Discuss the following:

(a)            adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs).

(b)            pharmacokinetic drug interactions.

(c)            progestogen-only oral contraceptives.

Suggested Answer:

(a)

NSAIDs are used clinically for their analgesic, anti-inflammatory and anti-pyretic actions which are mediated via inhibition of cyclooxygenase and thus prostaglandin synthesis. The commonly used NSAIDs are paracetamol, aspirin, mefenamic acid, ibuprofen and indomethacin.

Gastric or intestinal mucosal damage is the commonest adverse effect of the NSAIDs. Mucosal prostaglandins inhibit acid secretion and further exert a cytoprotective effect by promoting the secretion of mucus and by strengthening resistance of the mucosal barrier to back-diffusion of acid. Inhibition of prostaglandin biosynthesis is believed to account for the erosions, ulceration and bleeding caused by NSAIDs.

Urticaria, severe rhinitis and asthma occur in susceptible individuals, e.g. with nasal polyps, who are exposed to NSAIDs; notably aspirin; the mechanism may involve inhibition of synthesis of bronchodilator prostagladins.

Bleeding time may be prolonged due to the inhibition of thromboxane A₂ by platelets.

Renal toxicity is variable and may range from minor derangements of renal function to renal failure. Renal excretion of lithium, methotrexate and phenytoin may be decreased. Renal blood flow is reduced because the synthesis of vasodilator renal prostaglandins is inhibited; the result is sodium and fluid retention and arterial blood pressure may rise. Mixture of NSAIDs taken repeatedly cause grave and often irreversible renal damage, notably chronic interstitial nephritis, renal papillary necrosis and acute renal failure. The condition is most common in people who take high doses over years.

Aspirin is used for its anti-inflammatory, analgesic, anti-platelet and anti-pyretic effects. Use of aspirin is associated with a high incidence of gastric symptoms such as dyspepsia, heartburn, vomiting, epigastric distress, gastric erosion and bleeding. It is a common cause of allergies which manifest as severe rhinitis, urticaria, angioedema, asthma or shock. Salicylism (the symptoms of too high dose) is expressed as tinnitus and hearing difficulty, dizziness, headache and confusion. Epidemiological evidence relates aspirin use to the development of Reye’s syndrome (encephalopathy and hepatic damage) in children recovering from febrile viral infections.

Mefenamic acid is used for mild to moderate pain where inflammation is not marked. The principal adverse effects are diarrhoea, upper abdominal discomfort, peptic ulcer and haemolytic anaemia.

Indomethacin is used to relieve moderate to severe pain and the inflammation of rheumatoid disease, acute musculoskeletal disorders and gout. Its adverse effects include gastric irritation with ulcer formation, bleeding and perforation. Headache, vomiting, dizziness and ataxia occur.

(b)

Pharmacokinetic drug interactions occur when drugs interact remotely from the target site to alter plasma concentrations so that the amount of drug at the target site of clinical effect is altered. Clinically important adverse drug interactions become likely with drugs that have a steep dose-response curve and a small therapeutic index; drugs that are known enzyme inducers or inhibitors and drugs that exhibit saturable metabolism. The interactions may occur outside the body, at the site of absorption, during distribution, metabolism or excretion.

Intravenous fluids offer special scope for interactions when drugs are added to the reservoir or syringe, for a number of reasons. Drugs commonly are weak organic acids or bases. They are often insoluble and to make them soluble it is necessary to prepare salts. The mixing of solutions of salts can result in changes in their concentrations and pH. Serious loss of potency can result from incompatibility between an infusion fluid and a drug that is added to it. Mixed drugs formulated for injection in a syringe may cause interaction, e.g. protamine zinc insulin contains excess of protamine which binds with added soluble insulin and reduces the immediate effect of the dose.

Direct chemical interaction in the gut is a significant cause of reduced absorption. Antacids that contain aluminium and magnesium forms insoluble complexes with tetracyclines, iron and prednisolone. Cholestyramine interferes with absorption of thyroxine, digoxin and warfarin. Gut motility may be altered by drugs. Those having antimuscarinic effects, e.g. antidepressants, and opioid analgesics, reduce gastric emptying and delay absorption of other drugs.

Displacement from plasma protein binding sites may contribute to adverse reaction. A drug that is extensively protein bound can be displaced from its binding site by a competing drug, so raising the free concentration of the first drug. For a displacement interaction to become clinically important, a second mechanism usually operates: sodium valproate can cause phenytoin toxicity because it both displaces phenytoin from its binding site on plasma albumin and inhibits its metabolism. Displacement from tissue binding may cause unwanted effects. When quinidine is given to patients who are receiving digoxin, the plasma concentration of free digoxin may double because quinidine displaces digoxin from binding sites in tissue.

Enzyme induction by drugs and other substances accelerates metabolism and is a cause of therapeutic failure. Oral contraceptive steroids are metabolized more rapidly when an enzyme inducer, e.g. phenytoin, is added and unplanned pregnancy has occurred. Anticoagulant control with warfarin is dependent on a steady state of elimination by metabolism. Enzyme induction leads to accelerated metabolism of warfarin, loss of anticoagulant control and danger of thrombosis. Enzyme inhibition by drugs potentiates other drugs that are inactivated by metabolism, causing adverse reactions. Cimetidine is an inhibitor of microsomal P450 and so potentiates a large number of drugs such as theophylline, warfarin and phenytoin. Erythromycin inhibits a cytochrome P450 enzyme and impairs the metabolism of theophylline, warfarin, carbamazepine and methylprednisolone.

Clinically important interactions can also occur in the kidney. Reabsorption of a drug by the renal tubule can be reduced, and its excretion increased by altering urine pH: treatment of aspirin overdose by alkalinization of urine to promote its excretion. Organic acids are passed from the blood into the urine by acidic transport across the renal tubular epithelium. Penicillin is mostly excreted in this way. Probenecid, an organic acid that competes successfully with penicillin for this transport system, may be used to prolong the action of penicillin.

(c)

Progestogen-only contraception (‘mini-pill’) is taken every day throughout the 28-day cycle; a 3-month depot i.m. injection is an alternative. Subcutaneous implantation that release hormone for several years are in use; they can be removed surgically, e.g. Norplant, if adverse effects develop or pregnancy is desired.

Oral progestogen-only contraception is less effective but safer than combined formulations. Intramuscular progestogen is equal in efficacy to the combined pill. It works by inhibiting ovulation and by rendering the cervical mucus inhospitable to spermatozoa maximally 5 hours after a daily dose.

Progestogen-only contraception is particularly appropriate to women having an absolute contraindication for estrogen, e.g. history of thromboembolism, smokers, and for diabetics.

A missed oral dose allows even less latitude than the combined pill. If a dose is more than 3 hours late it should be taken at once and a barrier method used for 2 days.

A significant limitation to the use of the progestogen-only pill is erratic uterine bleeding. Ectopic pregnancy may be more frequent due to a fertilized ovum being held up in a functionally depressed fallopian tube. Other adverse effects are generally less than the combined pill (blood coagulation is unaffected).

The progestogens used orally include norgestrel, levonorgestrel, ethynodiol and norethisterone.