Transcript Pharmacodynamics What the drug does to the body?

Pharmacology
RHPT-365
Chapter 3:
PHARMACODYNAMICS
By
Majid Ahmad Ganaie
M. Pharm., Ph.D.
Assistant Professor
Department of Pharmacology
E mail: [email protected]
Overview
Drug(Ligand) + Receptor ⇋ Drug-receptor
complex  Biologic effect
“A drug doesn’t work unless it is bound”
Drugs only modify underlying biochemical
and physiological processes, they do not
create effects de novo (anew)
Topics of Discussion
• DRUG RECEPTOR INTERACTION
• DRUG DOSE-RESPONSE
RELATIONSHIP
• THERAPEUTIC INDEX
Drug Mechanisms (How Drugs Act?)
Receptor mechanisms:


Most drugs exert their effects by binding to receptors
This has the effect of either mimicking the body’s own
(endogenous) substances binding to receptors or preventing
their binding or actions
II. Non-receptor mechanisms: These include:
1.
2.
3.
4.
5.
6.
Changing Cell Membrane Permeability (Ion Channels)
Actions on enzymes
Carrier Molecules, e.g. uptake proteins
Changing Physical Properties
Combining with Other Chemicals
Anti-metabolites
I. Receptor Mechanisms
 Drugs typically exert their effects by interacting with
a receptor
 Chemical bonds



Electrostatic
Hydrogen bond
Van der Waals
 Binding
 Receptor selective
 Requires exact fit
 Usually reversible
+
Types of receptor-effector linkage: E, enzyme; G, G-protein; R, receptor.
Major Receptor Families
Ligand-Gated Ion Channels
1.



Regulation of flow of ions across cell membranes
Depolarization/Hyperpolarization of membrane
Associated with receptors for fast neurotransmitters

Nicotic receptor - Na+
Major Receptor Families
2. G-Protein coupled receptors – Largest family
 3 components
7 membrane-spanning α helices
 G protein – α subunit - GTPase & βγ
 cAMP / IP3/ Phospholipase A2/ ion Ch


Four Steps
Ligand binding
 G protein activation (cytoplasmic side)
 Activity of effector (ion channel or enzyme) changed
 Intracellular second messenger concentration changes
 cAMP: effector enzyme -- adenylyl cyclase, converting ATP to
cAMP – phosphorylates proteins

G-Protein Coupled Receptor
Major Receptor Families
3. Kinase-linked receptors
 Cytosolic enzyme activity as integral structure or function
 Most common tyrosine kinase activity (Kinase = Phosphate)
 Addition of phosphate changes 3D structure of protein

Insulin
Major Receptor Families
4. Nuclear receptors
 TWO main categories
Those present in cytoplasm form complex with ligand – migrate
to the nucleus eg. Steroid hormones
 Present in nucleus – ligands usually lipids




Binds to specific DNA sequences resulting in regulating gene
sequences – protein synthesis
Longer time course of action
Responsible for 10% of pharmacology and the
pharmacokinetics of 60% of all prescription drugs
Topics of Discussion
• DRUG RECEPTOR INTERACTION
• DRUG DOSE-RESPONSE
RELATIONSHIP
• THERAPEUTIC INDEX
Drug Dose-Response Relationship
 Graded dose-response relations
 Drug-Receptor binding
 Relationship of binding to effect
 Potency
 Efficacy
 Nature of interactions
 Agonists
 Antagonists
 Functional antagonism
 Partial agonists
Drug-receptor Binding
 Effect of dose on the
magnitude of drug binding
 Relationship of binding to
effect assumes



Magnitude proportional to
receptors bound
Maximum efficacy when all
receptors bound
Binding does not show
cooperation
Interactive Pharmacology
II. Non-receptor Mechanisms
1. Actions on Enzymes

Enzymes = Biological catalysts




Speed chemical reactions
Are not changed themselves
Some drugs alter enzyme activity & alter processes catalyzed by the
enzymes
Examples


Cholinesterase inhibitors
Monoamine oxidase inhibitors
2. Interacting With Carrier/Transporter Proteins

Example: Maprotiline inhibits NE carrier  blocks re-uptake of NE and increase its
concentrations at the synapse
3. Changing Physical Properties

