blank’ → proximal tubule reabsorbs more Sodium AND Lithium → Severe Lithium Toxicity (tremors, ataxia, seizures)

Alkalinization (Sodium Bicarbonate)

Ionizes weak acids (Aspirin, Phenobarbital), forcing clearance during overdose

Acidification (Ammonium Chloride / Ascorbic Acid)

Ionizes weak bases (Amphetamines, Quinidine), driving urinary elimination.

Benzodiazepines + Alcohol / Opioids: interaction type, Dangerous clinical outcome

Interaction Type: Additive GABAa/ Mu-receptor CNS depression

Dangerous Clinical Outcome: Severe respiratory depression, coma, death

Sildenafil + Nitroglycerin: interaction type, Dangerous clinical outcome

Interaction Type: Synergistic cGMP accumulation

Dangerous Clinical Outcome: Precipitous drop in blood pressure → Severe shock/MI.

ACE Inhibitor + Spironolactone: interaction type, Dangerous clinical outcome

Interaction Type: Additive Potassium retention

Dangerous Clinical Outcome: Life-threatening Hyperkalemia → Cardiac arrest.

Aminoglycoside + Furosemide: interaction type, Dangerous clinical outcome

Interaction Type: Additive Ototoxicity & Nephrotoxicity

Dangerous Clinical Outcome: Permanent deafness and acute tubular necrosis

MAO Inhibitor + SSRI / Meperidine: interaction type, Dangerous clinical outcome

Interaction Type: Excessive Synaptic Serotonin accumulation

Dangerous Clinical Outcome: Serotonin Syndrome (hyperthermia, rigidity, myoclonus).

Propranolol + Salbutamol: Interaction mechanism, Clinical consequence

Interaction Mechanism: Non-selective B-blocker competes with B2-agonist
Clinical Consequence: Severe bronchospasm in asthmatic patients.

Morphine + Naloxone: Interaction mechanism, Clinical consequence

Interaction Mechanism: Competitive antagonism at mu-opioid receptors
Clinical Consequence: Instant reversal of analgesia and opioid respiratory depression.

NSAIDs + Antihypertensives: Interaction mechanism, Clinical consequence

Interaction Mechanism: NSAIDs block renal prostaglandin synthesis (PGE2/ PGI2)
Clinical Consequence: Sodium/water retention that blunts the efficacy of ACEi, Diuretics, and B-blockers

Warfarin + Vitamin K: Interaction mechanism, Clinical consequence

Interaction Mechanism: Vitamin K bypasses Warfarin's blockade of VKORC1
Clinical Consequence: Complete loss of Warfarin anticoagulation (clot risk)

Tyramine-Rich Foods + MAO Inhibitors (Phenelzine, Tranylcypromine)

Hypertensive Crisis ("Cheese Effect" — triggered by aged cheese, red wine, cured meats).

Grapefruit Juice + Calcium Channel Blockers / Statins

Inhibits intestinal CYP3A4, increasing oral bioavailability by 200- 400%

St. John’s Wort + Cyclosporine / Digoxin / Warfarin

CYP3A4 and P-glycoprotein, causing organ transplant rejection (Cyclosporine failure) or loss of anticoagulation

Ginkgo Biloba / Garlic / Ginseng + Anticoagulants

Antiplatelet properties that additively increase bleeding risks without altering INR values

Digoxin + Amiodarone

Primary Mechanism: P-gp Inhibition & Reduced Clearance

PHLE board exam result: Digoxin Toxicity (Yellow-green halos, arrhythmias).

Lithium + Hydrochlorothiazide

Primary Mechanism: Reduced Renal Clearance via Na+ Depletion

PHLE board exam result: Lithium Toxicity (Ataxia, coarse tremors).

Warfarin + Trimethoprim-Sulfa

Primary Mechanism: CYP2C9 Inhibition & Protein Displacement

PHLE board exam result: Severe Bleeding / Soaring INR.

Methotrexate + NSAIDs

Primary Mechanism: Inhibition of Renal Transporters (OAT)

PHLE board exam result: Bone Marrow Suppression (Pancytopenia)

Terfenadine / Cisapride + Ketoconazole

Primary Mechanism: PCYP3A4 Inhibition leading to accumulation

PHLE board exam result: Torsades de Pointes (Fatal QT prolongation)

Metformin + Radiocontrast Dye

Primary Mechanism: Contrast-induced Acute Kidney Injury

PHLE board exam result: Severe Lactic Acidosis.

Check the Enzyme Type

If an item mentions Rifampicin, Phenytoin, or Carbamazepine, look for an answer describing decreased drug efficacy or treatment failure

Check the Elimination Path

If an item involves Lithium, Digoxin, or Methotrexate, look for a second drug that impairs renal clearance (Diuretics, NSAIDs, Transporter Inhibitors).

Differentiate Bleeding Mechanics

Warfarin + Enzyme Inhibitor (e.g., Metronidazole)

Warfarin + Aspirin/NSAID

Warfarin + Enzyme Inhibitor (e.g., Metronidazole)

Increases INR and causes bleeding.

Warfarin + Aspirin/NSAID

Increases bleeding risk via direct antiplatelet/ulcerogenic effects without changing the INR value.