pharmacodynamics

Law of Mass ActionWhen a drug (D) combines with a receptor (R), it does so at a rate which is dependent on the concentration of the drug and the concentration of the receptor.

D = drugR = receptor, DR = drug-receptor complexk1 = rate for association and k2 = rate for dissociation.KD = Dissociation ConstantKA = Association Constant

k1

[D] + [R] [DR] k2

k2 = KD = [D][R] k1 [DR]

1 = KA = k1 = [DR] KD k2 [D] [R]

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Log [Drug]

Dru

g-R

ecep

tor C

ompl

ex

SATURATION CURVE

[Drug] nM

DR


SATURATION CURVE

[DR]

[Drug] nM

RT = Bmax

RT = Total number of receptors

Bmax = Maximal number of receptors Bound

k2 = KD = [D][R] k1 [DR]

[DR] max


TIME COURSE

[DR]

Equilibrium

KD = Equilibrium Dissociation Constant

k2 = KD = [D][R] k1 [DR]

[D] + [R] = [DR]

0 10 20 30 40 50 60Time (min)


SATURATION CURVE

[Drug] nM

[DR]

KD

At equilibrium, the dissociation constant is KD and the affinity is K A = 1/KD Thus when [D] = KD , half the total number of receptors will be occupied.


Agonists and Antagonists

AGONIST• A drug is said to be an agonist when it binds to a receptor

and causes a response or effect. It has intrinsic activity = 1

+ + + + + -

- - - + - -

- - -

+ + +



ANTAGONIST• A drug is said to be an antagonist when it binds to a

receptor and prevents (blocks or inhibits) a natural compound or a drug to have an effect on the receptor. An antagonist has NO activity.

Its intrinsic activity is = 0


Agonists and AntagonistsPHARMACOLOGICAL ANTAGONISTS

1. CompetitiveThey compete for the binding site

• Reversible• Irreversible

2. Non-competitveBind elsewhere in the receptor (Channel Blockers).



FUNCTIONAL ANTAGONISTS

1. Physiologic Antagonists

2. Chemical Antagonist



Physiologic ANTAGONIST• A drug that binds to a non-related receptor, producing an

effect opposite to that produced by the drug of interest.

• Its intrinsic activity is = 1, but on another receptor.

Glucocorticoid Hormones Blood Sugar

Insulin Blood Sugar


Agonists and AntagonistsChemical ANTAGONIST• A chelator (sequester) of similar agent that interacts

directly with the drug being antagonized to remove it or prevent it from binding its receptor.

• A chemical antagonist does not depend on interaction with the agonist’s receptor (although such interaction may occur).

Heparin, an anticoagulant, acidic

If there is too much bleeding and haemorrhaging

Protamine sulfate is a base. It forms a stable inactive complex with heparin and inactivates it.www.freelivedoctor.com

Competition Binding

Log [I] nM

IC50

Binding of Drug D I = Competitorwww.freelivedoctor.com

Competition Binding

RANK ORDER OF POTENCY: A > B > C > D

Log [I] nM

IC50

A B C D

Four drugs


Drug Concentration

Res

pons

e

SEMILOG DOSE-RESPONSE CURVE

Effec

t or


Drug Concentration

Res

pons

e


ED50

50% Effect

Maximal EffectEff

ect o

r


SEMILOG DOSE-RESPONSE CURVEEF

FECT

POTENCYEFFICACY

ED50

Maximal Effect

Log [Dose]



RANK ORDER OF POTENCY: A > B > C > D

A B C D

EFFE

CT

Log [Dose]



RANK ORDER OF POTENCY: A > B > C > DRANK ORDER OF EFFICACY: A = C > B > D

A

B

C

D

RESP

ON

SE

ED50



PARTIAL AGONIST• A drug is said to be a partial agonist when it binds

to a receptor and causes a partial response.• It has intrinsic activity < 1.