Example: Mannitol


Changes osmotic balance across membranes
Causes urine production (osmotic diuresis)
Non-receptor Mechanisms, contd.
4. Changing Cell Membrane Permeability (Ion Channels)

Lidocaine (a local anesthetic)
 decreases
permeability of the nerve cell membrane to NA+  the rate of
depolarization of the nerve membrane, threshold for electrical excitability, &
propagation of the action potential

Verapamil & nefedipine (calcium channel blockers)
 Block
calcium channels  Ca influx into smooth and cardiac muscle  vasodialate
vascular smooth muscle & myocardial contractility, slow AV nodal conduction

Adenosine (an inhibitory neurotransmitter)
 Opens
potassium channels
5. Combining with Other Chemicals

Examples
 Antacids
 Chelating
toxicity
agents (e.g., dimercaprol) that bind heavy metals, and thus reduce their
Non-receptor Mechanisms, contd.
6. Anti-metabolites


An anti-metabolite is a chemical with a similar structure to a substance (a
metabolite) required for normal biochemical reactions, yet different enough to
interfere with the normal functions of cells, including cell division
Examples:


Anti-neoplastics e.g., 5-FU (5-fluorouracil)  inhibits RNA synthesis
Antimicrobials such as sulfonamide drugs, which inhibit dihydrofolate synthesis in
bacteria by competing with para-aminobenzoic acid
Potency
 Graded dose-response curve shows potency
 Determine Effective Concentration 50% EC50
ED50: The dose or concentration required to produce 50% of the
maximal effect
50%
Efficacy
 Efficiency is dependent on number of drug-receptor
complexes formed and corresponding cellular
response
 A drug with more efficacy is better than drug with
more potency
Nature of Interactions
 Agonist
 If a drug binds to a receptor and produces a biologic response
that mimics the response to the endogenous ligand
 Partial agonist
 Has intrinsic activity less than that of a full agonist
Theoretical occupancy and response
curves for full vs partial agonists
The occupancy curve is for both drugs, the response curves a and b are for full
and partial agonist, respectively. The relationship between response and
occupancy for full and partial agonist, corresponding to the response curves in
A. Note that curve a produces maximal response at about 20% occupancy,
while curve b produces only a submaximal response even at 100% occupancy.
Nature of Interactions
 Antagonist

Drugs that decrease the actions of the endogenous ligand.
 Reversible vs Irreversible
 Functional antagonism (physiologic antagonism)

Antagonist binds completely separate receptor initiating
effects functionally opposite of the agonist
 Epinephine binding to (β2 adrenergic receptor )
reversing Histamine-induced bronchoconstriction (H1
receptor)
Reversible vs irreversible competitive
antagonists
A. Reversible competitive
antagonism – log
concentration-effect curve
shifts to right without
change in slope maximum
B. Irreversible competitive
antagonism – Covalent bond
formed with receptor eg.
Aspirin & Omeprazole
1 = 50% occupancy
Body adapts to drugs
 Change in receptors
 Refractory period after effect of first dose - Desensitisation
 Loss or addition of receptors
 Internalization of receptors due to prolonged exposure to
agonist – and converse.
 Exhaustion of mediators
 Amphetamine release cathecholamine – stores depleted
 Increased metabolic degradation of drug
 Tolerance
 Physiological adaptation
Topics of Discussion
• DRUG RECEPTOR INTERACTION
• DRUG DOSE-RESPONSE
RELATIONSHIP
• THERAPEUTIC INDEX
Therapeutic Index
 Therapeutic index is the ratio of the dose that
produces toxicity : dose for clinically desired effective
response (50% o f population)
Therapeutic Index = TD50/ ED50
Therapeutic Index (T.I.), contd.
 High therapeutic index

NSAIDs

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Aspirin
Tylenol
Ibuprofen
Most antibiotics
Beta-blockers
 Low therapeutic index

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Lithium
Neuroleptics

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Phenytoin
Phenobarbital
Digoxin
Immunosuppressives
Summary
 Drugs only modify underlying biochemical and
physiological processes, they do not create effects
de novo (anew)
 4 ways drugs and receptors interact
 Dose-Response Curve



Potency vs Efficacy
4 Nature of Interactions
Body adapts to drug
 Therapeutic Index
References
 Howland et al (2006) Lippincott’s Pharmacology 3rd
Ed.
 Rang et al (2007) Rang & Dale’s Pharmacology 6th
Ed.