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Home , Agonist, Efficacy, Irreversible antagonist, Partial agonist, Potency (pharmacology), Receptor antagonist

Dynamics Kinetics Dr Lindsey Ferrie [email protected]

MRCPsych and

School of Biomedical Sciences Dynamics What the does to the body

What the body does to the drug Kinetics Lecture Outline - Dynamics

• • Antagonists • Dose response curves • Dose response curves • Affinity • Competitive • • Irreversible (non- • Partial/inverse agonists competitive)

Learning outcomes – Compare the affinity and efficacy of agonists and antagonists on the basis of their dose-response curves.

Drugs act at receptors as either agonists or antagonists

Agonist: • An is a (drug, or ) that combines with receptors to elicit a cellular response e.g. Antagonist • An antagonist is a drug which blocks the response to an agonist e.g. Agonist Antagonist

Receptor Agonist-receptor complex Antagonist- receptor complex Action

Effect Effect Dose-Response Curves

• Concentration – effect curve • Semi-logarithmic plot of agonist concentration against response

100

50

% Response % Response %

10 100 1000 10000 Agonist Concentration [Log] Agonist Concentration DOSE-RESPONSE RELATIONSHIPS

• GRADED • QUANTAL • Response of a particular • Drug doses system • (agonist or antagonist) • isolated tissue, • required to produce a • animal or specified response • patient determined in each • measured against member of a population agonist concentration Which is an example of a quantal dose response curve?

100

100

50

50

100,000 (%) 100,000

tumour expression / expression tumour

Ileum tissue contraction (mV) tissue contraction Ileum

10 100 1000 10000 10 100 1000 10000 Concentration (nM) [Log] Herceptin Concentration (mg/kg) Dose-Response Curves

Emax • Allow estimation of Emax 100 • Allow estimation of concentration or dose

required to produce 50% of

maximal response (EC50 or 50 EC ED50) 50

• Allow efficacy to be Response % determined • Allow to be 10 100 1000 10000 determined [Log] Agonist Concentration

Dose-Response Curves

Two state hypothesis

Occupancy Drug A K+1 β Response (agonist) + R AR AR* K-1 α 1. Affinity 2. Efficacy

• R = rested state • R* = activated state Drug Binding

Total

Total – Non specific = Specific Drug Drug Bound Drug Drug Bound Bmax

Non specific Drug Concentration Drug Concentration

• Saturation is easily measured i.e. maximum number of binding sites (Bmax) • BUT difficult to get a measure of how avidly the drug binds – affinity (KD) What is the KD telling us?

• The KD is a physiochemical constant like Avogadros number.

• The KD is the same for a given receptor and drug combination in any tissue, in any species (as long as the receptor is the same), anywhere in the universe.

• The KD can therefore be used to identify an unknown receptor.

• The KD can be used to quantitatively compare the affinity of different on the same receptor. 1. Affinity

• Agonists (and antagonists) have affinity

• Describes the tendency of the ligand to form a stable complex with the receptor.

• Determined by the number of bonds and the ‘level of fit’ between ligand and receptor.

• Characterised by the equilibrium constant (KA)

Affinity

Occupancy Activation Drug A K+1 β Response (agonist) + R AR AR* K-1 α 1. Affinity

• If we assume a direct relationship between receptor occupancy and response

• A lower KA indicates a tighter ligand-receptor interaction (higher affinity)

• Agonists with high potency tend to have high affinity

Affinity - examples

A B 100

A = Higher affinity

50 B = Lower affinity

EC50

% Response % A = Higher potency B = Lower potency

10 100 1000 10000

[Log] Agonist Concentration ‘True’ affinity can only be determined by binding-dose relationships Potency

“Potent drugs are those which elicit a response by binding to a critical number of receptors at low concentration (high affinity) compared with other drugs acting on the same system with lower affinity.”

• Potency dependent on: • Receptor density • Efficiency of stimulus-response mechanisms used • Affinity of drug • Efficacy of drug. 2. Efficacy

• When an agonist binds to a receptor, this induces a conformational change that sets off a chain of biochemical events - an ‘action’.

