Lesson 4 - Adverse Drug Effects (CEU 2024/25) PDF

Lesson 4 Adverse drug effects 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 Summary 1. Adverse Drug effects. 2. Mechanisms of drugs toxicity. 3. Teratogenic effects of drugs. 4. Therapeutic index 2 1. ADVERSE DRUG EFFECT...

Lesson 4 Adverse drug effects 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 Summary 1. Adverse Drug effects. 2. Mechanisms of drugs toxicity. 3. Teratogenic effects of drugs. 4. Therapeutic index 2 1. ADVERSE DRUG EFFECTS. According to the WHO, an adverse drug reaction (ADR) is a harmful and unintentional response to a drug administered in normal doses. ADRs can cause morbidity, mortality and healthcare costs.  1. ADVERSE DRUG EFFECTS. non-desired or non-expected consequence of the administration of a drug AT A NORMAL DOSE. – we could include all kind of noxious or harmful effects (trivial, serious or fatal). Drug administration implies a risk: we must balance the benefits/risk of the administration of a drug. The study of ADRs is the responsibility of the branch known as pharmacovigilance. UNIT 4: Adverse drug effects 3  ADRs can be classified in 6 groups: – A: Augmented pharmacological effects - dose dependent and predictable » Intolerance » Side Effects – B: Bizarre effects (or idiosyncratic) - dose independent and unpredictable – C: Chronic effects – D: Delayed effects – E: End-of-treatment effects – F: Failure of therapy UNIT 4: Adverse drug effects 4  1. ADVERSE DRUG EFFECTS. They can be classified in 6 groups: –A: Augmented pharmacological effects –B: –C: –D: –E: –F: UNIT 4: Adverse drug effects 5  1. ADVERSE DRUG EFFECTS. » Adverse Effects Type A or Augmented Pharmacological Effects Known adverse effects, usually – related to the dose, – Produce well-known effects, – quite frequent – Produce low-moderate consequences. UNIT 4: Adverse drug effects 6  1. ADVERSE DRUG EFFECTS. They can be classified in 6 groups: –A: –B: Bizarre effects or Idiosyncratic –C: –D: –E: –F: UNIT 4: Adverse drug effects 7  » Adverse Effects Type B or Idiosyncratic Idiosyncratic reaction: a genetically determined We can observe two types: reaction characterized by the ‘abnormal’ response of certain individuals to a drug. True Idiosyncrasy: » genetic causes. Acquired idiosyncrasy (allergic adverse effects): » not related to the dose, » low frequent » can not be predicted » serous risk for patients life. UNIT 4: Adverse drug effects 8  1. ADVERSE DRUG EFFECTS. They can be classified in 6 groups: –A: –B: –C: Chronic Effects –D: –E: –F: UNT 4: Adverse drug effects 9  » Adverse Effects Type C or Chronic long term adverse effects (adaptive mechanisms) of continuous treatment. – Tolerance and Rebound effect. Ex: Antidepressants UNIT 4: Adverse drug effects 10  » Adverse Effects Type C or Chronic – Tolerance and Rebound effect. Ex: Antidepressants Tolerance: Rebound effect: required higher dosis to reach same effect afterdiscontinuation or stop of a therapy Ø It ccurs when symptoms return, often more Ø A reduction in the effectiveness of a drug intensely, after the discontinuation or over time, requiring higher doses to reach reduction of a medication. the same therapeutic effect. Ø This can be particularly noticeable in Ø This can involve changes in receptor antidepressants. sensitivity or drug metabolism. Ø Ex: A person currently taking Ø Ex: A patient may need increasing doses of antidepressants may experience an increase an antidepressant to maintain its in anxiety or depression once the medication effectiveness, leading to potential risks of is discontinued. side effectsUNIT or dependency. 4: Adverse drug effects 10  1. ADVERSE DRUG EFFECTS. They can be classified in 6 groups: –A: –B: –C: –D: Delayed effects –E: –F: UNIT 4: Adverse drug effects 11  » Adverse Effects Type D or Delayed long term adverse effects that remain in latent state from months to years after the suspension of the drug therapy. These reactions may not be immediate and can take days, weeks, or even months to develop after starting the medication. – They produce fertility alterations, carcinogenesis and teratogenesis. UNIT 4: Adverse drug effects 12  » Adverse Effects Type D or Delayed – Examples: Thalidomide Aminoglycosides This class of antibiotics includes as It was first marketed in the late gentamicin, streptomycin, and neomycin. 