Assoc. Prof. Iv. Lambev E-mail: itlambev@mail.bg

1. Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology Adverse Drug Reactions (Summary) Assoc. Prof. Iv. Lambev E-mail: itlambev@mail.bg

2. Adverse reactions (ARs) is any undesirable or unintended consequence of drug administration. ARs include all kinds of noxious effects– trivial, serious or even fatal. All drugs are capable of producing ARs. Whenever a drug is given a risk is taken. The magnitude of risk has to be considered along with other therapeutic advantages in deciding whether to use or not one drug. ARs may develop promptly or only after prolonged medication or even after stoppage of the drug. An incidence of 10–25% ARs has been documented in different clinical studies. So drug ARs are not rare. They are more common with multiple drug therapy and in the elderly patients.

3. ARs have been classified in many ways. It is convenient to classify drug ARs under the following headings (by Bennett and Brown, 2003): Type A (Augmented) reactions will occur in everyone if enough of the drug is given because they are due to excess of normal, predictable, dose-related, pharmacodynamic effects. They are common and skilled management reduces their incidence, e.g. postural hypotension, hypoglycemia, hypokalemia. Type A reactions also include side, secondary and toxic effects of drugs.

4. Type B (Bizarre) reactions will occur only in some people. They are not part of the normal pharmacology of the drug, are not dose-related and are due to unusual attributes of the patient interact- ing with the drug. These effects are predictable where the mechanism is known (though predictive tests may be expensive or impracticable), otherwise they are unpredictable for the individual, although the incidence may be known. The class includes unwanted effects due to inherited abnormalities (idiosyncrasy) and immunological processes (drug allergy). These account for most drug fatalities.

5. Type C (Chronic) reactions due to long-term exposure, e.g. analgesic nephropathy, dyskinesias with levodopa. Type D (Delayed) reactions following prolonged exposure, e.g. carcinogenesis or short-term exposure at a critical time, e.g. teratogenesis. Type E (Ending of use) reactions, where dicontinuation of chronic therapy is too abrupt, e.g. of adrenal steroid causing rebound adrenocortical insufficiency, of opioid causing the withdrawal syndrome. F (Failures)– unwanted drug interactions.

6. Causes of drug ARs (1) The patient may be predisposed by age, genetic constitution, tendency to allergy, disease, personality, habits. (2) The drug. Anticancer agents are by their nature cytotoxic. Some drugs, e.g. digoxin, have steep dose-response curves and small increments of dose are more likely to induce augmented (type A) reactions. Other drugs, e.g. antimicrobials, have a ten- dency to cause allergy and may lead to bizarre (type B) reactions. Ingredients of a formulation, e.g. coloring, flavoring, sodium con- tent, rather than the active drug may also cause ARs. (3) The prescriber. ARs may occur because a drug is used for an inappropriately long time (type C), at a critical phase in pregnancy (type D), is abruptly discontinued (type E) or given with other drugs (unwanted interactions).

7. Severity of adverse drug reactions has been graded as: Minor: No therapy or antidote required. Moderate: Requires change in drug therapy, specific treatment or prolongs hospital stay by at least one day. Severe: Potentially life threatening, causes permanent damage or requires intensive medical treatment. Lethal: Directly or indirectly contributes to death of the patient.

8. Drug ARs can be minimized (but not altogether • eliminated) by observing the following practices • (by Tripathi, 2008): • Avoid all inappropriate use of drugs. • Use appropriate dose, route and frequency of drug administration. • Elicit and take into consideration previous history of drug ARs. • Elicit history of allergic diseases and exercise caution (drug • allergy is more common in patients with allergic diseases). • Rule out possibility of unwanted drug interactions. • Use correct drug administration technique (e.g. i.v. injection of • aminophyllne must be slow). • Carry out appropriate laboratory monitoring (e.g. prothrombin time • and INR with acenocoumarol and warfarin, serum drug levels with • lithium – 0.4–1 mmol/L).