Agonists and Antagonists1. COMPETITIVE ANTAGONIST

Reversible & SurmountableThe effect of a reversible antagonist can be overcome by more drug (agonist). A small dose of the antagonist (inhibitor) will compete with afraction of the receptors thus, the higher the concentration of antagonist used, the more drug you need to get the same effect. www.freelivedoctor.com


RECEPTOR RESERVE OR SPARE RECEPTORS.• Maximal effect does not require occupation of all

receptors by agonist.• Low concentrations of competitive irreversible

antagonists may bind to receptors and a maximal response can still be achieved.

• The actual number of receptors may exceed the number of effector molecules available.


Agonists and Antagonists1. COMPETITIVE ANTAGONIST

Irreversible & Non-surmountableThe effect of irreversible antagonists cannot be overcome by more drug (agonist). The antagonist inactivates the receptors.


Drug Concentration

LINEWEAVER-BURKE PLOT

1

1

KD

1

Effect

1Bmax

KD

Bmax

1

[D]


Agonists and AntagonistsSynergismThe combined effect of two drugs is

higher than the sum of their individual effects.

AdditivityThe combined effect of two drugs is equal

to the sum of their individual effects.www.freelivedoctor.com

Quantal Dose-response Curves

Frequency of distribution % population responding to drug A

1 10 20 30 40 50 60 70 80 90 100

Dose (mg/kg)

% p

opul

atio

n re

spon

ding


Quantal Dose-response Curves

Cumulative distribution of population responding to drug A

1 10 100

Dose (mg/kg) log scale

% p

opul

atio

n re

spon

ding

ED50ED90ED10


Therapeutic IndexToxi c eff

ect


Therapeutic indexTherapeutic Index = TxD50 ED50As long as the slopes of the curves are similar, however,

if not similar, we use the Standard Margin of safety:

Standard Margin of safety = TxD1–1 x 100 ED99

Which determines the percent to which the dose effective in 99% of the population must be raised to cause toxicity in 1% of the population.


Therapeutic IndexToxi c eff

ect

ED99

ED13ED1


APPENDIX


Law of Mass ActionWhen a drug (D) combines with a receptor (R), it does so at a rate which is dependent on the concentration of the drug and the concentration of the receptor.

k1

[D] + [R] [DR] (1) k2

D = drugR = receptor, DR = drug-receptor complexk1 = rate for association and

k2 = rate for dissociation. www.freelivedoctor.com

Law of Mass ActionAt equilibrium, the rate at which the radioligand binds to the receptor is equal to the rate at which it dissociates:

association rate = dissociation rate

k1 [D][R] = k2 [DR] (2) k2 = [D][R] k1 [DR] (3)

k2 = KD = [D][R] k1 [DR] (4)

Where KD is the equilibrium dissociation constant. The units for the KD are concentration units (e.g. nM). www.freelivedoctor.com

Law of Mass ActionAnother constant related to the KD is the affinity (KA) which is essentially equivalent to the reciprocal of the KD. The units for the KA are inverse concentration units (e.g. nM-1).

1 = KA = k1 = [DR] KD k2 [D] [R] (5)

The relationship between the binding of a drug to a receptor at equilibrium and the free concentration of the drug provides the basis for characterizing the affinity of the drug for the receptor. The mathematical derivation of this relationship is given below:

KD = [D][R] [DR] (6) KD [DR] = [D][R] (7)


Law of Mass ActionSubstitutions:

[RT] = [R] = [DR] … [R] = [RT] - [DR] (8) KD[DR] = [D]([RT] - [DR]) (9) KD[DR] = [D][RT] - [D][DR] (10) KD[DR] + [D][DR] = [D][RT] (11) [DR](KD + [D]) = [D][RT] (12)

[DR] = [D][RT] (13) [D] + KD

RT: Total number of receptorswww.freelivedoctor.com

Law of Mass Action [DR] = [D][RT] (13) [D] + KD

This relationship between specific binding [DR] and the free drug concentration [D] in (13) is essentially the same as the relationship between the substrate concentration ([S]) and the velocity of an enzymatic reaction (v) as described by the Michaelis-Menten relationship:

v = [S] Vmax

[S] + KM

Michaelis-Menten Relationship where Vmax denotes the maximum rate of the reaction and KM denotes the Michaelis constant, which is equivalent to the concentration of substrate required for half-maximal velocity


pharmacodynamics

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