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Pharmacodynamics - I

Dr. Jyoti M. Benni Dept. of USM-KLE, IMP Belgaum Learning outcomes • Describe the principles of with regard to the potential targets of - action - types -dose-response relationship (curve) -

2 Introduction: PK & PD

3 Pharmacodynamics

Pharmacodynamics is the study of actions of the drug on the body and their .

Stimulation Depression Irritation Replacement Modify immune status Anti-infective / Cytotoxic action

4 Mechanisms of Drug Action

Non-receptor mediated Receptor mediated • Physical • Receptors on the cell • Chemical membrane •

• Ion channels • Transporters • Receptors inside the cell • Antibody • Placebo

5

Non – receptor mediated mechanisms…

Physical property

. Physical property of the drug is responsible

E.g. Adsorption: activated charcoal in treatment of poisoning

Osmotic activity: magnesium sulfate for constipation

Radioactivity: radioactive iodine (I131 ) for hyperthyroidism

Radioopacity: barium sulfate as contrast media

6

Non – receptor mediated mechanisms…

Chemical action

Antacids - neutralize gastric acid

Chelating agents (EDTA) Used in heavy metal (LEAD)poisoning treatment

Oxidizing agents potassium permanganate as germicidal agent

7

Non – receptor mediated mechanisms…

Enzymes as targets of drug action Enzymes

Inhibition Stimulation

Enzyme Nonspecific Specific induction

Competitive Noncompetitive

8

Non – receptor mediated mechanisms…

Enzyme stimulation:

• Reactivation e.g. Injection pralidoxime → for treatment of Organophosphorus (insecticide) poisoning • Induction e.g. barbiturates → treatment of neonatal jaundice

Enzyme inhibition:

Non specific inhibition: Heavy metal salts, strong acids and alkalis.

These alter all the enzyme activity with which they come in contact

9 Specific Enzyme inhibition by

• A substance that decreases the velocity of an enzyme-catalyzed reaction is called an inhibitor.

10 Drug by Competitive inhibition Drug by Noncompetitive inhibition

drug drug

• Binds to the same site as • Binds to the site other than active substrate site • Only binds to free enzyme • Binds to either free enzyme or • Effect is reversed with ↑ in enzyme substrate complex. substrate concentration • Effect cannot be overcome by ↑ in • Vmax – same substrate concentration Km – increases • Vmax – decreases Km – same • Ex: Dopa decarboxylase – • Ex- Aspirin- cyclooxygenase carbidopa (Parkinson’s disease) (inflammation) cholinesterase – neostigmine • Omeprazole – H+K+ ATPase (myasthenia gravis) ( peptic ulcer) 11

The Michaelis - Menten constant (Km)

– the substrate concentration at which the rate of a reaction is half of Vmax

Vmax = 3.4 ½ V max= 1.7 Km = 0.4

Vmax – same Km – increases

Vmax – decreases Km – same

12

Non – receptor mediated mechanisms… Ion channels • Ex: local anesthetics – block Na+ channels Nifedipine blocks L-type of voltage sensitive Ca++ channels (antihypertensive)

13

Non – receptor mediated mechanisms… Transporters • Drugs produce their action by directly interacting with the transporter proteins to inhibit the ongoing physiological transport of the metabolite/ion

• Ex: – Fluoxetine blocks SERT (Depression) – Tiagabine blocks GAT1 (convulsions)

14

Non – receptor mediated mechanisms…

Antibody production Examples

• Stimulation of Antibody • BCG against Tuberculosis production in body • Polio vaccine against Polio

15

Non – receptor mediated mechanisms…

Placebo (Latin term – I shall please) . Dummy without Pharmacological activity

Uses – Relief of subjective symptoms eg. Anxiety, headache, insomnia – In Clinical trials to reduce bias

Influencing Factors Patient personality Drug -Injection, Capsule Doctor patient relationship

16 Receptor mediated drug action

The concept of drugs acting on receptors generally is credited to John Langley (1878).

