Pharmacodynamics

Dr. Asmah Nasser

Drug DoseAdministration

Drug Effect or Response

Pharmaceutical

Pharmacokinetics

Pharmacodynamics

Pharmacotherapeutics

Disintegrationof Drug

Absorption/distribution

metabolism/excretionDrug/Receptor

Interaction

Introduction

Pharmacodynamics: Study of the biochemical and physiologic effects of drugs and their

mechanisms of action.

Drug actionThe main ways by which drugs act are via

interaction with cell proteins, namely receptors, ion channels, enzymes and transport/carrier proteins.

In addition, drugs can work by themselves mechanically or chemically.

Its useful to know what are the basic principles of drug action.

Principles of Drug actionStimulation: Enhancement of the level of a

specific biological activity (usually already ongoing physiological process). E.g. adrenaline stimulates heart rate.

Depression: Diminution of the level of a specific biological activity (usually already ongoing physiological process). E.g. barbiturate depress the CNS.

Replacement: Replacement of the natural hormones or enzymes (any substance) which are deficient in our body. E.g. insulin for treating diabetes.

Cytotoxic action: Toxic effects on invading micro organisms or cancer cells.

How does all this happen?A drug can produce all the said effects by

virtue of any of the following action1. Through enzymes: a drug can act by either

stimulating or inhibiting an enzymeThrough receptors: this is when a drug

produces its response by attaching itself to a protein called as receptor which in turn regulates the cell function.

Receptor action is the most commonest way of producing action.

Continuation...2. Physical action: The physical property is

responsible for drug action. E.g. radioisotope I131 and other radioisotopes.

3. Chemical action: The drug reacts extracellularly according to simple chemical equations. E.g. antacids neutralising the gastric acid.

4

A deeper look into the receptorThe best-characterized drug receptors are

regulatory proteins, which mediate the actions of endogenous chemical signals such as neurotransmitters and hormones.

This class of receptors mediates the effects of many of the most useful therapeutic agents.

Word “Receptor” is used as a loose term

Other Receptors Other classes of proteins that have been

identified as drug receptors include 1. Enzymes, which may be inhibited (or,

less commonly, activated) by binding a drug (eg, dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate)

2. Transport proteins (eg, Na+/K+ ATPase, the membrane receptor for cardioactive digitalis glycosides)

3. Structural proteins (eg, tubulin)

Agonist & AntagonistWhen a drug binds to a receptor the

following can occur and based on this the drugs are classified.

Agonist: when a drug binds to the receptor and activates it to produce an effect

Antagonist: when a drug binds to a receptor and prevents the action of an agonist, but does not have an action on its own.

Tricky

Other termsInverse agonist: when a drug activates a

receptor to produce an effect in the opposite direction to that of the agonist

Partial agonist: when a drug binds to the receptor and activates it but produces a submaximal effect (by antagonising the full effect of the agonist)

Agonist & Inverse Agonist

Affinity & Intrinsic activityAffinity: It is the ability of a drug to bind to

the receptor (just bind)Intrinsic activity: It is the ability of a drug to

activate a receptor following receptor occupation.

AgonistAgonists are the chemicals that interact

with a receptor, thereby initiate a chemical reaction in the cell and produces effect .

Example—ACh is agonist at muscarinic receptor in heart cell.

Will have both Affinity and maximal Intrinsic activity

So, what is a receptor “agonist”?

Any drug that binds to a receptor and stimulates the functional activities

e.g.: Ach

Receptor

Acetylcholine

A Cell

Some Effect

AntagonistA drug that binds to the receptor and

blocks the effect of an agonist for that receptor

Atropine is antagonist of ACh at Muscarinic receptors.

Will have only Affinity but no Intrinsic activity

So, what is a receptor “antagonist”?Any drug that prevents the binding of

an agonisteg: Atropine (an anticholinergic drug)

Acetylcholine

AtropineDude, you’rein my way!

Inverse agonist

Inverse Agonists are the chemicals that interact with a receptor, but produces opposite effect of the well recognized agonist for that receptor

Will have Affinity and negative Intrinsic activity

Example: Flumazenil is an inverse agonist of Benzodiazepine

Inverse agonist

Any drug that binds to a receptor and produces an opposite effect as that of an agonist

Receptor

Inverse agonist

A Cell

Effect opposite to that of the true agonist

Partial agonistPartial agonist activates receptor to

produce an effect. Less response than a full agonist .

Partial agonist blocks the agonist action.

