Pharmacodynamics

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

Pharmaco dynamics
Principles & mechanism of drug action Receptor & Non- rec. mediated drug action Dose response relationships Therapeutic Index-Drug potency and efficacy Factors modifying drug action Drug interactions Adverse drug reactionsBioassay-

Pharmaceutical process Drug reaches the patient Pharmacokinetic process What body does to the drug Pharmacodynamic process What drug does to the body Pharmacotherapeutic process Therapeutic effect on the patient

PRINCIPLES [Types] OF DRUG ACTION

1. Stimulation
2. 3. Adrenaline Pilocarpine Depression Quinidine Morphine Barbiturates Irritation Bitters Counter irritants
4. Replacement Insulin Iron Levodopa 5. Cytotoxic action Penicillin, Chloroquine cyclophosphamide 6. Modification of immune status Vaccines Sera

Mechanism of Drug Action

Non-receptor mediated Physical Chemical Enzymes Ion channels Transporters Immune status Receptor mediated Receptors on the cell membrane Receptors inside the cell

Mechanism of Drug Action Non-receptor Mediated

Physical Osmosis Adsorption Demulcent Radioactivity Examples 20% Mannitol in Glaucoma Activated charcoal in poisoning Soothing effect of cough lozenges I131 in Hyperthyroidism

Mechanism of Drug Action Non-receptor Mediated

Chemical Antacids Chelation Enzymes Enzyme inhibition [Specific or non specific] Enzyme Stimulation Activation Induction Examples Neutralize acid in stomach BAL in Arsenic poisoning ACE inhibitors in HTN [specific] Phenol, formaldehyde[non specific]- [no therapeutic value] Pralidoxime in OP poisoning Enzyme inducers [Rifampicin]

Mechanism of Drug Action - Nonreceptor Mediated

Antibody production [Immune] Stimulation of AB production in body Ion channels Na channels Ca channels Transporters Serotonin transporter
GABA transporter

Examples BCG against TB, Polio vaccine against Polio

Quinidine in heart Nifedipine Blocked by Fluoxitine Blocked by Tiagabine

Mechanism of Drug Action

Non-receptor mediated Physical Chemical Enzymes Ion channels Transporters Immune status Receptor mediated Receptors on the cell membrane Receptors inside the cell

Mechanism of Drug Action - Receptor Mediated [Eg.Adrenergic Receptors, Muscarinic

receptors]

Receptor: Protein macromolecules Present on cell wall or Inside the cell To which drug binds, interacts, produces action

Drug[D] + Receptor[R] D-R-Complex Action

Receptor Mediated drug action Terms

Affinity: Ability of the drug to bind to receptor Intrinsic activity: Ability of drug to produce pharmacological activity after binding Agonist: Drug which binds and produces pharmacological action Antagonist: Binds but no action. [But blocks receptors] Partial agonist: Binds BUT less Action Inverse agonist:Binds BUT Produces action opp.of agonist Affinity + Intrinsic activity Eg. Morphine, Adrenaline Affinity + NO Intrinsic activity Eg. Naloxone, Atropine Affinity + LESS intrinsic activity-Pindolol Affinity + opp. Activity to agonist [b-carboline & GABA Rec]

Receptor super families Intracellular receptors

Minutes to Hours to Days

Receptor Super Families

MEMBRANE BOUND RECEPTORS

GPCR: Eg. Muscarinic, Adrenergic receptors

Ligand gated Ion channel: Eg. Nicotinic receptors Enzymatic: Eg. Insulin receptor INTRACELLULAR RECEPTORS Nuclear Receptors: Eg. Steroid, Thyroid hormone

Second Messengers[Effectors]
Binding of a hormone or drug to its receptor does not instantly produce clinical effects. Instead, a series of rapid biochemical events couples receptor binding to ultimate clinical effects. These biochemical events are called second messengers.
Binding

Biochemical events

cAMP Ca++

Second messengers Amplify signal

Functions of receptors
To carry signal into the cell To amplify signal

CONCEPT OF SPARE RECEPTORS

Some agonists could elicit maximal physiological effects by occupying only a small fraction of the total receptor population suggested that there were "spare receptors. Quick response for low concn of drug and fast dissociation [100% effect is produced when less than 100% of receptors
are occupied]

Eg.Neurotransmission
EC50=Kd50-No spare receptors EC50<Kd50-Spare receptors+++

Receptor Regulation
Down regulation Prolonged use of agonists [salbutamol 2] Receptor no. [ 2 receptors] Decreased efficacy Up regulation Prolonged use of antagonists [Propranolol] Receptor no. [ receptors] [Sudden withdrawal Increased sensitivity of adreno-receptorsAngina

Drug potency & Efficacy

Potency- Amount of drug required to obtain a particular response[More potent less dose] Efficacy-The ability of a drug to elicit a maximal response Aspirin is less potent[300mg] & less efficacious than morphine[10mg]

Pethidine is less potent[100mg] equally efficacious as morphine[10mg]

Dose-response [potency & effect]curve[DRC]

100%

E max

50%

EC50

Dose-response curves determine how much of a drug (X-axis) causes a particular effect, or a side effect, in the body (Y-axis).

Graded dose response curves

[Single subject- Continuous]

Linear [Simple]dose response curve

Log dose response curve

Advantages of Log-dose curve Large no.of doses can be plotted on a small graph paper Comparison of two or more drugs easier as middle portion is straight line

Quantal dose response curve

Quantal or all or none: frequency with which any drug evokes a all or none response in a population
97% 85% 35% 35% 100%

50% 11% 12% 3% 15% 4% 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 6 0 0

LD50 & ED50

4%

Cumulative DRC

Therapeutic index [TI]

LD50=Dose which kills 50% of sample population ED50=Dose which produces desired effect in 50% of sample

TI=

Median lethal dose[LD50 ]or Toxic Dose50]

Median effective dose[ED50]

Wider the TI-More safe the drug Eg.Penicillin -wide TI , Digoxin narrow TI
Certain safety factor = LD1/ED99 LD1=Lethal dose for 1% population ED99=Effective dose for 99% of population

Therapeutic range
Therapeutic range: Range between dose which produces minimal Th.effect and Max.acceptable adverse effect
Max.ADE

Acceptable-ADE

Min.Th.Effect

Therapeutic range

Combined effect of drugs

When 2 drugs are administered together:1. They may be Indifferent to each other 2. One may increase the action of the otherSynergism 3. Action may be decreased or abolished Antagonism