Drug[D] + Receptor[R]

DR-Complex

Action

17 Drug-receptor interaction: Terms

AGONIST ANTAGONIST (BLOCKERS) • Is a drug that • Is a drug that combines with the combines with the receptor but does not initiate any receptor and initiates a sequence of cellular response. biochemical or • It prevents the binding of an to physiological changes. the receptor. Eg. Propranolol, atropine • Eg. Adrenaline, • Types: Acetylcholine • Competitive antagonist • Types: • noncompetitive antagonist – – Full agonist

18 Drug-receptor interaction: Terms

Affinity: Ability of the drug to bind to the receptor

Intrinsic activity or : Ability of a drug to produce pharmacological activity after binding

1. possess both affinity and intrinsic activity (IA=1) 2. Antagonists possess affinity but lack intrinsic activity (IA=0)

19 Receptor: Types

(GPCRs) / nuclear receptors

20 Drugs acting through receptors : Transmembrane receptor signaling mechanisms

21 Transmembrane receptor signaling mechanisms

22 Intracellular receptors ex: steroid hormones exert their action on target cells via this receptor mechanism

24 Receptor regulation

25 Receptor Regulation

Down regulation Up regulation • Prolonged use of agonists • Prolonged use of antagonists ↓ [Propranolol] ↓ Receptor [β2] no. and sensitivity decreases Receptor no. and sensitivity ↓ increases ↓ Drug effect ↓ [Sudden withdrawal → ↑ Ex: Salbutamol in trt. of sensitivity of bronchial asthma  adrenoreceptors → Angina Decreased effect on chronic precipitates

use 26

Receptor Regulation

Target cells

27 Sites of action of agonists and antagonists

28 Receptor Antagonism Competitive Noncompetitive (Surmountable) (Unsurmountable)

. Binds with the same site on the . Binds to another site receptor

. . Antagonist resembles agonist No resemblance with agonist

. Surmountable by increasing . Not surmountable conc. of agonist . Flattening of DRC . Rightward shift of DRC Eg. Eg. Diazepam –Bicuculline Acetylcholine – Atropine Phenoxybenzamine- - Noradrenaline

29 Receptor antagonism

30 Dose Response Relationship

DRC: has 2 components

Dose- Plasma conc. relationship Plasma conc. – Response relationship

31 Dose response relationship

Potency of drug (X-axis) • Amount of the drug required to produce a certain response. – Ex: 1 mg of bumetanide produces same diuresis as 50mg of frusemide

Efficacy (Y-axis) • Indicates maximum response that can be produced by a drug – Ex: morphine produces a degree of analgesia not obtainable with any dose of aspirin

32 & Efficacy of a drug

Typical dose-response curve for drugs showing differences in potency and efficacy.

(EC50 = drug dose that shows fifty percent of maximal response.)

33 Therapeutic index (TI)

Definition: is the ratio of the dose that produces to the dose that produces desired clinical response.

TI = (TD50)

median effective dose (ED50)

Implications: • Indicates safety margin of a drug • Higher the TI, safer drug – More than 1

34 TI- calculation

• TI= 400/100 = 4

35 • Drugs with low TI have low safety margin E.g. digoxin, lithium, cyclosporine, warfarin

• Drugs with large TI: have high safety margin ex- paracetamol, penicillin

36 Lecture Summary

• Describe the principles of pharmacodynamics with regard to the potential targets of -Mechanisms of drug action -receptor : types, transducer mechanisms agonist / antagonist , affinity / Intrinsic activity

- dose-response relationship (curve) potency / efficacy -therapeutic index

45 MTF

•Regarding drugs acting through receptors

T A Agonists have affinity for the receptors F B Antagonists have intrinsic activity F C Antagonists down regulate the receptors F D Partial agonists are devoid of pharmacological actions T E Antagonists competitively block the actions of agonist

47 • Drugs can act through

T A ion channels T B transporters T C receptors T D antibody production T E placebo effect

48 SEQ

• Enumerate differences between competitive and noncompetitive drug receptor antagonism. • Define / Describe an agonist and antagonist. • Define TI of a drug. State the formula to calculate TI.

49 OSPE

50 OSPE Graph depicting dose response of a drug ‘X’ in the individuals OSPE Graph depicting the potency and efficacy of drugs