1950s as a sedative and anti-nausea Effective against a range of bacterial medication during pregnancy. infections, particularly gram-negative It was withdrawn from the market in bacteria. the early 1960s due to its association with severe birth defects, including Irreversible Ototoxicity: Aminoglycosides limb deformities (phocomelia) in can cause both cochlear (hearing) and infants born to mothers who took the vestibular (balance) dysfunction. drug during pregnancy. UNIT 4: Adverse drug effects 12  They can be classified in 6 groups: –A: –B: –C: –D: –E: End-of-treatment effects –F: 13  » Adverse Effects Type E or End-of-treatment effects. Appears after a sudden withdrawal of treatment. They are often associated with prolonged use or dependence on some drugs Example: narcotic abstinence. Manifestations: Physical Symptoms: Excessive sweating, tremors, nausea, vomiting, diarrea Psychological Symptoms: Anxiety, irritability, depression, insomnia. Behavioral Symptoms: Intense craving for the drug, difficulty concentrating. Mechanism Dependence: Prolonged use of narcotics can lead to physical dependence. When the drug is discontinued, the body reacts with withdrawal symptoms. *Reduce the narcotic dosage gradually to minimize withdrawal symptoms. UNIT 4: Adverse drug effects 14  They can be classified in 6 groups: –A: –B: –C: –D: –E: –F: Failure of therapy 15  1. ADVERSE DRUG EFFECTS. » Adverse Effects Type F or Failure of therapy Unespected Terapeutic Failure Example: contraceptive drugs and antibiotics Unplanned Pregnancy: Despite correct use of oral contraceptives, Persistent or Recurring Infection: an unintended pregnancy may Despite antibiotic use, the infection may occur. persist or recur (bacteric resistance) UNIT 4: Adverse drug effects 16 The severity of adverse drug reactions can be graded as: – Minor: No therapy or action required. – Moderate: Needs a modification in the drug therapy o other complementary actions (hospital, etc). – Severe: Life threatening condition, causing permanent damage or requiring intensive medical treatment. – Lethal: Producing the death of the patient directly or indirectly UNIT 17 Types of adverse drug reactions or related events: 1. Side effects 2. Secondary effects. 3. Toxic effects 4. Poisoning 5. Intolerance. 6. Tolerance 7. Idiosyncrasy 8. Tolerance 9. Dependence UNIT 4: Adverse drug effects 21 1. Side effects: Unintended effects that occur alongside the desired therapeutic effect. Side effects are common adverse reaction unwanted unavoidable at therapeutic doses. ACTIONS: 1. Reducing the dose, we reduce the side effect. 2. Side effect can be therapeutic in other context/patient. Example : Antihistamines and drowsiness UNIT 4: Adverse drug effects 22 1. Side effects 2. Secondary effects. 3. Toxic effects 4. Poisoning 5. Intolerance. 6. Tolerance 7. Idiosyncrasy 8. Tolerance 9. Dependence UNIT 4: Adverse drug effects 23 1. Secondary effects – indirect consequences of the primary action of the drug. Example: Antibiotics and superinfections. Antibiotics, while targeting and killing harmful bacteria causing an infection, can also disrupt beneficial bacteria in the body’s normal flora. This disruption can lead to the overgrowth of other pathogens, such as fungi or resistant bacteria, resulting in new infections called superinfections. These superinfections are unintended secondary effects of antibiotic treatment, arising from its impact on the body’s microbial balance. 24 1. Side effects 2. Secondary effects. 3. Toxic effects 4. Poisoning 5. Intolerance. 6. Tolerance 7. Idiosyncrasy 8. Tolerance 9. Dependence UNIT 4: Adverse drug effect 25  1. ADVERSE DRUG EFFECTS. 3. Toxic effects – result of excessive pharmacological action due to an overdose or prolonged use or abuse. Example: Laxatives TOXIC EFFETS OF LAXATIVES Prolonged use of laxatives can lead to electrolyte imbalance, dehydration, gastrointestinal distress, dependence, bowel damage, and kidney impairment. UNIT 4: Adverse drug effects 26  1. DRUGS ADVERSE EFFECTS. 1. Side effects 2. Secondary effects. 3. Toxic effects 4. Poisoning 5. Intolerance. 6. Tolerance 7. Idiosyncrasy 8. Tolerance 9. Dependence UNIT 4: Adverse drug effects 27  4. Poisoning can result from the use of high doses of a poison-drug, i.e. a life-threatening substance that severely alters vital functions. Example: Opioid overdose causing respiratory depression. Inhibition of the respiratory centers Opioids bind to the μ-opioid receptors in the brainstem, specifically in the medulla oblongata. This region controls the automatic rhythm of breathing. 28 1. Side effects 2. Secondary effects. 3. Toxic effects 4. Poisoning 5. Intolerance. 6. Tolerance 7. Idiosyncrasy 8. Tolerance 9. Dependence UNIT 4: Adverse drug effects 29 5. Intolerance: Adverse reaction to normal doses, often with an exaggerated response. – It is the opposite of tolerance. – Example: Metamizole Metamizole can cause intolerance in some patients, leading to severe allergic reactions or skin rashes despite being used at standard doses. UNIT 4: Adverse drug effects 30 1. Side effects 2. Secondary effects. 