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

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Module 2 1 pharmacodynamics l.jpg

Module 2# 1Pharmacodynamics

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, dose-response phenomena, and mechanisms of therapeutic and toxic action.


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2

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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3

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

  • Regulatory – change the activity of cellular enzymes

  • Enzymes – may be inhibited or activated

  • Transport – e.g. Na+ /K+ ATP’ase

  • Structural – these form cell parts


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5

dose response curves

k 1

[D] + [R] [DR] effect

k -1

k1/k-1 = affinity const.

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

at equilibrium:

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

so that: [DR] = k1

[D] [R] k-1

the lower the kd the more potent the drug


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Drug - Receptor Binding

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

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

Effect

DR Complex


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Drug-receptor interaction

k1

Drug + Free Receptor

Drug-receptor Complex

D

(100 - DR)

DR

k-1

Where:

D = drug concentration

DR= concentration of drug-receptor complex

100 - DR = free receptor concentration


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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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  • 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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% occupancy

6

dose response curves-2

effect = [DR] = Emax* [D]/([D]+EC50)

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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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

Potency


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Relative Potency axis

hydromorphone

morphine

codeine

Analgesia

aspirin

Dose


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7 axis

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 occupation


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10 axis

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 axis

  • 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 axis

Full agonist

Partial agonist

Response

Dose


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Antagonist Drug axis

  • 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 axis

  • 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 axis

  • 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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11 axis

Desensitization

  • agonists tend to desensitize receptors

    • homologous (decreased receptor number)

    • heterologous (decreased signal transduction)

  • antagonists tend to up regulate receptors


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8 axis

doseresponsecurves-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 axis

  • 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 axis

  • 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 axis

TD50 or LD50

Therapeutic Index =

ED50


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Drug A axis

100

sleep

death

Percent

Responding

50

0

ED50

LD50

dose


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Drug B axis

100

sleep

death

Percent

Responding

50

0

ED50

LD50

dose


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9 axis

The therapeutic index

  • The higher theTI 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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  • ion channel linked

    • (speedy)

  • G protein linked

    • (amplifier)

  • nuclear (gene) linked

    • (long lasting)

4

Signal transduction


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  • Structure: axis

  • 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).

1. G protein-linked receptors


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  • 2. Tyrosine-kinase receptors axis

  • 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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Intracellular receptors axis

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 axis

    • 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 (Ca axis2+) 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 axis

  • 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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12 axis

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.