FACTORS_MODIFYING_ACTIONS_&_DOSES_OF_DRUGS 20-1-11

FACTORS MODIFYING ACTIONS & DOSES OF DRUGS: 

FACTORS MODIFYING ACTIONS & DOSES OF DRUGS

1. AGE: 

1. AGE Rules / Formulae for calculating the doses in children and infants : - a. Young’s formula : - Age Age+12 b. Dilling’s formula : - Age 20 c. Clark’s formula to calculate infant dose :- Weight of infant in pounds 150 x Adult Dose x Adult Dose x Adult Dose

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2. BODY WEIGHT Chloramphenicol 15-25 mg / kg BW 3. BODY SURFACE AREA. Asparaginase: – 10,000 U/M 2 of surface area

4. SEX a. Menstruation b. Pregnancy – fetal development stages a. Blastocyst formation b. Organogenesis (17-60 days of gestation) c. Histogenesis & functional maturation Thalidomide when given during 1st trimester of pregnancy causes Phocomelia (seal limbs) & Amelia (absence of limbs) Sodium valproate causes spina bifida, CVS and digital congenital abnormalities phenytoin warfarin Anti-cancer drugs cyclophosphamide chlorambucil azathioprine : 

4. SEX a. Menstruation b. Pregnancy – fetal development stages a. Blastocyst formation b. Organogenesis (17-60 days of gestation) c. Histogenesis & functional maturation Thalidomide when given during 1 st trimester of pregnancy causes Phocomelia (seal limbs) & Amelia (absence of limbs) Sodium valproate causes spina bifida, CVS and digital congenital abnormalities phenytoin warfarin Anti-cancer drugs cyclophosphamide chlorambucil azathioprine

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c. Labour d. Lactation

5. ROUTE OF ADMINISTRATION. 6. TIME OF ADMINISTRATION. 7. EFFECT OF CLIMATE. 8. EFFECT OF ALTITUDE. 9. RACIAL DIFFERENCES Castor oil Ephedrine : 

5. ROUTE OF ADMINISTRATION. 6. TIME OF ADMINISTRATION. 7. EFFECT OF CLIMATE. 8. EFFECT OF ALTITUDE. 9. RACIAL DIFFERENCES Castor oil Ephedrine

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10. SPECIES DIFFERENCES:- Strychnine Histamine Belladona Preparations – Atropine-esterases 11. DOSAGE FORMS OF DRUGS.

AGE OF DRUG:- Out-dated Tetracyclines – converted to toxic Epianhydrotetracycline producing Fanconi-like syndrome Paraldehyde Chloroform 13. ABSORPTION, DISTRIBUTION & EXCRETION OF DRUGS. Sulfonamides, Penicillins, Salicyalates, Cephalosporins ------------------------------------------ Digitoxin, Emetine, Heavy metals : 

AGE OF DRUG:- Out-dated Tetracyclines – converted to toxic Epianhydrotetracycline producing Fanconi-like syndrome Paraldehyde Chloroform 13. ABSORPTION, DISTRIBUTION & EXCRETION OF DRUGS. Sulfonam ides, Penicillins, Salicyalates, Cephalosporins ------------------------------------------ Digitoxin, Emetine, Heavy metals

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14. PATHOLOGICAL CONDITIONS. 15. METABOLIC DISTURBANCES. Aspirin Nor-Adrenaline-vasoconstrictor effect is lost in metabolic acidosis Excessive iron absorption from GIT in iron deficiency anemia

16. TOLERANCE CLASSIFICATION A. PSEUDO –TOLERANCE Austria – Feudal kings – Arsenic trioxide B. TRUE TOLERANCE a. NATURAL: i. Species ii. Racial b. ACQUIRED: - i. Functional ii. Dispositional TISSUE TOLERANCE & CROSS-TOLERANCE: 

16. TOLERANCE CLASSIFICATION A. PSEUDO –TOLERANCE Austria – Feudal kings – Arsenic trioxide B. TRUE TOLERANCE a. NATURAL: i. Species ii. Racial b. ACQUIRED: - i. Functional ii. Dispositional TISSUE TOLERANCE & CROSS-TOLERANCE

17. TACHYPHYLAXIS (Acute Tolerance): 

17. TACHYPHYLAXIS ( Acute Tolerance) Indirectly acting sympathomimetics Tyramine Ephedrine Amphetamines except for hydroxyamphetamine

Differences: 

Differences Tolerance Tachyphylaxis Rate of development Inducing drugs Mode of development Remedy

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18. IDIOSYNCRASY Chloramphenicol – aplastic anaemia Halothane & Suxamethonium - malignant hyperthermia Practolol – oculomucocutaneous syndrome Clozapine – agranulocytosis 19. HYPERSUSCEPTIBILITY.

