8. kgs final PD by akashyap

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									Pharmacodynamics

K. Ganesh Shenoy, Lecturer

What Drug does to the Body?

It is the study of drug effects inside the body

Principles (Types) of drug action
• Stimulation of Physiological process • Inhibition of Physiological process • Replacement of Physiological substances • Cytotoxic effect

Mechanism of drug action • Through Receptors © • Through Enzymes

• Physical Action
• Chemical Action

Physical Action
• Radioactivity ….131I • Osmotic activity.. Mannitol

Chemical Action
• Antacids (Aluminum Hydroxide ) neutralizes gastric acid

• Chelating agents inactivates toxic
metals (BAL- Arsenic, Mercury)

Through Enzymes
• Most of the biological reactions are enzyme mediated • Enzymes are important targets of drug action. • Either by stimulating or by inhibiting, Drugs can increase or decrease the rate of reactions.

• Adrenaline stimulates

adenylyl cyclase
• Neostigmine inhibits cholinesterase

Receptors
• Receptor is a binding site for a drug or

a chemical agent
• It is a macromolecular component of cell situated on cell surface or inside the cell

Affinity It is the ability of the drug to bind to the receptor
Intrinsic activity It is the ability of the drug to activate and induce a conformational change in the receptor after occupying the receptor

The Receptor and Binding
PRE

Synaptic cleft

Receptor

POST

The Receptor and Binding
Chemicals (ligands) must bind to the receptor and remain bound long enough for the receptor to be activated. PRE

Synaptic cleft

POST

The Receptor - Specificity
Ligands bind to specific receptors. Not all ligands bind to all receptors
PRE

Synaptic cleft

POST

The Receptor - Specificity
There are a number of specific ligands and a number of associated receptors. PRE

Synaptic cleft

POST

• Agonist

• Antagonist
• Partial agonist

Agonist

•High affinity •High intrinsic activity

Agonist

Receptor

Agonist
• Agonists are the chemicals that interact with a receptor , thereby initiate a chemical reaction inside cell and produces effect • Eg : ACh is agonist at muscarinic receptor in heart cell • Will have both Affinity and maximal Intrinsic activity

Antagonist

•High affinity •No intrinsic activity
Agonist

Receptor

Antagonist
• A drug that binds to the receptor but can not activate it . It blocks the effect of an agonist for that receptor • d-tubocurarine is antagonist of ACh Nicotinic receptors at skeletal muscle end plate

• Has only Affinity but no Intrinsic activity

Antagonist

• Agonist • High affinity • High intrinsic activity • Antagonist: • High affinity • Low intrinsic activity

Partial agonist
• When given alone partial agonist activates receptor to produce an effect. But less response than a full agonist . • When given along with the agonist blocks the agonist action. Eg:Pentazocine • Will have Affinity but sub maximal Intrinsic activity

Action-Effect sequence
Drug action and Drug effect are not synonymous

Drug effect
• It is the ultimate change in biological

function as a consequence of drug
action

The type of response produced by the drug

Drug action
•

It is the initial combination of drug with

the receptor resulting in conformational
changes in cell

How and where the effect is produced
♣ Effects are measured and quantified while

actions are identified.

Transducer Mechanisms
• These are a series of intermediate steps between drug action and drug effect • Depending upon these transducer mechanisms drug receptors are categorised

• Intracellular receptors
• Enzymatic receptors • Tyrosine kinase receptors • Ion-Channel receptor • G-Protein coupled Receptors

Nature of receptors: Physiological receptors – cholinergic,adrenergic,histaminergic,steroid, prostaglandin. Drug receptors – benzodiazepine receptor, thiazide receptor, cardiac glycoside receptor Silent receptors – plasma proteins

Receptor regulation
Down regulation (desensitization, refractoriness): Continued exposure of a receptor to an agonist leads to decreased response to that agonist. E.g. • Bronchial asthma patients treated continuously with salbutamol • Parkinsonian patients treated with Levodopa

Mechanism: • masking or internalization of the receptor • decreased synthesis/increased destruction of the receptor (down regulation)

Up regulation: • Prolonged deprivation of the agonist or prolonged use of antagonists results in supersensitivity of the receptor E.g.
• Sudden discontinuation of propranolol (β blocker) in angina pectoris → withdrawal syndrome such as nervousness, anxiety, palpitation, tachycardia, rise in BP, ↑ incidence of angina or even MI. This is due to up regulation or supersensitivity of  adrenoceptors.

