BBC2 K58Pharmacodynamic (2)

Dr.Datten Bangun,MSc,SpFKDr.Zulkarnain Rangkuty,MKes

Dept.Farmakologi & TherapeutikFak.Kedokteran USU

Medan

Drug-Receptor Interactions

• Agonists or stimulants – Initiate a desired response – Intrinsic activity

• Antagonist– Decrease/prevent the response

• Response - function of number occupied receptors

Drug-Receptor Theories

• Hypothesis of Clark

“ The Pharmacologic effect of the drug depends on the percentage of the receptors occupied”

If receptors are occupied, maximum effect is obtained.

Chemical binding follow the Law of Mass Action.

Drug-Receptor Theories

• Hypothesis of Ariens and Stephenson“ Effectiveness of a drug lasts as long as the

receptor is occupied. Many substance possess different effect , some have high affinity for the receptor, some have low affinity and some are not effective, and those ineffective substances block or inhibit the receptor.”

It is also called Occupation Theory.

Drug-Receptor Theories

• Hypothesis of Paton“ Effectiveness of a drug does not

depend on the actual occupation of the receptor but by obtaining proper stimulus”

This is also known as the Rate Theory.

Drug-Receptor Theories

• Lock and Key Hypothesis“ The drug molecule must fit into the

receptor like a key fits into the lock”

Known as the Intrinsic Activity.

How do drugs act?

• All that drugs can do is mimic the physiological activity of the body’s own molecules

• Block the physiological activity of the body’s own molecules

Chemistry of Drug receptors Interactions

• The binding of drugs to receptors can involve different types of interactions such as ionic, hydrogen bonding, hydrophobic, van der Waals, and covalent.

• Mostly reversible.

• Covalent is the strongest (irreversible)

Affinity

• Is the strength of the reversible interaction between a drug and its receptor

• The affinity of a drug for its receptor is determined by its chemical structure

• Selectivity

Efficacy

• The ability of the drug to produce a physiological response (maximal effect Emax) after binding to its receptor.

• Also referred to as intrinsic activity.• Comparable to maximum velocity of enzyme

catalyzed reactions Vmax

K+1 and K-1 are association and dissociation constants respectively and K2 is efficacy. At equilibrium:

k+1[A][R] = k-1[AR]

The ratio k-1/k+1 = [A][R]/[AR] = KD (equilibrium dissociation constant)KD is also the concentration of the drug that will occupy 50% of the receptors.

The smaller the KD the higher the affinity of the drug for its receptors. The reciprocal of KD is the affinity constant

DRUG-RECEPTOR INTERACTION

Agonists and Antagonists:

AGONIST• A drug is said to be an agonist when it binds to a

receptor and causes a response or effect. It has intrinsic activity = 1

+ + + + + -

- - - + - -

- - -

+ + +

Depolarization

Agonists

• A drug that has a higher affinity for the active conformation than for the inactive conformation will drive the equilibrium to the active state and thereby activate the receptor.

• Drugs that bind to physiological

receptors and mimic the regulatory effects of the endogenous signaling compounds are termed agonists

Full agonist

• Is sufficiently selective for the active conformation that at a saturating concentration it will drive the receptor essentially completely to the active state

Agonists

PARTIAL AGONIST• A drug is said to be a partial agonist when it

binds to a receptor and causes a partial response.

• It has intrinsic activity < 1• Contoh: - buprenorphine thd endorphin receptor

Partial agonists

• Agents that are only partly as effective as agonists no matter the amount employed.

• Mimic the actions but with reduced intensity

• Has moderately greater affinity for R a than for R i

Inverse agonist

• Stabilize the receptor in its inactive conformation.

• Produce opposite effect of an agonist

• Has preferential affinity for R i

Regulation of the activity of a receptor with conformation-selective drugs.

Drug-Receptor InteractionsDose response curves

Reveal the affinity and effective concentration of a series of drug analogs

Dose response curve

Antagonists

ANTAGONIST• A drug is said to be an antagonist when it binds to a

receptor and prevents (blocks or inhibits) a natural compound or a drug to have an effect on the receptor. An antagonist has NO activity.

