Pharmacodynamics: Dr. Dwi Indria Anggraini, MSC., Spkk. Pharmacology and Pharmacy Dept. Lampung University

PHARMACODYNAMICS
dr. Dwi Indria Anggraini, MSc., SpKK.

Pharmacology and Pharmacy Dept.
Lampung University
Introduction
Pharmacodynamics
Ø The study of biochemical and physiological effects of
drugs and their mechanism of action
Ø What the drugs do to the body
How drugs act?

PDs
General principles:
Interaction between drug with living systems
• binding drugs to the cells
• desensitization and tachyphilaxis
Molecular aspects:
• target for the drug action
• receptor protein
• ion channels as drug targets
• control for receptor expression
• receptor and disease
Binding of drug molecules to the cells
• drugs act on target protein:
• receptors
• ion channels
• enzymes
• carriers
• drug specificity: individual classes of drug bind ONLY to

certain target, and individual targets recognize ONLY
certain classes of drugs
• No one drugs COMPLETELY specific in their actions.

Increasing the dose à can lead to side-‐effects
(exp: TCA à can block various receptors à lot of SE)
RECEPTOR:
Is target molecules, present on the cell surface/intra-‐
cellularly, that bind a drug and mediates its
pharmacologic actions (elicit specific effect)
• D + R à D-‐R complex à effect
• Drug – Receptor interaction Efficacy

• D – R à activation à response (agonist)
• in between (partial agonist)
• D – R à no activation à no response (antagonist)
• Tendency of D to bind R : affinity

Agonists, antagonists and efficacy:
D acting on the physiologic R : agonist or antagonist
• Agonists:
• agent that can bind a R and mimic the regulatory effect of
endogenous substance /elicit response/effect
• the potency depends on
• affinity (tendency to bound to the R)
• efficacy (ability to initiate the changes à effect)
• Antagonists:
• bind a R without the regulatory effect of endogenous
substance ; block the binding of endogenous substance
Graded dose-‐response curve
• Magnitude of the drug effect depends on conc. at receptor
• drug dose
• characteristic of drugs (rate of A, D, M)
• efficacy: maximal response produced by a drug à
• Σ D-‐R complex and efficiency of the cellular action
• potency: how much drug is required to elicit a given
response
• << the dose needed for a given response à >> potent
• determined by affinity of R to the D
• slope of the dose-‐response curve
Binding of D to the R:
• If >2 D compete for the same R à each will reduce affinity of the
other
• Drug antagonism
if the effect of one drug is diminished in the presence of another drug
a. chemical antagonism (interaction in solution)
b. PK antagonism (affecting A,D,M,E)
c. antagonism by R block ( both drugs bind to the same R);
d. non-‐competitive antagonism (drug interrupt R -‐ effector)
e. Physiological antagonism (2 drugs produce opposing physiologic effect)
Antagonists will reduce affinity AND efficacy
of other drugs
Desensitization & Tachyphylaxis
•The loss of a drug’s effect, esp. if it’s given repeatedly
/continuously
• It takes time to happen & to recover (days – weeks)
• Mechanism involved:
a. changes in R
b. loss of R
c. exhaustions of mediators
d. enhanced D metabolism
e. compensatory physiological mechanism
f. extrusion of D from the cells (resistance)
Molecular aspects
Targets for drug actions:
a. Receptors
b. Ion channels
c. Enzymes
d. Carrier molecules
Receptors:
Ion channels:
a. ligand-‐gated ion channels (= ionotropic receptors)
it’s open only if R is occupied by the agonist
exp: vasodilators (Ca-‐channel blockers)
b. voltage-‐gated ion channels
it’s open when cell membrane is depolarized
exp: sulfonylurea (release insulin)
Enzymes:
• Drugs is substrate analogue à competitive inhibitor of
certain enzyme
exp: aspirin (COX inhibitor)
• Drug as false substrate à abnormal metabolite produced
exp: 5FU (anti cancer, replace uracil)
• Pro-‐drug à active drug (catalyzed by enzyme)
Transporters/carrier molecules:
• Normal transport
• Drug inhibit NE uptake (exp: reserpine)
• Drug as false substrate (exp: methyldopa)
Type of Rs:
1. Ligand-‐gated ion channels:
• = ionotropic receptors
• Involved mainly in fast synaptic transmission
• Time scale: milliseconds
• Exp: GABA-‐R, nicotinic Ach-‐R
2. G-‐protein-‐coupled receptors:
• = metabotropic receptors
• G-‐protein is a membrane protein (consist of αβγ subunit)
• Drug binds to α-‐subunit à activates other subunit
• Time scale: seconds
• Exp: muscarinic Ach-‐R
3. Kinase-‐linked & related receptors:
• à gen transcription and protein synthesis
• Main effect: control cell growth & differentiation
• Time scale: hours
• Exp: some hormone (e.g. insulin) –R
4. Nuclear receptors:
• R is intranuclear à D must enter the cell first
• Effect: gene transcription à protein synthesis
• Time scale: hours
• Exp: receptor for steroid hormone, thyroid hormone
Receptors for Physiological Regulatory Molecules
2 functions of R:
• Ligand binding
• Message propagation (signaling) à to effector protein OR
to transducer (intermediary cellular signaling molecules: second
messenger , exp: cAMP, NO, Ca++, etc)
Receptor-‐effector system is called by signal-‐transduction pathway
But….not all the drugs work through the R

