Porphyria is a group of disorders in which there is excess production and excess excretion of porphyrins and their precursors. They are usually genetic and are caused due to defects in the haem metabolic pathway. However, other factors like infection, pregnancy, mensuration, starvation may precipitate the attack.

Sulphonamides, barbiturates (methohexitone and thiopental), and phenytoin are considered to be precipitants so are not safe to use
Chloral hydrate is thought to be safe to use.
Etomidate lacks proper studies and may be used with caution but it is generally advised not to use this drug especially if other alternatives are available.

Adrenaline is released by the adrenal glands, acts on ? 1 and 2, ? 1 and 2 receptors, and is responsible for fight or flight response.

It acts on ? 2 receptors in skeletal muscle vessels-causing vasodilation.

It acts on ? adrenergic receptors to inhibit insulin secretion by the pancreas. It also stimulates glycogenolysis in the liver and muscle, stimulates glycolysis in muscle.

It acts on ? adrenergic receptors to stimulate glucagon secretion in the pancreas
It also stimulates Adrenocorticotrophic Hormone (ACTH) and stimulates lipolysis by adipose tissue

Ketamine is a phencyclidine (hallucinogenic) derivative that is administered in a dose of 2 mg/kg and acts by blocking NMDA (N-methyl-D-aspartate) receptors of glutamate.

It is a powerful bronchodilator agent and is, therefore, an intravenous anaesthetic of choice in bronchial asthma (halothane is an inhalational anaesthetic agent of choice for bronchial asthma). It is also used in the management of refractory status epilepticus.

It is an acid solution with an elimination half-life of three hours.

It has S (+) enantiomer and R (-) enantiomer. the S(+) enantiomer is two to four times more potent than the R(-) and is less likely to produce hallucinations.

Its use is contraindicated in patients with ischaemic heart disease because it increased sympathetic outflow leading to tachycardia and increased cardiac output which in turn increases the myocardial oxygen demand.

With a history of drug abuse, the patient is likely dependent on and tolerant to opioids. He is also likely to experience significant pain from his injuries. Providing adequate pain relief with regular paracetamol and NSAIDs in combination with a pure opioid agonist while at the same time avoiding occurrence of acute withdrawal syndrome is the goal.

Administering a baseline dose of opioid corresponding to the patient’s usual opioid use plus an opioid dose required to address the level of pain the patient experience can help prevent opioid withdrawal. The best approach is by empowering the patient to use patient controlled analgesia (PCA). The infusion rate, bolus dose and lock-out time are adjusted accordingly. Using PCA helps in avoiding staff/patient confrontations about dose and dosing interval.

2.5 mg heroin is equivalent to 3.3 mg morphine. This patient is usually on 200 mg of heroin per 24 hours. The equivalent dose of morphine is 80 × 3.3 =254 mg per 24 hours (11 mg/hour).

Epidural or spinal opioids might be the best choice for providing a systemic dose of opioids when patients are in remission to avoid withdrawal. Lumbar vertebral fractures is a contraindication to this route of analgesia.

The long half life of Oral methadone make titration to response difficult. Also, absorption of methadone by the gastrointestinal tract is variable. It is therefore NOT the best choice for acute pain management.

Unionised molecules are more likely than ionised molecules to cross membranes (such as the blood-brain barrier).

Because alfentanil and fentanyl are weak bases, the Henderson-Hasselbalch equation says that the ratio of ionised to unionised molecules is determined by the parent compound’s pKa in relation to physiological pH.

Alfentanil has a pKa of 6.5, while fentanyl has a pKa of 8.4.
At a pH of 7.4, 89 percent of alfentanil is unionised, whereas 9% of fentanyl is.

As a result, alfentanil has a faster onset than fentanyl.

Fentanyl is 83% plasma protein bound
Alfentanil is 90% plasma protein bound.

Alfentanil’s pharmacokinetics are affected by its higher plasma protein binding. Because alfentanil has a low hepatic extraction ratio (0.4), clearance is determined by the degree of protein binding rather than the time it takes to take effect.

Loop diuretics act by causing inhibition of Na+ K+ 2Cl– symporter present at the luminal membrane of the ascending limb of the loop of Henle.

