Staphylococcus aureus colonizes the nasopharynx in >20% of the general population.

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to flucloxacillin.

Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis.

All ?-lactam antibiotics like penicillin interfere with the synthesis of the bacterial cell walls. The ?-lactam antibiotics inhibit the transpeptidases so that cross-linking (which maintains the close-knit structure of the cell wall) does not take place

Dystonia is characterised by repetitive twisting movements or abnormal postures. They are classified as either primary or secondary.

Primary dystonia is a genetic disorder that is inherited in an autosomal dominant pattern.
Secondary dystonia can be caused by focal brain lesions, Parkinson’s disease, or certain medications.

The following drugs cause the most common drug-induced dystonic reactions:
Antipsychotics, antiemetics (especially prochlorperazine and metoclopramide), and antidepressants.

Following the administration of the neuroleptic prochlorperazine, 16 percent of patients experience restlessness (akathisia) and 4% experience dystonia.

Several published reports have linked the anaesthetics thiopentone, fentanyl, and propofol to opisthotonos and other abnormal neurologic sequelae. Dystonias following a general anaesthetic are uncommon. Tramadol has been linked to serotonin syndrome, while remifentanil has been linked to muscle rigidity.

The following are some of the risk factors:

Positive family history
Male
Children
An episode of acute dystonia occurred previously.
Dopamine receptor (D2) antagonists at high doses and recent cocaine use

Dystonia is treated in a variety of ways, including:

Benztropine (as a first-line therapy):

1-2 mg intravenous injection for adults
Child: 0.02 mg/kg to 1 mg maximum

Benzodiazepines are a type of benzodiazepine (second line treatment).

Midazolam:

1-2 mg intravenously, or 5-10 mg IV/PO diazepam

Antihistamines with anticholinergic activity (H1receptor antagonists):

Promethazine 25-50 mg IV/IM, or diphenhydramine 50 mg IV/IM (1 mg/kg in children) are used when benztropine is not available.

Sodium-chloride symporter inhibitor.

The thiazide sensitive sodium chloride symporter is inhibited by thiazides at the proximal portion of the distal convoluted tubule leading to increased sodium and water excretion. Increased delivery of sodium to the distal portion of the distal convoluted tubule promotes potassium loss. This is why thiazides are associated with hyponatraemia and hypokalaemia.

Carbonic anhydrase inhibitors are used mainly in the treatment of glaucoma. They act on the proximal convoluted tubule to promote bicarbonate, sodium and potassium loss.

Sodium potassium chloride symporter is inhibited by Loop diuretics.
Epithelial sodium channels are inhibited by Amiloride.
Drugs which lead to nephrogenic diabetes insipidus such as lithium and demeclocycline, are Inhibitors of vasopressin.

When a drug is given via intravenous infusion, the plasma concentration rises exponentially as a wash-in curve until it reaches steady-state concentration (the point at which the infusion rate is balanced by the elimination rate or clearance). To reach this steady state, the drug will take 4-5 half-lives.

Cpss (target plasma concentration at steady state) and clearance (CL) in ml/minute or litre/hour are the two factors that determine the infusion rate or dose (ID) in mg/hour of a drug.

ID = Cpss × CL

We know the infusion rate is 20 ml/hour in this case. The drug’s concentration is 5 mg/mL. The patient is receiving 100 mg of the drug per hour, with a 20 L/hour clearance rate.

ID = Cpss × 20

Therefore,

Cpss = 100 mg/20000 ml

Cpss = 0.005 mg/mL or 5 mcg/mL

Muscle fibre myosin ATPase histochemistry is used to divide the biochemical classification into two groups: type 1 and type II.

Type I (slow twitch) muscle fibres rely on aerobic glycolytic and aerobic oxidative metabolism to function. They have a lot of mitochondria, a good blood supply, a lot of myoglobin, and they don’t get tired easily.

Because they contain more motor units, Type II (fast twitch) muscle fibres are thicker. They are more easily fatigued, but produce powerful bursts. The capillary networks and mitochondria are less dense in these white muscle fibres than in type I fibres. They have a low myoglobin content as well.