à antacid, mannitol
Regulation of R:
Regulation of synthesis & degradation
• Multiple mechanism
• From other R OR from feedback regulation by their own signaling output
Includes:
• Desensitization: cont stimulation of cells by agonist
• = down regulation = adaptation = refractoriness
• The phenomenon is called by TACHYPHILAXIS !!!
Disease caused by R malfunction:

• Type 2 diabetes à insulin resistance
• Myasthenia gravis à autoimmune depletion of nicotinic Ach-‐R
• Deficiency of androgen à loss of R
• Graves’ Disease (hyperthyroidism) à auto-‐Ab to TSH-‐R
Concentration-‐effect relationship
4 characteristic variables:
• Potency Pharmacodynamic
• Maximal efficacy variability
• Slope
• Individual variation
PD variability:
• Between subjects AND Within subject
• Factors affecting: internal and external
• Genetic Alter PK of the drug à effect
• Age • sub-theraputic
• Disease • therapeutic
• toxicity
• Other drugs
The Therapeutic Index
ED50 :
dose of the drug required to produce specified effect in 50% of
population
LD50 :
dose of the drug required to produce death in 50% of
experimental population
TI = LD50/ED50
The bigger is the TI à the safer is the drug
ADR and DRUG TOXICITY
ADR (Adverse Drug Reaction)
> any drug has potential to do harm
> it is the common cause of iatrogenic disease!
> idiosyncratic: if it’s encountered infrequently
-‐ mechanism-‐based (angioedema) OR
-‐ off-‐target action (anaphylaxis to penicillin)

ADR and DRUG TOXICITY
Therapeutic Drug Monitoring
Many factors that alter drug disposition …need TDM (in special case)
• drug with narrow therapeutic window (range of plasma conc. between required for
efficacy – toxicity occurs)
• drug with low TI
• drug with effect (+ or -‐) that is difficult to monitor
• drug with large variability of plasma conc.

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PHARMACODYNAMICS

dr. Dwi Indria Anggraini, MSc., SpKK.

Ø What the drugs do to the body

How drugs act?

• drug specificity: individual classes of drug bind ONLY to

• No one drugs COMPLETELY specific in their actions.

• D + R à D-­‐R complex à effect

• Drug – Receptor interaction Efficacy

• Tendency of D to bind R : affinity

Receptor-­‐effector system is called by signal-­‐transduction pathway

But….not all the drugs work through the R

Disease caused by R malfunction:

ADR (Adverse Drug Reaction)

> any drug has potential to do harm

> it is the common cause of iatrogenic disease!

> idiosyncratic: if it’s encountered infrequently

-­‐ mechanism-­‐based (angioedema) OR

-­‐ off-­‐target action (anaphylaxis to penicillin)

• drug with low TI

• drug with large variability of plasma conc.

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• D + R à D-‐R complex à effect

Receptor-‐effector system is called by signal-‐transduction pathway

-‐ mechanism-‐based (angioedema) OR

-‐ off-‐target action (anaphylaxis to penicillin)