3. Toxic effects 4. Poisoning 5. Intolerance. 6. Tolerance 7. Idiosyncrasy 8. Dependence UNIT 4: Adverse drug effects 31  6. Tolerance: is a physiological adaptation where the body becomes less responsive to a drug after repeated use, necessitating increased doses to reach the same effect. the progressive reduction of the therapeutic effect Ex: Nasal decongestant sprays Decongestants, such as pseudoephedrine and oxymetazoline, work by constricting blood vessels in the nasal passages to reduce swelling and congestion. With prolonged use, the body may become accustomed to the drug, and its effectiveness may decrease. Consequences: Continued use can lead to rebound congestion (rhinitis medicamentosa), where nasal congestion worsens once the medication is stopped, creating a cycle of increased use. UNIT 4: Adverse drug effects 32 1. Side effects 2. Secondary effects. 3. Toxic effects 4. Poisoning 5. Intolerance. 6. Tolerance 7. Idiosyncrasy 8. Dependence UNIT 4: Adverse drug effects 33 8. Dependence is a state in which drug use has a higher priority than personal satisfaction: It is due to: 1. Drug abuse (illicit). 2. Drug addiction (compulsive). 3. Drug habituation (less intensive) 4. Physical-psychological dependence. 5. Withdrawal reactions. UNIT 4: Adverse drug effects 34 Summary 1. Drugs adverse effects. 2. Mechanisms of drugs toxicity. 3. Teratogenic effects of drugs. 4. Therapeutic index 35  2. MECHANISM OF DRUG TOXICITY HEPATOTOXICITY Hepatocytes are exposed to reactive metabolites of drugs as these are formed by CYP450 enzymes. – Liver damage is produced by several mechanisms of cell injury; paracetamol exemplifies many of these. Paracetamol overdose can cause severe hepatotoxicity (liver damage) due to the accumulation of toxic metabolites. The liver loses its ability to correctly metabolise paracetamol, which accumulates as toxic metabolites causing liver necrosis Immediate medical treatment is essential to prevent serious outcomes, often involving antidotes like N-acetylcysteine to restore liver function and mitigate damage. UNIT 4: Adverse drug effects 36  2. MECHANISM OF DRUG TOXICITY HEPATOTOXICITY Cell death often occurs by apoptosis. – Non-covalent interactions: lipid peroxidation generation of cytotoxic reactive oxygen species depletion of reduced glutathione modification of sulfhydryl groups on key enzymes (e.g. Ca2+- ATPase) and structural proteins. -Covalent interactions Ex: adduct formation between a metabolite of paracetamol (NAPBQI: N-acetyl-p-benzoquinone imine) and cellular macromolecules Covalent binding to protein can produce an immunogen; binding to DNA can cause carcinogenesis and teratogenesis. UNIT 4: Adverse drug effects 38  2. MECHANISM OF DRUG TOXICITY NEFROTOXICITY Renal tubular cells are exposed to high concentrations of drugs and metabolites when urine is concentrated. – can cause tissue necrosis – EX: Inhibition of prostaglandin synthesis by non-steroidal anti- inflammatory drugs (NSAIDs) causes vasoconstriction and lowers glomerular filtration rate. UNIT 4: Adverse drug effects 39 Summary 1. Drugs adverse effects. 2. Mechanisms of drugs toxicity. 3. Teratogenic effects of drugs. 4. Therapeutic index 40  3. TERATOGENIC EFFECTS OF DRUGS Teratogenesis is the disturbed growth process involved in the production of a malformed neonate. Mutagenesis involves modification of DNA. – Mutation of proto-oncogenes or tumour suppressor genes leads to carcinogenesis. – Drugs are relatively uncommon (but not unimportant) causes birth defects and cancers. UNIT 4: Adverse drug effects 41  3. TERATOGENIC EFFECTS OF DRUGS Mechanism of Teratogenesis The timing of the teratogenic insult in relation to foetal development is crucial in determining the type and extent of damage. Mammalian fetal development passes through three phases. – blastocyst formation – organogenesis – histogenesis and maturation of function. A teratogenic agent is any factor that can cause abnormalities in the development of an embryo or fetus, leading to congenital malformations or birth defects UNIT 4: Adverse drug effects 42 3. TERATOGENIC EFFECTS OF DRUGS 43 3. TERATOGENIC EFFECTS OF DRUGS phocomelia : malformation of mb 44 3. TERATOGENIC EFFECTS OF DRUGS 45 Summary 1. Drugs adverse effects. 2. Mechanisms of drugs toxicity. 3. Teratogenic effects of drugs. 4. Therapeutic index 46  4. THERAPEUTIC INDEX Therapeutic Index measure of the margin of safety of a drug, by drawing attention to the relationship between the effective and toxic doses: – where LD50 is the dose that is lethal in 50% of the population, and ED50 is the dose that is ‘effective’ in 50%. UNIT 4: Adverse drug effects 47 Questions?????