Muscle fibres of type II (fast twitch) are divided into three types:

Type IIa – aerobic/oxidative metabolism is used.
Type IIb – anaerobic/glycolytic metabolism is used by these fibres.

When compared to skeletal muscle, cardiac and smooth muscle twitch at a slower rate.

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.

In first order kinetics the rate of elimination is proportional to plasma concentration.

Rate of elimination is described by the following equation:

C = C0. e^-kt

Where:
C=drug concentration,
C0= drug concentration at time zero (extrapolated),
k = rate constant and
t = time.

The initial concentration of this drug is 12 mcg/ml therefore:

The plasma concentration will have halved to 6 mcg/ml at 2 hours.
The plasma concentration will have halved to 3 mcg/ml at 4 hours and
The plasma concentration will have halved to 1.5 mcg/ml t 6 hours.

Patients who present for surgery may be on prescription medication or natural/herbal therapies. These have relevance for anaesthesia since they can cause drug interactions.

Ephedra (Ma Huang) is a drug derived from the plant Ephedra sinica that is used as a CNS stimulant, weight reduction aid, and asthma therapy. It is a combination of alkaloids that includes ephedrine which stimulates noradrenaline release from pre-synaptic neurones by acting directly on alpha and beta adrenoreceptors. The use of sympathomimetic drugs together can cause cardiovascular instability.

Ginkgo Biloba contains anti-oxidant characteristics and is used to treat Alzheimer’s disease, vascular dementia, and peripheral vascular disease. It lowers platelet adhesiveness and raises the risk of bleeding by decreasing platelet activating factor (PAF), especially in individuals who are also taking anticoagulants and antiplatelet drugs.

The extract from St. John’s Wort is utilised as an antidepressant because it is a cytochrome P450 isoenzyme inhibitor as well as a serotonin uptake inhibitor. When drugs like fentanyl or tramadol are used during an anaesthetic, there is a risk of serotonin syndrome developing.

The root of a pepper is used to make kava (Piper methysticum). It is a weak GABAA agonist which has the potential to augment the effects of propofol and benzodiazepines, which are volatile anaesthetics.

Garlic is made from the allium sativum plant and is used to treat hypertension and hyperlipidaemia. It includes cysteine, which inhibits platelet aggregation irreversibly, amplifying the effects of aspirin and NSAIDs.

Echinacea is a common herbal medicine that stimulates the immune system by modulating cytokine signalling. In individuals who require organ transplantation, it should be avoided.

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.

Dopamine (DA) is a dopaminergic (D1 and D2) as well as adrenergic ? and?1 (but not ?2 ) agonist.

The D1 receptors in renal and mesenteric blood vessels are the most sensitive: i.v. infusion of a low dose of DA dilates these vessels (by raising intracellular cAMP). This increases g.f.r. In addition, DA exerts a natriuretic effect by D1 receptors on proximal tubular cells.

Moderately high doses produce a positive inotropic (direct?1 and D1 action + that due to NA release), but the little chronotropic effect on the heart.

Vasoconstriction (?1 action) occurs only when large doses are infused.

At doses normally employed, it raises cardiac output and systolic BP with little effect on diastolic BP. It has practically no effect on nonvascular ? and ? receptors; does not penetrate the blood-brain barrier—no CNS effects.

Dopamine is used in patients with cardiogenic or septic shock and severe CHF wherein it increases BP and urine outflow.

It is administered by i.v. infusion (0.2–1 mg/min) which is regulated by monitoring BP and rate of urine formation

The potency of local anaesthetics is directly proportional to lipid solubility because they need to penetrate the lipid-soluble membrane to enter the cell.

Protein binding has a direct relationship with the duration of action because the higher the ability of the drug to bind with membrane protein, the higher is the duration of action.

Higher the pKa of a drug, slower the onset of action. Because a drug with higher pKa will be more ionized than the one with lower pKa at a given pH. Local anaesthetics are weak bases, and unionized form diffuses more rapidly across the nerve membrane than the protonated form. As a result drugs with higher pKa will be more ionized will diffuse less across the nerve membrane.

