Topic 2.3-2.4: Neuromuscular - Drug agonists and antagonists

Pharmacological principles - meaning

what drugs do to the body, the mechanisms of action and dose-response relationship

Pharmacokinetics - def

what body does to drug

factors affecting ligand binding - summary list (3)

1. receptor ligand concentration

2. occupation → governed by affinity and receptor occupancy

3. action → governed by efficacy

ligand affinity - def

measure of attraction of a ligand for a biological target

high affinity ligands bind to target rapidly and for longer

ligand affinity - equilibrium constant

receptor occupancy and Law of Mass Action

rate of reaction is proportional to the concentration of its reactants

at equilibrium: forward rate = backwards rate and K_A = k-1/k+1

fractional receptor occupancy: [AR]/[R]_t = [A]/(K_A+[A]) 

• when [A] = K_A, fractional receptor occupancy is 0.5

ligand efficacy - def (3)

likelihood/ tendency of bound ligand to activate a receptor

Depends on ability of agonist to induce receptor activation (intrinsic efficacy) + stimulus-response coupling from receptor activation to tissue response

Drug with zero efficacy = no ability to activate a receptor -> antagonist

receptor binbindingdign and receptor activation

binding ≠ activation

Eg. antagonists bind to receptor and prevent activation of downstream signalling

dose-response relationship

Dose determines the benefits and harms of a drug

limitation of drug concentration-effect cruves

cannot be used to measure the affinity of agonists -> response is not directly proportional to receptor occupancy

dose-response relationship - E_max

maximal response drug can produce -> can differ for the same agonist in different tissues due to receptor density and or coupling

Intrinsic efficacy = drug-dependent component of efficacy

potency - meaning

drug concentration required to elicit a given effect -> typically 50% of max effect (EC₅₀)

Partial agonist can have higher, equal to lower potency compared to full agonist

receptor reserve - meaing

system has spare receptors

receptor reserve - full vs partial agonists

full agonists: receptor pool is larger than needed for full response -> system has receptor reserve

partial agonists: all receptors occupied -> system has no receptor reserve

desensitization vs tolerance

Effect of drug can gradually diminish upon continuous or repeated administration

Desensitization (tachyphylaxis) = minutes or less

Tolerance = hours to days or weeks

causes of desensitization/ tolerance - list (4)

• Receptor internalisation

• Change in receptor expression

• Exhaustion of mediators

• Physiological adaptation

features of good therapeutic agonists (2)

Often high affinity/ potency/ efficacy but not alway→ eg sometimes partial agonists are preferred over full agonists

High selectivity to prevent adverse side effects -> affinity at target receptor vs non-target receptors

features of good therapeutic agonists - examples of partial agonists preferred (3)

• Salbutamol (ß2-adrenoreceptors) to treat asthma -> no desensitisation of target receptors

• Sumatriptan (5-HT1A receptors) to treat asthma -> no heart attacks as effective vasoconstriction of coronary arteries is less likely

• Buprenorphine (μ-opioid receptors) to treat pain -> less euphoric and addictive effects

antagonist - def

molecule that interferes with interaction of an agonist and a receptor protein or a molecule that blocks constitutive elevated basal response of a physiological system

types of antagonists - branch diagram (6)

• receptor or non-receptor antagonists

• receptor antagonists can bind to orthosteric or allosteric site and be reversible or irreversible

• non-receptor antagonists can be chemical or functional

reversible competitive antagonists - summary (6)

1. most common and most important type of antagonism in lab and clinic -> high potency and selectivity can be achieved

2. Binds to agonist binding site (orthosteric site) without activating receptor and prevents agonist from binding to that site

3. Does not stay bound to receptor -> dissociates and rebounds continuously

4. Addition of competitive antagonist shifts effect v agonist concentration curve to the right -> apparent potency of agonist is reduced 

5. Antagonism can be overcome with enough agonist -> surmountable

6. Antagonism quantified by K_{B ->} sometimes K_D

reversible competitive antagonists - example

naloxone (opioid receptor antagonist) -> rapid reverse effects of morphine and other opioids and used to treat opioid overdose

reversible competitive antagonists - factors affecting competition (2)

1. Concentration of agonist vs antagonist

2. Receptor affinity of agonist vs antagonist

reversible competitive antagonists - partial agonists

Partial agonists can act as antagonists by altering response of an agonist with higher efficacy that binds to the same site -> acts like a reversible competitive antagonist

Decreased potency and higher EC₅₀ + surmountable

reversible competitive antagonists - IC₅₀ value meaning

concentration of antagonist required to reduce a response to a fixed concentration of agonist by 50%

dependent on concentration of agonist -> more agonist requires more antagonist for the same about of inhibition

limitation of inhibition curves

says nothing about type of inhibition

irreversible competitive antagonist - summary (6)

1. Binds to agonist binding site (orthosteric site) covalently without activating receptor or dissociates very slowly→ prevents agonist from binding to that site

2. Affects numbers of available receptors at a given time point

3. At high enough concentration: irreversible competitive antagonists cannot be outcompeted -> insurmountable inhibition

4. Insurmountable when maximum effect of agonist is reduced -> may not show reduced max if receptor reserve exists

5. Decreases potency and increases EC₅₀

6. Mainly used as experimental tool -> few drugs used clinically

irreversible competitive antagonist - example

phenoxybenzamine covalently binds to alpha-adrenoreceptors and blocks effect of catecholamines

treatment of phaeochromocytoma (tumour in adrenal medulla)

non-competitive antagonist - summary (2)

1. Binds to same receptor but has a different binding site to the agonist

2. Influences receptor function by changing conformation of receptor

non-competitive antagonist - effects of binding (3)

• Increase/ decrease affinity of agonist to orthosteric site

• Increase/ decrease efficacy of agonist

• Can skew coupling of receptor towards different intracellular signalling pathways -> biased agonism

non-competitive antagonist - example

benzodiazepines = positive allosteric modulators of GABAA receptor

potentiates effects of inhibitory transmitter GABA to cause anxiolytic, sedative anticonvulsant effects

chemical antagonist - summary (3)

1. Antagonising molecule directly binds to or destroys the ligand -> ligand can no longer bind to its target

2. Uncommon among small molecule drugs

3. Common for therapeutic antibodies

chemical antagonist - small molecule drug example

protamine = cationic peptide that neutralises and antagonises heparin which is anionic

used in cardiac and vascular surgery

chemical antagonist - therapeutic antibody example

mepolizumab = anti-IL-5 antibody that prevents IL-5 from binding to its receptor

reduces recruitment and survival of eosinophils for anti-asthma effects

chemical antagonist - PROTACS summary (2)

proteolysis-targeting chimeras for "drugging the undruggable"

Bifunctional small molecules that can bind to receptor and induce ubiquitin-mediated degradation of target proteins via recruiting E3

functional (physiological) antagonists - summary

Oppose biological effects of an agonist by acting at a different receptor as an agonist

functional (physiological) antagonists - example

salbutamol is an agonist at ß2-adrenoreceptors that causes airway smooth muscle relaxation

antagonises effects of endogenous contractile agonists that act at different receptor → eg. acetylcholine at muscarinic receptors and leukotrienes at LTC4 receptors

features of good therapeutic antagonists

Generally high affinity and high selectivity -> binds to target and doesn't bind to non-targets

All drugs have more than one action so increasing concentration will reduce selectivity 

principles of pharmacodynamics to understand - list (7)

• Affinity

• Efficacy

• Potency

• Receptor density

• Receptor reserve

• Selectivity

• Types of antagonism