Drug Interaction – Dr.

Ahmed Morad - By: Khalid EL-Khamisy – FOPPU19 - LEC 4

Drug interaction of beta blockers

• β-blockers decrease cardiac output → central sympathetic out flow → decrease renin release

• Non-selective β-blockers if combined with insulin in Type 1 diabetes → hypoglycemic coma (fatal)
1) block hypoglycemic symptoms (tachycardia, adrenergic sweating, peripheral v.c.) → silent coma.
Insulin

2) Block β2-mediated glycogenolysis → hypoglycemia → induce prolonged hypoglycemic coma if co-

administered with insulin → ↑ mortality Should be taken with extreme caution for type 1 diabetic
patients
• Clonidine is selective α2 agonist (presynaptic receptor in nerve ending control → control NE
after clonidine

release) reduce BP.

withdrawal

• Use of α2-agonist for long periods → downregulation of α2 receptors

• Post synaptic α1 receptors are sensitized to NE upregulation.
• Clonidine withdrawal: NE release from nerve ending ↑ hypertensive effect
• If β blocker block β2 mediated hypotension → unopposed alpha effect
• Beneficial drug interaction → inhibit reflex tachycardia.

with DHP CCB,

nitrates and
direct
vasodilators
• β-blockers are contraindicated with non-dihydropyridine CCB → massivecardiac
depressant effect (complete heart block)

Pharmacokinetics DDI of propranolol

• Propranolol (non - selective) is an enzyme inhibitor of CYP2D6.
• Enzyme inducers such as rifampicin and phenobarbitone induce metabolism of propranolol (↓ effect).
• Enzyme inhibitors (Fluoxetine, paroxetine) → ↑ propranolol toxicity
• Basic drugs have high affinity to α1 acid glycoprotein: quinidine compete with propranolol ↑ its free
plasma levels.

Drug disease interactions of β-blockers.

• Beneficial drug disease interaction in cases of hypertension and stable angina
• Harmful drug disease interaction in case of vasospastic angina (as it blocks β2 - mediated coronary
vasodilation)
• Contraindicated in case of heart block, phaeochromocytoma and bronchial asthma.

Alpha 2 agonist drug interactions

• TCA inhibit reuptake of NE→ ↑ its levels post synaptically → downregulation of α2
With
presynaptically.
TCA
• Alpha 2 agonist effect is ↓ if administered after TCA

1|Page
Drug Interaction – Dr. Ahmed Morad - By: Khalid EL-Khamisy – FOPPU19 - LEC 4

Drug interactions of CCB

DHP with organic nitrates severe hypotension and reflex tachycardia
DHP with β blockers ↓ reflex tachycardia (benefit)
Non - DHP with β blockers heart block

• Verapamil, diltiazem and nicardipine are enzyme inhibitors of CYP 3A4 which is responsible for metabolism
of 60% of drugs → ↑ toxicity of diazepam and vardenafil.

Drug interactions of organic nitrates

With DHP severe vasodilation and severe hypotension and reflex tachycardia
With β blockers ↓ reflex tachycardia (benefit)
severe vasodilation and severe hypotension → reflex tachycardia →severe
With sildenafil (PDE5 inhibitor)
anginal attacks with high mortality rate

Drug interactions of cardiac glycosides

• Cardiotonic effect of digoxin depends on inhibition Na+/K+ ATPase pump (Na+ efflux and k+ influx)
• Hyperkalemia → antagonize effect of digoxin effect.
• Hypokalemia → ↑ effect of digoxin ↑ its toxicity.
• Fab fragments (antigen binding) binds digoxin used for digoxin poisoning (specific antidote)
Digoxin cause bradycardia by two mechanisms
Inhibit reflex sympathetic stimulation due to ↓
Direct vagal stimulation
output in HF patients
Drug interaction.
Thiazide, loop diuretics and carbonic anhydrase inhibitors Hypokalemia → ↑ effect of digoxin ↑ toxicity
Potassium sparing diuretics, ACEIs, ARBs Hyperkalemia antagonizes effect of digoxin
Digoxin is highly bound to displace digoxin from albumin binding sites ↑
Phenytoin and salicylates
plasma protein its plasma levels.
Azoles (inhibitors) ↑ its effect and toxicity
Digoxin is metabolized by
liver microsomal enzymes Rifampicin, barbiturates,
↑ digoxin metabolism
and phenytoin
Digoxin is degraded by
Broad spectrum antibiotics ↑ digoxin bioavailability
bacterial flora
• Quinidine class 1a sodium channel blocker ↓ HR but has paradoxical tachycardia due to
With
anticholinergic effect (vagal inhibitory effect)
quinidine
• Digoxin inhibits this effect (previous digitalization of patient before quinidine administration)

