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Pharmacodynamics

3009 PHM Devinder Arora School of Pharmacy

Following this lecture you should be able to:

Define what is a receptor Define what is an agonist and what is the difference between a full, partial and inverse agonists Explain what is an antagonist and what is the difference between competitive and non competitive antagonist How to measure a drug-receptor interaction: dose response curve

Describe EC50, Emax, and KA, and how to measure these from a dose response curve
Describe the concept of constitutive activity

Describe the concept of spare receptors

Describe different types of antagonism Understand the theory of allostery

Explain the concepts of drug desensitization and describe different mechanism responsible for desensitization

Pharmacodynamics
Corpora non agunt nisi fixata A drug will not work unless it is bound

Drug + Drug target Physiological response

Most of the drug targets are protein molecules

Protein targets for drug binding

Receptors Enzymes Carrier molecules Ion channels

 Specificity is reciprocal
individual classes of drug bind only to certain targets, and individual targets recognize only certain classes of drug

No drugs are completely specific in their actions In many cases, increasing the doses of a drug will cause it to affect targets other than the principal one, and this can lead to side effects

Drug-Receptor interaction:
Drug Adrenaline

Receptor

-Receptor

Pharmacological effect

Force and rate of heartbeat

Receptor: Physiology
Any target molecule through which soluble physiological mediators produce their effects
Hormones, neurotransmitters, inflammatory mediators etc.

e.g. acetylcholine receptors, cytokine receptors, steroid receptors, growth hormone receptors Generally the term receptors indicates a recognition molecule for a chemical mediator

Receptor: Pharmacology
Any target molecule with which a drug molecule has to combine in order to elicit its specific effect
Any foreign molecule rather than an endogenous mediator

Voltage sensitive sodium channels receptors for local anaesthetics The enzyme DHFR as the receptors for methotrexate

Receptor: cell biology

Various cell surface molecule involved in the cell to cell interactions that are important in immunology, cell growth, migration and differentiation
T-cell receptors, integrins, Toll receptors etc.

These receptors differ from conventional pharmacological receptors

they respond to proteins attached to cell surfaces or extracellular structures, rather than the soluble mediators

Receptors:
Carrier proteins as receptors
Low density lipoprotein receptor play a key role in lipid metabolism Transferrin receptor involved in iron absorption
A receptor is a target molecule (protein) which recognises endogenous chemical signals (hormones, NT, inflammatory mediators, etc.), or a drug molecule and produces their physiological and biochemical effects

Concept of affinity vs. efficacy

Ligand: a molecule that binds a receptor Affinity
The ability of the drug to bind to a receptor High affinity = strong binding produce effects at low conc.

Low affinity = less strong binding require high conc. to produce an effect

Efficacy /Intrinsic activity

The ability of a drug, once bound to a receptor, to activate the receptor and produce a pharmacological response Some agonists can have the same affinity but differential efficacy

Depends upon the drug-receptor complexes formed and the efficiency of the coupling of receptor activation to cellular responses

Agonists, partial agonists and antagonists

An agonist is a drug which binds to the receptor and produces an pharmacological effect
Thus it has affinity + Efficacy

A partial agonist has affinity for a receptor but less intrinsic activity (lower efficacy compared to an agonist acting at the same receptor) An antagonist is a drug which binds (thus competes for binding against other ligands), but does not activate the receptor
It has affinity but no Efficacy

An antagonist can be
Competitive (reversible) Noncompetitive (irreversible)

Agonists: types
Agonist binds to the receptor activates the receptor produces a maximal response Partial agonist binds to the receptor activates the receptor produces a submaximal response
Inverse agonist binds to the inactive state of constitutively active receptor produces a negative response

Agonist

Antagonist

Drug

Drug

Receptor

Receptor

Pharmacological effect

NO Pharmacological effect

Antagonist
Competitive Non-competitive

Drug

Drug

Receptor

Receptor

NO Pharmacological response

NO Pharmacological effect

How do we measure or quantify a drug-receptor interaction: Dose response curve (DRC): Concentration response
curve; Concentration response relationship

When a drug is administered, the response will increase in proportion to the dose until all the receptors are occupied saturation
Increasing the dose farther will not produce any further increase in the response From a dose-response curve you can gather important information including

Dose response curves

EC50 dose or conc. of a drug that produces 50% of maximal (half maximal) response. It is a measure of potency of a drug

Emax maximal effect produced by a drug. It is a measure of efficacy of a drug

KA conc. of a drug that occupies 50% of the total number of receptors at equilibrium

Arithmetic vs. log scale of dose - which one is better?

