Transcript Pharmacodynamics of Ibuprofen

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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
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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
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Competitive inhibitor of angiotensin converting enzyme (ACEi), potent
vasoconstrictor
Indications:
– Acute hypertension, hypertension
– heart failure, left ventricular dysfunction after MI
– diabetic nephropathy
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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
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Pharmacodynamics
– MOA: prevent the conversion of angiotensin I to angiotensin II
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
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NSAIDS may moderately increase BP
 Effectiveness of hypotensive agents is decreased
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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 coadministered with NSAIDS like ibuprofen
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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
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]
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 increase rennin release
 increase GFR through vasodilatory effect
 increase water and sodium excretion
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No prostaglandin, no rennin release, no vasodilation,
no increase in GFR and no increase in water and
sodium excretion  increased circulatory volume still
remains
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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
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Ibuprofen and Aspirin
 Decreased cardioprotective effect and anti-platelet
activity caused by competitive inhibition of platelet
cyclooxygenase
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Ibuprofen and Alcohol
 combined local effect as well as inhibition of
prostaglandins leading to decreased integrity of the GI
lining.
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
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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 StevensJohnson syndrome
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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
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 512;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.
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.