9. (1) Side effectsare unwanted pharmacodynamic effects that occur at therapeutic doses. They can be predicted from pharmacological profile of a drug. Very often reduction of dose relieves the symptoms. In many cases a side effect may be based on the same action as the therapeutic effect, e.g. M-cholinolytics atropine is used in preanaesthetic medication for its antisecretory action – produces xerostomia (dryness of mouth) as a side effect. Side effect may also be based on a different peculiarity of drug action, e.g. estrogens cause nausea which is unrelated to their main antiovulatory action. Atropine

10. (2) Secondary effects are indirect consequences of a primary action of the drug, e.g. suppression of bacterial flora by aminopenicillins, cephalosporines, tetracyclines, chloramphenicol, fluoroquinolones or co-trimoxazole results in the development of endogenous superinfections. (3) Toxic effects are the result of excessive pharmaco- logical action of the drug due to overdosage or prolonged use. Overdosage may be absolute (accidental, homicidal, suicidal) or relative (e.g. usual dose of aminoglycoside antibiotics in presence of renal failure). Toxic effects are predictable and dose related. They result from functional alteration (in high dose atropine causes delirium) or drug induced tissue damage (hepatic paracetamol necrosis).

11. Acute paracetamol poisoningoccurs specially in small children who have low hepatic glucoronide conjuga- ting ability. If a large dose (> 150 mg/kg or > 10 g in adult) is taken, serious toxicity can occur. Letal dose is 250 mg/kg. N-acetyl-p-benzoquinoneimine (NABQI)is a highly reactive arylating metbolite of paracetamol which detoxi- fied by conjugation with glutathione. When a very large do- ses paracetamol are taken, glucuroconjugation capacity is saturated, more NABQI is formed, hepatic glutathione is depleted and NABQI binds covalently to proteins in liver cells (and renal tubules) causing necrosis. In chronic alco- holic even 5–6 g/d taken for a few days can result in hepa- totoxicity because ethanol induces CYP 2E2, that metabo- lizes paracetamol, to NABQI. Treatment needs activated charcoal, given orally or through the tube to prevent GI ab- sorption, and acetylcysteine (150 mg/g by i.v. infusion).

12. Basic & Clinical Pharmacology – 10th Ed. (2007): Metabolism of paracetamol to hepatotoxic metabolites (NABQI etc.) (GSH – glutathione; SG – glutathione moiety) Daily dose > 7.5 g: hepatotoxicity and nephrotoxicity NABQI NB: Acetylcysteine and GSH contain –SH groups.

13. Poisoning may result from dosages of drugs. Specific • antidotes (receptor antagonists, chelating agents or • specific antibodies are available only for few poisons. • General supportive and symptomatic treatment include: • Termination of exposure • Prevention of GI absorbtion of ingested poisons with suspension • of 20–40 g of activated charcoal in 200 ml water. • Maintenance of patient airway (artificial respiration, if needed). • Maintenance of blood pressure and heart beat by fluid infusion, • pressor agents, cardiac stimulants, if needed. • Hastening elimination of poison by inducing diuresis (furosemide, • mannitol), altering urinary pH (alkalinisation for acidic drugs, • acidification for basic drugs), haemodialysis and haemoperfusion • (passage of blood through a column of charcoal or absorbent resin)

14. (4) Intolerance is the appearance of characteristic toxic effects of a drug in a patient at therapeutic doses, e.g. only a few doses of carbamazepine may cause ataxia in some people; one tablet of chloroquine (250 mg) may cause vomiting and abdominal pain in some individuals. Intolerance indicates a low threshold of the individual to the action of drugs. (5) Allergic reactions occur only in a small part of the population exposed to the drug. Prior sensitization is needed and a latent period of at least 1–2 weeks is required after the first exposure. The drug or its metabolite acts as antigen (AG) or more commonly hapten (incomplete AG – drugs with small molecules which become antigenic only

15. after binding with an endogenous protein) and induce production of antibody (AB)/sensitized lymphocytes. Chemically related drugs often show cross sensitivity. One drug can produce different types of allergic reactions. The course of drug allergy is variable. An individual previously sensitive to a drug may subsequently tolerate it without a reaction. There areseveral types of allergic re- actions: humoral (type I–III) and cell mediated (type IV). Type I (anaphylactic) reactions – immediate hyper- sensitivity. Reaging antibodies (IgE) fix to the mast cells. On exposure to the drug, AG/AB reaction takes place on the mast cell surface releasing mediators (histamine, 5-HT,

16. LT-C4, LT-D4, PGs, PAF etc.) resulting in urticaria, itching, angioedema, asthma, rhinitis or anaphylactic shock. The manifestations occur quickly after challenge. ACE inhibitors – swelling of lips

17. Type II (cytolytic) reactions. Drug + component of specific tissue cell act as AG. The resulting antibodies (IgG, IgM) bind to the target cells. On reexposure AG/AB reaction takes place on the surface of these cells, comple- ment is activated and cytolysis occurs, e.g. thrombocyto- penia, agranulocytosis, aplastic anaemia, haemolysis, organ damage (liver, kidney, muscle), systemic lupus erythematosus.

