Neuropharmacology Overview and Case Study

Neuropharmacology

• Neuropharmacology is the study of how drugs affect the nervous system, including the brain, spinal cord, and peripheral nerves
• Focuses on understanding the interactions between drugs and neural cells (neurons and glial cells) to influence their function, signalling, and behaviour.
• Includes psychopharmacology (drug effects on emotion and cognition), neuropsychopharmacology (drug effects on the nervous system), and medical neuropharmacology (effects of medicines and their side effects).
• Also includes in vitro neuropharmacology (drug effects on isolated tissues or neurons, determining concentration-response relationships) and in vivo neuropharmacology (drug effects in organisms and animals, determining dose-response relationships).

Case Story 1

• Picrotoxin is a GABA A receptor antagonist.
• It inhibits the function of GABA A receptors, reducing GABAergic inhibition and increasing neural excitability.
• Derived from a plant, commonly called the "fish plant."
• Its seeds are traditionally used to stun or stupefy fish.
• GABA is the brain's major inhibitory neurotransmitter. Inhibiting its receptors leads to increased neural activity, potentially causing seizures.
• Picrotoxin can act as an antidote for barbiturate toxicity, counteracting the excessive inhibitory effects of barbiturates on the central nervous system.

Case Story 2

• A 52-year-old man experienced nausea, vomiting, and acute dyspnea after consuming pufferfish (Lagocephalus sceleratus) liver and gonads.
• Symptoms included perioral paresthesias, muscle weakness, progressive respiratory failure, bradypnea, bradycardia, and cardiac arrest.
• He was resuscitated, intubated, and stabilized, but remained in a deep coma.
• Diagnosis of tetrodotoxin (TTX) poisoning, confirmed by clinical features and timing of symptoms.
• TTX blocks sodium channels, preventing action potential generation and propagation.
• Blocking sodium channels blocks neurotransmitter release.
• Treatment included supportive care in the ICU.

Case Story 3

• Curare vine contains d-tubocurarine, an antagonist at acetylcholine receptors (specifically nicotinic acetylcholine receptors).
• Blocking these receptors prevents acetylcholine binding, inhibiting muscle contraction, and causing paralysis.
• The primary active compound in curare vine is d-tubocurarine.
• The graph shows the effects of d-tubocurarine on muscle twitch tension in EDL (extensor digitorum longus) and diaphragm muscles.
• IC50 values for EDL and diaphragm are 0.3 μM and 1.8 μM, respectively.
• Death occurs due to diaphragm paralysis, leading to respiratory failure.
• EDL (extensor digitorum longus) muscle is not vital for survival, so paralysis occurs first.
• TTX and curare are antagonists of sodium and acetylcholine receptors, respectively, leading to severe dysfunction and potentially death.

Ligands and Receptors

• A ligand is any chemical that binds to or combines with a receptor.
• A receptor is a cellular macromolecule or assembly of macromolecules concerned with chemical signaling between and within cells.
• Binding of ligands to receptors is an active process which depends on the shapes and charge properties of both ligand and site. This can facilitate or prevent further binding events.
• Ligands that are produced naturally by the body are called endogenous ligands.
• Ligands made in a laboratory are exogenous ligands.

Radioligand Binding

• In radioligand binding assays, a radioactively labelled ligand is incubated with a tissue preparation.
• This allows quantification of the binding to receptors.
• Washing the preparation removes loosely bound drug molecules, leaving only tightly bound ligands.
• Radioactively labelled ligands help assess binding to the receptor site under investigation.
• This allows calculation of specific and nonspecific binding sites
• Non-specific binding refers to ligands not binding to the precise receptor site, but in non-specific binding to the membrane or tissue

Agonists and Antagonists

• Ligands may be classified as agonists or antagonists, depending on their effect on receptor function.
• Agonists evoke effects in biological tissues and can be full, partial or inverse.
• Antagonists do not have effects of their own, but block effects evoked by agonists.
• Competitive antagonists compete with agonists for the same receptor binding site.
• In non-competitive antagonism, the antagonist binds to a different site, and the shape and function of the receptor is altered. The efficacy of the agonist is impacted.
• Competitive antagonism reduces the efficacy of the agonist, but with enough agonist, the maximum efficacy can still be reached.
• Non-competitive antagonism reduces both the efficacy of the agonist and the potency of an agonist.

Concentration-Response Curves

• Logarithmic plots of concentration and response are often used to display concentration-response relationships.
• EC₅₀ (Effective Concentration 50) refers to the concentration of an agonist that produces 50% of its maximal response.
• E_max (Maximum Response) denotes the maximum response (or biological effect) that an agonist can elicit.
• Potency is the concentration of an agonist required to produce a specific effect.
• Efficacy is the maximum biological effect a drug can produce when interacting with a receptor.

Non-Linear Relationships

• Maximal responses can occur even when not all receptors are occupied (spare receptors).
• Some receptors have a hyperbolic relationship between occupancy and response, where spare receptors enhance sensitivity to agonists.
• A non-linear relationship may exist between receptor occupancy and biological response.

Pharmacokinetics

• Absorption, distribution, metabolism, and excretion (ADME) of drugs are important processes in drug activity.
• Bioavailability is the fraction of a drug that reaches systemic circulation.
• Various routes of drug administration, including oral, intravenous, and intramuscular, have advantages and disadvantages.
• Factors influencing bioavailability like membrane permeability, enzymatic reactions in the body and the route of administration influence efficacy and potency.

Ethanol Use and Effects

• Ethanol is ingested through various beverages.
• The body handles ethanol via four processes: absorption, distribution, metabolism, and excretion.
• Ethanol passes through the blood-brain barrier.
• Effects of ethanol are dependent on concentration (e.g., low BAC = euphoria, high BAC = severe impairments ).