Pharmacokinetics

and

Pharmacodynamics

Moderator: Dr Shruthi

Definitions

Pharmacokinetics

Relationship between

drug dose and drug

concentration in in

plasma.

Absorption distribution

and clearance.

Pharmacodynamics

Relationship between

plasma drug concentration

and pharmacologic effect.

Potency efficacy and

therapeutic window

Pharmacokinetics

Volume of

distribution:volume = amount (dose)/conc.

Central volume of

distribution:Reflects the volume of heart,

great vessels and venous

volume of the upper arm.

Peripheral volume of

distribution:

Inter compartmental clearance.

Mammillary model

Vdss: Volume of distribution at steady

state.

Vdss= central volume+ peripheral volume

ClearanceThe volume completely

cleared of drug per unit time.

Actual rate is, clearance times

the concentration.

Hepatic Clearance

Renal Clearance

Tissue Clearance

Distribution Clearance

Protein Binding

First and zero order processes:

Zero order: processes continuing at a constant rate.

First order: rate proportional to the amount

Compartmental

pharmacokinetic models:

Increased volume of distribution

Increased clearance

Multi-compartment models

Pharmacodynamics

Classic receptor theory:

Receptor: component of cell that interacts selectively

with extracellular compound to initiate a cascade of

biochemical events.

The amount of drug at the receptor is a function of dose,

time and pharmacokinetic properties of the drug.

Agonists and antagonists:

Agonists Mimic endogenous

hormones when bound

to receptor.

Full agonists- completely

activate receptor

Partial agonists-only

partially activate

receptor

Antagonists

Competitive antagonists

Non competitive

antagonists

Inverse agonists

Neutral antagonists

Competitive

antagonist

Allosteric site

Agonlst

AntagonistsCompetitive Antagonist

Antagonist binds with the same receptor as the agonist

Antagonist resembles chemically with the agonist

Parallel rightward shift of agonist DRC The same maximal response can be

attained by increasing dose of agonist (surmountable antagonism) The antagonist appears to have

inactivated a certain number of agonist molecules

Intensity of response depends on the concentration of both agonist and antagonist

Examples: ACh-Atropine,Morphine-Naloxone, Vecuronium -ACh

Non competitveAntagonist

Binds to another site of receptor

Does not resemble the agonist

Flattening of agonist DRC

Maximal response is suppressed(unsurmountableantagonism)

The antagonist appears to have inactivated a certain number of receptors

Maximal response depends only on the concentration

of antagonist

Diazepam-Bicuculline

Receptor States:

Spontaneous

conversion of

receptors from an

inactive to active

stateG- guanine nucleotide

E-

Equilibrium between inactive

receptors and active receptors

is tissue specific and depends

on the type of ligand

administered.

Midazolam

Bretazenil

Flumazenil

RO 19-4063

Receptor structure:

G-protein coupled receptor:

Most abundant

type of receptor

in the body.

Ion channels:Most hypnotics act through

the potentiation of GABA

and GABAa ligand gated

ion channels.

They permit certain drugs to

directly alter membrane

potential.

ION PUMPS:

e.g sodium posassium

ATPase pump.

Second messengers:

cAMP

PKa Functional proteins

Gi

GDP

GTP

Increased

interaction

with calcium

Troponin

Better

excitation-contraction

coupling

Ca+2

Increased cardiac contractility Faster relaxation

Faster

sequestration ofCa2• in S R

Phospholamban

Clinical evaluation of

drug effects:

Potency and Efficacy

Potency

The effect of a given dose of a drug.

Quantity of drug that must be administered to produce a specific effect.

Efficacy

Intrinsic ability of a

drug to produce a

given physiologic

or clinical effect.

The concentration-response curve is shifted to the right (B➙C) in the presence of a competitive antagonist after desensitization.

Curve C might also represent an agonist with lower receptor affinity (Ka) or potency than curve B (or both).

Curve A represents an agonist with higher receptor affinity or potency than curve B.

Effective Dose and Lethal

DoseEffective Dose

ED50

The dose of a drug

required to

produce a specific

effect in 50% of

individuals to

whom it is

administered.

Lethal dose LD50

The dose of a drug

required to

produce death in

50% of patients.

Variability in drug

response

Pharmacogenetics

Genetic polymorphisms

Genetic variability in pharmacokinetics

Genetic variability in pharmacodynamics

Patient physiology:Age:1.Total body water

2.Lean body mass

3.Liver volume and liver blood flow

4.Cardiac output

5.Albumin levels decreased

6.Alpha1 glycoprotein increased

Disease states

Drug Interactions Desensitization:Waning of physiologic responsiveness to a drug over time.

TACHYPHYLAXIS- rapid development of tolerance when doses of a drug given in quick succession result in marked reduction in response.

E.g. Ephedrine, Tyramine, Nicotine

TOLERANCE- Requirement of higher doses of a drug to produce a given response.

E.g. tolerance to analgesic and euphoric action of morphine.

Cross tolerance: Development of tolerance to pharmacologically related drugs

E.g. Alcoholics are relatively tolerant to barbiturates

Increased receptor sensitivity:

Long term exposure to a drug leads to compensatory

responses by the receptor system.

Drug resistance:

Tolerance of micro-organisms to inhibitory effect of anti

microbials.

References

Millers 7th edition

Clinical Anesthesiology- Millers

Stoeltings handbook of pharmacology

and physiology in anesthetic practice

Essentials of medical pharmacology, K D

Tripathi

Thank You