Ren Oh, a 68 y.o male. Tries to jog 16 km in

preparation to join an upcoming marathon.

Ibuprofen

• Class: – NSAID (Propionic acid derivative) with analgesic and antipyretic

properties• Indications:

– Symptomatic treatment of arthritis (osteo, rheumatoid, JRA)– Pain management in dysmenorrhea– Temporary relief of minor aches and pains.

• Pharmacokinetics– Preparations: Oral, topical, IV– Absorption: 80% oral through GI tract– Distribution: 90-99% protein bound– Metabolism: 90% Hepatic oxidation, CYP450 (2C9), 2 hr half life– Excretion: <10% Unchanged urinary excretion, metabolites excreted

renally• Pharmacodynamics

– MOA: Nonselective COX inhibitor

Captopril

• Competitive inhibitor of angiotensin converting enzyme (ACEi), potent vasoconstrictor

• Indications: – Acute hypertension, hypertension– heart failure, left ventricular dysfunction after MI– diabetic nephropathy

• Pharmacokinetics– Preparations: Oral tablets, unstable in aqueous solutions– Absorption: 60-75% oral through GI tract, reduced by food to 30-

40%– Distribution: 25-30% protein bound– Metabolism: 50% Hepatic oxidation, CYP450 (2D6), 2 hr half life– Excretion: >95%, 40-50% Unchanged urinary excretion, half-life is

less than 3h• Pharmacodynamics

– MOA: prevent the conversion of angiotensin I to angiotensin II

Other Possible Clinical Scenarios

1) 50 year old male with hypertension started on captopril. He started experiencing severe headaches since he started intake of the ACEi.

2) 53 year old male CEO with mild hypertension complaining of knee pain after a round of golf decides to take some pain reliever.

3) 38 year old obese female smoker, noted to have high BP on more than one occasion, taking Advil for dysmenorrhea complained of nape pain after fighting with a lesbian lover

Mechanism of drug interaction based on PD and PK

Drug Interaction Effects

NSAIDS may moderately increase BP Effectiveness of hypotensive agents is

decreased In a study, captopril given at the same

time as ibuprofen did not decrease both systolic and diastolic BP

There is inhibition of the effect of captopril when co-administered with NSAIDS like ibuprofen

Pharmacodynamics of Ibuprofen-Captopril Interactions

Opposing effects on prostacyclin levels Captopril has the ability to stimulate synthesis

of prostacyclin (vasodilatory prostaglandin)

Indomethacin, NSAIDS, aspirin and other salicylates inhibit antihypertensive response▪ Cyclooxygenase becomes inhibited by

ibuprofen▪ Cyclooxygenase plays a key role in the

synthesis of prostaglandins▪ Prostaglandin synthesis is inhibited

Pharmacodynamics of Ibuprofen-Captopril Interactions

Captopriland ibuprofen have opposing effects on tubular Na and waterhandling, which are attenuated by the addition of the other drug.

Prostaglandin Effects on the Kidney (largely PGE2 and PGI2) [Basic and Clinical Pharmacology, 10th edition by Katzung]

increase rennin release increase GFR through vasodilatory effect increase water and sodium excretion

No prostaglandin, no rennin release, no vasodilation, no increase in GFR and no increase in water and sodium excretion increased circulatory volume still remains

Pharmacokinetics of Ibuprofen-Captopril Interactions

Other drug interactions with Ibuprofen

Ibuprofen and SRIs Studies show increased bleeding episodes in patients

treated with psychotropic agents that interfere with serotonin reuptake. Concurrent use of NSAIDs or aspirin was found to potentiate the risk

Ibuprofen and Aspirin Decreased cardioprotective effect and anti-platelet

activity caused by competitive inhibition of platelet cyclooxygenase

Ibuprofen and Alcohol combined local effect as well as inhibition of

prostaglandins leading to decreased integrity of the GI lining. 

Other Drug Interactions with Captopril Antacids: decrease absorption of captopril Clonidine: normal onset of the hypertensive

action of captopril is delayed when px treated with clonidine are shifted to captopril

Corticosteroids: antagonises hypotensive effect Digoxin: increase in plasma concentration of digoxin thus increased risk of digoxin-related side effects

Diuretics: potentiate antihypertensive effect of captopril

Immunosuppresants: (azathioprine and cyclophosphamide) blood dyscrasias in patients with renal failure who were also taking captopril

Levodopa: increases the hypotensive action of captopril

Lithium: increased serum concentration of lithium if used concomitantly with captopril

Potassium supplements, salt substitutes: hyperkalemia

Probenecid: reduces renal clearance of captopril and thus enhances hypotensive effect of captopril

Procainamide: concomitant use with captopril allegedly increases risk of neutropenia and Stevens-Johnson syndrome

Other Drug Interactions with Captopril

Recommendations

Therapy must be monitored since the effect of the interaction is rapid .

Alternative anti-inflammatory therapy should be considered.

Continued monitoring of blood pressure in the course of use of the both drugs.

Patients at risk for this drug interaction:- the elderly- those with CHF- hypertensive patients with low renin

concentrations

References

Donat, F. et al. Interactions between ibuprofen and antihypertensive drugs: Incidence and clinical relevance in dental practice. Med Oral Patol Oral Cir Bucal. 2008 Nov 1;13(11):E717-21.

John Parry Griffin, P. F. D'Arcy, Patrick Francis D'Arcy. A manual of adverse drug interactions. 1997. USA: Elsevier, 649 pages. 

Halawa B. Effect of indomethacin and ibuprofen on blood pressure of patients treated with nifedipine or captopril. Pol Tyg Lek. 1993 Apr 5-12;48(14-15):313-5.

Katzung, et al. Basic and Clinical Pharmacology, 11th ed. 2009

Ashraf Mozayani, Lionel P. Raymon. Handbook of drug interactions: a clinical and forensic guide. 2004. USA: Humana Press, 663 pages.

Sultana N, Arayne MS, Quraishi RU. In vitro interactions of captopril with NSAID's. Pak J Pharm Sci. 2006 Jul;19(3):202-7.

References

Llorca CS, Serra MPM, Donat FJS. Interactions between ibuprofen and antihypertensive drugs: incidence and clinical relevance in dental practice. Med Oral Patol Oral Cir Bucal. 2008 Nov 1; 13 (11):E717-21.