A/Prof. Ken Rodgers School of Life Sciences

Contents

What are agonists and antagonists?

Affinity vs efficacy

Partial agonists and spare receptors

Types of receptor antagonism

Desensitization and tachyphylaxis

Drug toxicity

References

  • Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson, G (2016) Pharmacology, 8th Edition, Churchill Livingstone, Sydney.
  • How drugs act: general principles– Section 1, part 2

What are Agonists and Antagonists?

What is an agonist?

  • Drug, hormone, toxin, autacoid or neurotransmitter that elicits a biological effect when it interacts with receptors – bethanechol (used for urinary retention) combines with muscarinic ACh receptor
  • Bethanecholmimics action of ACh (the neurotransmitter at these receptors)
  • Magnitude of signal depends on number of receptors occupied and/or rate of formation of drug-receptor complexes
  • Signal amplified by intracellular mechanism

What is an antagonist?

A drug which interacts with a receptor, does not elicit a biological effect and blocks or reverses the effect of an agonist

Agonist v antagonist

Affinity vs efficacy

Other definitions 1

  • What is affinity?
    • Relative tendency of a drug to combine with its receptor
  • What is intrinsic activity or efficacy?
    • Capacity of a drug to produce a pharmacological effect after binding to its receptor ie the maximal possible effect than can be produced by the drug (Emax)
  • Agonists possess?
    • Affinity and intrinsic activity
  • Antagonists possess?
    • Affinity but lack intrinsic activity

Affinity

  • The response of the cell is a product of affinity and efficacy (intrinsic activity)
  • Drug A fits the receptor better than Drug B
  • Drug A has a greater affinity for this receptor than Drug B

Intrinsic activity/efficacy

  • The response of the cell is due to affinity and intrinsic activity
  • Drug C has a greater intrinsic activity at this receptor than Drug A

Partial agonists and spare receptors

Other definitions 2

  • Partial agonist
    • Compound which interacts with a receptor but produces less than the maximum effect – less intrinsic activity or efficacy. Even with 100% receptor binding it does not produce a maximal response.
    • Eg. buprenorphine (partial agonist at µ opioid receptor) produces less analgesia than morphine (full agonist)
  • Spare receptors
    • Implied, when the maximum effect is produced with less than 100% receptor occupancy. Requires functional as well as binding studies.

Biased agonism

Two agonists bind at the same site on the receptor yet the red agonist is better at evoking response 1 and the green agonist is better at evoking response 2.

Types of receptor antagonism

Type of receptor antagonism

  • Competitive
    • Compete for the binding site
      • Reversible
      • Irreversible
  • Non-competitive (Allosteric modulation)
    • Bind elsewhere eg. Ion channel blockers

Types of antagonism 1

  • Reversible competitive antagonist
    • Agonist competes with antagonist for same receptor
    •  [antagonist] progressively inhibits the agonist response
    • Parallel shift of dose response (DR)-curve to the right and ED50 is altered
    • But blockade CAN be reversed by a higher dose of agonist
    • ie the same Emax is reached
      • eg atropine (muscarinic receptor antagonist)

Types of antagonism 1

  • Reversible competitive antagonist
    • Agonist competes with antagonist for same receptor.
    • Parallel shift of DR-curve to the right and ED50 is altered.
    • But blockade CAN be reversed by a higher dose of agonist.
    • The same Emax is reached
      • eg atropine (muscarinic receptor antagonist)

Types of antagonism 3

  • Irreversible competitive antagonist
    • Antagonist binds at same site.
    • Antagonist dissociates slowly, or not at all, from the receptors – irreversible bond (eg covalent bond)
    • No change in the antagonist occupancy takes place when the agonist is applied.
    • Thus blockade CANNOT be reversed by higher dose of agonist
    • Prevent agonists from producing any effect – Emax is  but the agonist acts normally at the unoccupied receptors
    • Thus no shift in DR-Curve ie. no change in ED50 for agonist
      • eg. methysergide (5-HT receptor antagonist) used in Rx of migraine
      • eg. α-neurotoxins from snake venom (nicotinic receptor antagonist)