Mechanism: • Unmasking, proliferation of the receptors or accentuation of the signal amplification by the transducer.

Dose-Response relationship

• Dose

Response

• Increases in response until it reaches maximum, Later it remains constant despite increase in dose .. Plateau effect

DOSE RESPONSE CURVE
After this point increase in dose doesn’t increase the response

% of Response

DOSE of drug

LOG DOSE RESPONSE CURVE
Dose response curve…...

Log

Dose response curve…...

DRC

LOG DRC

Log DRC
• Sigmoid shape

( Normal DRC is rectangular hyperbola)
• Response is proportional to log dose

• Wider range of drug doses can be easily
displayed on graph

Characteristics of DRC (Log DRC)
• Position of DRC - Potency

• Height of DRC - Efficacy
• Slope of DRC
– Steep DRC
– Flat DRC

Potency

Efficacy

• Maximum effect of the • Dose of a drug that drug required to produce 50% of maximal effect (ED 50) • Height of the curve • Relative Positions of the DRC on x-axis indicates the efficacy of the drug on x-axis • More left the DRC, more potent the drug • Taller the DRC ,more efficacious the drug

100%

A

B

% of BP Reduction

75% 50% 25%

0%
10mg 20mg 30mg 40mg 50mg 200mg

Doses

Potency of Drug G > Drug R
100%

>

Drug B B

G

R

% of BP Reduction

75% 50% 25%

0%
10mg 20mg 30mg 40mg 50mg 200mg

Doses

Efficacy

% of Response

Drug Doses

• Drug B is less potent but equally efficacious as drug A • Drug C is less potent and less efficacious than drug A • Drug C is equally potent and less efficacious than drug B • Drug D is more potent than A,B ,C and less efficacious than A and B,
and equally efficacious as drug C

Hydralazine.. steep

Fall in BP

Thiazides.. Flat

Drug Dose

SLOPE
STEEP DRC • Moderate increase in dose leads to more increase in response • Dose needs individualization for different patients • Unwanted and Uncommon FLAT DRC • Moderate increase in

dose leads to little
increase in response • Dose needs no

individualization for
different patients • Desired and Common

ED 50
• Dose of a drug that is required to

produce 50% of maximal effect

ED50
100%

% of BP Reduction

75% 50% 25%

0%
10mg 20mg 30mg 40mg 50mg 200mg

Doses of Propranolol

ED50

Quantal dose response curve: • Certain pharmacological effects which cannot be quantified but can only be said to be present or absent (all or none) are called as quantal responses. • eg. A drug causing vomiting, ovulation etc.

50

ED50

40

30

# of Subjects

20

10

0

1

3

5

7

9

11

13

15

Threshold Dose

• These curves plot the % of a population responding to a specified drug effect (prefixed) versus dose or log dose. • They permit estimation of median effective dose (ED50) • ED50: It is the dose of the drug which produces desired effect in 50% of the population

LD50: Median lethal dose

The dose at which lethality is observed in 50% of subjects. TD50: Median toxic dose
The dose at which a particular toxic effect is produced in 50% subjects

EFFECT

Therapeutic range
300mg 300-3000mg 3000mg

• The gap between the therapeutic effect DRC and the adverse effect DRC defines the safety margin or the therapeutic index of a drug.

Therapeutic index
Is a measure of drug safety
In animal experiments TI can be measured Median lethal Dose Median Effective dose = LD50 ED50 Greater the value, safer is the drug. Eg: Digitalis, Li has have low TI, Penicillin has high TI

TI =

Spare receptors If maximal response is obtained with less than full occupation of receptors

Inert binding sites Components of endogenous molecule that bind a drug but does not initiate events leading to drug effects Eg: plasma albumin, acid glycoprotein

Therapeutic window
• With certain drugs, therapeutic effect is seen only over a narrow range of plasma drug concentration. Both below & above this range, beneficial effects are less.
Eg: Tricyclic

antidepressants Clonidine Glipizide

Combined effect of drugs
• When 2 or more drugs are given together they exhibit either Synergism or Antagonism

Synergism
1. Additive

2. Supraadditive (potentiation )

Synergism
• Additive(summation)

