Pharmacology 1

PHARMACODYNAMICS
PHARMACODYNAMICS
-- is the study of the detailed MECHANISM OF ACTION by which drugs
produce their pharmacologic effects
Signal transduction
pathway by which the
Binding of the drug receptor activates
Alteration of
to its site of action secondary messenger cellular processes
molecules

RECEPTORS
-- are specific molecules in a biologic system with which drugs interact to produce
changes in the function of the system
-- biologic site of action

-- receptors are selective

RECEPTORS
I. DRUG-RECEPTOR INTERACTION

A. Concepts and Terms

1. AFFINITY
 is the ability of the drug molecule to bind with its receptor
2. INTRINSIC ACTIVITY
 is the ability of the drug to generate an impulse which activates the biological
effector system
RECEPTORS
I. DRUG-RECEPTOR INTERACTION
B. Classification of Ligands/Drugs
1. AGONIST
 has both affinity and intrinsic activity
• Full Agonist
-- is a drug capable of fully activating the effector organ system
-- produces al of the expected effects
• Partial Agonist
-- produces less than the full effect even when it has saturated the receptors
-- *with the presence of a full agonist, it acts as an antagonist
• Inverse Agonist
-- have much more affinity to the inactive site thereby decreasing or abolishing any
constitutive activity
RECEPTORS
I. DRUG-RECEPTOR INTERACTION
B. Classification of Ligands/Drugs
2. ANTAGONIST
 has affinity but without an intrinsic activity
Types of antagonism:
A. Based on Mechanism of Action
1. Physiological Antagonism
-- binding of 2 agonists in different receptors producing opposite effects
example: Epinephrine administration during anaphylaxis
RECEPTORS
I. DRUG-RECEPTOR INTERACTION
A. Based on Mechanism of Action
2. Pharmacologic Antagonism
-- binding of 2 drugs to the same receptor with opposing effects
example: Administration of Dobutamine and Propranolol

3. Chemical Antagonism
-- inactivation due to chemical interaction
example: Heparin overdose is treated with Protamine sulfate
Dimercaprol is the antidote for lead poisoning

4. Dispositional/ Pharmacokinetic Antagonism

-- alteration of pharmacokinetic parameters
example: Administration of activated charcoal and ipecac in the management of poisoning
RECEPTORS
I. DRUG-RECEPTOR INTERACTION
B. Based on Reversibility/ Irreversibility
1. Reversible Antagonism
-- antagonist binds with the receptor in non-covalent links

2. Irreversible Antagonism
-- antagonist binds with the receptor in covalent links
example: Aspirin is an irreversible inhibitor of COX
Organophosphates are irreversible inhibitor of acetylcholinesterase
Prasugrel is an irreversible antagonist of P2Y12 receptors
RECEPTORS
I. DRUG-RECEPTOR INTERACTION
C. Based on Surmount ability of interaction
1. Competitive Antagonism
-- the agonist of given in high enough concentrations, can displace the
antagonist and fully activate the receptors

2. Non-competitive Antagonism
-- the agonist of given in high enough concentrations, cannot displace the
antagonist thereby cannot activate the receptors
PHARMACODYNAMICS
II. DOSE-RESPONSE RELATIONSHIP
A. DRUG-RECEPTOR THEORIES

1. Hypothesis of Clark
-- the pharmacological effect depends on the percentage of receptors occupied.
-- the drug must have an affinity to the receptor.
-- if all receptors are occupied, maximum effect is obtained.

3. Hypothesis of Ariens and Stephenson

-- drug must have both affinity and intrinsic activity
-- effectiveness lasts as long as the receptor is occupied (Occupation Theory)
PHARMACODYNAMICS
II. DOSE-RESPONSE RELATIONSHIP
A. DRUG-RECEPTOR THEORIES

3. Hypothesis of Paton
-- Also known as the Rate Theory
-- Effectiveness does not depend upon the actual occupation of the receptor by the drug,
but upon obtaining the proper stimulus only. The stimulus occurs at the moment the drug
attaches itself to the receptor.

