DRUG

INTERACTIONS
Code: PO 802
 ANTIHYPERTENSIVE DRUGS
INTERACTIONS
I. β-Adrenergic Blockers:
- High lipid soluble drugs like
propranolol (a non selective β
blocker) are hepatically cleared
- Hydrophilic ones like atenolol (a
selective β blocker) depend mainly
on renal excretion (require dose
adjustment in renal impairment)
 ANTIHYPERTENSIVE DRUGS
INTERACTIONS
 Some interactions may increase
action of β-Adrenergic Blockers
- Hepatic enzyme inhibitors
- Non DHP CCBs and amiodarone
(↓heart conduction)
• Some interactions may decrease action
of β-Adrenergic Blockers
- Hepatic enzyme inducers

- NSAIDs related to ↓ PGs

 ↓ its vasodilatory effects
 ↓ natriuresis in the loop of Henle and
collecting tubule, and ↓ its ability to
partially antagonize ADH
 ↓natriuretic effect of dopamine and of
natriuretic peptides
→ (↑ Na and water retention → ↑BP)
• β-Adrenergic Blockers may affect actions
of other drugs:
- Clonidine withdrawal (hypertension
crisis→↑circulating catecholamines→
unopposed vasoconstriction)
- Insulin misuse (↓ signs [tachycardia] and
response to hypoglycemia [β2 mediated
glycogenolysis])
- Prazosin (→ inhibit compensatory response
of body to peripheral vasodilation
[tachycardia and ↑cardiac output]→↑
hypotensive response to 1st dose)
- Sympathomimetics (propranolol +
terbutaline) (↓ terbutaline action)
II. Calcium Channel Blockers:
Verapamil Diltiazem Dihydropyridines
Peripheral Vasodilation Increase Increase Marked increase
↓afterload
Coronary Blood Flow Increase Increase Marked increase

Contractility Marked Decrease No change

decrease /decrease
SA/AV conductivity Decrease Decrease NO change
Heart Rate Marked Decrease Increase
decrease
 Some interactions may increase action of
CCBs
- Hepatic enzyme inhibitors
(Verapamil, diltiazem and nifedipine
highly susceptible to hepatic metabolism
whereas amlodipine and felodipine less
susceptible (longer half life))
- Long acting nitrates, α blockers, quinidine
(excess peripheral hypotension)
-B blockers, digitallis, amiodarone
(excess decrease in heart conduction)
-Disopyramide (excess –ve chrono and
potent –ve inotropic effect→ caution in
patients with LV dysfunction)
• Some interactions decrease action of
CCBs
- Hepatic enzyme inducers

- Less susceptible to NSAIDs

interaction compared to β blockers,
diuretics, ACEI & ARB
• CCBs may affect action of other
drugs:
- Verapamil, diltiazem and nicardipine
inhibit hepatic metabolism
• Exceptions:
- Nifedipine, amlodipine (not affecting
hepatic metabolism)
- Digoxin (verapamil, diltiazem → ↓P
glycoprotein →↑ digoxin level,
both ↓ AV conduction →cardiac
arrest)
 ANTIHYPERTENSIVE DRUGS
INTERACTIONS
III. Diuretics:
1) Loop diuretics
 Some interactions decrease its action
(e.g. NSAIDs) (↓vasodilatory effects of
PGs and ↓ natriuresis)
- probenecid (interferes with its urinary
excretion)
- Loop diuretics increase digoxin toxicity
(excess hypokalemia)
- Loop diuretics increase Li toxicity (impair
Li excretion and increase its
reabsorption)
2) Thiazide diuretics
• Some interactions decrease its action
e.g. NSAIDs (same as loop diuretics),
probenecid (same as loop diuretics more
significant here)
- Thiazide diuretics increase digoxin
toxicity (excess hypokalemia)
- Thiazide diuretics increase Li toxicity
(same as loop diuretics more significant
here)
 ANTIHYPERTENSIVE DRUGS
INTERACTIONS
IV. Vasodilators:
1) Nitrates
 Some interactions increase its action:

- Sildenafil (powerful vasodilation and

life threatening hypotension)
- B blockers and CCBs (triple therapy)