The aminosteroid rocuronium is the neuromuscular blocking agent in question.

0.3 mg/kg is the effective dose 95 (ED95) (the dose required to depress the twitch height by 95 percent )
The dose for intubation is 0.6 mg/kg.
75 seconds is the time it takes to reach 95 percent depression of the first twitch of the train of four (ToF) or the onset time.
The clinical duration or time to 25% recovery of the first twitch of the train of four (ToF) is 33 minutes.

A modified cyclodextrin can quickly reverse both rocuronium and vecuronium (sugammadex).

It is more fat-soluble than vecuronium, with the liver absorbing the majority of the drug and excreting it in the bile. The only metabolite found in the blood (17-desacetylrocuronium) is 20 times less potent than the parent drug and is unlikely to cause neuromuscular block.

Despite its quick onset of action (60-90 seconds), suxamethonium arguably is still the neuromuscular blocker of choice for a quick sequence induction. Rocuronium is becoming increasingly popular for this purpose.

Daptomycin alters the curvature of the membrane, which creates holes that leak ions. This causes rapid depolarization, resulting in loss of membrane potential. Thus it interferes with the outer membrane of gram-positive bacteria resulting in cell death.

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

The statement Epinephrine is formulated as 1 in 1000 solution means 1 gm epinephrine is present in 1000 ml of solution.

Mivacurium is metabolised primarily by plasma cholinesterase at an In vitro rate of about 70% that of succinylcholine. Mivacurium is contraindicated in patients with genetic and acquired plasma cholinesterase deficiencies.

The clearance of atracurium is by Hoffman degradation and ester hydrolysis in the plasma and is independent of both hepatic and renal function.

Rocuronium is eliminated primarily by the liver after metabolises to a less active metabolite, 17-desacetyl-rocuronium. Its duration of action is not affected much by renal impairment.

Vecuronium undergoes hepatic metabolism into 3-desacetyl-vecuronium which has 50-80% the activity of the parent drug. It undergoes biliary (40%) and renal excretion (30%). The aminoglycoside antibiotics possess additional neuromuscular blocking activity. The potency of gentamicin > streptomycin > amikacin. Calcium can be used to reverse the muscle weakness produced by gentamicin but not neostigmine. When vecuronium and gentamycin are given together the effect on neuromuscular blockade is synergistic.

Significant residual neuromuscular block 2 hours after the administration of these drugs is unlikely In this scenario.

Any recovery from neuromuscular blockade with suxamethonium in a patient with deficiency of plasma cholinesterase demonstrate four twitches on a train of four count.

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.

Perioperative and postoperative analgesia can both be provided by an inguinal hernia field block. The Iliohypogastric and ilioinguinal nerves, as well as the skin, superficial fascia, and deeper structures, must be blocked for maximum effectiveness. The local anaesthetic should ideally have a long duration of action, be highly concentrated, and have a volume of at least 30 mL.

Plain bupivacaine has a maximum safe dose of 2 mg/kg body weight.

Because the patient weighs 75 kg, 150 mg bupivacaine can be safely administered. Both 30 mL 0.5 percent bupivacaine (150 mg) and 60 mL 0.25 percent bupivacaine (150 mg) are acceptable doses, but 30 mL 0.5 percent bupivacaine represents the optimal volume and strength, potentially providing a denser and longer block.

The maximum safe dose of plain lidocaine has been estimated to be between 3.5 and 5 mg/kg. The patient weighs 75 kg and can receive a maximum of 375 mg using the higher dosage regimen:

There are 200 mg of lidocaine in 10 mL of 2% lidocaine (and therefore 11 mL contains 220 mg)
200 mg of lidocaine is contained in 20 mL of 1% lidocaine.

While alternatives are available, Although the doses of 11 mL lidocaine 2% and 20 mL lidocaine 1% are well within the dose limit, the volumes used are insufficient for effective field block for this surgery.