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20. SYNERGISM (Greek words: syn-together, ergo – to work) a. Summation (Addition) GAs like Chloroform, ether in general anaesthesia Ephedrine & Aminophylline in bronchial asthma b. Potentiation

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POTENTIATION Co-trimoxazole (sulphamethoxazole 400mg + Trimethoprim 80mg) acts as double-edged weapon in inhibiting synthesis of bacterial DNA ADVANTAGES Of septran over individual drugs

ANTAGONISM. Types: - a. Chemical antagonism. Antacids vs Gastric HCl Dimercaprol vs Arsenic b. Physiological antagonism Adrenaline vs histamine in anaphylactic shock : 

ANTAGONISM . Types : - a. Chemical antagonism. Antacids vs Gastric HCl Dimercaprol vs Arsenic b. Physiological antagonism Adrenaline vs histamine in anaphylactic shock

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c. Pharmacological antagonism i. Competitive (Reversible) Atropine versus Acetylcholine at muscarinic receptors Naloxone versus Morphine at opoid receptors Atenolol versus Adrenaline at beta 1 receptors ii. Non-competitive (Irreversible) Phenoxybenzamine versus Adrenaline / nor-adrenaline at alpha 1 receptors

22. COMBINATION OF DRUGS a. ENZYME INDUCTION b. ENZYME INHIBITION c. COMPETITIVE INHIBITION sulfonamides -- phenytoin phenylbutazone, coumarin-derivatives -- tolbutamide : 

22. COMBINATION OF DRUGS a. ENZYME INDUCTION b. ENZYME INHIBITION c. COMPETITIVE INHIBITION sulfonamides -- phenytoin phenylbutazone, coumarin-derivatives -- tolbutamide

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Enzyme Induction Enzyme Inducers PHENOBARBITONE PHENYLBUTAZONE PHENYTOIN MEPROBAMATE RIFAMPICIN CARBAMAZEPINE Ch. alcoholism BENZO  pyrene in Tobacco smoke Clofibrate DEXAMETHASONE Chronic Alcoholism Warfarin

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ENZYME INHIBITORS Types Competitive inhibitors quinidine Reversible non - Competitive inhibitors – KETOCONAZOLE Suicide inhibitors- Gestodene CIMETIDINE KETOCONAZOLE ERYTHOMYCIN CHLORAMPHENICOL ISONIAZID PROPYLTHIOURACIL ALLOBARBITONE Suicide inhibitors SECOBARBITONE SPIRONOLACTONE Inhibitors of intestinal P-gycoprotein (P-gp) Verapamil Certain components of grape fruit juice Drugs expelled by P-gp are digoxin, cyclosporine

Competitive substrate inhibition: 

Competitive substrate inhibition Sulphonamides inhibit the metabolism of Phenytoin Phenylbutazone & coumarins inhibit the metabolism of tolbutamide.

EMOTIONAL FACTORS PLACEBOS Psychosomatic disorders (Bronchial asthma, Angina pectoris) : 

EMOTIONAL FACTORS PLACEBOS Psychosomatic disorders (Bronchial asthma, Angina pectoris)

24. ALLERGY a. Immediate / Acute Allergic Reactions a. Mild. b. Severe/Fatal Anaphylactic shock (anaphylaxis) b. Delayed Allergic Reactions called Serum Sickness: 

24. ALLERGY a . Immediate / Acute Allergic Reactions a . Mild. b. Severe/Fatal Anaphylactic shock (anaphylaxis) b. Delayed Allergic Reactions called Serum Sickness

ANAPHYLAXIS DEFINITION: 

ANAPHYLAXIS DEFINITION Anaphylaxis may be defined as a rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells or basophils in individuals or animals previously sensitized to the antigen.

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ADENYLATE CYCLASE

GENERAL FEATURES OF PRIMARY & SECONDARY CHEMICAL MEDIATORS OF ANAPHYLAXIS: 

GENERAL FEATURES OF PRIMARY & SECONDARY CHEMICAL MEDIATORS OF ANAPHYLAXIS Chemotactic Vasoactive Spasmogenic

CHEMICAL MEDICATORS OF ANAPHYLAXIS: 

CHEMICAL MEDICATORS OF ANAPHYLAXIS Histamine. 5-Hydroxytryptamine (Serotonin). Slow Reacting Substance of Anaphylaxis. (SRS-A) Eosinophilic Chemotactic Factor of Anaphylaxis (ECF-A). Neutrophilic Chemotactic Factor of Anaphylaxis (NCF-A). Prostaglandins. Platelet Activating Factor (PAF) Kinins / Leukotrienes

DRUGS THAT MAY CAUSE ANAPHYLAXIS: 

DRUGS THAT MAY CAUSE ANAPHYLAXIS Horse serum (ATS etc) Penicillins. Cephalosporins. Plasma expanders e.g dextran, polygeline. Parenteral Vit. B complex. Aminoglycoside Antibiotics. Amphotericin-B L-Asparaginase Others .