(excess hypotension)
• Other interactions:
- Hydralazine (beneficial interaction and
less nitrate tolerance)
- Nitrates mediate their vasodilatory effects
through interaction with protein
thiol→consumption→ nitrate tolerance
- Hydralazine possibly through its
antioxidant →↓oxidative stress→ preserve
protein thiol and↓ vasoconstriction
mediated by peroxynitrite formation.
2) α blockers (e.g.prazocin and doxazocin)
•Some interactions increase its action (e.g.
CCBs and nitrates)
excess hypotension
 ANTIHYPERTENSIVE DRUGS
INTERACTIONS
V. ACE inhibitors:
 Some interactions increase its action
- Diuretics (overdiuresis)

- K retaining diuretics (spironolactone)

(hyperkalemia)
 Some interactions decrease its action

- NSAIDs (same as before)

 +VE INOTROPIC AGENTS DRUGS
INTERACTIONS
Digoxin:
- Mechanism of its positive inotropicity:
- Competes with K for inhibition of Na K
ATPase→↑Nai →↑Na Ca exchanger →↑Cai
→↑ contractility
- Hypokalemia increases digoxin toxicity
- Hyperkalemia decreases digoxin toxicity
Some interactions increase its action
- Verapamil, quinidine, amiodarone,
propafenone (↓P glycoprotein)
- Diuretics (excess hypokalemia)

- Tetracycline (↓inactivation by intestinal

flora and ↑ bioavailability)
- Erythromycin (↓inactivation by
intestinal flora and ↓ P glycoprotein)
 +VE INOTROPIC AGENTS DRUGS
INTERACTIONS
- Tricyclic antidepressant
(↑absorption of digoxin by ↓ in gastric
emptying rate)
 +VE INOTROPIC AGENTS DRUGS
INTERACTIONS
 Some interactions decrease its action
- Cholestyramine (↓absorption by
binding to drug)
- Cancer chemotherapeutic agents
(↓absorption by damaging of intestinal
mucosa)
 ANTITHROMBOTIC AND
THROMBOLYTIC AGENTS
1) Warfarin:
 Some interactions increase its action
- Sulfinpyrazone (protein binding
displacement)
- Sulfonamide (protein binding
displacement and inhibits its hepatic
metabolism)
- Hepatic enzyme inhibitors
Exceptions:
- Grape fruit juice (does not act on the CYP
2C9 but does act on the 3A4)
- Hepatic disease (↓clotting factors
synthesis)
- Hyperthyroidism (↑clotting factors
metabolism)
- Cephalosporin (↓ vit K synthesis)
 Some interactions decrease its action
- Diet rich in vit K (↑synthesis of clotting
factors)
- Cholestyramine (↓absorption by binding
to drug)
- Tricyclic antidepressant (↓ its absorption
by ↓ in gastric emptying rate)
- Hepatic enzyme inducers
 ANTITHROMBOTIC AND
THROMBOLYTIC AGENTS
 Actions on other drugs:
- Hypoglycemics (warfarin inhibits its
hepatic metabolism)
2) Salicylates:
Aspirin
 Some interactions increase its action
- Other NSAIDs or corticosteroid (↑↑ risk
of GI bleeding)
- Heparin (excess bleeding)
- Warfarin (excess bleeding)
- Carbonic anhydrase inhibitors
(↓ blood pH → ↑ salicylate toxicity in
overdose)
- Metabolic acidosis→↓blood pH → more
salicylate in non ionized form
→↑salicylate cellular uptake→↑salicylate
toxicity
 ANTITHROMBOTIC AND
THROMBOLYTIC AGENTS
 Some interactions decrease its action:
- Antiacids e.g. bicarbonates (↑ urine pH
and ↑ renal clearance)
 Aspirin effect on actions of other drugs:
- Hypoglycemic drugs (aspirin ↑ insulin
sensitivity, ↓ rates of hepatic glucose
production, ↓renal tubular excretion, → ↑
action of hypoglycemic drugs)
- Sulfinpyrazone: aspirin has a dual effect
on uric acid levels (low doses decrease
renal excretion of sodium urate and thus ↓
uricosuric effect of sulfinpyrazone while
very high doses (>3000mg/day) ↑excretion
of uric acid)
 ANT INFECTIVE AGENTS
1) Bacterial cell wall inhibitors
 Penicillin

- Probenecid (delays penicillin elimination)