Will have Affinity but sub maximal Intrinsic activity

Partial agonistProduces a submaximal response

True agonist

Partial agonistOh!!!, I shouldHave been here

Submaximal effect

Types of ReceptorsAre they specific?

usually, but not always

Are there subtypes?sometimes …example:

there are several types of epinephrine receptors

1 Receptors in Heart

2 Receptors in Bronchioles

Epinephrine

A ProblemEpinephrine is a non-specific drug: it is an

agonist for BOTH 1 and 2 receptors

Why might this be a problem for someone with asthma and hypertension?

A SolutionMore specific agonists have been developed:

eg: terbutaline is a more specific 2 agonist that is used for treating people with asthma

Major Concepts

Drugs often work by binding to a “receptor”

Receptors are found in the cell membrane, in the cytoplasm, and in the nucleus

Anything that binds to a receptor is a “ligand”

Drug-Receptor interactionIn most cases, a drug (D) binds to a receptor (R)

in a reversible bimolecular reaction

Antagonists can bind to the receptor and occupy its binding site and, therefore, participate only in the first equilibrium.

Agonists, on the other hand, have the appropriate structural features to force the bound receptor into an active conformation (DR*).

This conformational change leads to a series of events causing a cellular response.

Assessment of Receptor Occupation Measure of Affinity

kd is a relative measure of affinity of a drug for its receptor.

It varies inversely with the affinity of the drug for its receptor

High-affinity drugs have lower kd values and occupy a greater number of drug receptors than drugs with lower affinities.

Drug-receptor interactionGenerally the intensity of response

increases with doseThe drug receptor interaction obeys the

law of mass action Emax X [D] KD+[D]E=

Law of mass actionE is observed effect at dose [D] of a drugEmax is the maximal responseKD is the dissociation constant of a drug

receptor complexKD is usually equal to the dose of a drug at

which half maximal response is produced

Classification of receptorsG-protein coupled receptorsIon channelsEnzymatic receptorsIntracellular receptors (regulates gene

expression)

Ion channelsThe cell surface enclose ion channels specific

for Ca2+, K+, or Na+

These ion channels are controlled by the receptors

E.g. Gs opens Ca2+ channels in the myocardium and skeletal muscle and Gi opens the K+ channels in heart

Some receptors also modulate the ion channels without the intervention of coupling proteins or 2nd messengers

E.g. benzodiazepines modulating Cl- channels in the brain

Ion channels

Dose Vs Response

Increases in response until it reaches maximum, Later it remains constant despite increase in dose .. Plateau effect

DOSE RESPONSE CURVE

DOSE of drug

% o

f Res

pons

e After this point increase in dose doesn’t increase the response

Log dose response curveThe dose response

curve is a rectangular hyperbola

If the doses are plotted on a logarithmic scale, the curve becomes sigmoid

A linear relationship between log of dose and the response can be seen

Efficacy and PotencyEfficacy is the maximal response

produced by a drugIt depends on the number of drug-

receptor complexes formed Potency is a measure of how much drug is

required to elicit a given responseThe lower the dose required to elicit given

response, the more potent the drug is

ED50

It is the dose of the drug at which it gives 50% of the maximal response

A drug with low ED50 is more potent than a drug with larger ED50

Log drug concentration

% o

f res

pons

e

100%

50%

0%10mg 20mg 30mg 40mg 50mg

75%

25%

200mg

Potency of Drug A >Drug B > Drug CA B C

Efficacy and Potency

C

Potency 

Dose of a drug that required to produce 50% of maximal effect (ED 50)

Relative Positions of the DRC on x-axis

More left the DRC, more potent the drug

Efficacy 

Maximum effect of the drug

Height of the curve  on x-axis indicates the

efficacy of the drugTaller the DRC ,more

efficacious the drug

Probing question A 55-year-old woman with congestive heart

failure is to be treated with a diuretic drug. Drugs X and Y have the same mechanism of diuretic action. Drug X in a dose of 5 mg produces the same magnitude of diuresis as 500 mg of drug Y. This suggests that

Drug Y is less efficacious than drug X Drug X is about 100 times more potent than drug Y Toxicity of drug X is less than that of drug Y Drug X is a safer drug than drug Y Drug X will have a shorter duration of action than

drug Y because less of drug X is present for a given effect

Slope of DRCThe slope of midportion of the DRC varies

from drug to drugA steep slope indicates small increase in dose

produces a large change in response

Drug Dose

Fall

in B

P

Hydralazine.. steep

Thiazides.. Flat

SLOPE STEEP DRC

Moderate increase in dose leads to more increase in response

Dose needs individualization for different patients

Unwanted and Uncommon

FLAT DRCModerate increase in

dose leads to little increase in response

Dose needs no individualization for different patients

Desired and Common

Quantal dose response curvesThe quantal dose-effect curve is often

characterized by stating the median effective dose (ED50), the dose at which 50% of individuals exhibit the specified quantal effect.