PREVENTION OF ANAPHYLAXIS: 

PREVENTION OF ANAPHYLAXIS 1. Previous history of allergy to a drug / product (Penicillin) 2. Skin tests for detection of allergy e.g Penicillin: Scratch test (Scratch the skin through a drop of sol - containing 10,000 units of penicillin G/ml). Central wheal after 10 min. Patch Test Intradermal Test 0.05 ml Penicilloyl Polylysine. OR 0.02 ml of 100 units/ml sol. of Penicillin. G IgE titer in plasma

TREATMENT OF ANAPHYLAXIS: 

TREATMENT OF ANAPHYLAXIS I. First-line Drug ADRENALINE (Epinephrine) 1:1000 sol 0.3-0.5 ml I/M, if patient is in shock, NEVER I/V or sub-cut II. Second-line Drugs a. CORTICOSTEROIDS Hydrocortisone sodium succinate 100mg I/V. OR Dexamethasone upto 4mg I/V followed by Predinisolone: Orally (50-100mg in divided doses)

b. ANTIHISTAMINES (H1 – Antagonists) Promethazine HCL 0.5-1 mg/kg BW I/V. OR Diphenhydramine 50-100 mg I/V c. MISCELLANEOUS DRUGS Aminophylline 6mg/kg BW I/V. Isoprenaline: I/V Infusion. Metaraminol 1.5-5 mg I/V. : 

b. ANTIHISTAMINES (H1 – Antagonists) Promethazine HCL 0.5-1 mg/kg BW I/V. OR Diphenhydramine 50-100 mg I/V c. MISCELLANEOUS DRUGS Aminophylline 6mg/kg BW I/V. Isoprenaline: I/V Infusion. Metaraminol 1.5-5 mg I/V.

SUPPORTIVE TREATMENT I/V Fluids Oxygen Tracheostomy Endotracheal Intubation: 

SUPPORTIVE TREATMENT I/V Fluids Oxygen Tracheostomy Endotracheal Intubation

25. DRUG DEPENDENCE : 

25. DRUG DEPENDENCE

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WHO Definition It is a state, psychic and sometimes also physical, resulting from the interaction between a living organism and a drug, characterized by behavioural and other responses that always include a compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects and sometimes to avoid the discomfort of its absence. Tolerance may or may not be present. A person may be dependent on more than one drug.

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COMPONENTS OF DRUG DEPENDENCE a. Euphoria. b. Tolerance. c. Psychic dependence (Habituation) “Is a condition in which a drug produces a feeling of satisfaction and a psychic drive that require periodic or continuous administration of the drug to produce pleasure or to avoid discomfort”. d. Physical dependence “It is a state in which the body achieves an adaptive state that manifests itself by intense physical disturbances when the drug is withdrawn”. e. Withdrawal syndrome / Abstinence syndrome.

DRUGS CAUSING DEPENDENCE a. Drugs causing severe psychic as well as physical dependence Opioids: Morphine, Codeine, Pethidine Ethyl Alcohol Barbiturates Benzodiazepines Amphetamines: 

DRUGS CAUSING DEPENDENCE a. Drugs causing severe psychic as well as physical dependence Opioids: Morphine, Codeine, Pethidine Ethyl Alcohol Barbiturates Benzodiazepines Amphetamines

Drugs that cause only Psychic Dependence Cocaine, LSD (Lysergic acid diethylamide), Cannabis (Hashish) Nicotine in tobacco, Caffeine (coffee, tea): 

Drugs that cause only Psychic Dependence Cocaine, LSD (Lysergic acid diethylamide), Cannabis (Hashish) Nicotine in tobacco, Caffeine (coffee, tea)

Management of Drug Dependence : 

Management of Drug Dependence Principles of treatment are : Gradual or sudden withdrawal of the drug. Substitution therapy. Psychotherapy and occupational therapy. Specific drug therapy e.g. antabuse in alcohol addiction. Correction of nutritional deficiencies. Community treatment and rehabilitation. The treatment should preferably be carried out in a specialized institution under expert guidance.

PHARMACOGENETICS Definition A branch of pharmacology dealing with genetic influences on drug response in some individuals of a population : 

PHARMACOGENETICS Definition A branch of pharmacology dealing with genetic influences on drug response in some individuals of a population

GENETIC FACTORS. : 

GENETIC FACTORS. Atypical pseudocholinesterase:- Succinylcholine (Suxamethonium) is hydrolysed by pseudocholinesterase. Genetically abnormal pseudocholinesterase Apnoea. Acetylation status: Slow & Fast acetylators Inherited as an autosomal recessive trait Slow acetylator phenotype – about 50 % 0f blacks & white in the USA Much less common in Asians & eskimos Genetically determined defects in the CYP dependent oxidative metabolism of: Debrisoquin, Phenacetin, Phenformin (extensive metabolizers and poor metabolizers) Hydroxylation of anticonvulsant Mephenytoin: Poor hydroxylators & Fast hydroxylators

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Acetylator Status slow & fast acetylators b. Pseudocholinesterase Deficiency / Atypical Pseudocholinesterase Hydrolysis of Suxamethonium c. Glucose – 6 – Phosphate Dehydrogenase Deficiency Drugs liable to cause haemolysis in G-6 PD deficient subjects: Antimalarials: Pamaquine, Chloroquine Sulphonamides Analgesics---- Aspirin Nitrofurons Sulphones Miscellaneous

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d. Acatalasia (H 2 O 2 ) e. Vitamin D Resistance f. Warfarin Resistance.