Furosemide, torsemide, bumetanide, ethacrynic acid, furosemide, piretanide, tripamide, and mersalyl are the important members of this group

The main use of loop diuretics is to remove the oedema fluid in renal, hepatic, or cardiac diseases. Thus they are useful in the treatment of acute heart failure. These can be administered i.v. for prompt relief of acute pulmonary oedema (due to vasodilatory action).

Hypokalaemia, hypomagnesemia, hyponatremia, alkalosis, hyperglycaemia, hyperuricemia, and dyslipidaemia are seen with both thiazides as well as loop diuretics

A compound that contains an asymmetric centre (chiral atom or chiral centre) and thus can occur in two non-superimposable mirror-image forms (enantiomers) are called chiral compounds.

Desflurane, Halothane, and isoflurane are chiral compounds but Sevoflurane is not a chiral compound.

Because alpha glucosidase inhibitors slow starch digestion in the small intestine, glucose from a meal enters the bloodstream more slowly and can be matched more effectively by an impaired insulin response or sensitivity, glucose from a meal enters the bloodstream more slowly and can be matched more effectively by an impaired insulin response or sensitivity.

Biguanides decrease hepatic glucose output while increasing glucose uptake in peripheral cells.

The meglitinides are secretagogues that act on a different site of the KATP receptors.

Insulin secretion is stimulated by sulphonylureas, which stimulate insulin secretion from pancreatic beta cells. The KATP channels are inhibited by these substances.

Insulin-sensitive genes are influenced by thiazolidinediones, which increase the production of mRNAs for insulin-dependent enzymes. As a result, the cells make better use of glucose.

Ketamine is usually used as a racemic mixture, i.e. (R/S)-ketamine. For over 20 years, use of the more potent (S)-enantiomer by anaesthesiologists has become a preferred option due to the assumption of increased anaesthetic and analgesic properties, a more suitable control of anaesthesia, and of an improved recovery from anaesthesia.

The use of ketamine in anaesthesia and psychiatry may be accompanied by the manifestation of somatic and especially psychomimetic symptoms such as perceptual disturbances, experiences of dissociation, euphoria, and anxiety.

The action of class 1 anti-arrhythmic is sodium channel blockade. Subclasses of this action reflect effects on the action potential duration (APD) and the kinetics of sodium channel blockade.

Drugs with class 1A prolong the APD and refractory period, and dissociate from the channel with intermediate kinetics.

Drugs with class 1B action shorten the APD in some tissues of the heart, shorten the refractory period, and dissociate from the channel with rapid kinetics.

Drugs with class 1C action have minimal effects on the APD and the refractory period, and dissociate from the channel with slow kinetics.

The ?-2 adrenoceptor has three subtypes (2a, 2b and 2c). The receptors are generally presynaptic, meaning they prevent noradrenaline from being released at nerve endings. Both the central and peripheral nerve systems are affected by the ?-2 agonists. ?-2 agonists cause drowsiness, analgesia, and euphoria centrally in the locus coeruleus (in the brainstem), lower the MAC of volatile anaesthetic drugs, and are used to treat acute withdrawal symptoms in chronic opioid addicts.

The most common impact of ?-2 agonists on heart rate is bradycardia. The adrenoreceptors ?-1 and ?-2 are blocked by phenoxybenzamine.

Clonidine is a selective agonist for the ? -2 receptor, having a 200:1 affinity ratio for the ?-2: ?-1 receptors, respectively.

Tizanidine is similar to clonidine but has a few key variances. It has the same sedative, anxiolytic, and analgesic characteristics as clonidine, although for a shorter period of time and with less effect on heart rate and blood pressure.

Dexmedetomidine, like clonidine, is a highly selective ?-2 adrenoreceptor agonist having a higher affinity for the ?-2 receptor. In the case of ?-2: ?-1 receptors, the affinity ratio is 1620:1. It has a biphasic blood pressure impact and induces a brief rise in blood pressure and reflex bradycardia (activation of ?-2b subtypes of receptors in vascular smooth muscles), followed by a reduction in sympathetic outflow from the brainstem and hypotension/bradycardia.

A prodrug is methyldopa. It blocks the enzyme dopa-decarboxylase, which converts L-dopa to dopamine (a precursor of noradrenaline and adrenaline). It is also converted to alpha-methyl noradrenaline, a centrally active agonist of the ?-2 adrenoreceptor. These two processes contribute to its blood pressure-lowering effect. Without a rise in heart rate, cardiac output is generally maintained. The heart rate of certain patients is slowed.