18. Type III (retarded, Arthus) reactionsare mediated by circulating antibodies (predominantly IgG). AG/AB complex binds complement and precipitates on vascular endothelium giving rise to a destructive inflammatory response. Manifestations are rashes, serum sickness (fever, arthralgia, lymphadenopathy), polyarteriitis nodosa, Stevens–Johnson syndrome (erythema muliforme, arthritis, nephritis, myocarditis, mental symptoms). These symptoms usually subsides in 1–2 weeks. Stevens–Johnson syndrome after oral intake of Co-trimoxazole (Color Atlas and Synopsis of Clinical Dermatology, 1999)

19. Type IV (delayed hypersensitivity) reactions. They are mediated through production of sensitized T-lymphocytes carrying receptors for the AG. On contact with AG T-lym- phocytes produce lymphokines which attract granulocytes and generate an inflammatory response, e.g. contact der- matatitis, some rashes, fever, photosensitization. These type allergic reactions generally take > 12 h to develop. Treatment of drug allergy The offending drug must be immediately stopped. Most mild ARs (some skin rashes) subside without treatment. Antihistamine (H1-blockers desloratadine, levocetirizine) are beneficial in type I reactions (urticaria, rhinitis,

20. swelling of lips) and some skin rashes. In case of anaphylactic shock or angioedema of larynx: a) Put the patients in reclining position, administer oxygen and perform cardiopulmonary resuscitation if required. b) Inject adrenaline 0.5 mg/1 ml i.m. (not i.v.); repeat every 5 to 10 min if the patient does not improve. This is only life saving measure. c) Administer a H1-blocker (e.g. chlorpheniramine 10–20 mg i.m. or slow i.v.). It may adjuvant value. d) In severe/recurrent cases inject slow i.v. methylpredni- solone or betamethasone. It acts slowly but is specially valuable for prolonged reactions and in asthmatics.

21. (Tripathi, 2008) Skin test (intradermal, patch) or intranasal test may forewarn in case Type I hypersensitivity but not in other types.

22. (6) Idiosyncrasy is genetically determined abnormal reactivity to a drug and other xenobiotics. Certain ARs of some drugs are largely restricted to individuals with a particular genotype. Acetylation is an important route of metabolism for many drugs that possess an amine (-NH2) group. Most individuals are either rapid or slow acetylators but the proportion of each varies greatly between races. Some 90% of Japanese are rapid acetylators whereas in Western populations the proportion is 50% or less. Isoniazid may cause peripheral neuropathy in slow acetylators on standard doses

23. and pyridoxine is added to the antituberculosis regimen where there is special risk, e.g. in diabetes, alcoholism, renal failure. Acute hepatocellular necrosis with isoniazid is more common in rapid acetylators, perhaps because they more readily form an hepatotoxic metabolite. Sulphasalazine (used for rheumatoid arthritis) causes ARs more frequently in slow acetylators, probably because of the sulphapyridine, component which is inactivated by acetylation. Bacterial resistance to drugs is genetically determined and is of great clinical importance.

24. Individuals who are Glucose-6-phosphate dehydrogenase (G6PD) deficient may suffer from acute haemolysis if they are exposed to certain oxidant substances, including drugs (dapsone, methylene blue, nitrofurantoin, primaquine, fluoroquinolone, some sulphonamides). Charac- teristically there is an acute haemolytic episode 2–3 days after starting the drug. The haemolysis is self-limiting, only older cells with least enzyme being affected. The condition is common in African, Mediterranean, Middle East and South East Asian. The porphyrias comprise a number of rare, genetically determined enzyme defects in haem biosynthesis.

25. Porphyrins represent precursors of haem. But in people with porphyria the various porphyrins accumulate. Acute porphyrias are characterized by severe attacks of neurovisceral dysfunction precipitated principally by a wide variety of drugs (and by alcohol and infection too). Certain peculiarities of an individual (for which no definite genotype has been described) are included among idiosyncratic reactions, e.g. phenobarbital causes excitement and mental confusion in some patients.

