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BBC2 K58Pharmacodynamic (2)
Dr.Datten Bangun,MSc,SpFKDr.Zulkarnain Rangkuty,MKes
Dept.Farmakologi & TherapeutikFak.Kedokteran USU
Medan
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Drug-Receptor Interactions
• Agonists or stimulants – Initiate a desired response – Intrinsic activity
• Antagonist– Decrease/prevent the response
• Response - function of number occupied receptors
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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.
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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.
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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.
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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.
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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Inverse agonist
• Stabilize the receptor in its inactive conformation.
• Produce opposite effect of an agonist
• Has preferential affinity for R i
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Regulation of the activity of a receptor with conformation-selective drugs.
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Drug-Receptor InteractionsDose response curves
Reveal the affinity and effective concentration of a series of drug analogs
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Dose response curve
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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
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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
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AntagonistsPHARMACOLOGICAL ANTAGONISTS
1. CompetitiveThey compete for the binding site
• Reversible• Irreversible
2. Non-competitveBind elsewhere in the receptor (Channel Blockers).
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Antagonists
FUNCTIONAL ANTAGONISTS
1. Physiologic Antagonists
2. Chemical Antagonist
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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
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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.
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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.
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Changes in agonist concentration-effect curves produced by a competitive antagonist
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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.
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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
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Changes in agonist concentration-effect curves produced by an irreversible antagonist
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Non competitive antagonism
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Effect of antagonist on agonist dose response curve
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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.
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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.
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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
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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)
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PHARMACOKINETIC ANTAGONISM
One drug decreases the effect of another by reducing its absorption or enhancing it metabolism or elimination.
(e.g. Phenobarbital/warfarin).
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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.
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Quantal dose response curves
Used for:-pregnant/non pregnant-dead /not dead-coma/not coma
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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.
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Determination of therapeutic index
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