Pharmacodynamics Reviewer

DRUG RECEPTORS AND PHARMACODYNAMICS

Pharmacodynamics Actions/effects of the drug on the body Determines the group in which the drug is

classified and plays a major role in deciding whether a group is appropriate therapy for particular symptom or disease

Receptors Specific molecules in a biologic system

with which drugs interact to produce changes in the function of the system

Determine the quantitative relations between dose or concentration of drug and pharmacologic effects

Selective in choosing a drug molecule to bind to avoid constant activation by promiscuous binding of many different molecules

Changes its function upon bidning in such a way that the function of the biologic system is altered in order to have pharmacologic effect

Selectiv in ligand-binding characteristics (respond to proper chemical signals and not to meaningless ones)

Mediate the actions of both pharmacologic agonists and antagonists

Majority are proteins which provide the necessary diversity and specificity of shape and electrical charge

Interaction between the drug and the receptor is the fundamental event that initiates the action of a drug

Receptor Site/Recognition Site - Specific binding region of the

macromolecule- High and selective affinity to the drug

molecule Classification of Receptors

A. Regulatory Protein- Best characterized drug receptors- Mediates the action of endogenous

chemical signals like neurotransmitters, autacoids and hormones

- Mediates the effects of the most useful therapeutic agents

B. Enzymes- Inhibited (or less commonly, activated) by

binding a drug- Eg, dihydrofolate reductase, the receptor

for methotrexate C. Transport Proteins- Eg, Na+/K+ ATPase, the membrane

receptor for digitalis

D. Structural Proteins- Eg, tubulin, the receptor for colchicine, an

anti-inflammatory drugEffectors

Molecules that translate the drug-receptor interaction into a change in cellular activity

Eg, adenyl cyclase Some receptors are also effectors A single molecule may incorporate both

the drug binding site and the effector mechanism

Drug Concentration and ResponseGraded Dose-Response Curve

Response of a particular receptor-effector system is measured against increasing concentration of a drug

Graph of the response versus the drug dose

Sigmoid curve Efficacy (Emax) and potency (EC50) are

derived from this curve The smaller the EC50, the greater the

potency of the drugEmax

Maximal response that can be produced by a drug

All receptors are occupied No response even if the dose is increased

EC50 Concentration of drug that produces 50%

of maximal effect Smaller EC50 – more potent

Bmax Total number of receptor sites All receptors have been occupied

Kd Equilibrium dissociation constant Concentration of drug required to bind

50% of the receptors


Measure of the affinity of a drug for its binding site on the receptor

Smaller Kd – greater affinity of drug to receptor

Curve A Agonist Response in the absence of

antagonistCurve B

After treatment with low concentration of antagonist, the curve is shifted to the right

Maximal response is preserved because the remaining available receptors are still in excess

Curve C Produced after larger concentration of

antagonist, the available receptors are no longer “spare”, sufficient enough to mediate an undiminished maximal response

Curve D and E With higher concentrations of antagonist,

reduce the number of available receptors to the point that maximal response is diminished

EC50 may approximate the Kd that characterizes the binding affinity of the agonist for the receptor

Coupling Transduction process between the

occupancy of receptors and production of specific effect

Highly efficient coupling can be elicited by a full agonist and spare receptors

Spare Receptors Maximal drug response is obtained at less

than maximal occupation of the receptors Not qualitatively different from nonspare

receptors, not hidden or unavailable Temporal in character, when occupied,

they can be coupled to respond, there is still effect

Drugs with low binding affinity for receptors will be able to produce full response even at low concentration

Compare concentration for 50% of maximal effect (EC50 with concentration for 50% maximal binding Kd)

Kd > EC50 with spare receptors Effect of the drug-receptor interaction may

persist for a longer time than the interaction itself

Actual number of receptors may exceed the number of effectors available

Inert Binding Sites Non-regulatory molecules of the body Binding with these molecules will result to

no detectable change in the function of the biologic system

Buffers the concentration of the drug Bound drugs do not contribute directly to

the concentration gradient that drives diffusion

Eg, albuminAgonist

Binds to the receptor and directly or indirectly bring about an effect

Full activation of the effector system Partial Agonist

Produces less than the full effect, even when it has saturated the receptors

Acts as an inhibitor in the presence of a full agonist

Antagonist Binds but do not activate the receptors Blocks or competes with agonist

Classification of AntagonistA. Competitive Antagonist


- Competes with agonist receptor- Binds to the receptor reversibly without

activating the effector system - Antagonist increases the agonist

concentration needed for a given degree of response

- Concentration-effect curve is shifted to higher doses (eg, horizontally to the right of the dose axis)

- Same maximal effect is reached - Effects are overcome by adding more

agonist- Increases the median effective dose

(ED50)

- 2 Therapeutic Implications 1) Degree of inhibition produced by

the competitive antagonist depends on the concentration of antagonist (eg, propanolol)

2) Clinical response to a competitive antagonist depends on the concentration of agonist that is competing for binding to the receptor

B. Irreversible Antagonist- Binds with the receptor via covalent bonds- Antagonist’s affinity to the receptor maybe

so high- Receptor is not available to bind the

agonist- Concentration-effect curve moves

downward - No shift of the cruve in the dose axis- Emax is not reached- No increase in median effective dose

(ED50) unless there are spare receptors - Duration of action is relatively independent

of its own rate of elimination- More dependent on the rate of turnover of

receptors

- Eg, phenoxybenzamine binding with alpha

receptors

C. Chemical Antagonist- Does not depend on interaction with the

agonist’s receptor- Drug that interacts directly with the drug

being antagonized to remove it or to prevent it from reaching its target

- Eg, protamine used to counteract the effect of heparin making it unavailable for interaction with proteins involved in the formation of blood