• Effect of drugs A + B= Effect of Drug A +
Effect of Drug B • Drug effect will simply add up • Eg: Paracetamol + Ibuprofen

Synergism
• Supraadditive (potentiation)
• The effect of the combination is greater than the individual effects of the components

• effect of drug A + B > effect of drug A +

effect of drug B
Eg: Acetylcholine + Neostigmine Levodopa + carbidopa

Antagonism
When one drug decreases the effect of other drug effect of drug A + B < effect of drug A +effect of drug B

• • • •

Physical antagonism Chemical antagonism Physiological antagonism Receptor mediated antagonism

Physical antagonism
• Activated Charcoal used in poisoning, which adsorbs the poison material, later get excreted

Chemical antagonism
• Chelating agents used in heavy metal poisoning…forms insoluble complexes with metals which gets excreted eg: BAL chelates arsenic Antacids neutralize gastric acid

Physiological antagonism
• Also called as functional antagonism • Two drugs act on different receptors and produce opposite effects on same physiological system Eg: Use of adrenaline in anaphylaxis Adrenaline and Histamine actions on BP and Bronchial smooth muscle Glucagon and insulin

Receptor mediated antagonism

• Competitive • Irreversible

COMPETITIVE • Antagonist binds with same receptor

IRREVERSIBLE • Antagonists bind to same receptors irreversibly with strong covalent bonds • Effect can be overcome • Effect cannot be overcome by adding more agonist by adding more agonist • Parallel rightward shift of DRC • Apparently reduces potency of agonist • Eg: Acetyl Choline and Atropine • Downward shift of DRC

• Apparently reduces efficacy of agonist
• Eg: Phenoxybenzamine & NE

Drug dosage: 1.Standard dose: oral contraceptives, penicillin 2.Regulated dose: antihypertensives, hypoglycaemics, diuretics 3.Target level dose: antiepileptics, antidepressants 4.Titrated dose: anticancer drugs, corticosteroids

Fixed dose ratio combination preparations Advantages : 1.Convenience and better patient compliance 2.Drug combinations can be synergistic - sulphamethoxazole + trimethoprim - levodopa + carbidopa 3.Therapeutic effect may add up while side effects may not 4.Side effect of one may be counteracted by the other - thiazide + triamterene

Disadvantages: • Patient may not need all the drugs • Dose can not be individualized • Time course of action may be different • Adverse effect can not be ascribed • Contraindication to one component contraindicates the combination • Altered renal or hepatic function may differently affect the pharmacokinetics of the components

Adverse drug reactions
“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

1. Dose related A. Side effects: unwanted ,unavoidable pharmacodynamic effects that occur at therapeutic doses eg: Antihistaminics cause sedation Codeine produces constipation

B. Secondary effects: indirect consequence of primary action of a drug Eg: Tetracyclines cause superinfection Corticosteroids weaken immunity C.Toxic effects: excessive pharmacological action due to overdose or prolonged use Eg: Respiratory failure by morphine Bleeding due to heparin

Poisoning
• Results from large doses of drugs because „it is the dose which distinguishes a drug from a poison‟. • Severely affects one or more vital functions.

Principles of treatment of acute poisoning
• Removal of the poison: I. Induction of emesis : syrup of ipecac gastric lavage C/I to emesis: Comatose patients, Convulsions, Kerosene Corrosive poison ii. Prevention of absorption from GIT: Aspiration and lavage Activated charcoal Universal antidote:2 parts of powdered charcoal+1 part of tannic acid + 1 part of magnesium oxide

• Elimination of the poison Induction of diuresis: mannitol, frusemide Alteration of urinary pH Hemodialysis • Administration of specific antidote: Benzodiazepines –flumazenil Paracetamol – N-acetyl cysteine Opioids – naloxone Organophosphates – atropine , pralidoxime • Supportive measures: ABC

2. Non-dose related Drug allergy (drug hypersensitivity) :
• An abnormal response to a drug due to Ag:Ab reaction resulting in the release of various mediators

• Immunologically mediated reaction • Produces symptoms unrelated to the pharmacodynamic profile of the drug and largely independent of doses.

• •

Associated with humoral antibodies: Types I, II and III. Associated with cell mediated immunity: Type IV (Delayed hypersensitivity).