4. Lock and Key Hypothesis

-- the drug molecule must “fit into the receptor” like a “key fits into a lock” (intrinsic activity)
PHARMACODYNAMICS
III. DOSE-RESPONSE GRAPH
A. Graded Dose-Response
-- the graded-dose response curve represents the response of a particular
receptor-effector system measured against increasing concentrations of a drug

Parameters:
Efficacy (Ɛ)
- maximum achievable response
- the greatest effect (Emax) an agonist can produce if
the dose is taken to the highest tolerated level
Ceiling dose
-minimum dose that produces maximal response
Potency (EC50)
-the dose producing 50% of the maximum response
-the smaller the EC50, the greater the potency of
the drug
PHARMACODYNAMICS
III. DOSE-RESPONSE GRAPH
B. Quantal Dose-Response Relationship
-- shows the minimum dose required to produce a specified response in each member
of the population

Parameters:
Effective Dose 50 (ED50)
- effective dose in 50% of the given population
Lethal Dose 50 (LD50)
- lethal dose in 50% of the population
Therapeutic Index
-measurement of the relative safety of the drug
PHARMACODYNAMICS
III. DOSE-RESPONSE GRAPH
B. Quantal Dose-Response Relationship
PHARMACODYNAMICS
MOLECULAR MECHANISMS OF ACTION OF DRUGS
OUTLINE:
A. Target Protein Mediated
1. Structural Proteins
2. Regulatory Proteins
a. Voltage-Gated Channels
b. Carriers
c. Enzymes
d. Receptors
B. Non-Target Protein Mediated
PHARMACODYNAMICS
A. TARGET-PROTEIN MEDIATED
- the drug will bind to the ACTIVE SITE of the protein to create its effect
1. STRUCTURAL PROTEINS
-proteins/ biomolecules that form cell framework/ cytoskeleton
examples: Anti-mitotic agents such as Vinca alkaloids, Taxols, Colchicine, and Griseofulvin

2. REGULATORY PROTEINS
-ability to regulate cellular activity or function
a. Voltage-Gated Channels
-- conduct changes in electrical signals
-- movement of ions (Na, K, Ca, Mg, Cl, PO4)
example: Sodium-channel blockers act as antiarrhythmic agents, local anesthetics, and anticonvulsants
Potassium-channel blockers act as antiarrhythmic agents, antidiabetic agents (insulin secretagoue)
Calcium-channel blockers act as antihypertensive agents
PHARMACODYNAMICS
A. TARGET-PROTEIN MEDIATED

2. REGULATORY PROTEINS
b. Carriers
-- cell membrane proteins with specific binding sites which undergo conformational changes
-- movement of ions (Na, K, Ca, Mg, Cl, PO4)
example: Digoxin inhibiting the Na+/K+-ATPase pump
Proton Pump Inhibitors inhibiting the K+/H+ pump

c. Enzymes
-- biological catalysts
example: NSAIDs inhibiting COX
Zileuton inhibiting LOX
MAOIs inhibiting MAO
PHARMACODYNAMICS
A. TARGET-PROTEIN MEDIATED
2. REGULATORY PROTEINS
d. Receptors
Ligand-gated ion channel/ Ionotropic G-protein coupled/ Metabotropic
Onset of effect: Milliseconds -- secondary messenger release
Location: Cell membrane Onset of effect: Seconds
Example: Nicotinic receptors (agonist) Location: Cell membrane
GABA receptors (agonist)
Gs Stimulatory effect on Adenylyl Cyclase Increase cAMP

Gi Inhibitory effect on Adenylyl Cyclase Decrease cAMP

Gq Activation will release Phospholipase Release of calcium from SR

C which will synthesize DAG and IP3
PHARMACODYNAMICS
A. TARGET-PROTEIN MEDIATED
2. REGULATORY PROTEINS
d. Receptors
Enzyme-linked Gene transcription/ Nuclear
Onset of effect: Minutes Onset of effect: Hours
Location: Cell membrane Location: Nucleus
Example: Insulin receptors Example: Hormonal receptors
PHARMACODYNAMICS
B. NON TARGET-PROTEIN MEDIATED
1. COLLIGATIVE MECHANISM
example: Mannitol exerts its effect via osmosis

2. DIRECT CHEMICAL INTERACTION

a. Acid-Base Neutralization
example: Antacids used in hyperacidity

b. Complexation/Chelation
example: Antidotes for heavy metal poisoning