Similarly, the dose required to produce a particular toxic effect in 50% of animals is called the median toxic dose (TD50) If the toxic effect is death of the animal, a median lethal dose (LD50) may be experimentally defined

Quantal dose-effect curves are used to generate information regarding the margin of safety (Therapeutic index)

Quantal DRC

Therapeutic index

Therapeutic index (TI)Lethal dose (LD50) is estimated only in

preclinical animal studies LD50 is not calculated in humans-OFCOURSESo we use the term “safety margin” of a drug

or “therapeutic window”

Therapeutic windowIt is a more clinically relevant index of

safetyIt describes the dosage range between the

minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose

E.g. theophylline has an average minimum plasma conc of 8 mg/L and the toxic effects are observed at 18 mg/L

The therapeutic window is 8 – 18 mg/L

Therapeutic range

EFFE

CT

Toxic effect

Therapeutic effect

8 mg/L 18mg/L8-18mg/L

Min

imum

ther

apeu

tic e

ffect

Min

imum

tole

rabl

e ad

vers

e ef

fect

Clinical significanceDrugs with a low TI should be used with

caution and needs a periodic monitoring (less safe)

E.g. warfarin, digoxin, theophyllineDrugs with a large TI can be used

relatively safely and does not need close monitoring (highly safe)

E.g. penicillin, paracetamolOther terms used: wide safety margin,

narrow safety margin

Synergism and antagonism When two drugs are given together or in

quick succession 3 things can happen:1. Nothing (indifferent to each other)2. Action of one drug is facilitated by the

other (synergism)3. Action of one drug may decrease or inhibit

the action of other drug (antagonism)

Synergism Two types:1. Additive effect: the effect of two drugs

are in the same direction and simply add up.

Effect of drug A + B = effect of drug A and B

2. Supraadditive effect (potentiation): the effect of combination is greater than the individual effect of the components.

Effect of drug A + B > effect of drug A + effect of drug B

Antagonism Different types of antagonism1. Physical: based on physical property of a

drug. E.g. activated charcoal adsorbs alkaloids

and prevents their absorption (in alkaloid poisoning)

2. Chemical: based on chemical properties resulting in an inactive product.

E.g. chelating agents complex metals (used in heavy metal poisoning)

Contd..3. Physiological antagonism: two drugs act

on different receptors or by different mechanisms, but have opposite effects

E.g. histamine and adrenaline on bronchial smooth muscle and BP

E.g. several catabolic actions of the glucocorticoid hormones lead to increased blood sugar, an effect that is physiologically opposed by insulin.

4. Receptor antagonism

Receptor antagonismThis when an antagonist interferes with

the binding of the agonist with its receptor and inhibits the generation of a response

Receptor antagonism is specificE.g. an anticholinergic will decrease the

spasm of intestine induced by cholinergic agonists but not the one induced by histamine

Receptor antagonism can be competitive and noncompetitive

Competitive antagonismCompetitive ---

Surmountable Competes with agonist

in reversible fashion for same receptor site

Necessary to have higher concentration of agonist to achieve same response

Competitive agonist

Noncompetitive antagonismNoncompetitve ---

Insurmountable Antagonist binds to

a site different to that of an agonist

No matter how much agonist -- antagonism cannot be overcome

COMPETITIVE Antagonist binds with

same receptorChemical resemblance

with agonist Parallel rightward

shift of DRCApparently reduces

potency of agonistIntensity of response

depends both on antagonist and agonist concentration

Eg: Acetylcholine and Atropine

NONCOMPETITIVE Another site of receptor

bindingDoes not resemble Flattening of DRC

Apparently reduces efficacy of agonist

Intensity of response depends mainly on antagonist concentration

Eg: phenoxybenzamine (for pheochromocytoma)

Receptor Numbers and ResponsesThe NUMBER and AFFINITY of receptors

may changeAn increase in receptor number is called

UPREGULATIONA decrease in receptor number is called

DOWNREGULATION

Upregulation of ReceptorsUpregulation: An increase

in the number of receptors on the surface of target cells, making the cells more sensitive to a hormone or another agent.