Types of antagonism 4

Types of antagonism 3

  • Irreversible competitive antagonist
    • Antagonist dissociates slowly, or not at all, from the receptors – irreversible bond (eg covalent bond)
    • No change in the antagonist occupancy takes place when the agonist is applied
    • Thus blockade CANNOT be reversed by higher dose of agonist
    • Prevent agonists from producing any effect – Emax is  but the agonist acts normally at the unoccupied receptors
    • Thus no shift in DR-Curve ie. no change in ED50 for agonist
      • eg. methysergide (5-HT receptor antagonist) used in Rx of migraine
      • eg. α-neurotoxins from snake venom (nicotinic receptor antagonist)

Types of antagonism 5

  • Non-competitive antagonism or allosteric modulation of receptor function
    • Bind at a site close to but distinct from the agonist receptor site
    • Only have an effect on receptors that are activated
    • May be an ion channel or G-protein linked to the receptor ie block in receptor-effector linkage since it acts at different site
      • Eg. suxamethonium(depolarising muscle relaxant)desensitises nicotinic receptor ion channel
      • Eg. calcium antagonists (eg verapamil and nifedipine) non-specific block of contractions by other drugs

Types of antagonism 6

non-comp antagonism

Types of antagonism 7

  • Physiological Antagonism
    • Blockade of an effect due to production of an effect in the opposite direction (acts via separate cells or separate physiological systems or opposing receptors)
    • Eg. In gut – ACh contraction mediated through muscarinic receptor antagonised by noradrenaline (Nad) relaxation mediated through beta receptor
  • Weak partial agonists can also seem to be like competitive antagonists
  • If receptors are constitutively active the addition of a weak agonist can actually decrease receptor activation these are known as ‘inverse agonists’

Desensitization and tachyphylaxis

Desensitization and tachyphylaxis 1

  • Synonymous terms – a drug effect which gradually diminishes over a few seconds to minutes
  • Causes
    • Change in receptors
      • Receptor resulting in tight binding of agonist without opening of ion channel
    • Exhaustion of mediators
      • Depletion of neurotransmitters or second messengers

Tolerance (days or weeks to develop)

  • Causes
    • Increased metabolic degradation
      • Induction of metabolic enzymes eg barbiturates/ethanol in liver
    • Physiological adaptation
      • Eg. side effects (nausea, sleepiness) sometimes tend to subside
    • Translocation of receptors (hours)
      • Receptors may be internalised by endocytosis and degraded in lysosomes eg. gonadotrophin-releasing hormone inhibits gonadotrophin release by continuous receptor stimulation (usually pulsatile) used in prostatic cancer.

Drug Toxicity

Drug toxicity 1

  • “All things are poisons, nothing is without poisonous qualities. It is only the dose which makes a thing a poison”

Paraphrased from Paracelsus (1493-1541)

  • Potency provides little information about the dose of drug at which toxic effects manifest themselves
  • Determined from the LD50 (median lethal dose)
    • Dose of drug that is lethal to 50% of subjects

Drug Toxicity 2

  • Thus therapeutic index (LD50/ED50) gives an idea of the relative margin of safety of a drug
  • Greater this ratio the safer the drug
    • Must be >1.0 to be therapeutic agent, <2.0 typically see toxicity at therapeutic dose
  • Therapeutic index:
    • Digoxin (Rx heart failure)= 1.5-2.0, vs.
    • Penicillin (antibiotic) >100 (non-allergic patients)

Drug Toxicity 2

  • Thus therapeutic index (LD50/ED50) gives an idea of the relative margin of safety of a drug
  • Greater this ratio the safer the drug and must be >1.0 to be therapeutic agent, <2.0 typically see toxicity at therapeutic dose
  • Therapeutic index:
    • Digoxin (Rx heart failure) = 1.5-2.0, vs.
    • Penicillin (antibiotic) >100 (non-allergic patients)
  • Depends on therapeutic use – certain situations (eg. anaesthesia) may require higher dose of drugs than other situations (eg. sedation, sleep)
  • Since the ED50 goes up while the LD50 remains unchanged, the therapeutic index goes down (ie greater risk of toxicity)

Therapeutic Index

Drug targets: receptors

Drug targets: enzymes

Drug targets: enzymes