Pharmacodynamics

Dr.U.P.Rathnakar
MD.DIH.PGDHM

Adverse Drug Effects

Any undesirable or unintended consequence of drug administration Any response to a drug that is noxious and unintended and that occurs at doses used in man for the prophylaxis, diagnosis, or therapy of disease or for modification of physiological function WHO Adverse event: Any untoward event that occurs during treatment not necessarily with causal relation ship to treatment

Adverse Drug Reactions [ADR]

Drugs used for favorable response Unfortunately also produce ADR

ADR: Severity
Minor: No tt required Moderate: Requires change in tt, change of drug Severe: Potentially life threatening, permanent damage Lethal: Directly or indirectly contributes to death

ADR
Type A[Augmented] Extension of pharmacological actions Predictable Dose dependent High incidence Low mortality Dose reduction Eg. Blurring of vision & dryness of mouth [atropine] Hypoglycemia[Glipizide] Type B [Bizarre] Immunological/genetic Not predictable Qualitative[not dose dependent] Low incidence High mortality Discontinue drug Eg. Anaphylaxis due to Penicillin , Hemolysis due to primaquine

ADR Type A[augmented]

Side effects: Unwanted ,unavoidable pharmacodynamic effects at therapeutic doses Eg. Antihistaminics cause sedation Secondary effects: Indirect consequence of primary action of a drug Eg. Tetracyclines cause super infection Toxic effects: Due to overdose or prolonged use Eg. Respiratory failure by morphine Coma by barbiturates

ADR
Type B[Bizarre] Allergy/hypersensitivity Idiosyncratic Type C[Continuous use] [dependence, organ toxicity] Type D[Delayed effect] Mutagenicity, carcinogenicity, teratogenic effect Type E[End of use] [withdrawal, HPA axis suppression]

Intolerance
Low threshold to the action of drug Eg. EPS with single dose of Metoclopromide

Idiosyncrasy
A genetically determined reaction An unusual individual reaction to food or a drug Eg. Barbiturates cause excitement and mental confusion Chloramphenicol causes aplastic anemia

Drug allergy (drug hypersensitivity)

Immunologically mediated reaction Types of drug allergy 1. Anaphylactic-Type I 2. Cytolytic-Type II 3. Immune complex mediated[Arthus]: -Type III 4. Delayed hypersensitivity -Type IV

Type 1

Eg. Betalactam antimicrobial agents

Type 1 [Anaphylactic]
Exposure to drug Eg.Penicillin IgE AB Fixed to mast cells Re-exposure

Treatment:
Medical emergency Inj.Adrenaline[1:1000] 0.3 to 0.5 ml i.m. Inj.Hydrocortisone 100 mgi.v. Inj.Diphenhydramine 25mg i.v. Oxygen i.v. fluids

AG+AB

Release of mediators: Histamine, 5-HT, PGs, LTs, PAF

Anaphylactic shock: Hypotension, Bronchospasm, Urticaria Etc.

Type II[Cytotoxic]

Eg. Sulfa, thiazides, quinidinepuprura, hemolysis

Type II [Cytolytic]
Drug+Tissue=AG IgG, IgM- AB Re exposure

Exposure to drug Eg.Quinine

Tissue+AB

Complement
Eg. Hemolysis by Quinine, Quinidine

Cell destruction

Type III
AG+AB IgG Eg. Serum sicknes [Fever, urticaria, joint pain, lymphadenopathy]

Deposited on vascular endothelium

Penicillin, Sulfa NSAIDs

Complement fixation

Destructive inflammatory response

Type IV[cell mediated, delayed]

Eg.Contact dermatitis by metals, ointments

Type IV [Delayed]

Inflammatory response Delayed by 2-3 days Not AB related Cell mediated Eg. Contact dermatitis with LA creams

Photosensitivity
[Pt. taking a drug develops reaction on body parts exposed to light]

Phototoxicity [hyperpigmentation[desquamation] Sensitization of the skin by drugs UV radiation Cutaneous reaction-Photosensitivity Stopped when drug stopped Photo allergy [eczematous, papular] Persists even after drug withdrawal Examples????

Carcinogenicity & mutagenicity

Ability of the drug to cause cancer and genetic defects respectively Eg. Tobacco, anticancer drugs

Iatrogenic diseases:
iatros = physician (physician induced diseases): Parkinsonism Phenothiazines Peptic ulcer Aspirin,corticosteroids Hepatitis - Isoniazid

Drugs frequently cause allergic reactions

Penicillins Cephalosporin Sulfonamides Tetracyclines Quinolones Antitubercular drugs Salicylates Carbamazapine ACE inhibitors Local anesthetics

Teratogenicity
terataos = monster Capacity of the drug to cause fetal abnormalities when administered to pregnant mother I. Pre-implantation: conception to 17 days-Abortion ii.Organogenesis: 18-55 days-Deformities iii.Growth and development: 56 days onwards

Thalidomide Phocomelia Corticosteroids Cleft lip TC- Discolouration of teeth, retarded bone growth

PREGNANCY CATEGORIES
Category A [ANIMALS [-] Humans[-]-------------No risk Studies have failed to demonstrate a risk to the fetus Category B [ANIMALS [-] Humans[Not known] [ANIMALS [+] Human[none] ---No evidence of risk Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no studies in pregnant women.

Category C [ANIMALS [++] Humans[Not known] [Consider risk benefit before use] Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Category D [Humans risk ++] [Benefit may outweigh risk] There is positive evidence of human fetal risk - but potential benefits may warrant use of the drug in pregnant women despite potential risks. Category X [Abnormalities demonstrated] [Not to be used in pregnant women] Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Organ toxicity
Hepatotoxicity: INH, Rifampicin Nephrotoxicity: Aminoglycosides Ototoxicity: Aminoglycosides, Frusemide

Ocular toxicity: Ethambutol, Chloroquine

Drug dependence
A state of Psychological or physical dependence Due to interaction - living organism+Drug Characterized by behavioral and other responses Always includes a compulsion to take the drug continuously or periodically

Psychological: Intense desire to take drug and immense satisfaction later Physical: Physiological equilibrium is maintained by drug

Poisoning
Poisons in small doses are the best medicines; and useful medicines in too large doses are poisonous William Withering 1789

Poisoning
Large enough dose of a drug Substance which endangers life Accidental or suicidal

Poisoning Principles of treatment

1.Resuscitation and maintenance of vital functions Airway, BP, Body temp., Blood sugar 2. Termination of exposure Fresh air, remove wet clothes, wash, 3. Prevention of absorption Gastric lavage, Activated charcoal, 4. Hastening elimination Diuresis, Altering urine pH, Hemodialysis 5. Antidotes if available

Prevention of adverse effects

Right dose, route, frequency Previous history drug allergy and allergic diseases Rule out drug interactions Correct technique of administration TDM if appropriate

Clinical significance of ADR

Common 3-5% of admissions Increases duration of stay Initially reversible Awareness-ADR or new symptoms Surgeries are avoided [gynecomastia and spironolactone] Reduce the no.of drugs

Pharmacovigilance
Actively look for adverse drug effects Activities relating to detection, assessment, understanding and prevention of adverse effects or any other drug related problem Causality assessment 1. Temporal relationship 2. Previous knowledge 3. Dechallenge 4. Rechallenge
Information collected by Regional centers to Zonal centers to National centers to Uppsala monitoring center (Sweden)

Definite, probable, possible or doubtful