26. Porphyria cutanea tarda. Periorbital and molar violaceous coloration, hyperpigmentation, and hypertrichosis on the face; bullae, crusts, and scars on the dorsa of the hands.

27. (7) Drug dependence is a state arising from repeated, periodic or continuous administration of a drug, that results in harm to the individual and sometimes to society (Bennett ad Brown, 2003).The subject feels a desire, need or compulsion to continue using the drug and feels ill if ab- ruptly deprived of it (abstinence or withdrawal syndrome). Drug dependence is characterized by: • Psychological dependence: there is emotional distress if the drug is withdrawn. • Physical dependence: there is a physical illness if the drug is withdrawn. • Tolerance.

28. Psychological dependence develops when individual believe the optimal state of wellbeing is achieved only through the action of drugs. It may start as liking for the drug effects and may progress to compulsive drug use in some individuals. The intensity of psychological dependence may vary from desire to craving. Reinforcement is the ability of drug to produce effects that make the user whish to take it again. Opioids, cocaine and amphetamine are strong reinforcers, while benzodiazepines are week reinforcers.

29. Physical dependence is an altered physiological state produced by repeated administration of a drug which necessitates the continued presence of the drug to maintain physiological equilibrium. Discontinuation of the drug results in a characteristic withdrawal (abstinence) syndrome. Drugs producing physical dependence are depressants of CNS: opioids (morphinomimetics), barbiturates, benzodiazepines, alcohol. Central nervous stimulants such as amphetamines and cocaine produce little or no physical dependence.

30. Drug abuse means the use of psychotropic substances in a way that would “constitute a public health and social problem”. For regulatory agency “drug abuse” refers to any use of an illicit drug. Drug addiction is a pattern of compulsive drug use characterized by overwhelming involvement with the use of a drug. Amphetamines, cocaine, cannabis, LSD are drugs which produce addiction but little or no physical dependence. Drug habituation is less intensive involvement with the drug, so that its withdrawal produces only mild discomphort without physical dependence (e.g. tea, coffee, tobacco).

31. Types of drug dependence (Bennett, Brown, 2003) Morphine-type: — psychological dependence severe — physical dependence severe; develops quickly — tolerance marked — cross-tolerance with related drugs — naloxone induces abstinence syndrome. Barbiturate-type: — psychological dependence severe — physical dependence very severe; develops slowly at high doses — tolerance less marked than with morphine — cross-tolerance with alcohol and benzodiazepines

32. Amphetamine-type: — psychological dependence severe — physical dependence slight: psychoses occur during use — tolerance occurs. Cannabis-type: — psychological dependence — physical dependence dubious (no characteristic abstinence syndrome) — tolerance occurs. Cocaine-type: — psychological dependence severe — physical dependence slight — tolerance slight (to some actions).

33. Alcohol-type: — psychological dependence severe — physical dependence with prolonged heavy use — cross-tolerance with other sedatives. Tobacco-type: — psychological dependence — physical dependence. Drug mixtures: Barbiturate-amphetamine mixtures induce a characteristic alteration of mood that does not occur with either drug alone — psychological dependence strong — physical dependence occurs — tolerance occurs. Heroin-cocaine mixtures: similar characteristics.

34. (8) Drug withdrawal syndrome– sudden interruption • of therapy with certain drugs (glucocorticoids, antiepileptic • drugs, CV drugs etc.) usually results in ARs, mostly in • form of worsening of the clinical condition for which the • drug was being used. Examples: • Frequency of seizures may increase on sudden withdrawal • of an antiepileptic drug. • Worsening of angina pectoris of acute myocardial infarction • may result from stoppage of beta-blockers of nitrovasodilators. • Severe hypertension and sympathetic overactivity may occur • shortly after discontinuing clonidine. • In all these cases is very important to keep patient’s • compliance and/or to stop drug gradually.

35. (9) Effects of prolonged administration: Chronic organ toxicity (types C and D reactions) Eye. Toxic cataract can be due to chloroquine and related drugs, adrenal steroids (topical and systemic), phenothiazines and alkylating agents. Corneal opacities occur with phenothiazines and chloroquine. Retinal injury occurs with thioridazine (particularly of the antipsychotics), chloroquine and indomethacin. Nervous system. Tardive dyskinesias occur with neuroleptics; polyneuritis with metronidazole; optic neuritis with ethambutol.