Its intrinsic activity is = 0

DRUG ANTAGONISMThere are 5 main types:

1.Competitive antagonism (Reversible or irreversible)

2.Non-competitive antagonism

3.Physiological antagonism

4.Chemical antagonism

5.Pharmacokinetic antagonism

AntagonistsPHARMACOLOGICAL ANTAGONISTS

1. CompetitiveThey compete for the binding site

• Reversible• Irreversible

2. Non-competitveBind elsewhere in the receptor (Channel Blockers).

Antagonists

FUNCTIONAL ANTAGONISTS

1. Physiologic Antagonists

2. Chemical Antagonist

Antagonists

Physiologic ANTAGONIST• A drug that binds to a non-related receptor, producing an

effect opposite to that produced by the drug of interest.

• Its intrinsic activity is = 1, but on another receptor.

Glucocorticoid Hormones Blood Sugar

Insulin Blood Sugar

Histamin Blood Pressure Adrenalin Blood Pressure

Antagonists

Chemical ANTAGONIST• A chelator (sequester) of similar agent that interacts

directly with the drug being antagonized to remove it or prevent it from binding its receptor.

• A chemical antagonist does not depend on interaction with the agonist’s receptor (although such interaction may occur).

Heparin, an anticoagulant, acidic

If there is too much bleeding and haemorrhaging

Protamine sulfate is a base. It forms a stable inactive complex with heparin and inactivates it.

Agonists and Antagonists1. COMPETITIVE ANTAGONIST

a.Reversible & SurmountableThe effect of a reversible antagonist can be overcome by more drug (agonist). A small dose of the antagonist (inhibitor) will compete with a

fraction of the receptors thus, the higher the concentration of antagonist used, the more drug you need to get the same effect.

Changes in agonist concentration-effect curves produced by a competitive antagonist

Agonists and Antagonists1. COMPETITIVE ANTAGONIST

b.Irreversible & Non-surmountableThe effect of irreversible antagonists cannot be overcome by more drug (agonist). The antagonist inactivates the receptors.

NON-COMPETITIVE ANTAGONISM

One drug reduces the effect of another, not by competing for the same receptors, but by interfering with its signaling mechanism.(e.g. Ach/calcium antagonists).

Results in reduction of slope and maximum response of agonist

Changes in agonist concentration-effect curves produced by an irreversible antagonist

Non competitive antagonism

Effect of antagonist on agonist dose response curve

Agonists and Antagonists

RECEPTOR RESERVE OR SPARE RECEPTORS.• Maximal effect does not require occupation of all

receptors by agonist.• Low concentrations of competitive irreversible

antagonists may bind to receptors and a maximal response can still be achieved.• The actual number of receptors may exceed the

number of effector molecules available.

Agonists and Antagonists

SynergismThe combined effect of two drugs is

higher than the sum of their individual effects.

AdditivityThe combined effect of two drugs is

equal to the sum of their individual effects.

PHYSIOLOGICAL ANTAGONISM

Two drugs acting on separate receptorsproduce effects that are opposite, thus Mutually canceling their actions.

(e.g. histamine/salbutamol on bronchial smooth muscle) or histamine and omperazol on gastric acid secretion

CHEMICAL ANTAGONISM

• Two drugs interact in solution to neutralize each other. No receptors are involved.

(e.g. effect of chelating agents on heavy metals such as effect of dimercaprol on arsenic)

PHARMACOKINETIC ANTAGONISM

One drug decreases the effect of another by reducing its absorption or enhancing it metabolism or elimination.

(e.g. Phenobarbital/warfarin).

Quantal dose response relations (curves)

• Is the relationship between the dose and the proportion (%) of the population in which the drug produces the effect.

• These types of curves are useful in determining the relative effectiveness for different drugs in producing a specific desired or undesired effect as well as the relative safety.

• Useful in estimating ED50 (the median effective dose) which is the dose that gives a specific response in 50% of the population.

Quantal dose response curves

Used for:-pregnant/non pregnant-dead /not dead-coma/not coma

Therapeutic index

• Is the ratio of the dose that results in an undesired (toxic) effect to that which results in a clinically desired effect in a population.

Therapeutic index =TD50/ED50

• Values of TD50 and ED50 for this purpose are derived from quantal dose-response curves.

Determination of therapeutic index