Phentolamine is a short-acting antagonist of peripheral ?-1 and ?-2 receptors that causes peripheral vascular resistance to reduce and vasodilation to increase. It’s used to treat hypertensive situations that aren’t life threatening (e.g. hypertension from phaeochromocytoma).

A baroreceptor reflex commonly causes reflex tachycardia when systemic vascular resistance drops.

Noradrenaline also called norepinephrine belongs to the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter.

They have sympathomimetic effects acting via adrenoceptors (?1, ?2,?1, ?2, ?3) or dopamine receptors (D1, D2).

May cause reflex bradycardia, reduce cardiac output and increase myocardial oxygen consumption

Drugs cross the placenta by Simple, Ion channel and Facilitated diffusion; Exocytosis and Endocytosis, Osmosis, and Active transport (primary and secondary)

The following factors influence rate of diffusion across the placenta:

Protein binding
Degree of ionisation
Placental blood flow
Maternal and foetal blood pH
Materno-foetal concentration gradient.
Thickness of placental membrane
Molecular weight of drug <600 Daltons cross by diffusion
Lipid solubility (lipid soluble molecules readily diffuse across the placenta)

Rocuronium has a F/M ratios of 0.16, a 30% plasma protein binding, low lipid solubility, a low volume of distribution (0.25L/kg), and a high molecular weight (530Da).

The ideal agent for this case should have low blood: gas coefficient, pleasant smell, and high oil: gas coefficient (potent with a low Minimum alveolar coefficient (MAC)). Among the given options, Sevoflurane is perfect with 0.692 blood: gas partition coefficient and is low pungency, and is sweet.

Other drugs with their blood: gas partition coefficient and their smell are given as:
Blood/gas partition coefficient MAC Smell
Enflurane 1.8 1.68 Pungent, ethereal
Desflurane 0.42 7 Pungent, ethereal
Halothane 2.54 0.71 Sweet
Isoflurane 1.4 1.15 Pungent, ethereal

Propofol is a short-acting medication used for starting and maintenance of general anaesthesia, sedation for mechanically ventilated adults, and procedural sedation.
The dose of propofol is 1-2 mg/kg.

Dose of some other important drugs are listed below:
Thiopental dose: 3-7 mg/kg
Ketamine dose: 1-2 mg/kg
Etomidate dose: 0.3 mg/kg
Methohexitone dose: 1.0-1.5 mg/kg

Sugammadex is a modified cyclodextrin that works as an aminosteroid neuromuscular blocking (nmb) reversal agent. By encapsulating each molecule in the plasma, it rapidly reverses rocuronium and, to a lesser extent, vecuronium-induced neuromuscular blockade. Consequently, a  concentration gradient favours the movement of these nmb agents away from the neuromuscular junction.  Pancuronium-induced neuromuscular blockade at low levels has also been reversed.

By inhibiting voltage-dependent calcium channels at the neuromuscular junction, antibiotics in the aminoglycoside group potentiate neuromuscular blocking agents. This can be reversed by giving calcium but not neostigmine or sugammadex.

Sugammadex will not reverse the effects of mivacurium, which belongs to the benzylisoquinolinium class of drugs.

A phase II or desensitisation block occurs when the motor end-plate becomes less sensitive to acetylcholine as a result of an overdose or repeated administration of suxamethonium. The use of neostigmine has been shown to be effective in reversing this weakness.

30mL 0.5% bupivacaine, 1mL 1 in 1,000 adrenaline and 89mL 0.9% N. Saline is the correct answer.
Initial concentration of bupivacaine is 0.5% with a volume of 30mL

The volume is doubled (60mL) by the addition of 0.9% N. saline (30mls) and the concentration of bupivacaine is halved to (0.25%).

If the volume is doubled again (120mL) by the addition of further 0.9% N. saline (59mls) the final concentration of bupivacaine is halved again to 0.125%. Total N. saline = 89mls

The 1 mL of 1 in 1000 adrenaline has also been diluted into the final volume of 120 mL making it a 1 in 120000 concentration.

Opioid should be avoided in the caesarean section as it crosses the placental membrane and causes respiratory depression.

