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Module 2 #1 Pharmacodynamics
Kash Desai 966-2723 HSc A120 k.desai@usask.ca

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Drug Receptors and Pharmacodynamics (how drugs work on the body)

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

exacting requirements (size, shape, stereospecificity)

can be agonists (salbutamol), or antagonists (propranolol) receptors have signal transduction methods
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Drug Receptor
A macromolecular component of a cell with which a drug interacts to produce a response Usually a protein

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Types of Protein Receptors

1. Regulatory change the activity of cellular enzymes 2. Enzymes may be inhibited or activated 3. Transport e.g. Na+ /K+ ATPase 4. Structural these form cell parts

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dose response curves

k1 [D] + [R] k -1 [DR]

effect

at equilibrium:
[D] x [R] x k1 = [DR] x k-1 so that: [DR] = k1

k1/k-1 = affinity const. k-1/k1 = dissociation const.(kd)

[D] [R]

k-1

the lower the kd the more potent the drug

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Drug - Receptor Binding

D+R
Affinity

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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Drug Receptor Interaction

DR Complex

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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Isolated Muscle Contraction Drug-receptor interaction Arithmetic Scale

100

Percent Maximum

Drug + Free Receptor 75 D (100 - DR)

50

k1

k-1

Drug-receptor Complex DR

Where:

D = drug concentration
DR=
0 concentration 0.00 0.25of

25

drug-receptor complex 0.50 0.75 1.00

100 DR = free receptor concentration 2004-2005

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

k-1/k1 = dissociation constant (kd)

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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)

What can we learn?

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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dose response curves-2

effect = [DR] = Emax * [D]/([D]+EC50) % occupancy

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Concept: spare receptors

Arithmetic Dose Scale

Rate of change is rapid at first and becomes progressively smaller as the dose is increased Eventually, increments in dose produce no further change in effect i.e., maximal effect for that drug is obtained Difficult to analyze mathematically
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Log Dose Scale

transforms hyperbolic curve to a sigmoid (almost a straight line) compresses dose scale proportionate doses occur at equal intervals straightens line easier to analyze mathematically
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Ethyl Alcohol: Arithmetic vs log Sleep scale of dose

Number Responding

30
% fall in blood pressure

50 40 30 20 10 0 -2 -1
0.1 0.3 Control L-NAME

50

% fall in blood pressure

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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Why are there spare receptors?

allow maximal response without total receptor occupancy increase sensitivity of the system
spare receptors can bind (and internalize) extra ligand preventing an exaggerated response if too much ligand is present The receptor theory assumes that all receptors should be occupied to produce a maximal response. In that case at half maximal effect EC50=kd. Sometimes, full effect is seen at a fractional receptor 2004-2005 occupation

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Agonists and antagonists

agonist has affinity plus intrinsic activity antagonist has affinity but no intrinsic activity partial agonist has affinity and less intrinsic activity competitive antagonists can be overcome

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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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Agonist Dose Response Curves

Full agonist
Partial agonist

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)

heterologous (decreased signal transduction)

antagonists tend to up regulate receptors

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dose response curves-3

quantal dose response curves (used in populations, response is yes/no)

Therapeutic index =Toxic Dose50/Effective Dose50 2004-2005 (TD50/ED50)

DR Curve: Whole Animal

Graded response measured on a continuous scale Quantal response is an either/or event
relates dose and frequency of response in a population of individuals often derived from frequency distribution of doses required to produce a specified effect
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Effectiveness, toxicity, lethality

ED50 - Median Effective Dose 50; the dose at which 50 percent of the population or sample manifests a given effect; used with quantal dr curves TD50 - Median Toxic Dose 50 - dose at which 50 percent of the population manifests a given toxic effect LD50 - Median Toxic Dose 50 - dose which kills 50 percent of the subjects
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Quantification of drug safety

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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The therapeutic index

The higher the TI the better the drug.
TIs vary

from: 1.0 (some cancer drugs)

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.

ion channel linked

(speedy)

3. G protein linked
(amplifier)

4. nuclear (gene) linked

(long lasting)

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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.

Ion channel receptors

Structure:
Protein pores in the plasma membrane

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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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2. Calcium ions Ca2+

2. Calcium Ions (Ca2+) and Inositol Trisphosphate

Calcium more widely used than cAMP

used in neurotransmitters, growth factors, some hormones

Increases in Ca2+ causes many possible responses: Muscle cell contraction Secretion of certain substance Cell division
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Two benefits of a signal-transduction pathway 1. 2. A. Signal amplification Signal specificity

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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