Four questions,
answered in full.

Affinity is the ability of a ligand to bind a receptor; efficacy or intrinsic activity is its ability, once bound, to activate the receptor and generate a response. An agonist has both affinity and efficacy. A full agonist can produce the system’s maximal response; a partial agonist has lower efficacy and a lower E_max even at full receptor occupancy; an inverse agonist stabilises the inactive receptor state and reduces constitutive activity below baseline.

An antagonist has affinity but no efficacy and prevents agonist action. A reversible competitive antagonist competes at the same (orthosteric) site, is surmountable, causes a parallel right shift of the agonist log concentration–response curve, increases EC₅₀ and reduces potency without changing E_max. A non-competitive antagonist prevents receptor activation through a different/allosteric mechanism and is insurmountable; in a simple system E_max falls. An irreversible orthosteric antagonist also becomes insurmountable once receptor reserve is exhausted.

1. GABA_A receptor: pentameric ligand-gated Cl⁻ channel. Propofol, thiopentone and etomidate positively modulate GABA action at β-subunit-containing receptors, increasing GABA-mediated Cl⁻ conductance, hyperpolarising neurons and producing hypnosis.
2. NMDA receptor: glutamate-gated excitatory cation channel conducting Na⁺ and Ca²⁺. Ketamine blocks the channel non-competitively, reducing excitatory transmission and producing dissociative anaesthesia and analgesia.
3. Glycine receptor: inhibitory ligand-gated Cl⁻ channel, potentiated to a lesser degree by propofol and thiopentone.
4. Neuronal nicotinic acetylcholine receptor: excitatory ligand-gated cation channel; inhibition by propofol and thiopentone reduces excitatory neurotransmission.
5. Other anaesthetic-sensitive ion channels: two-pore-domain K⁺ channels increase background K⁺ conductance and hyperpolarisation; HCN channel modulation alters pacemaker currents and neuronal excitability.

First-order kinetics: the elimination rate is proportional to drug amount or plasma concentration, so a constant fraction is removed per unit time. Therefore k, clearance and half-life remain constant while the system is linear. C_t = C₀e^−kt. Concentration falls exponentially on a linear plot and as a straight line on a semilog plot. Most drugs at therapeutic concentrations follow first-order kinetics.

Zero-order kinetics: a capacity-limited elimination pathway is saturated and works at V_max, so a constant amount is removed per unit time independent of concentration. Concentration falls as a straight line on a linear plot; fractional elimination, apparent clearance and half-life are not constant. At lower concentrations the pathway becomes unsaturated and reverts to first-order kinetics. Examples are ethanol, phenytoin at saturating concentrations, high-dose salicylate and thiopentone during prolonged high-dose infusion.

After dissolution or release from the dosage form, most drugs cross the rectal mucosa by passive diffusion according to Fick’s law. Absorption is often incomplete and variable because the rectum has a small absorptive surface, little fluid for dissolution, variable contact time and blood flow, and may contain faeces; diarrhoea or expulsion shortens contact, while the formulation, drug concentration, lipid solubility, pK_a/ionisation and mucosal integrity also matter.

First-pass exposure depends on where absorption occurs. The upper rectum drains through the superior rectal vein → inferior mesenteric vein → portal vein → liver, so drug undergoes hepatic first pass. The lower rectum drains through the middle and inferior rectal veins → internal iliac/systemic circulation, partially bypassing initial hepatic metabolism. Venous anastomoses and uncertain placement make this avoidance incomplete and unpredictable. Bioavailability and time to peak concentration are therefore formulation- and drug-dependent. Examples include paracetamol, diclofenac, diazepam, midazolam, ketamine and barbiturates.