Even though inhalational and intravenous anaesthetic agents readily cross the placenta, they do not have significant effects on APGAR score when used in clinical doses.

Vecuronium and suxamethonium are highly polar molecules and thus do not cross the placenta in significant amounts.

Primary FRCA is concerned with two issues. The first is a working knowledge of the Henderson-Hasselbalch equation, and the second is a working knowledge of logarithms and antilogarithms.

The pH at which the drug exists in 50 percent ionised and 50 percent unionised forms is known as the pKa.

To calculate the proportion of ionised to unionised form of a drug, use the Henderson-Hasselbalch equation.

pH = pKa + log ([A-]/[HA])

or

pH = pKa + log [(salt)/(acid)]
pH = pKa + log ([ionised]/[unionised])

Hence, if the pKa − pH = 0, then 50% of drug is ionised and 50% is unionised.

In this example:
7.4 = 8.4 + log ([ionised]/[unionised])
7.4 − 8.4 = log ([ionised]/[unionised])
log −1 = log ([ionised]/[unionised])

Simply put, the antilog is the inverse log calculation. In other words, if you know the logarithm of a number, you can use the antilog to find the value of the number. The antilogarithm’s definition is as follows:

y = antilog x = 10x

Antilog to the base 10 of 0 = 1, −1 = 0.1, −2 = 0.01, −3 = 0.001 and, −4 = 0.0001.

[A-]/[HA] = 0.1

Assuming that we can apply the approximation [A-] << [HA} then this means the acid is 0.1 x 100% = 10% ionised so the percentage of (non-ionized) acid will be 100% – 10% = 90%

When the loading dose of Digoxin is given, the primary thing to consider is the volume of distribution. The volume of distribution is the proportionality factor that relates the total amount of drug in the body to the concentration. LD is computed as:

LD = Volume of distribution X (desired plasma concentration/bioavailability)

Digoxin is an anti-arrhythmic drug with a large volume of distribution and high bioavailability, and only a small percentage of Digoxin is bound to plasma proteins (,20%).

In the case, since the arrhythmia is not life-threatening, there is no need for the medication to work rapidly.

The mechanism of action of macrolides is inhibition of bacterial protein synthesis by preventing peptidyltransferase from adding to the growing peptide which is attached to tRNA to the next amino acid.

The Beers criteria, a US set of criteria for good prescribing in the older patient, preclude the use of metoclopramide in Parkinson’s disease. The Adverse Reactions Register of the UK Committee on Safety of Medicines (CSM) for the years 1967 to 1982 contained 479 reports of extrapyramidal reactions in which metoclopramide was the suspected drug; 455 were for dystonic-dyskinetic reactions, 20 for parkinsonism and four for tardive dyskinesia. Effects can occur within days of initiation of treatment and may take months to wear off.

Other antiemetics are available, such as cyclizine (Valoid), domperidone and ondansetron, which would be more appropriate to use in those with Parkinson’s disease.

Cyclizine is a piperazine derivative with histamine H1 receptor antagonist and anticholinergic activity. It is used for the treatment of nausea, vomiting, (particularly opioid-induced vomiting), vertigo, motion sickness, and labyrinthine disorders.

Prochlorperazine is an antipsychotic known to cause tardive dyskinesia, tremor and parkinsonian symptoms and is therefore likely to exacerbate Parkinson’s disease. Prochlorperazine is not favoured for older patients because of the increased risk of stroke and transient ischaemic attack (TIA).

Droperidol and phenothiazine are also potent antagonists on D2 receptors and must also be avoided.

Drug elimination is the termination of drug action, and may involve metabolism into inactive state and excretion out of the body. Duration of drug action is determined by the dose administered and the rate of elimination following the last dose.

There are two types of elimination: first-order and zero-order elimination.

In first-order elimination, the rate of elimination is proportionate to the concentration; the concentration decreases exponentially over time. It observes the characteristic half-life elimination, where the concentration decreases by 50% for every half-life.

In zero-order elimination, the rate of elimination is constant regardless of concentration; the concentration decreases linearly over time. A constant amount of the drug being excreted over time, and it occurs when drugs have saturated their elimination mechanisms.

Since phenytoin is observed in elevated levels, the elimination mechanisms for it has been saturated and, thus, will have to undergo zero-order elimination.