With 1 in 200,000 epinephrine, the maximum safe dose of lidocaine is 7 mg/kg. The patient can be given 525 mg in this case. Even with epinephrine, 60 mL of 1% lidocaine is 600 mg, which could be considered an overdose.

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.

Erythromycin binds to the 50s subunit of bacterial rRNA complex and inhibits protein synthesis.

Vancomycin binds to the acyl-D-ala-D-ala portion of the growing cell wall in a susceptible gram-positive bacterium. After binding, it prevents the cell wall from forming the cross-linking.

Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid. Tetrahydrofolic acid is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis.

The elimination of phenytoin follows first order kinetics. Plasma concentrations determine the rate of elimination. The relationship between drug X plasma concentration and time is described by an exponential process in the following equation used to describe the rate of elimination:

C = C0. e-kt

C=drug concentration, C0= drug concentration at time zero (extrapolated), k = rate constant and t=time

As enzyme systems become saturated when phenytoin concentrations are above the usual range, clearance of the medication becomes zero-order. The medication is metabolised at a constant pace, regardless of its plasma levels. Aspirin and ethyl alcohol are two more significant examples of medications that operate in this way.

A plot of drug concentration with time is a washout exponential curve.

A graph of concentration with time is a straight line i.e. Zero-order kinetics

The amount eliminated per unit time is constant defines the point at which zero order kinetics commences.

Elimination involves a rate-limiting reaction operating at its maximal velocity is incorrect.

The half life of the drug is proportional to the drug concentration in the plasma corresponds to a definition of first-order kinetics.

Hepatotoxicity due to halothane administration is relatively common and is a major factor in its rapidly declining use. Type 1 hepatotoxicity has an incidence of 20% to 30%. A comprehensive report in 1969 demonstrated an incidence of type 2 hepatotoxicity (hepatitis) of 1 case per 6000 to 20000 cases, with fatal cases occurring approximately once in 35000 patients following a single exposure to the anaesthetic. This incidence of fatal cases increases to approximately 1 in 1000 patients following multiple exposures. Following this study was a large-scale review in the United Kingdom, which showed similar results. To put this into perspective, there is only a single case of hepatotoxicity confirmed after the administration of desflurane and 2 cases per 1 million after enflurane. By the 1970s, halothane was the most common cause of drug-induced liver failure.

Halothane-induced hepatotoxicity has a female to male ratio of two to one. Younger patients are less likely to be affected; 80% of the cases are typically in patients 40 years or older. Other risk factors include obesity and underlying liver dysfunction. Medications such as phenobarbital, alcohol, and isoniazid may play a role in affecting CYP2E1 metabolism, increasing one’s risk.

Mivacurium, when administered at doses greater than 0.2 mg/kg,increases the risk for hypotension, tachycardia, and erythema. This is due to the ability of mivacurium to release histamine with increasing dose. Contrary to this fact, anaphylaxis is rare for mivacurium because of the short duration of histamine release.

The effective dose 50 (ED50) of mivacurium is between 0.08-0.15 mg/kg. It is administered slowly to prevent and decrease the risk of developing adverse effects.

Mivacurium has a high potency thus a longer duration of action, however this is not the answer that we are looking for.

Although drug metabolism takes longer for mivacurium than succinylcholine, it has no effect on the dose required for intubation.

Nausea and vomiting occur commonly due to Chemoreceptor Trigger Zone (CTZ) stimulation by dopamine (Domperidone but not metoclopramide can be used for the treatment of this vomiting)

Dopamine itself cannot cross the blood-brain barrier (BBB) but its precursor levodopa can cross BBB.

Dopamine can modulate extrapyramidal symptoms like acute dyskinesia, tardive dyskinesia, Parkinsonism, and Neuroleptic malignant syndrome.

Dopamine inhibits the secretion of prolactin from the pituitary gland.

Structural isomers have a similar molecular formula, but they have a different structural formula as their atoms are arranged in a different manner. Such small changes lead to the differential pharmacological activity. Enflurane and isoflurane are two prime examples of structural isomers.