Both are highly lipid-soluble IV induction agents with rapid brain uptake and rapid awakening after a single bolus mainly by redistribution. Propofol is more highly protein bound, has a larger apparent volume of distribution and far greater clearance through hepatic conjugation plus extrahepatic metabolism; its metabolites are inactive. Thiopentone has lower clearance, accumulates in muscle and fat, and its hepatic oxidative metabolism becomes capacity-limited during prolonged/high-dose administration. Consequently propofol is suitable for infusion, TIVA and repeated sedation, whereas thiopentone recovery becomes progressively prolonged and it is unsuitable for routine maintenance by infusion.

Hypoalbuminaemia increases the free fraction of both drugs. Acidaemia increases the unionised fraction of thiopentone, a weak acid with pK_a about 7.6, and can increase brain delivery; propofol has pK_a about 11 and is already almost entirely unionised at physiological pH. Reduce and titrate both agents in hypovolaemia, low cardiac output, older age and organ dysfunction because altered central volume, perfusion and sensitivity can matter more than a simple change in terminal half-life.

Both produce dose-dependent hypnosis, EEG slowing and burst suppression, and reduce cerebral metabolic rate for oxygen (CMRO₂), cerebral blood flow (CBF), cerebral blood volume and intracranial pressure (ICP), while largely preserving cerebral autoregulation and CO₂ reactivity. Both can reduce mean arterial pressure, so cerebral perfusion pressure may fall despite lower ICP. Neither provides analgesia.

Propofol is antiemetic and commonly produces injection pain and transient excitatory movements; thiopentone is not antiemetic, may be antanalgesic at subhypnotic concentrations and can precipitate acute porphyria. Both are anticonvulsant at adequate doses and may terminate seizures, but propofol's seizure-like movements do not necessarily represent cortical seizure activity. Both lower cerebral metabolic demand, but improved neurological outcome from routine pharmacological “cerebral protection” has not been established.

A chiral molecule exists in stereoisomeric forms that are non-superimposable mirror images, usually because a tetrahedral carbon is bonded to four different substituents. These mirror-image forms are enantiomers and their absolute configuration is designated R or S by the Cahn–Ingold–Prelog system. R/S configuration is independent of the direction of optical rotation, (+)/(−).

Enantiomers have essentially the same bulk physicochemical properties in an achiral environment, but interact differently with chiral proteins such as voltage-gated sodium channels, receptors, plasma proteins and metabolising enzymes. They may therefore differ in potency, selectivity, protein binding, metabolism and toxicity. Bupivacaine is a racemate; levobupivacaine is the pure S(−)-enantiomer. Ropivacaine is manufactured as the pure S(−)-enantiomer of the propyl homologue. S-enantiomer preparations show less stereoselective cardiac sodium-channel block and lower CNS/cardiotoxic potential than racemic bupivacaine, although no local anaesthetic is free of systemic toxicity.

Differential blockade is the differing susceptibility of nerve fibres and modalities to local anaesthetic, allowing pain and autonomic transmission to be blocked at concentrations that relatively spare touch, proprioception and motor function. Susceptibility reflects fibre diameter, myelination and internodal distance, sodium-channel subtype/state and firing frequency, and the concentration/duration of local anaesthetic reaching the axon.

Small myelinated B fibres are highly susceptible; nociceptive C and Aδ fibres are blocked at lower concentrations than larger Aβ/Aα fibres supplying touch, proprioception and motor function. In myelinated nerves, conduction fails when enough consecutive nodes of Ranvier—commonly about 2–3—are blocked. Rapidly firing, depolarised nociceptive fibres show frequency/use-dependent block because open and inactivated sodium channels have greater local-anaesthetic affinity. Larger motor fibres have a higher minimum blocking concentration than sensory fibres, so dilute bupivacaine can provide analgesia with relative motor preservation, while increasing concentration produces progressively denser sensory and motor block.

As plasma lignocaine rises: 1–5 µg·mL⁻¹ produces analgesic/antiarrhythmic effects; 5–10 causes circumoral numbness, tinnitus and muscle twitching, with systemic hypotension and myocardial depression; 10–15 causes seizures and unconsciousness; 15–25 causes apnoea and coma; and >25 µg·mL⁻¹ causes severe cardiovascular depression/collapse.