Types of drug allergy Type – I (anaphylactic) reactions: • Also called immediate hypersensitivity • IgE mediated acute allergic reaction. urticaria, itching, angioedema, asthma, rhinitis or anaphylactic shock eg: Penicillins, Aspirin, Lignocaine • Is a medical emergency, should be treated promptly.

Type II reactions (cytolytic): • IgG or IgM mediated • The antibody reacts with cell bound antigens & cause activation of complement – destroys the cells • Eg: blood tranfusion reactions, hemolytic anaemia produced by quinine, quinidine, cephalosporins etc., agranulocytosis, organ damage, SLE

Type III (Arthus) reaction: • Immune complex mediated • Mainly IgG mediated • Eg: serum sickness(fever, urticaria, joint pain, lymphadenopathy) with penicillins, sulfonamides Acute interstitial nephritis caused by NSAIDs Stevens – Johnson syndrome with sulfonamides

Type IV (Cell mediated or delayed hypersensitivity) • Mediated by sensitized T lymphocytes ; re exposure to antigen leads to local inflammatory response • Manifestations seen after 2-3 days of exposure to sensitizing antigen. • Eg: Contact dermatitis due to local anaesthetic creams, topical antibiotics and antifungal agents, photosensitization

Treatment of drug allergy:
For anaphylaxis • O2 , CPR • Inject adrenaline (1:1000) 0.3-0.5 ml i.m • Antihistaminics – inj. Diphenhydramine 25-50mg i.m or i.v Chlorpheniramine • Glucocorticoids – inj. Hydrocortisone 100-200 mg i.v

Photosensitivity: • Cutaneous reaction resulting from a drug induced sensitization of the skin to UV radiation • Sulphonamides, demeclocycline erythema, edema, blistering, hyperpigmentation, desquamation • Chloroquine - eczema, papular rash

Intolerance: • Appearance of characteristic toxic effects of a drug at therapeutic doses. EPS with single dose of triflupromazine Ataxia with carbamazepine Idiosyncrasy: • Genetically determined abnormal reactivity to a chemical. • An unusual individual reaction to food or a drug Eg: Barbiturates - excitement and mental confusion Chloramphenicol - aplastic anemia

Drug dependence: A state resulting from the interaction between a living organism and a drug,characterised by behavioral and other responses that always include a compulsion to take the drug continuously or periodically

Psychological dependence: a feeling of
satisfaction and a psychic drive that require periodic or continuous administration of the drug to produce pleasure or to avoid discomfort Eg: opioids, cocaine, LSD

Reinforcement: ability of the drug to produce
effects that make the user wish to take it again

Physical dependence: altered physiological
state produced by repeated administration of a drug which necessitates the continued presence of the drug to maintain physiological equilibrium

Drug abuse: • An overpowering desire to continue taking the drug • A tendency to increase the dose • A tendency to withdrawal symptom Principles of treatment of drug dependence • Hospitalization • Gradual or sudden withdrawal • Substitution therapy • Psychotherapy and occupational therapy • Specific drug therapy • Correction of nutritional deficiencies • Rehabilitation

Teratogenicity: terataos = monster
capacity of the drug to cause fetal abnormalities when administered to pregnant mother I. Fertilization and implantation: conception to 17 days-failure of pregnancy ii.Organogenesis: 18-55 days of gestationdeformities iii.Growth and development: 56 days onwardsdevelopmantal and functionalabnormalities

• Thalidomide – phocomelia • Anticancer drugs – multiple defects, fetal death • Corticosteroids – cleft lip, cardiac defects • Phenytoin – cleft lip/palate, microcephaly • Lithium - fetal goiter cardiac and other abnormalities • Indomethacin/Aspirin– premature closure of ductus arteriosus • Valproic acid – neural tube defects

Carcinogenicity & mutagenicity:
Ability of the drug to cause cancer and genetic defects respectively Iatrogenic diseases (physician induced diseases) : iatros = physician • functional disturbances caused by drugs Parkinsonism – phenothiazines Peptic ulcer – aspirin, corticosteroids hepatitis - isoniazid

SPECIFIC TOXICITY OF SOME PERTICULAR DRUGS

Prevention of adverse effects to drugs: • Elicit previous history of drug reactions • Elicit history of allergic diseases • Rule out the possibilities of drug interactions • Adopt correct drug administration technique


								
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