- Ampicillin + sulbactam (β lactamase

inhibitor→↓ bacterial resistance)
 Cephalosporin

- Probenecid (same as penicillin)

- Antiacids, H2 blockers, PPI (↑ stomach pH
→ ↓ absorption)
 ANT INFECTIVE AGENTS
- Anticoagulants, NSAIDS and anti-
platelets (↓ vit K → ↑ bleeding
tendency)
- alcohol (disulfiram-like reaction)→ N,V,
flushing, shortness of breath
- Ceftriaxone is contraindicated in
newborns receiving calcium-containing
IV solutions (fatal pptn in lung and
kidneys)
 ANT INFECTIVE AGENTS
 Imipenem (carbapenem class)
- dehydropeptidase inhibitor (cilastatin)
Intentional!
Imipenem is hydrolyzed by
dehydropeptidase to nephrotoxic
metabolite.
Cilastatin inhibits dehydropeptidase and
thus imipenem nephrotoxicity
 ANT INFECTIVE AGENTS
2) Protein synthesis inhibitors
 Tetracycline

- Food (↓ absorption except doxycycline

and minocycline)
- Antiacids, dairy products, Ca, Fe, Mg
(↓ absorption)
- Minocycline does not chelate calcium
→slightly affected by dairy products)
 ANT INFECTIVE AGENTS
 Macrolides (↓ liver metabolism
except Azithromycin)
- Drugs affected by hepatic metabolism
 Chloramphenicol

- ↓ liver metabolism
 Linezolid (weak MAOI)

- Tyramine and sympathomimetics

 Aminoglycosides

- loop diuretics and ethacrynic acid

(↑ototoxicity)
- amphotericin B and polymyxins
(↑ nephrotoxicity)
- skeletal muscle relaxants (e.g. baclofen)
(↑ activity)
 ANT INFECTIVE AGENTS
3) Intermediatory metabolism
inhibitors
 Sulfonamides (↑ action of following drugs
by protein binding displacement)
- oral anticoagulants
- phenytoin
- sulfonylurea oral hypoglycemic agents
 Co-Trimoxazole (combination
inhibits sequential steps in bacterial
folic acid synthesis )
Trimethoprim (DHF reductase
inhibitor)
+ Sulfamethoxazole (PABA analogue
acts as DHPteroate synthetase
inhibitor):
- more powerful than using each of
them alone
4) Urinary Tract Antiseptics:
 Methenamine
acidic pH in urine → formaldehyde
(active metabolite) + NH3
- Hepatic dysfunction (↓urea synthesis,
↑NH3) (exacerbate encephalopathy)
- urinary akalinizers e.g. acetazolamide
and sodium bicarbonate (↓antibacterial
activity)
- sulfonamides (forms insoluble
complex→↓ oral absorption)
 ANT INFECTIVE AGENTS
 Nalidixic acids
- Warfarin (↑ anticoagulant activity by protein
binding displacement)
- Probenecid (↓ nalidixic efficacy and ↑ its
systemic s.e.)
5) Antimicrobials Used in
Tuberculosis:
 Isoniazid (acetylation in liver →
hepatotoxic metabolite)
- Rifampin, alcohol and pyrazinamide (↑
isoniazid hepatotoxicity)
- Aluminum-containing antacids
(↓absorption)
- Tyramine and sympathomimetics
(hypertension crisis due to MAOI)
- SSRIs (serotonin syndrome) (N, V, diarrhea,
rapid HR, confusion, agitation, tremors,
sweating, shivering)
6) Miscellaneous Antibacterial Drugs:
 Quinolones
- Fluoroquinolones ↓ liver metabolism → ↑
activities of some drugs (e.g.anticoagulants,
theophylline, caffeine)
- Multivalent cations (antacids, milk products,
Al, Mg, Ca, Fe, Zn) (insoluble chelation
complex formation→ ↓ absorption)
- Sucralfate (↓ absorption by direct binding of
fluoroquinolone by sucralfate itself and
aluminum content of sucralfate salt)
 Azoles
 ↓hepatic metabolism (ketoconazole &
itraconazole inhibit CYP3A4 but
fluconazole does not (except at high
doses)
 Antacids, H2 blockers & proton pump
inhibitors (↑gastric pH)
→↓ bioavailability of ketoconazole &
itraconazole.
 ANT DIABETIC AGENTS
I) Insulin:
- Non selective β blockers (↓ signs and
response to hypoglycemia)
- Clonidine use (↓ signs and response
to hypoglycemia in diabetic patients)
Some interactions decrease its action
- Antipsychotics (e.g. clozapine ↓insulin
sensitivity at peripheral tissues)
- Corticosteroids (↓insulin sensitivity at
peripheral tissues)
- Diuretics ( e.g.↓insulin sensitivity at
peripheral tissues)
- Some sympathomimetic drugs
(promote hepatic glycogenolysis
through β2 receptor)
 Some interactions increase its action
- Guanethidine (by affecting the release
of catecholamines)
- Fibrates (↑insulin sensitivity at
peripheral tissues)
- Octreotide ( e.g. somatostatin analogue
inhibits the actions of glucagon and
growth hormone and delays the
absorption of carbohydrate from the
gut)
II) Oral hypoglycemics:
- Sulfonylureas (e.g. glibenclamide) are
metabolized in the liver. They also bind to
plasma proteins and are susceptible to
inhibitors or inducers of p-glycoprotein
- Biguanides (e.g. metformin) is renally
excreted and may have increased toxicity
with drugs that impair renal function.
- Metformin is negligibly bound to
plasma protein or affected by P-
glycoprotein
Interactions:
- Non selective β blockers (similar to insulin)