D. Physiologic Antagonist - Makes use of the regulatory pathway- Effects that are less specific and less easy

to control- Binds to a different receptor producing an

effect opposite to that produced by the drug it is antagonizing

- Examples o Glucocorticoids catabolic effects of

increase in sugar is physiologically opposed by insulin

o Histamine causes bronchoconstriction in asthmatic patients, opposed by bronchodilators like salbutamol and epinephrine

Signalling MechanismsA. Lipid soluble drugB. Transmembrane receptor-protein

intracellular enzymatic activity is regulated by a ligand that binds to the protein’s extracellular domain

C. Transmembrane receptor that binds and stimulates a protein tyrosine kinase (eg, insulin)

D. Ligand-gated transmembrane ion channel which regulates the opening of the ion


channel (eg, GABA, excitatory acetylcholine)

E. Transmembrane receptor is coupled with an effector enzyme by G protein which modulates production of an intracellular second messenger (eg, cathecolamine (epinephrine))

Intracellular 2nd MessengersA. cAMP- Mediates hormonal responses

o Mobilization of stored energy (breakdown of carbohydrates in the liver stimulated by cathecolamines)

o Conservation of water by the kidneys mediated by vasopressin

o Calcium homeostasis by parathyroid hormone

o Heart rate and contraction by beta-adrenomimetic cathecolamines

B. Calcium and Phosphoinositides - Bind to receptors linked to G proteins

while others bind to receptor tyrosine kinases

- Crucial step is the stimulation of membrane enzyme phospholipase C

C. cGMP- Few signalling roles in a few cell types like

the intestinal mucosa and vascular smooth muscle cells

- Causes relaxation of vascular smooth muscles by a kinase-mediated mechanism

Receptor Desensitization Response gradually diminishes even if the

drug is still there (after reaching an initial high level of response)

Reason is not known Structure Activity Relationship

Cells use more than one signalling mechanism to respond to the drug

Quantal Dose-Response Curve Graph of the fraction of a population that

shows a specified response to increasing doses of a drug

Minimum dose required to produce a specific response is determined in each member of the population

Sigmoid curve ED50

Median effective dose 50% of the individuals manifested the

desired therapeutic effect TD50

Median toxic dose

50% of the individuals manifested the toxic effects

LD50 Median lethal dose

Therapeutic Index Ratio of the TD50 (or LD50) to the ED50

determined from the quantal dose-response curves

Increased therapeutic index – wide margin of safety

Represents an estimate of the safety of the drug

A very safe drug might be expected to have a very large toxic dose and a much smaller effective dose

o Eg, ED50 of 3 mg and the LD50 is 150 mg

o Therapeutic index is 50 (150/3) Therapeutic Window

Dosage range between the minimum effective therapeutic concentration or dose (MEC) and the minimum toxic concentration or dose (MTC)

More clinically relevant index of safety Eg, theophylline

o MEC = 7-10 mg/L (average of 8 mg/L)

o MTC = 15-20 mg/L (average of 18 mg/L)

o Therapeutic window = 8-18 mg/LMaximal Efficacy

Maximal effect (Emax) an agonist can produce if the dose is taken to very high levels

Determined mainly by the nature of receptors and its associated effectors

Measured with a graded dose-reponse curve but not with quantal dose-response curve

Potency Amount of drug needed to produce a given

effect In the graded dose-response curve, the

effect chosen is the 50% of the maximal effect and the dose is (EC50)

In the quantal dose-response curve, ED50, TD50, and LD50 are variables in 50% of the population

Drug B is the most potent


Drugs A, C, and D have equal maximal efficacy and greater maximal efficacy than Drug B

Variation of Reponses in IndividualsA. Idiosyncratic Response- Caused by differences in metabolism

(genetic) or immunologic mechanisms- Response to the drug is unknown or

unusual B. Hyporeactive Response - Intensity of the drug is decreased- Large dose of the drug is needed to have

an effect C. Hypereactive Response - Intensity of the drug is increased or

exaggerated D. Tolerance- Decreased sensitivity acquired as a result

of exposure to the drug E. Tachyphylaxis - Tolerance develops after a few doses

Variations in Drug Responsiveness 1. Alteration on the concentration of the drug

that reaches the receptor due to absorption, distribution and elimination differences

2. Variation in the concentration of the endogenous ligands (chemicals produced by the body that binds to receptors, eg, cathecolamines)

3. Alterations in number/function of receptors- Down regulation : decrease in # of

receptors- Up regulation : increase in the # of

receptors - Overshoot Phenomenon/Rebound

Hypertension o Drug has been taken for a long

time, then abruptly discontinued

o Eg, propanolol (beta-blocker)o Gradual decrease of taking the

drug by decreasing/tapering the dose

4. Changes in 2nd messengers5. Clinical selectivity - Give the drug that really acts on the

disease- No drug causes a single specific

effect only, they are selective but never specific

- Beneficial and toxic effects may be mediated by the same receptor-effector mechanism

What to Do to Avoid/Circumvent Toxic Effects Give low doses Carefully monitor the patient Employ ancillary procedures Use a safer drug if possible Beneficial and toxic effects are mediated

by identical receptors but in different ways o Heparin

Low doses for prevention of blood clots

Very high doses causes internal bleeding

Monitor PT, PTT and bleeding parameters

o Steroids Give lowest dose possible Give adjunctive drugs Anatomic selectivity (lungs-

by inhalation)o Antihistamines

H1 receptors – H1 blocker H2 receptors – H2 blocker

Documents

Pharmacodynamics Reviewer