Adenosine is the first line for AV nodal re-entry tachycardia. An initial dose of 6 mg is given, and a consequent second dose or third dose of 12 mg is administered if the initial dose fails to terminate the arrhythmia.

Aside from Adenosine, a vagal manoeuvre (e.g. carotid massage) is done to help terminate the supraventricular arrhythmia.

Amiodarone is not a first-line drug for supraventricular tachycardias. Digoxin and Propranolol can be considered if the arrhythmia is of a narrow complex irregular type. Verapamil is an alternative to Adenosine if the latter is contraindicated.

The leading cause of perioperative anaphylaxis in the UK currently are antibiotics. They account for 46% of cases with identified causative agents. Co-amoxiclav and teicoplanin between them account for 89% of antibiotic-induced perioperative anaphylaxis

Neuromuscular blocking agents (NMBAs) are the second leading cause and account for 33% of case.

Chlorhexidine (0.78/100,000 administrations)
Co-amoxiclav (8.7/100,000 administrations)Suxamethonium (11.1/100,000 administrations)
Patent blue dye (14.6/100,000 administrations)
Teicoplanin (16.4/100,000 administrations)

Anaphylaxis to chlorhexidine periop poses a significant risk in the healthcare setting because of its widespread use with some being fatal.

The Wolff-Parkinson-White syndrome (WPWS) is linked to an additional electrical conduction pathway between the atria and ventricles. This accessory pathway (bundle of Kent), unlike the atrioventricular (AV) node, is incapable of slowing down a rapid rate of atrial depolarization. In other words, a short circuit bypasses the AV node. Patients with a rapid ventricular response or narrow complex AV re-entry tachycardia are more likely to develop atrial fibrillation or flutter.

Digoxin can promote impulse transmission through this accessory pathway if a patient with WPWS develops atrial fibrillation because it works by blocking the AV node. This can cause ventricular fibrillation and an extremely rapid ventricular rate. As a result, it’s not advised.

Adenosine, beta-blockers, and calcium channel blockers, among other drugs that interfere with AV nodal conduction, are also generally contraindicated.

The class III antiarrhythmic drugs amiodarone and ibutilide (K+ channel block) and procainamide (Na+ channel block) are the drugs of choice.

Cell membrane pore formation, Bacterial DNA damage, Peptidoglycan cross-linking inhibition, and peptidoglycan synthesis inhibitor are always lethal and such mechanisms are possible only in bactericidal drugs. But Protein synthesis inhibition would only prevent cell replication or cell growth and is responsible for bacteriostatic effects of the drug.

Rifampicin is a derivative of a rifamycin (other derivatives are rifabutin and rifapentine). It is bactericidal against both dividing and non-dividing mycobacterium and acts by inhibiting DNA-dependent RNA polymerase. Thus this drug inhibits RNA synthesis.

Glyceryl trinitrate (GTN) has a significant first pass metabolism. About 90% of a dose of GTN is metabolised in the liver by the enzyme glutathione organic nitrate reductase.

An INSIGNIFICANT amount of metabolism occurs in the intestinal mucosa.

There is approximately 1% bioavailability after oral administration and 38% after sublingual administration.

GTN does NOT cause gastric irritation and it is well absorbed in the gastrointestinal tract.

The volume of distribution of GTN is 2.1 to 4.5 L/kg. This is HIGH.

When responsiveness diminishes rapidly after administration of a drug, the response is said to be subject to tachyphylaxis. This may be due to frequent or continuous exposure to agonists, which often results in short-term diminution of the receptor response.

Many mechanisms may be responsible, such as blocking access of G protein to activated receptor, or receptor molecules internalized by endocytosis to prevent exposure to extracellular molecules.

Tolerance occurs when larger doses are required to produce the same effect. This may be due to changes in receptor number or function due to exposure to the drug.

Desensitization refers to the common situation where the biological response to a drug diminishes when it is given continuously or repeatedly. It is a chronic loss of response, occurring over a longer period than tachyphylaxis. It may be possible to restore the response by increasing the dose (or concentration) of the drug but, in some cases, the tissues may become completely refractory to its effect.

Drug dependence is defined as a psychic and physical state of the person characterized by behavioural and other responses resulting in compulsions to take a drug, on a continuous or periodic basis in order to experience its psychic effect and at times to avoid the discomfort of its absence.