For example, there is an increase in uterine oxytocin receptors in the third trimester of pregnancy, promoting the contraction of the smooth muscle of the uterus

Downregulation of ReceptorsEg: Downregulation:

prolonged use of propranolol can DECREASE the number of 1 receptors

Prolonged & frequent use of short acting 2 receptor agonists decrease the number of 2 receptors

Clinical relevance:A patient’s response to drug

therapy may change over time

Rats!Where did they

all go?!?

Tolerance Gradual reduction in response to drugs

is called as tolerance Requirement of higher dose to produce a

given response It occurs over a period of time E.g. tolerance to sedative-hypnotics Many reasons for tolerance1. Pharmacokinetic reasons-chronic use

leads to enhanced clearance-less effective concentration

2. Pharmacodynamic reasons (reduced number and/or affinity of the receptors to the drugs)-downregulation

TachyphylaxisRapid desensitization

to a drug produced by inoculation with a series of small frequent doses.

A rapidly decreasing response to a drug following its initial administration

E.g. ephedrine, tyramine, nicotine.

Spare receptorsIn some cases, the response elicited by a

drug is proportional to the fraction of receptors occupied

More commonly, a maximal response can be achieved when only a small fraction of receptors are occupied by an agonist

Receptors are said to be spare when maximal response can be elicited by an agonist at a conc. that does not result in occupancy of the full complement of available receptors

No qualitative difference form non spare receptors

Graphical representation of a spare receptor (refer to notes section below for explanation)

Spare receptors, KD and EC50KD is the concentration of the agonist at

which 50% of the receptors are occupiedIf the number of receptors increase many

fold (spare receptors) THEN:A much lower concentration of agonist is

sufficient to produce 50% of maximal response (EC50)

Occupation of spare receptors is determined by comparing the EC50 with Kd

If EC50 is less than Kd, spare receptors are said to exist

Factors affecting Drug ActionIt is a rule rather than an exception that

there is a large variation in the drug response for the same dose in different individuals.

Pharmacokinetic handling of the drug

Number or state of receptors

Variations in neurogenic/hormonal tone

Contd..Body Size/Wt.The average adult dose refers to individuals

of medium builtFor exceptionally obese and lean and for

children the dosage should be calculated based on body wt.

Individual Dose = BW (Kg)/70 x average adult dose

Dosage calculation based on surface area more appropriate for children

Contd..Age Extreme care has to be taken while

administering drugs to children and elderlyDrug metabolizing enzymes are very poor

and in case of elderly they might have some other diseases

Reduced doses are ideal for these age groups.

Contd..GeneticsDeficiency of some enzymes may lead to drug

toxicity because of poor or absence of metabolism

Route of drug administrationIV route has quicker and prominent action

when compared to oral routePsychological role is also a major determinant

of drug effect

Contd..

Pathological statesAny underlying pathology may alter the drug

responseSpecial care is taken if the patient has renal or

hepatic impairment as the drugs are not eliminated and it may lead to severe drug toxicity.

Alzheimer’s disease – memory loss- failure to take medications

Contd..Co-administration of other drugsOne drug may affect the drug action of

others, it may be useful or it may be harmful.

Drug interactions play a very important part of therapeutics.

Diet & environmental factors too play a important role in deciding the drug action.

Things to know In pharmacodynamics you SHOULD know by now:

1. Principles of drug action2. Agonist & its types3. Antagonist and its types (on DRC)4. Spare receptors 5. Affinity-intrinsic activity6. Potency-efficacy (explain with DRC)7. Therapeutic index and its calculation8. Classification of receptors9. G-protein coupled receptors10. Second messenger concept (role of cAMP and

IP3 & DAG)11. Downregulation & upregulation of receptors

Practice Question When tested under identical conditions with all

statistical requirements rigidly applied, drug X has the following parameters: LD50=0.5 mg/Kg

Ed50=0.5 µg/Kg. The therapetic index is1. 0.0012. 0.13. 1.04. 105. 1000

Practice Question In the absence of other drugs, pindolol causes

an increase in heart rate by activating beta adrenoceptors. In the presence of highly effective beta stimulants, however, pindolol causes a dose-dependent, reversible decrease in heart rate. Therefore, pindolol is probably

An irreversible antagonist A physiologic antagonist A chemical antagonist A partial agonist A spare receptor agonist

Practice question

Which line is most efficacious?

Which is more potent?