UNWANTED DRUG EFFECTS

1. UNWANTED DRUG EFFECTS J. Mojžiš

2. SIDE EFFECTS OF DRUGS WHO deffinition of drug side effects: any response to drugwhich is: • unexpected • damaging organism • appearing in dosingused in prophylaxis, diagnosis or modification ofphysiological functions (therapy)

3. Out of definition • mistakes in dosing • drug abuse • accidental or suicidal intoxications • inadequate dosing • changes in bioavailability

4. Occasionally- impurities-vehicle- degradation products

5. Type A (Augmented) reactions • pharmacologically predictable • usually cause low mortality • occur at normal doses and tend to resolve on dose reduction • the most common type of ADR (80% of all ADRs)

6. Type A • reaction appears in whole population • it is dose-dependent • symptoms are similar to pharmacological properties of drug • reaction can appear during first contact with drug

7. Type A - mechanism • the mechanism of action can vary: • a primary therapeutic action of the drug at its primary site (bradycardia with -blockers, haemorrhage with anticoagulants) • a primary action at a different site (GI bleeding with NSAID)

8. They may be avoided by • assessing predisposing factors e.g. genetics - slow acetylators may experience peripheral neuropathy with INH • using low doses and adjusting to therapeutic end pointse.g. antihypertensives and blood pressure. • adjusting for renal or hepatic functione.g. avoid prolonged sedation with benzodiazepines in hepatic failure

9. Type B (Bizarre) reactions • not predictably related to the pharmacology of the drug • idiosyncratic and will occur only in some individuals • not usually dose related  may have high mortality • they include allergic reactions  reactions due to inherited abnormalities (haemolysis in G6PD deficiency) • rarer (20% of all ADRs) (their occurrence will be minimised by taking drug history and family history and by avoiding certain drugs in certain disease states (NSAID in asthmatics) • if an ADR of this type occurs, the drug must be stopped

10. Type C (Continuous) reactions due to long term use e.g. tardive dyskinesias with antipsychotics Type D (Delayed) reactions teratogenesis, carcinogenesis

11. Type E (End of use)reactions • this type of reaction may also be seen as the appearance of a symptom that did not exist before initiation of the therapy • rebound convulsions on withdrawal of carbamazepine in non-epileptic patients

12. Severity of drug side effects • Mild: no interruption of treatment (antihistaminics  sedative effect) • Middle: change of regimen is needed (iron  nausea) • Severe: interruption of treatment is mandatory (PNC  anaphylactic reaction)

13. 1. Allergy Differs from toxicity in: • reaction appears only in part of population • it is not dose-dependent • symptoms differ from pharmacological effect • reaction is a result of previous sensitisation • allergene  protein or hapten  circulating antibodies are present

14. Allergic reactions • acute-anaphylaxis (circulating antibodies) • delayed-tuberculine hypersensitivity (sensitised cells) Hypersenzitivity induction: • antigenes • haptens

15. Hypersensitive reactions classification • systemic (anaphylaxis, fever, vasculitis) • skin (urticaria, erythema, photosensitivity) • lung (asthma, pneumonia) • hepatal (cholestatic, hepatocellular) • renal (glomerulonephritis, interstitial nephritis) • bone marrow (myelosuppresion)

16. Examples: • anaphylaxis (hormones, enzymes, ATB, LA) • fever (ATB, sulfonamides) • skin (majority of drugs) • lung (ASA, ATB) • liver (imipramine, INH) • kidneys (allopurinol, captopril) • bone marrow (majority of drugs)

17. 2. Teratogenity • 1. week of pregnancy(embryo is killed if harmful drug acts) • 1. trimester-organogenesis(most dangerous stage for malformation development) • rest of pregnancy – growth  development of some organ systems(CNS, endocrine, musculoskeletal) • labour (application of drug to mother  direct or indirect effect in child-morphine)

18. Physician responsability • eliminate inadequate drug use • the best risk / benefit ratio drug choice • information of pregnant patients • exact diagnosis and evidence of malformations

19. Examples: • antineoplastics(high risk teratogenity) • antiepileptics(applied with the risk of malformations) • lithium(right heart damage) • coumarines(nasal hypoplasia, growth retardation) • antithyroidaldrugs(fetal hypothyroidism) • TTC(interference with calcification)

20. GENDER- pregnancy C o n f i r m e d teratogens (in h u m a n s): thalidomide (phocomelia), cytostatics-antimetabolites, lithium (cardiac defects), warfarin (chondrodysplasia punctata), sex hormones (cardiac defects, multiple abnormalities) S u s p e c t e d teratogens (evidence is inconclusive, the impact of diseases?): antiepileptics (phenytoin, carbamazepine- craniofacial defects), P o t e n t i a l teratogens (in a n i m a l s): chemotherapeutics (metronidazole), sulphonamides- trimethoprim

21. Gross malformations thalidomide - phocomelia

23. 3. Carcinogenity Examples: • antineoplastics (secondary malignities) • diethylstilbestrol (vaginal ca)

24. How to minimize drug side effects • individualisation of therapy • information about interactions • relatively frequent in newborns or elderly • more frequent in prolonged therapy • identify initial symptoms of side effects (patients) • optimalisation of pharmacotherapy

25. DRUG DEPENDENCE DRUG ABUSE

26. MAIN PSYCHOACTIVE SUBSTANCE (-)-trans-delta-9-tetrahydrocannabinol TETRAHYDROCANNABINOL CONTENT (%) Herbal cannabis 0.5 - 5 Cannabis resin 2 - 10 Cannabis oil 10 - 30 CANNABISCannabis sativa L.

