Pharmacology 2a – Mechanisms of Drug action 2

Anil Chopra

  1. Briefly explain what you understand by the term 'structure-activity relationship'.
  2. Differentiate between the four principal types of drug antagonism. Give one example of each type of antagonist.
  3. Name the four main families of receptors. On what basis are they distinguishable?
  4. Describe the different types of receptor-linked transduction mechanisms and give examples of receptors which utilise each signal transduction pathway.
  5. Explain the functional consequences of different signal transduction pathways e.g. the different time-courses of observed responses.
  6. Define 'drug tolerance'. Briefly describe the five different cellular mechanisms that may account for, or contribute to, this phenomenon.

Drug – receptor interactions:

Antagonists

-affinity but no efficacy

-2 types

  • Competitive
  • Same site as agonist
  • Surmountable
  • Shift the dose-response curve RIGHT
  • Eg. Atropine. Propanolol (beta blocker)
  • Irreversible
  • Binds tightly or to a different site on the receptor but still blocks the response to the receptor.
  • Insurmountable – cannot be overcome by increasing agonist concentration.
  • E.g. hexamethonium (anti-hypertensive drug)
  • Shifts the dose-response curve right and reduces the maximum response.

-Receptor reserve

  • Where in some tissues, you don’t need to stimulate 100% of the receptors to get 100% response. E.g. smooth muscle
  • Increases the sensitivity of the tissue.
  • Increases the speed of response.

Types of Drug Antagonism

-Receptor blockade:

  • This is where the antagonist literally blocks the binding site i.e. has affinity but no efficacy. Normally they are competitive and irreversible.
  • This can be overcome with high doses of agonist
  • Resulting in a parallel shift of the dose depended curve to the right.

-Physiological Antagonism

  • Bind to different receptors which produce the opposite effects of the same tissue e.g. Noradrenaline vs. histamine (effect on blood pressure) NA causes constriction, histamine causes vasodilation.

-Chemical antagonism

  • Interaction in solution
  • E.g. dimercaprol  binds to heavy metal ions to form a complex which is easy to excrete. It is used with people who have metal poisoning (e.g. lead poisoning).

-Pharmacokinetic antagonism

  • Antagonist reduces the concentration of the active drug at site of action.
  • Decrease absorbtion / increase metabolism / increase excretion
  • E.g. barbiturates – enzyme inducers in the liver. Leads to increased metabolism and therefore reduces the effects of drugs if co-administered.

Drug Tolerance

Gradual reduction in responsiveness to a drug over a period of (days/weeks) with regular administration. If the decrease occurs quickly  tachyphylaxis.

e.g. benzodiazepines (good at stopping seizures but if given over a period of time, the anti-seizure effectiveness is lost)

  1. Pharmacokinetic Factors

-Increase rate of metabolism the more you take it.

-E.g. barbiturates (liver enzyme inducers) / alcohol.

  1. Loss of Receptors

-By membrane endocytosis, because the cell thinks that the cell is being over-stimulation

-Receptor “down-regulation”

-β – adrenoreceptors.

NB – receptor up-regulation also exists.

  1. Change in receptors

-Receptor desensitisation

  • Conformation change of the receptor such that the receptor doesn’t bring about response any more.
  • E.g. Acetylcholine receptors at neuromuscular junction
  1. Exhaustion of Mediator Stores

-Amphetamines (comes into contact with Noradrenaline neurones in the brain so then Noradrenaline leaks out into the synaptic cleft)

  1. Physiological Adaptation

-Bodies homeostatic responses shift response of antagonists e.g. increase in blood pressure by drugs is cancelled out by bodies homeostatic response by lowering blood pressure

-Can also cause development of tolerance to side effects of drugs.

Receptor Families

4 types based on  Molecular structure

 Signal transduction systems

Type 1: Ion channel-linked receptors

 Fast responses (m secs)

 nAChR; GABAA

Type 2: G-protein-coupled receptors

 Slower responses (secs)

1-adrenoceptors (heart)

Type 3:Tyrosine kinase-linked type

 insulin/growth factors (mins)

Type 4:Intracellular steroid type receptors

 steroids/thyroid hormones (hrs)

 regulate DNA transcription

Type 1 / Type 2 / Type 3 / Type 4
Ion-Channel Linked Receptors / G-protein Coupled Receptor / Tyrosine-Kinase Linked Receptors / Receptors Linked to Gene Transcription (nuclear receptors)
Location / Membrane / Membrane / Membrane / Intracellular
Effector / Channel / Enzyme or channel / Enzyme / Gene transcription
Coupling / Direct / G-protein / Direct or Indirect / Via DNA
Timescale / M secs / Secs / Mins / Hours
Structure / Many different sub-units, generally 4-5 forming a single protein / A single protein with no subunit. Has 7 transmembrane α-helices as the binding domain with an intra-cellular G-protein coupling domain / A single α-helix which passes through the membrane. The catalytic domain contains the tyrosine kinase which phosphorylates tyrosine / Close to nucleus and causes changes in DNA transcription. Has a binding domain and a DNA-bindning domain (“zinc fingers”)
Examples / Nicotinic ACh
GABAA / Muscarinic ACh
Adrenoceptors / Insulin Receptor
Cytokine Receptors / Steroid receptors
Thyroid Hormone receptors