- Clonidine (similar to insulin)

Some interactions decrease its action

- Antipsychotics (similar to insulin in addition
to interference with insulin release and
insulin inactivation)
- Corticosteroids (similar to insulin)

- Diuretics (similar to insulin and decrease

insulin release possibly due to hypokalemia)
- Sympathomimetic drugs (same as insulin)
- Hepatic enzyme inducers (e.g. rifampicin
induces drug liver metabolism in addn to P
glycoprotein induction)
- CCBs (inhibition of insulin secretion)

 Some interactions increase its action

- Guanethidine (similar to insulin)

- Fibrates (similar to insulin in addn to

displacement from their plasma protein
binding sites, alterations in their renal
excretion and inhibition of hepatic
metabolism)
- Octreotide (similar to insulin)
- Phenylbutazone (inhibition of renal
excretion, liver metabolism and
displacement from protein binding sites)
- Quinolones (inhibition of liver metabolism
and increasing insulin secretion)
- Salicylates (aspirin) (by interfering with
renal tubular excretion, some studies show
↓ rates of hepatic glucose production and ↑
peripheral insulin sensitivity by high aspirin
dose)
- Sulfonamides (↓ liver metabolism and
displacement from protein binding sites)
- Antiacids and PPI (↑ gastric pH ↑ solubility
of sulphonylureas ↑ absorption)
- H2 antagonists (e.g. cimetidine similar to
antiacid in addn to ↓liver metabolism and ↓
renal excretion)
- Azoles (↓ liver metabolism)
 DRUGS USED IN TREATMENT OF
ASTHMA (BRONCHODILATORS)
I) β2 agonists
Some interactions decrease its
action
- Non selective β blockers (block the β2
receptors in the bronchi→
bronchoconstriction )
- Aspirin and other NSAIDs (inhibition of
cyclooxygenase PGs synthesis and
predominating leukotrienes production)
Some interactions increase its toxicity
- K depleting drugs (↑ ↑ hypokalemia →
risk of serious cardiac arrhythmias)
- Ipratropium (↑risk of glaucoma in
susceptible patients by blocking
drainage of aqueous humour)
- Salbutamol (↑risk of glaucoma in
susceptible patients by increase in
production of aqueous humour)
 DRUGS USED IN TREATMENT OF
ASTHMA (BRONCHODILATORS)
II) Theophylline
Some interactions decrease its
action
- Hepatic enzyme inducers (↑ metabolism)
- Hyperthyroidism (↑ metabolism)
- High-protein diets (↑ metabolism)
Some interactions increase its action
- Hepatic enzyme inhibitors (↓ metabolism)
- Hypothyroidism (↓ metabolism)
- High-carbohydrate diets (↓ metabolism)
Some interactions increase its
toxicity (hypokalemia)
- β2 agonists (↑ ↑ hypokalemia)

- Diuretics (↑ ↑ hypokalemia)