36. Pulmotoxicty. Amiodarone may cause pulmonary fibrosis. • Sulphasalazine is associated with fibrosing alveolitis. • Nephrotoxicity: Aminoglycosides, polymyxines, gold salts. • Hepatotoxicity: Methotrexate, paracetamol, halothane. • Carcinogenesis. The principal mechanisms are: • Alteration of DNA (genotoxicity, mutagenicity). • •Immunosuppression. A wide range of cancers develop • in immunosuppressed patients, e.g. after organ • transplantation and cancer chemotherapy. • •Hormonal. Long-term use of estrogen replacement in • postmenopausal women induces endometrial cancer.

37. (10) Teratogenisity represents the fetal abnormalities of a drug, administered to the pregnant mother (by Tripathi, 2008). The placenta does not strictly constitute a barrier and any drug can cross to a greater or lesser extent. The embryo is one of the most dynamic biological systems and in contrast to adults, drug effects are very often are irreversible. The thalidomide disaster (1958–1962) resulting in 10 000 of babies born with phocomelia and other defects focused attention to these type of drug adverse effects. Тhe biggest medical tragedy of modern times

38. The Australian obstetrician William McBridgeand the German pediatrician Widukind Lenzsuspected a link between birth defects and the drug, and this was proved by Lenz in 1961.McBride was later awarded a number of honours includinga medal and prize moneyby theL'Institut de la Vie in Paris.

39. Phocomelia – seal like limbs (W. Lenz, K. Knapp. Thalidomide embryopathy. Dtsch Med Wochenschr. 1962 Jun 15; 87:1232–42). Germany: 2500 babies

40. UK: 456 babies

41. USA: 17 babies In 1962, the Unated States Congress enacted laws requiring tests for safety during pregnancy before a drug can receive approval for sale in the U.S.

43. (S)-thalidomide (R)-thalidomide • Thalidomide is racemic – it contains both left- and right-handed • isomers. The (R) enantiomer is effective against morning sickness. • The (S) is teratogenic and causes birth defects. Theenantiomers • can interconvert in vivo. The (S) enantiomer intercalates (inserts) • into DNA in G–C (guanine – cytosine) rich regions.

44. Drugs can affect the fetus at follow stages: • Fertilization and implantation – from conception to 14–17 • days: failure of pregnancy (which often goes unnoticed). • Embryogenesis (organogenesis) – between 15–18 to 55 • days of gestation: most vulnerable period, deformities • are produced. • Fetogenesis (growth and development) – from 56 days of • gestation to birth: developmental and functional abnormali- • ties can occurs, e.g. aminosides can cause ototoxicitiy, • ACE inhibitors – hypoplasia of cranium, lungs and kidneys; • NSAIDs may induce premature closure of d. arteriosus. • The type of malformation depends on the drug as well as • stage of exposure to the teratogen.

45. Embryogenesis Dorland’s Illustrated Medical Dictionary (2003, 2004)

46. Schematic diagram of critical periods of human development (By Moore KL: The Developing Human: Clinically Oriented Embryology, 4th ed. Saunders, 1988.)

47. Pregnancy Risk Categories (PRCs) – FDA A B C The FDA (USA) has established 5 categories to indicate the potential of systematically absorbed drug for causing birth defects. The key differentiation among the categories rests upon the reliability of documentation and the risk:benefit ratio (Lacy et al., 1998). D X

48. PRC A: Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first trimester with no evidence of risk in later trimesters. The possibility of fetal harm appears remote. Examples: Folic acid, T4, Magnesium sulfate (inj.!) PRC B: The animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an ARs (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester and there is no evidence of later trimesters. Examples: penicillins, erythromycin, paracetamol, lidocaine.

49. PRC C: The studies in animals have revealed ARs on the fetus (teratogenic, embryocidal or other effects) and there are no controlled studies in women, or studies in women are not available. Drug should be given only if the potential benefits justify the potential risk to the fetus. Examples: atropine, adrenaline, thiopental, bisoprolol. PRC D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g. if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used are ineffective.). Examples: phenytoin, valproate, diazepam, lorazepam.

50. PRC X: Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindi- cated in women who are or may become pregnant. Examples: thalidomide, estrogens, isotretionoin, ergometrine.