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Module 2 #1 Pharmacodynamics
Kash Desai 966-2723 HSc A120 k.desai@usask.ca
2004-2005
The action of a drug on the body, including receptor interactions, doseresponse phenomena, and mechanisms of therapeutic and toxic action.
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Pharmacodynamics
(how drugs work on the body)
many drugs inhibit enzymes Enzymes control a number of metabolic processes A very common mode of action of many drugs in the patient (ACE inhibitors) in microbes (sulfas, penicillins) in cancer cells (5-FU, 6-MP) some drugs bind to: proteins (in patient, or microbes) the genome (cyclophosphamide) microtubules (vincristine)
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Pharmacodynamics
most drugs act (bind) on receptors
in or on cells form tight bonds with the ligand
Drug Receptor
A macromolecular component of a cell with which a drug interacts to produce a response Usually a protein
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effect
at equilibrium:
[D] x [R] x k1 = [DR] x k-1 so that: [DR] = k1
[D] [R]
k-1
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DR Complex
Affinity measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor Covalent bonds are stable and essentially irreversible Electrostatic bonds may be strong or weak, but are usually reversible
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Effect
Efficacy (or Intrinsic Activity) ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but NOT efficacy
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Percent Maximum
k1
k-1
Drug-receptor Complex DR
Where:
D = drug concentration
DR=
0 concentration 0.00 0.25of
25
Dose (ug/ml)
Drug-receptor interaction At equilibrium: [D] x [R] x k1 = [DR] x k-1 so that: [DR] = k1 [D] [R] k-1
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At equilibrium: [D] x [R] x k1 = [DR] x k-1 so that: [DR] = k1 [D] [R] k-1
k-1/k1 = dissociation constant (kd)
Ke (k1/k-1) is called the affinity constant DR is the response; D is concentration of drug when DR = 50 percent (effect is half maximal), D (or EC50) is equal to kd or the reciprocal of the affinity constant response is a measure of efficacy drugs that have parallel dose-response curves often have the same mechanism of action
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Number Responding
30
% fall in blood pressure
50 40 30 20 10 0 -2 -1
0.1 0.3 Control L-NAME
50
20
40 30 20 10
10
3
Control L-NAME
0 0.1 0.31
10
0
1
1
3
2
10
Acetylcholine nmol/kg
Acetylcholine nmol/kg
5.28
5.40
5.52
5.64
5.76
5.88
6.00
Dose (g/kg)
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Potency
Relative position of the dose-effect curve along the dose axis Has little clinical significance for a given therapeutic effect A more potent of two drugs is not clinically superior Low potency is a disadvantage only if the dose is so large that it is awkward to administer
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Relative Potency
hydromorphone morphine
Analgesia
codeine
aspirin
Dose
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10
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Agonist Drugs
drugs that interact with and activate receptors; they possess both affinity and efficacy two types Full an agonist with maximal efficacy Partial an agonist with less then maximal efficacy
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Response
Dose
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Antagonist Drug
Antagonists interact with the receptor but do NOT change the receptor they have affinity but NO efficacy two types
Competitive Noncompetitive
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Competitive Antagonist
competes with agonist for receptor surmountable with increasing agonist concentration displaces agonist dose response curve to the right (dextral shift) reduces the apparent affinity of the agonist i.e., increases 1/Ke
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Noncompetitive Antagonist
drug binds to receptor and stays bound irreversible does not let go of receptor produces slight dextral shift in the agonist DR curve in the low concentration range this looks like competitive antagonist but, as more and more receptors are bound (and essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect 2004-2005
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Desensitization
agonists tend to desensitize receptors homologous (decreased receptor number)
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Therapeutic Index =
TD50 or LD50
ED50
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Drug A
100
sleep
death
Percent 50 Responding
0 ED50
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LD50
dose
Drug B
100
sleep
death
Percent Responding
50
0 ED50
LD50
dose
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to:
>1000 (penicillin)
Drugs acting on the same receptor or enzyme system often have the same TI: (eg 50 mg of hydrochlorothiazide about the same as 2.5 mg of indapamide)
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Signal transduction
1. enzyme linked
(multiple actions)
2.
3. G protein linked
(amplifier)
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1.
G protein-linked receptors
Structure: Single polypeptide chain threaded back and forth resulting in 7 transmembrane helices
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Theres a G protein attached to the cytoplasmic side of the membrane (functions as a switch).
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2.
Tyrosine-kinase receptors
Structure: Receptors exist as individual polypeptides Each has an extracellular signal-binding site
An intracellular tail with a number of tyrosines and a single helix spanning the membrane
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3.
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Intracellular receptors
Not all signal receptors are located on the plasma membrane. Some are proteins located in the cytoplasm or nucleus of target cells. The signal molecule must be able to pass through plasma membrane. Examples: ~Nitric oxide (NO) ~Steroid (e.g., estradiol, progesterone, testosterone) and thyroid hormones of animals).
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B.
Second Messengers Small, nonprotein, water-soluble molecules or ions Readily spread throughout the cell by diffusion Two most widely used second messengers are: 1. Cycle AMP
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Signal amplification Proteins persist in active form long enough to process numerous molecules of substrate Each catalytic step activates more products then in the proceeding steps
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Summary
most drugs act through receptors there are 4 common signal transduction methods the interaction between drug and receptor can be described mathematically and graphically agonists have both affinity (kd) and intrinsic activity () antagonists have affinity only antagonists can be competitive (change kd) or non-competitive (change ) when mixed with agonists agonists desensitize receptors. antagonists sensitize receptors.
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