Ren Oh, a 68 y.o male. Tries to jog 16 km in preparation to join an upcoming marathon.

1. Ren Oh, a 68 y.o male. Tries to jog 16 km in preparation to join an upcoming marathon.

2. 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

3. 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

4. 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

5. Mechanism of drug interaction based on PD and PK

6. 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

7. 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

8. Pharmacodynamics of Ibuprofen-Captopril Interactions

9. Pharmacokinetics 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

10. 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. 

11. 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

12. Other Drug Interactions with 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

13. 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

14. 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.

15. 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.