Tolerance And Adverse Drug Reactions PDF

College of Medicine – ‫كلية الطب‬ Dr. Asmaa Fady Ph D., JMHPE, MSc, MCBBCh – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 1 College of Medicine – ‫كلية الطب‬ By the end of the lecturer, the student will be able to: 1. Recognize patterns of adverse drug reactions (ADR) according to the [AB...

College of Medicine – ‫كلية الطب‬ Dr. Asmaa Fady Ph D., JMHPE, MSc, MCBBCh – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 1 College of Medicine – ‫كلية الطب‬ By the end of the lecturer, the student will be able to: 1. Recognize patterns of adverse drug reactions (ADR) according to the [ABCDE Classification]; Augmented, Bizzar, Chronic, Delayed, End of use. 2. Differentiating the points of difference between the predictive versus the idiosyncratic types 3. Classify types of immune adverse reactions. 4. Distinguish difference between tolerance and desensitization ( Tachyphylaxis ) and reasons for their development – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 2 medicine from we want what Therabiotic effect College of Medicine – ‫كلية الطب‬  Definition :is an unwanted or harmful reaction experienced following the administration of a drug. Adverse drug reactions (ADRs) life-threatening anaphylaxis Common sideeffects. Course Name and – ‫اسم ورقم المقرر‬ No. 10/17/2023 3 College of Medicine – ‫كلية الطب‬  Clinical principle: No drug has only one effect. Drugs are described by their most therapeutic effect. Therefore, we tried to obtain the maximum effect with the minimum side effects. E.g: Drug Use#1 Use#2 Lidocaine Local anesthetic Cardiac antiarrhythmic Quinidine Anti-malaria Cardiac antiarrhythmic drag is named with primary name its Course Name and – ‫اسم ورقم المقرر‬ No. 10/17/2023 4 College of Medicine – ‫كلية الطب‬ Patients: • Young, or old or female. I • Taking multiple therapies. I mature f diseases f hormons • Having more than one medical problem • Positive history of allergy or a previous reaction to drugs College of Medicine – ‫كلية الطب‬ They are classified into:  Type A= Augmented and Predictable, Related to the normal pharmacology of drugs.  Type B= Bizarre and unpredictable, Not related to the normal pharmacology of drugs.  Type C = Chronic effects after long use of drugs.  Type D = Delayed effects of drugs. effect a pear after some time  Type E = End of dose effects.  Type F = Failure of therapy. – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 6 Predictable undesirable effects related to the normal pharmacological actions of the drug: 1- Side Effect: ‫(مباشرة ) ال مفر منها تحدث في كل الناس‬ Unavoidable undesirable normal actions produced by therapeutic dose of the drug. Example: Dry mouth induced by atropine when used as antispasmodic. Bascoban happen to all population 2- Secondary Effect: )‫ممكن تحدث او ال تحدث (غير مباشرة‬ Bad effect consequent to normal therapeutic action of the drug. Example: Oral broad-spectrum antibiotics that kill Intestinal flora will decrease Vit B & Vit K synthesis and leads to superinfection. College of Medicine – ‫كلية الطب‬  indirect harm – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 7 College of Medicine – ‫كلية الطب‬ 3- Over-dose:  Exaggerated normal action due to high blood level of the drug either: acute overdose 1- Single large dose: Insulin in large dose induces hypoglycemia 2- Accumulation of repeated doses: Digitalis.choronic notinsingle exposure 4- Super-sensitivity (Intolerance): ‫رد فعل طبيعي ومتوقع ولكنه مبالغ فيه‬ Exaggerated normal action in response to small therapeutic dose of normal Sml the drug. 50mstooMB 8Sen 5mi so 30 HB Inc is Example: Sympathomimetics cause exaggerated tachycardia in hyperthyroidism. 5- Cytotoxic Effects: Cardio-toxicity , Hepato-toxicity Nephro-toxicity & Neuro-toxicity in the form of deafness )aminoglycosides) use it only for certain time and make sure the patient 10/17/2023 8 College of Medicine – ‫كلية الطب‬ dm u y lg s There are two subclasses: 1) allergy & 2) Idiosyncrasy 1)Immunologic (Allergy or Hypersensitivity): abnormal unpredictable reaction usually due to AG-AB reaction  It is not due to an extension of the active pharmacologic properties of the drug  Bizarre, novel responses  It is an allergic or hypersensitivity reaction occurs as a result of an immunologic mechanism (i.e. antigen/antibody reaction).  Pharmacologically unexpected, unpredictable. – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 9 College of Medicine – ‫كلية الطب‬ Allergy: means :  NOT all patients  NOT all drugs  NOT with first exposure  Do NOT reuse drug again – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 10 College of Medicine – ‫كلية الطب‬ A) Type I (Immediate, Anaphylactic or IgE mediated): a- First exposure leads to production of IgE on the surface of the mast cell.  a- Second exposure: Antigen/Antibody (IgE) reaction on Mast cell Degranulation Release of allegro-toxins e.g. Histamine.  b- Manifestations: fever, rash, urticarial, conjunctivitis, rhinitis, angio-edema, bronchial asthma, G.I.T. disturbances & even anaphylactic shock.  Ttt by antihistaminic, corticosteroids, adrenaline am desensitization.  mast cell an – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 11 College of Medicine – ‫كلية الطب‬ B) Type II (Auto-allergy or Cytolytic):  a- Antigen + Antibody (IgG & IgM) + Complement on surface of organ cell Cell damage.  