Stereoisomers are those substances that have a similar molecular and structural formula, but the arrangement spatially of atoms are different and have optical activity.

Enantiomers are a pair of stereoisomers, which are non-superimposable mirror images of each other. They also have chiral centres of molecular symmetry. Ketamine is considered as an example of racemic mixture (contain 50% R and 50% S enantiomers)

Geometric isomers contain a carbon-carbon double bond (i.e. C=C) or a rigid carbon-carbon single bond in a heterocyclic ring. Cis-atracurium is one example.

Dynamic isomers or Tautomers are a pait of unstable structural isomers, which are present in equilibrium. One isomer can easily change after the change in pH. Midazolam and thiopentone are their examples.

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

Atypical antipsychotic drugs include risperidone and quetiapine. They not only inhibit dopamine receptors in the limbic system, but also histamine (H1) and alpha2 adrenoreceptors. When combined with general and/or central neuraxial block, this might result in severe hypotension.

Donepezil (Aricept) is an acetylcholinesterase (AChE) inhibitor that increases the neurotransmitter acetylcholine in the cerebral cortex and hippocampus in a reversible, non-competitive manner. It is used to reduce the advancement of Alzheimer’s disease symptoms (AD). Rivastigmine and galantamine are two more drugs that work in the same way.

Ginkgo Biloba contains anti-oxidant characteristics and is used to treat early-stage Alzheimer’s disease, vascular dementia, and peripheral vascular disease. It lowers platelet adhesiveness and decreases platelet activating factor (PAF) increasing the risk f bleeding, especially in individuals who are also taking anticoagulants and antiplatelet medication.

Memantine is an antagonist of the NMDA receptor. Synaptic plasticity, which is thought to be a critical component of learning and memory, can be inhibited at high doses. The use of ketamine is a relative contraindication since antagonism of this receptor can cause a dissociative state.

The measure of drug potency or therapeutic response is the ED95. This is defined as the dose of a neuromuscular blocking drug required to produce a 95% depression of muscle twitch height. The ED50 and ED90 describe a depression of twitch height by 50% and 90% respectively.

The ED95 (mg/kg) of the commonly used neuromuscular blocking agents are:

suxamethonium: 0.27
rocuronium: 0.31
vecuronium: 0.04
pancuronium: 0.07
cisatracurium: 0.04
mivacurium: 0.08

Entonox is a gas that consists of 50% oxygen and 50% Nitrous oxide. Nitrous oxide is sometimes used for anaesthetics but in this combination, it works as a short-acting painkiller.

Under normal working conditions, it exists only in gaseous form in a cylinder. The gauge pressure of a full Entonox cylinder is 137 bar.

Entonox cylinders should be stored horizontally at a temperature above 0 C. At temperatures below this the nitrous oxide component may separate.

Pseudocritical temperature and pseudocritical pressure can be defined as the molal average critical temperature and pressure of mixture components. In other words, the pseudo-critical temperature is the temperature at which the two gases separate. The pseudo-critical temperature of Entonox is approximately -5.50 C

Accumulation of morphine-6-glucuronide is a risk factor for opioid toxicity during morphine treatment. Morphine is metabolized in the liver to morphine-6-glucuronide and morphine-3-glucuronide, both of which are excreted by the kidneys. In the setting of renal failure, these metabolites can accumulate, resulting in a lowering of the seizure threshold. However, it does not occur in all patients with renal insufficiency, which is the most common reason for accumulation of morphine-6-glucuronide; this suggests that other risk factors can contribute to morphine-6-glucuronide toxicity.

The active metabolites of codeine are morphine and the morphine metabolite morphine-6-glucuronide. The enzyme systems responsible for this metabolism are: CYP2D for codeine and UGT2B7 for morphine, codeine-6-gluronide, and morphine-6-glucuronide. Both of these systems are subject to genetic variation. Some patients are ultrarapid metabolizers of codeine and produce higher levels of morphine and active metabolites in a very short period of time after administration. These increased levels will produce increased side effects, especially drowsiness and central nervous system depression.