Contraction of muscle produced by a drug 100

Contraction of muscle produced by a drug 100

% contraction

% contraction

75 50 25 0 1 3 10 30

75 50 25 0 0.1 0.3 1 3 10 30

Arithmetic scale

Log scale

Dose of drug (mg)

Dose of drug (mg)

Rate of change is rapid at first and becomes progressively smaller as the dose is increased Eventually, increments in dose produce no further change in effect i.e., maximal effect for that drug is obtained Difficult to analyze mathematically

Transforms hyperbolic curve to a sigmoid (almost a straight line) Compresses dose scale Proportionate doses occur at equal intervals Straightens line Easier to analyze mathematically

Calculating potency from DRC:

drug effectiveness is dependent upon its maximal efficacy, NOT the potency

Efficacy Drug A = Drug B = Drug C Potency Drug A > Drug B > Drug C

equi-efficacious but not equi-potent

Efficacy from DRC:

Potency Drug A = Drug B = Drug C Efficacy Drug A > Drug B > Drug C

equi-potent but not equi-efficacious

Effect of agonist on receptor activity

100 Receptor activity 75 50 25 Inverse agonist Log drug concentration

Full agonist

Partial agonist

 The tendency of a drug to bind to its receptors is governed by its affinity The tendency of a bound drug to activate its receptor is denoted b its efficacy

Drug-receptor interaction
Drug-Receptor binding in most cases is transient, i.e. the drug molecule binds and dissociates, binds again and so on. Each binding triggers a signal

A
Equilibrium between drug molecule and its receptor association and dissociation

Drug molecule

A
Receptor

A B

If we put two drugs (A & B) acting at the same receptor, they will compete for the receptor due to the transient binding. The drug with a higher concentration will have a greater chance of binding

Equation for drug-receptor interaction

Simple version:

[D] + [R]

k +1 k -1

[DR]

effect
K+1/k-1 = affinity constant (ka) k-1/k+1 = dissociation constant (kA)

at equilibrium: [D] x [R] x k+1 = [DR] x k-1 so that: [DR] [D] [R]
kA = k-1/k+1 receptor

k+1 = k -1

- or -

K-1 [D] [R] = K+1 [DR]

the lower the kA the more affinity the drug has for the

D is concentration of drug ; DR is the response, response is a measure of efficacy, maximal effect or efficacy is denoted as Emax

KA: the equilibrium constant

Characteristic of drug and receptor = k-1/k+1 For drug binding to receptor: rate constant reverse reaction/rate constant forward reaction How quickly drug binds receptor; how long stays bound Numerically equals conc. of drug required to occupy 50% of receptor sites at eqlb.
Describes affinity of drug for receptor Higher KA lower affinity of drug for receptor

Lower KA higher affinity of drug for receptor

Lower KA identifies lower conc. at given level of occupancy And given response

Rectangular hyperbola

Symmetrical sigmoidal curve

Partial agonists - usefulness

A partial agonist produces less than full effect when given alone A partial agonist acts as an antagonist in the presence of a full agonist (blocks the full effect of an agonist) Therapeutic use of a partial agonist e.g. buprenorphine, an opioid analgesic, has a lower abuse potential, lower level of physical dependence, and greater safety in overdose compared with a full agonist such as morphine. Sometimes the antagonist properties of a partial agonist are desirable (providing some agonist activity and at the same time blocking the endogenous full agonists). Clinical example: pindolol for high blood pressure and abnormal heart rhythms (It will reduce the excessive stimulation due to norepinephrine)

Inverse Agonists

Some receptors are always active, even without the presence of an agonist constitutively active receptors Inverse agonists has high affinity for R than for R* Shift the eqlb. to the left

Inverse agonist

Concept of allosteric modulation

Allosteric modulation: the regulation of receptor by binding of an effector molecule at the allosteric site (i.e. a site other than the active site) Effectors that enhance the activity are allosteric activators and those that decreases the activity are inhibitors
Usually acts by causing a conformational change in the receptor leading to a change in the binding affinity of the ligand Allosteric ligands modulate the activation of the primary ligand