It is called cytolytic because (the antibodies produced by the immune response bind to antigens on the patient's own cell surfaces and causes cellular damage) cell – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 12 College of Medicine – ‫كلية الطب‬ C) Type III (Immune Complex–Mediated in the circulation): a- Antigen + Antibody (IgG ) + Complement circulates in the blood then ppt. on endothelial cell Damage of endothelium. Vasculitis. Arthus reaction b- Polymorphonuclear (category of white blood cells ) cells are attracted to the site Result in inflammation and tissue injury Complix us to th i n d – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 13 College of Medicine – ‫كلية الطب‬ D) Type IV (Delayed or Cell Mediated) : a- Antigen + Sensitized T-lymphocyte Inflammation (contact dermatitis).  Delayed hypersensitivity is a function of T Lymphocytes, not antibody. I insteade of antibodies creation – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 14 College of Medicine – ‫كلية الطب‬ There are two subclasses: 1) allergy & 2) Idiosyncrasy 2) Idiosyncratic:  1-Unpredictable abnormal response due to genetic abnormality.  2- Occurs on first exposure.  3- Examples: ❖ Succinylcholine apnea in patients with abnormal PseudoCholine Esterase activity. V Rare when we want write it down – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 15 College of Medicine – ‫كلية الطب‬ Effects of prolonged use of a drug:    1- Tolerance The usual therapeutic dose doesn't induce the desirable effect. The patient had to increase the dose to obtain the same effect. 2-Drug Dependence: advanced tolerance: (craving for the drug, withdrawal symptoms on drug stoppage) 3- Iatrogenic Disease. GO meyosis medreiases – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 16 Definition: It is a gradual decrease in responsiveness to repeated administration of a drug. For instance, when morphine or alcohol is taken repeatedly.  Generally, tolerance leads to increasing doses of a drug being required to produce the same effect. Examples: Decreased response to drugs after their repeated (long) use e.g. Morphine & nitrates. College of Medicine – ‫كلية الطب‬  write this spin point Bad purple 17 College of Medicine – ‫كلية الطب‬ * Remember Characteristics of Acquired Tolerance:  1- Reversal, stop of the drug for some time Regain normal sensitivity.  2- Varies from one drug to another: Rapid with ephedrine & very slow with adrenaline  3- Does not affect all actions to the same extent: Long use of morphine Rapid tolerance to analgesia BUT NO tolerance to miosis or constipation. – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 18 College of Medicine – ‫كلية الطب‬ Change in Kinetics 1- Absorption: Long use of Ethanol Atrophic gastritis. Hepaticmicrosomalenzyme p 2- Metabolism: Phenobarbital is a HME inducer own metabolism (Auto induction). increases its Change in Dynamics 3- Down-regulation of receptors: Salbutamol Down-regulation of beta2-receptors. 4- Endogenous substances: Morphine Endogenous Endorphins & Enkephalins – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 19 College of Medicine – ‫كلية الطب‬ 2- Drug Dependence: a- Habituation:  - Psychic dependence.  - Sudden stop of the drug Psychic craving for the drug.  - Example: (Coffee & tea). MorphinAverk b- Addiction: analgesia is ness nappy Constepation  - Psychic and Physical dependence.  - Sudden stop of the drug Withdrawal (Abstinence) syndrome, Usually the reverse of what the addicting agent does.  - Exemple: Amphetamine, Morphine, Ethanol, etc. 3- Iatrogenic Disease: Drug-induced disease. (treatment with antipsychotics induces 10/17/2023 parkinsonian like manifestations) 20 parkensontreatmentdopaminasophvania on highdopamn Igtat give inhibition College of Medicine – ‫كلية الطب‬ of dopamine end Delayed effects appearing after long use of the drug: 1- Teratogenicity (fetal malformation)  1- Drug-induced fetal malformations. Especially when drugs are taken during the first trimester (First 3 months of pregnancy).  2- Examples:  a- Thalidomide (Absent long bones) absent limbs.  b- Phenytoin cleft palate.jojo 2- Mutagenicity & Carcinogenicity:  - Tobacco smoking Bronchogenic carcinoma. – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 21 College of Medicine – ‫كلية الطب‬ These are effects of sudden stopping of drug use (Drug Withdrawal), include: 1- Abstinence syndromes of addicting drugs as morphine, cocaine, barbiturate. 2- Worsening of existing disease.. – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 22 College of Medicine – ‫كلية الطب‬ 1- Primary Failure: Failure of insulin treatment of Type I diabetes mellitus . The drug never worked with patient 2- Secondary Failure: a- Occurrence of tolerance. b- Drug interactions – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 23 down regulation to the receptor College of Medicine – ‫كلية الطب‬    Desensitization describes the signal attenuation in response to continuous stimulation of cells by receptor agonists. That can account for desensitization and the development of pharmacodynamic tolerance. The term tolerance is used to describe a more gradual loss of response to a drug that occurs over days or weeks due to repeated administration. tolerance gradual loss of response tachyphylaxis sudden loss of response Course Name and – ‫اسم ورقم المقرر‬ No. 10/17/2023 24 The term Tachyphylaxis occurs very rapidly, sometimes with the initial dose. Tachyphylaxis: (Acute acquired tolerance) College of Medicine – ‫كلية الطب‬  Mechanism of Tachyphylaxis  Change in receptors  Loss of receptors  Increased metabolic degradation.  Active extrusion of drug from cells (mainly relevant in chemotherapy). This exam as a cases – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 25 College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ No. 10/17/2023 26