• Efficacy: • describes the ability of an agonist to activate a receptor i.e. to evoke an ‘action’ at the cellular level • is determined by the nature of the receptor-effector system • refers to the maximum effect an agonist can produce regardless of dose Efficacy of Agonists

Occupancy Activation Drug A K+1 β Response (agonist) + R AR AR* K-1 α 2. Efficacy

• Full agonist (high efficacy) - AR* very likely • produce a maximum response while occupying only a small % of receptors available

• (low efficacy) - AR* less likely • unable to produce a maximum response even when occupying all the available receptors

Full and Partial Agonists

• With full agonists, the maximum response produced corresponds to the maximum response that the tissue can give. • A partial agonist is a ligand that combines with receptors to elicit a maximal response which falls short of the maximal response that the system is capable of producing

100

Full agonist

Partial agonist

50

Agonist KA efficacy % Response % (M3) (uM)

carbacol 23 1.0

10 100 1000 10000 McN-A-343 8 0.5 [Log] Agonist Concentration Examples: Partial Agonists

• • receptor partial agonist for smoking cessation. • • – partial agonists at selected receptors. Over simplification!

• Two state model predicts that a receptor can exist in two forms AR and AR* • Increasing evidence suggests receptors can activate in the absence of ligands i.e. R* (constitutive activity) or change state depending on GPCR function. • Ternary complex model (four active states!)

ARG AR*G

AR AR*

RG R*G

R R* Inverse agonists • Have higher affinity for the AR (inactive) state than for AR* (active) state

• Many ‘classical’ competitive antagonists display activity: (H2), pirenzepine (M2), (M)

• ~85% of competitive antagonists are actually inverse agonists (Kenakin, 2004)

Examples;

• β-carbolines on GABAA receptors – anxiogenic rather than

Allosteric Modulators

• acting on a GABAA receptor

GABA Orthosteric GABA BZ binding site allosteric Cl- current BZ

BZ GABA

Cl- Cl- current  Increases KA for GABA  Increase efficacy of GABA Allosteric Modulators

Positive (PAM) Negative (NAM)

• Not active alone but • Not active alone but increase affinity and/or decrease affinity and/or efficacy of endogenous efficacy of agonists

• Examples: • Examples: • • mGluR5 dipraglurant ??? • Propofol • The results shown below were obtained in a comparison of positive ionotropic agents (drugs used in heart failure to increase cardiac contractility). Which statement is correct?

1. Drug A is most effective

2. Drug B is least potent

3. Drug C is most potent

4. Drug B is more potent than Drug C and more effective than Drug A

5. Drug A is more potent than Drug B and more effective than Drug C. Lecture Outline - Dynamics

• Agonists • Antagonists • Dose response curves • Dose response curves • Affinity • Competitive • Efficacy • Irreversible (non- • Partial/inverse agonists competitive)

Learning outcomes – Compare the affinity and efficacy of agonists and antagonists on the basis of their dose-response curves.

General classes of antagonists

 Chemical  Binding of two agents to render active drug, inactive  Commonly called chelating agents  Example - protamine binds (sequesters) heparin.

 Physiological  Two agents with opposite effects cancel each other out.  Example – glucocorticoids and

 Pharmacological  Binds to receptor and blocks the normal action of an agonist on receptor responses

Efficacy and Antagonists

Pure antagonists do not by themselves cause any ‘action’ by binding to the receptor

What effect does this have on efficacy? Occupancy Activation Drug A K+1 β Response (agonist) + R AR AR* K-1 α 1. Affinity 2. Efficacy

 Full agonist (high efficacy) - AR* very likely

 Partial agonist (low efficacy) - AR* less likely

 Antagonist (no efficacy) – AR* does not exist Pharmacological

1. Competitive  Binds and prevents agonist action but can be overcome with increased agonist concentration.  Causes parallel shift to right of the agonist-response curve 2. Irreversible (non-competitive)  Binds and forms irreversible covalent bonds with receptor  Causes parallel shift to right of the agonist-response curve and reduced maximal asymptote. 3. Non-competitive  Signal transduction rather than receptor effects  Downstream responses are blocked (e.g. Ca2+ influx)  Reduces slope and maximum of dose response curve

1. The Competitive Antagonist

 AGONIST (A) + RECEPTOR (R)  AR COMPLEX  ACTION  ANTAGONIST (D) + RECEPTOR (R)  DR COMPLEX  NO ACTION

100

Agonist Agonist + Antagonist

50 % Response %

10 100 1000 10000 [Log] Agonist Concentration In the presence of the competitive antagonist