27. Common illicit forms-plant loose herbal material, blocks of compressed herbal material vegetable fibre herbal material Abuse pattern Usually smoked (0.5 to 1g of plant material) Common illicit forms-resin fine powder fine powder compressed compressed resin pressed or rolled Abuse pattern Smoked (alone, or mixed with tobacco Orally ingested (food, tea) CANNABIS

28. Common illicit forms-oil dark viscous oil Abuse pattern Smoked (1 - 2 drops put on tobacco or wiped on paper) Orally ingested Certain common street names marihuana khif hashish honey oilred oil CANNABIS

29. CANNABISPHARMACOLOGICAL EFFECTS • Sought-after effects • sense of well being, euphoria, pleasurable state of relaxation • enhancement of sensory experiences (sight, smell, taste and hearing) • Short-term effects • increased appetite • increased pulse rate • reddening of the eyes • impaired intellectual and physical performance • with larger dosessensations may be sharpened • thinking becomes slow and confused • in very large doses, the effects of cannabis are similar to those of a hallucinogen • may cause anxiety and panic, or precipitate a psychotic episode • Long-term effects • development of moderate tolerance • possible psychological dependence • loss of interest in sustained activity • Cannabis smoke contains 50% more tar than smoke from cigarette; with regular use, risk of lung cancer, chronic bronchitis, and other lung diseases increases

30. CANNABISMEDICAL USE THC (manufactured synthetically, dronabinol) • anti-emetic substance in cancer chemotherapy • to stimulate appetite, especially in AIDS patients Possible therapeutic uses of cannabis (plant material) • to ease nausea and vomiting from cancer chemotherapy • to stimulate appetite, especially in AIDS patients • to lower intraocular pressure associated with glaucoma • to decrease muscle spasms, for instance, associated with generalized epilepsy

31. MAIN PSYCHOACTIVE SUBSTANCE Cocaine COCAINE CONTENT (%) Coca leaves 0.5 - 2.5 Coca paste 30 - 80 Crack up to 90 COCACoca Bush (Erythroxylon)

32. Coca leaf green to yellow-greenish elliptical leaves Pattern of use/abuse chewed brewed as tea Coca paste can vary from a brown gummy material to an off-white creamy or beige coloured coarse powder Pattern of use/abuse smoked / inhaled (alone, or mixed with tobacco) orally ingested COCA

33. Cocaine, crack, free base white or off-white crystalline powder with a characteristic odour crack: hard white rocks Pattern of use/abuse Cocaine: sniffed/snorted smoked Crack/Free base: injected Certain common street names bazuco (paste) crack star dust COCA

34. COCAPHARMACOLOGICAL EFFECTS • Sought-after effects • feelings of physical and mental well being, euphoria • increased alertness and energy • postponement of hunger and fatigue • Short-term effects • loss of appetite • faster breathing, increased heart rate and blood pressure • increased body temperature, sweating, dilation of pupils • bizarre, erratic, sometimes violent behaviour • larger doses: hallucinations, sense of power and superiority, restlessness, hyperexcitability, irritability which can lead to panic and paranoid psychosis (disappears if discontinued) • excessive doses may lead to convulsions, seizures, stroke, cerebral hemorrhage or heart failure

35. COCAPHARMACOLOGICAL EFFECTS • Long-term effects • destruction of tissues in nose if sniffed • respiratory problems if smoked • infectious diseases, abscesses, if injected • malnutrition, weight loss • disorientation, apathy, confused exhaustion due to lack of sleep • development of tolerance • strong psychological dependence • with continued use a state similar to paranoid psychosis may develop • after stopping, there usually follows a long period of sleep and then depression • during the crash, death from respiratory failure may occur

36. COCAMEDICAL USE Cocaine as a local anaesthetic, in particular: • in surgery of the ear, nose and throat • never inject !

37. MAIN PSYCHOACTIVE SUBSTANCES Morphine Codeine ALKALOID CONTENT (%) Morphine 4 - 21 Codeine 0.7 - 3 Thebaine 0.2 - 1 Papaverine 0.5 - 1.3 Noscapine 2 - 8 OPIUMOpium Poppy (Papaver Somniferum L.)

