2004-2005. module 2 # 1 pharmacodynamics kash desai 966-2723 hsc a120 k.desai@usask.ca

2004-2005

2004-2005

Module 2# 1

Pharmacodynamics

Kash Desai966-2723HSc A120

k.desai@usask.ca

2004-2005

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

The action of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action.

2004-2005

Pharmacodynamics(how drugs work on the body)

many drugs inhibit enzymesEnzymes 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+ ATP’ase 4. Structural – these form cell parts

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dose response curves

[D] + [R] [DR] effect

k 1

k -1

at equilibrium:

[D] x [R] x k1 = [DR] x k-1

so that: [DR] = k1

[D] [R] k-1

k1/k-1 = affinity const.

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

the lower the kd the more potent the drug

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D + R 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

Drug - Receptor Binding

Affinity

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Drug Receptor Interaction

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

DR Complex Effect

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0.00 0.25 0.50 0.75 1.00

Per

cent M

axim

um

0

25

50

75

100

Isolated Muscle Contraction

Arithmetic Scale

Dose (ug/ml)

Where:

D = drug concentration

DR= concentration of drug-receptor complex

100 - DR = free receptor concentration

Drug + Free Receptor Drug-receptor ComplexD (100 - DR)

k1

k-1 DR

Drug-receptor interaction

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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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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

• 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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dose response curves-2

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

% occupancy

Concept: spare receptors

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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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5.28 5.40 5.52 5.64 5.76 5.88 6.00

Num

ber

Res

pondin

g

0

10

20

30

Ethyl Alcohol: Sleep

0.10.31 3 100

10

20

30

40

50

L-NAMEControl

Acetylcholine nmol/kg

% fa

ll in

blo

odpr

essu

re

-2 -1 0 1 20

10

20

30

40

50

L-NAME

Acetylcholine nmol/kg

Control

0.1 0.3 1 3 10

% fa

ll in

blo

od p

ress

ure

Arithmetic vs log scale of dose

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Potency

Relative position of the dose-effect curve along the dose axisHas little clinical significance for a given therapeutic effectA more potent of two drugs is not clinically superiorLow potency is a disadvantage only if the dose is so large that it is awkward to administer

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Analgesia

Dose

hydromorphone

morphine

codeine

aspirin

Relative Potency

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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

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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 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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Response

Dose

Full agonist

Partial agonist

Agonist Dose Response Curves

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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

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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-3quantal dose response curves (used in populations, response

is yes/no)

Therapeutic index =Toxic Dose50/Effective Dose50 (TD50/ED50)

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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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dose

Drug A

sleepdeath

100

50

0ED50 LD50

PercentResponding

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dose

Drug B

sleepdeath

100

50

0ED50 LD50

PercentResponding

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The therapeutic index

The higher the TI the better the drug.

TI’s 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 receptorsStructure:

•Single polypeptide chain threaded back and forth resulting in 7 transmembrane å helices

•There’s 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 å 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

2. Calcium ions Ca2+

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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. Signal amplification

2. Signal specificity

A. 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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