Principles of Pharmacology - Drug Action at Receptors

Principles of Pharmacology – Drug Action at Receptors

Receptors in Cell Signaling

• Receptors are protein macromolecules typically inserted across the lipid bilayer of the cell.
• They perform two main functions:
  • Recognition or detection of extracellular molecules.
  • Transduction: Upon detecting an extracellular molecule, they bring about changes in cell activity.
• Receptors interact with or bind certain chemicals, such as hormones or neurotransmitters, with high specificity.

Specificity of Receptors

• Receptors are selective about the molecules they bind.
• They are often named or classified based on the drugs they bind. For example, nicotinic acetylcholine receptors bind acetylcholine and the drug nicotine.
• Pharmacologists exploit this specificity by designing drugs that bind only to certain receptor subtypes found in different cells, leading to fewer side effects.

Drug-Receptor Binding

• Binding of drug (D) to receptor (R) is typically reversible:
  D + R \rightleftharpoons DR
• A plot of the proportion of receptors occupied (p) versus drug concentration [D] is a rectangular hyperbola.
• A plot of the proportion of receptors occupied (p) versus log [D] is a symmetrical sigmoid.

Affinity and KD

• Affinity is quantified as the molar concentration of drug required to occupy 50% of the receptors at equilibrium. This concentration is termed KD.
• Drugs with high affinity have a low KD, often in the micro (10^{-6}) or nano (10^{-9}) molar range.

KD as Equilibrium Dissociation Constant

• The rates of forward and backward reactions are:
  • Rate of FORWARD reaction = k_{+1}[D][R]
  • Rate of BACKWARD reaction = k_{-1}[DR]
• At equilibrium, backward rate equals forward rate:
  k{-1}[DR] = k{+1}[D][R]
• The equilibrium dissociation constant, KD, is defined as:
  KD = \frac{k{-1}}{k{+1}} = \frac{[D][R]}{[DR]}

Implications of KD

• KD measures how tightly a receptor holds onto a drug once they bind.
• Receptors are continually bombarded by chemicals, but only those with affinity will bind.
• High affinity drugs (low KD) bind to the receptor's "sweet spot" and remain bound for a relatively long time, indicating a slow dissociation rate (small k_{-1}).

Agonists: Affinity and Efficacy

• Many drugs have affinity for a receptor but do little else upon binding.
• Agonists bind to and activate the receptor, possessing efficacy.
• Agonist binding induces a conformational change in the receptor, leading to a cellular or tissue response.

Receptor Activation

• Activation of receptor (R) by an agonist (A) produces a biological response:
  A + R \rightleftharpoons AR \rightarrow AR^* \rightarrow response
• Efficacy is the drug's ability to activate the receptor, specifically the transition from AR to AR*.

Adrenaline and Receptor Activation

• The hormone adrenaline (epinephrine) activates the β2 adrenoceptor, a transmembrane protein with around 400 amino acids, by causing a conformational change.
• Remarkably, adrenaline is about the size of a single amino acid.

Types of Agonists

• Agonists bind to receptors (affinity) and activate them (efficacy).
• Naturally occurring neurotransmitters and hormones (e.g., adrenaline, acetylcholine, insulin, dopamine) are agonists.
• Agonists can be full or partial:
  • Full agonists have high efficacy and are very effective at activating receptors.
  • Partial agonists have low efficacy and are less effective at activating receptors.

Full vs. Partial Agonists

• Full agonists often produce a maximal response while occupying only a fraction of available receptors (spare receptors).
• Partial agonists may fail to produce a full response even when occupying all available receptors.
• Differences are evident in log concentration vs. response curves.

EC50 vs. KD

• It's tempting to assume an agonist produces a 50% response (EC50) when occupying 50% of receptors (KD), but this is NOT usually the case.
• The overall response to an agonist depends on both affinity and efficacy; receptor occupancy depends only on affinity.
• Numerous steps exist between drug binding and the measured response.

EC50 and Receptor Occupancy

• The EC50 for an agonist is not the same as the concentration required to occupy 50% of the receptors (KD).

Antagonists

• Many clinically useful drugs are antagonists, inhibiting the effects of neurotransmitters, hormones, or other drugs.
• Several distinct forms of antagonism exist.

Forms of Antagonism

• Chemical: One drug inactivates another chemically (e.g., dimercaprol in arsenic poisoning) - receptors not involved.
• Pharmacokinetic: One drug alters how the body handles another (e.g., antacids reduce phenytoin absorption) - receptors not involved.
• Physiological: Two drugs produce opposing effects, canceling each other out (e.g., noradrenaline increases heart rate, acetylcholine decreases it). Both drugs are agonists acting on different receptors.

Receptor-Based Antagonists

• Competitive antagonists compete with agonists for the same receptor site but do not activate it (affinity but zero efficacy).
  • Can be reversible or irreversible.
• Non-competitive antagonists act at a different site on the receptor or an associated molecule.
  • Can also be reversible or irreversible.

Reversible Competitive Antagonists

• Examples: pancuronium, cetirizine, propranolol.
• Inhibit the effects of neurotransmitters or hormones.
• Their inhibitory effects can be overcome by increasing the agonist concentration (surmountable blockade).
• Reversible competitive antagonists produce a parallel shift to the right of the agonist log concentration vs. response curve.

Irreversible Competitive Antagonists

• These drugs also shift the agonist log concentration-response curve, but the shift is not parallel.
• The inhibition they produce cannot be overcome by increasing agonist concentration (non-surmountable).