38. Raw opium sticky or hard, dark brown material in any form Abuse pattern smoked chewed eaten Medicinal opium fine brown powder pastilles syrup Production pulverizing of raw opium drying at 60°C adjusting morphine content (10%) OPIUM

39. Crude morphine finely ground powder compressed blocks in many cases with "999" trade mark tablets Abuse pattern injected Average dose 10-20 mg Certain common street names ah-pen-yen noir(e) hop O chandu sukhteh OPIUM

40. HEROIN Heroin is a semi-synthetic opiate synthesized from morphine Abuse pattern injected inhaled ("chasing the dragon") sniffed/snorted Smoked Average dose 5-15 mg, up to 250 mg a day Certain common street names boy H harry horse joy powder junk smack white lady white stuff HEROIN

41. OPIUM, MORPHINE, HEROINPHARMACOLOGICAL EFFECTS • Sought-after effects • sense of well being by reducing tension, anxiety and depression • euphoria • in large doses warmth, contentment, relaxed detachment from emotional as well as physical distress • relief from pain (analgesia) • Short-term effects • sometimes nausea and vomiting • constricted pupils • drowsiness, inability to concentrate, apathy, lessened physical activity • acute overdose can result in death due to respiratory depression

42. OPIUM, MORPHINE, HEROINPHARMACOLOGICAL EFFECTS • Long-term effects • rapid development of tolerance and physical and psychological dependence • constipation • menstrual irregularity • infectious diseases, abscesses, if injected • damage of structures in nose, if sniffed/snorted • respiratory problems, if smoked • decreased appetite leading to malnutrition, weight loss chronic sedation • apathy leading to self-neglect • abrupt withdrawal results in moderate to severe withdrawal syndrome which is generally comparable to a bout of influenza (cramps, diarrhea, running nose, tremors, panic, chills and sweating)

43. OPIUM, MORPHINE, HEROINMEDICAL USE Opium and opiates are still widely used in medicine • as analgesic (pain killer; e.g., morphine) • as cough suppressant (e.g., codeine) • against diarrhoea in some countries • heroin is under investigation for the maintenance therapy for heroin addicts

44. Opioidis a generic term applied to opiates and their synthetic analogues, with actions similar to those of morphine, in particular the capacity to relieve pain. FENTANYLS are short-acting highly potent narcotic analgesics (pain killers). Potency compared to morphine fentanyl 80- 200 -methylfentanyl 200-1000 carfentanil 3000 Lofentanil 6000 3-methylfentanyl 7000 OPIOIDS

45. Common forms liquid pharmaceutical preparations for injection white / off-white to brown powders Abuse pattern injected intravenously smoked snorted Average dose 1-50 µg PHARMACOLOGICAL EFFECTS Sought-after, short-term and long-term effects of the fentanyls are indistinguishable from those of heroin, but they are up to hundreds of times more potent. Certain common street names China white synthetic heroin OPIOIDS

46. OPIOIDSMEDICAL USE Fentanyls are mainly used: • as pain killers • as anaesthetic during surgery

47. Common forms tablets and capsules liquids (gel) in capsules for injection Abuse pattern orally ingested injected Average dose 0.25 - 30 (100) mg Duration of action Alprazolam short Temazepam short Flunitrazepam intermediate Diazepam long Chlordiazepoxide long Half-life short: < 10 hours intermediate: 10-24 hours long: > 24 hours CNS DEPRESSANTSBENZODIAZEPINES

48. BENZODIAZEPINESPHARMACOLOGICAL EFFECTS • Sought-after effects • relief of tension, mental stress and anxiety • positive feelings of calmness, relaxation and well being in anxious individuals • improved coping with situational pressures or psychological problems • enhancement of the "high" induced by other drugs, or relief of side effects associated with over-stimulation or withdrawal of other drugs (i.e., as part of a pattern of multiple drug use)

49. BENZODIAZEPINESPHARMACOLOGICAL EFFECTS • Short-term Effects • diminished emotional responses to external stimuli, e.g. pain • reduced inhibition, mental activity and alertness; drowsiness, lethargy and impairment of clarity of thought and impaired judgement may occur • initial increase of risk of accidental injury due to depressant effects • with larger doses, possible impairment of muscle coordination, dizziness, low blood pressure, and/or fainting • unlike barbiturates, large doses of benzodiazepines are rarely fatal unless combined with other drugs or alcohol

50. BENZODIAZEPINESPHARMACOLOGICAL EFFECTS • Long-term effects • headache, irritability, confusion, memory impairment, depression, insomnia and tremor as a result of chronic high dose use • development of tolerance: • after two weeks - ineffective as sleeping pills • after a few months - ineffective against anxiety • development of psychological and physical dependence • abrupt cessation after prolonged use leads to withdrawal syndrome (insomnia, anxiety, perceptual hypersensitivity, tremor, irritability, nausea and vomiting, and even mental confusion and life-threatening convulsions)