Major example is valium and GABA binding to benzodiazepine receptor

Competitive antagonism
When the agonist is alone, a lower dose can produce maximal effect Agonist molecule A A Receptor In the presence of a competitive antagonist a higher dose of agonist is required to produce the same effect
Competitive antagonist molecule Agonist molecule

B A A

A B

Receptor

e.g. acetylcholine agonist atropine competitive antagonist at muscarinic receptors

Competitive (reversible) antagonist shifts the DRC to the right

Competitive antagonism
If you do a series of concentration-effect curves for the agonist in the absence and presence of various concentrations of the antagonist and measure the EC50 values and plot on a concentration-effect graph

Non-competitive antagonism
When the agonist is alone, a lower dose can produce maximal effect Agonist molecule A In the presence of a non-competitive antagonist even a higher dose of agonist cannot produce maximal effect
Non-competitive antagonist molecule Agonist molecule

A A

A
B

A
Receptor

Receptor

e.g. noradrenaline- agonist phenoxybenzamine non-competitive antagonist at receptors

EC50, KA and spare receptors

Here there are a total of 10 receptors
10 receptors produce maximal response

5 receptors produce half-maximal response

Half-maximal response

EC50 = 5 concentration that produces half-maximal response

KA = 5 concentration that occupies 50% of receptors In this case EC50 = KA; there are no spare receptors

Here there are a total of 20 receptors only 10 are required to produce a maximal response
10 receptors produce maximal response

5 receptors produce half-maximal response

Half-maximal response

EC50 = 5 - concentration that produces half-maximal response KA = 10 - concentration that occupies 50% of receptors When EC50 < KA ; it suggests existence of spare receptors

When all receptors need to be occupied for a full response: then EC50 = KA i.e. the concentration of a drug which produces half-maximal response (EC50) will equal the concentration that

occupies half the number of total receptors (KA)

Spare receptors allow maximal response without total receptor occupancy increase sensitivity of the system spare receptors can bind (and internalize) extra ligand preventing an exaggerated response if too much ligand is present

Other types of antagonism

Physiological (functional) antagonism - the antagonist has the opposite biological action of the agonist, reducing the agonist effect by action on a different receptor (on which it itself an agonist). ACh and Phenylephrine in blood vessels. Pharmacokinetic antagonism the antagonist reduces free concentration of drug at target either by reducing drug absorption or increasing elimination. Phenobarbital and CYP P450. Chemical antagonism Chemical antagonist combines with drug to produce insoluble, inactive complex. Protamine sulphate neutralises action of heparin. Non-competitive antagonism antagonist doesnt block receptor but the signal transduction process initiated by receptor. Ca2+ channel blockers prevent smooth muscle contraction evoked by various agonists.

Desensitization & tachyphylaxis

Gradual decrease in the therapeutic effect of a drug after repeated / continuous use
Desensitization or tachyphylaxis: develops in a few minutes
Tolerance: gradual decrease in the responsiveness to a drug Drug resistance: loss of effectiveness of antimicrobial or antitumor drugs

Desensitization & tachyphylaxis

Mechanisms include:
change in receptors: conformational or phosphorylation changes translocation of receptors: internalization of receptors exhaustion of mediators: depletion of an essential intermediate substance increased metabolic degradation of the drug: increased metabolic degradation physiological adaptation: nullified by a homeostatic response; little is known active extrusion of drug from cells (mainly relevant in cancer chemotherapy: transporter/drug uptake changes

Therapeutic index (TI)

Therapeutic index is the ration of the dose that produces toxicity to the dose that produces a therapeutic effect in a population of individuals TI = TD50/ED50 TD50 is the dose that produces a toxic effect in half of the population ED50 is the dose that produces a therapeutic effect in half of the population

TI is a measure of a drugs safety

Larger TI wide margin between doses that are effective and doses that are toxic

Warfarin: Narrow therapeutic index

Therapeutic window

100 % of patients
Desired therapeutic effect

Unwanted adverse effect

50

0 Log conc. of the drug in plasma

Penicillin: Large therapeutic index

Therapeutic window
100 % of patients
Desired therapeutic effect
Unwanted adverse effect

50

0
Log conc. of the drug in plasma