• Agonist curves have the same form • Agonist curves are displaced to the right • Agonist curves have the same maximal response • The linear portion of the curves are parallel

• This is because the competitive antagonist • binds reversibly with the receptor • gives rise to antagonism which can be overcome by an increased concentration of agonist The dose ratio

• Agonist plus increasing concentrations of competitive antagonist. + Antagonist

100

Agonist Dose Ratio agonist concentration in the presence of an antagonist (x)

50 EC50 agonist concentration (dose) in the absence of antagonist

% Response % (y) x

10 100 1000 10000 y [Log] Concentration Schild Plot for Competitive Antagonist

Schild Equation Schild Plot r -1 = [B]

Kb 1)

- Log Kb

(r

• r = dose ratio Log • B = antagonist conc • Kb = antagonist Log antagonist conc [B] (nmol/l) pA2 values

• Describes the activity of a in simple numbers.

• “the negative logarithm of the molar concentration of antagonist required to produce an agonist dose ratio equal to 2”.

pA2 = - log Kb

• Only if relationship is linear and slope of Schild plot = 1 • i.e. only if a competitive antagonist. Implications for the clinician

• The extent of antagonist inhibition depends upon the concentration of the competing agonist • Varies in response to normal physical activity as well as disease states.

• The extent of inhibition depends on the antagonist’s concentration. • Inter individual differences in or influence plasma concentrations. 2. The

• AGONIST (A) + RECEPTOR (R)  AR COMPLEX  ACTION • ANTAGONIST (D) + RECEPTOR (R)  DR COMPLEX  NO ACTION

100 Agonist

Agonist + Antagonist

50 % Response %

10 100 1000 10000 [Log] Agonist Concentration In the presence of the irreversible antagonist

• Agonist curves do not have the same form • Agonist curves have a reduced maximal response

• This is because the irreversible antagonist • binds irreversibly with the receptor • gives rise to antagonism which cannot be overcome by an increased concentration of agonist Irreversible Competitive Antagonism

+ Antagonist 100

Agonist

• Increased EC50

EC50 50 • Duration of effect is related to receptor

turnover. % Response % EC50 • Receptor reserves allow parallel shift to EC50 right. 10 100 1000 10000 [Log] Concentration Weak partial agonists are similar to irreversible antagonists!

10 10

0 Full Agonist 0 Full Agonist

50 Partial Agonist 50 Agonist +

Antagonist

% Response % % Response %

10 100 1000 10000 10 100 1000 10000 [Log] Concentration [Log] Concentration Competitive vs. Irreversible Antagonists

Competitive Irreversible • common type of • much less common antagonism type of antagonism

• examples include: • examples include:

• cimetidine at the H2 • at receptor the a1 adrenoceptor • at the oestrogen receptor

3. The Non-Competitive Antagonist

+ Antagonist 100

Agonist • Blocks signal transduction EC50 50 events. • E.g.

% Response % bocks Ca2+ influx EC50 • Reduces slope EC50 and maximal 10 100 1000 10000 effect. [Log] Concentration Therapeutic Window/Index (TI)

Risk:benefit ratio (TI) = TD50 or LD50 ED50 ED50

Small TI e.g. Warfarin Large TI e.g Penicillin 10 10

0 0

50 Unwanted 50 Desired adverse Desired

Unwanted % patients % % patients % therapeutic effect therapeutic effect effect

10 100 1000 10000 10 100 1000 10000 [Log] drug plasma concentration [Log] drug plasma concentration Summary - dynamics

You should now be able to: • Explain the differences in format of a dose response curve (graded vs. quantal) • Explain the two state hypothesis of agonist- receptor interactions. • Describe the difference between the affinity, efficacy and potency of an agonist. • Explain the differences between full, partial and inverse agonists. Summary - dynamics

You should now be able to:

• Explain the three general classes of antagonism • Define the effect of a competitive, irreversible competitive and non-competitive antagonist on an agonist dose response curve. • Appreciate how we quantify antagonism using the schild equation and schild plot. • Explain how the risk/benefit ratio is determined with the therapeutic window.