2|Page
Drug Interaction – Dr. Ahmed Morad - By: Khalid EL-Khamisy – FOPPU19 - LEC 4

Drug interactions of antiarrhythmic drugs

With antacids • Quinidine is weakly basic drugs → ↑ its absorption and toxicity
With acetazolamide • Quinidine causes urinary alkalinization → ↑ renal tubular reabsorption
With atropine, • Anticholinergic effect of quinidine has atropine like action → dry mouth,
phenothiazines, TCA and blurred vision, urinary retention, glaucoma, tachycardia, hyperthermia, and
1st GEN antihistamines constipation
• enzyme inhibitor (CYP 3A4) ↑ toxicity of warfarin.
Amiodarone • Enzyme inhibitor (CYP 2C9) ↑ toxicity of propranolol (2C9,2D6)
(antiarrhythmic drug) • metabolized by CYP 3A4 which inhibited by grapefruit and azoles while
induced by rifampicin.

Drug interactions of antihyperlipidemic drugs

• Bile acid binding resins bind bile acid in intestine prevent enterohepatic circulation → adsorb potent drugs
such as NSAIDs, digoxin, diuretics, valproic acid, sulfonylureas, warfarin→ ↓ effect.
• Overcome by spacing (2 hours) → prevent drug interaction in GIT.
• Atorvastatin, simvastatin are metabolized by CYP 3A4 which inhibited by macrolides, and azoles while
induced by rifampicin.
• Rosuvastatin is metabolized by CYP 2C9 (inhibitors like amiodarone and azoles ↑ statin effect)
• Statin + fibrates → increased risk of myopathy → myoglobinuria and nephrotoxicity

3|Page
Drug Interaction – Dr. Ahmed Morad - By: Khalid EL-Khamisy – FOPPU19 - LEC 4

Drug Interacting Drug Clinical Effect Clinical Clinical Management

Relevance
Avoid using together, monitor
Verapamil, Diltiazem bradycardia, AV Block High
HR, BP, and ECG
β-blockers

Antidiabetic drugs, Suppression of

High Monitor blood sugars
insulin Neuroglycopenic symptoms
↓ bronchodilator activity, Avoid in asthma, COPD. Use
Bronchodilators Moderate
bronchial spasm selective β-blockers
↑ digoxin levels, digoxin Avoid use together, ↓ digoxin
Digoxin toxicity (mainly with High dose by up to 50%,Monitor
Verapamil,
Diltiazem

verapamil) digoxin levels

Use atenolol, bisoprolol
Hepatic interaction leading
ornebivolol (also when using
Carvedilol,Metoprolol to high blood levels of Moderate
potent hepatic enzyme inducers
Verapamil
or inhibitors)
↑ digoxin toxicity due to
Digoxin High Monitor blood K levels
hypokalemia
Aspirin (withthiazide
↑ blood uric acid levels Moderate Monitor blood uric acid levels
diuretics)
Diuretics

↓ antihypertensive effect Monitor BP, avoid use of

NSAIDs Moderate
of loopdiuretics NSAIDs,use Acetaminophen
Hypokalemia, ↓ Avoid use together, monitor
Steroids antihypertensive effect due Moderate serum K levels and BP,
to sodium retention supplement Potassium
Ototoxicity (with loop Avoid use together, monitor for
Aminoglycoside Moderate
diuretics) ototoxicity
Monitor BP, don’t use together in
Diuretics Additive hypotensive action Moderate
volume depleted Patients
Potassium sparing Hyperkalemia when used
High Monitor blood K levels, avoid use
diuretics together
together in renal function
ACEIs, ARBs

Hyperkalemia when used

ACEIs, ARBs High derangement
together
↓ antihypertensive action
NSAIDs due to sodium and fluid Moderate
retention
Avoid use together
↓ antihypertensive action
High-dose aspirin due to sodium and fluid Moderate
retention
Centrally acting
depressant agents
Clonidine

(hypnotics, tranquillizers, Avoid use together, instruct

High
neuroleptics, Additive sedative effects patient to avoid driving, use
antiepileptic, some anti- machinery, prevent falls
depressants, H1-
antihistamine, alcohol)

4|Page