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 neuroleptic malignant syndrome (NMS) is a rare complication in response to neuroleptic or antipsychotic medication.

The main features are:
– Elevated creatinine kinase
– Hyperthermia and tachycardia
– Altered mental state
– Increased white cell count
– Insidious onset over 1-3 days
– Extrapyramidal dysfunction (muscle rigidity, tremor, dystonia)
– Autonomic dysfunction (Labile blood pressure, sweating, salivation, urinary incontinence)

Management is supportive of ICU care, anticholinergic drugs, increasing dopaminergic activity with Amantadine, L-dopa, and dantrolene, and non- depolarising neuromuscular blockade drugs.

Since Olanzapine is a potential cause of NMS it is not a treatment.

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.

Prilocaine is the drug of choice for intravenous regional anaesthesia. 0.5% prilocaine (40 ml) is indicated for this condition.
Lidocaine is another alternative for this condition but volume and dose are likely to be inadequate for the procedure.

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

The reasons for adding adrenaline to a local anaesthetic solution are:

1. To Increase the duration of block
2. To reduce absorption of the local anaesthetic into the circulation
3. To Increase the upper safe limit of local anaesthetic (2.5 mg/kg instead of 2 mg/kg, in this case).

The addition of adrenaline to bupivacaine does not affect its potency, lipid solubility, protein binding, or pKa(8.1 with or without adrenaline).

The pH of bupivacaine is between 5-7. Premixed with adrenaline, it is 3.3-5.5.
The onset of a local anaesthetic and its ability to penetrate membranes depends upon degree of ionisation. Compared with the ionised fraction, unionised local anaesthetic readily penetrates tissue membranes to site of action. The onset of action of solution B is slower. this is because the relationship between pKa(8.1) and pH(3.3-5.5) of the solution results in a greater proportion of ionised local anaesthetic molecules compared with solution A.

Always call for help early. This patient is at risk of gastro-oesophageal reflux, which is why a rapid sequence induction has been chosen. The patient is not pregnant, and the surgery is not urgent.

Plan A is to perform a rapid sequence induction under optimal conditions and secure the airway with a tracheal tube.

No more than three attempts with a direct laryngoscope (plus one attempt with a videolaryngoscope) should be made to intubate the trachea. Keep in mind that suxamethonium is wearing off. Ensuring adequate neuromuscular blockade at this stage is crucial; this might include administering a non-depolarizing relaxant if oxygenation can be maintained with bag-mask ventilation. Given the non-immediate nature of the surgery, there should be a low threshold to abandon intubation attempts and resort to Plan B.

An alternative strategy can then be planned.

The most important initial step is to declare a “failed intubation.” This will prevent further intubation attempts and alert your assistant that Plan A has failed. Maintaining oxygenation and anesthesia is also critical before implementing Plan B.

Do not administer another dose of suxamethonium. Insert a supraglottic airway if oxygenation fails and adequate ventilation cannot be maintained.

Plan D follows the declaration of a CICO (Cannot Intubate, Cannot Oxygenate) situation.

Marsh (adult) model, when used with children caused over-estimation of plasma concentration. To address this issue Kataria et al developed a three-compartmental model for propofol in children. The pharmacokinetic models used by Target controlled infusion (TCI) systems are used to calculate the relative sizes of the central (vascular), vessel-rich peripheral, and vessel-poor peripheral compartments. The relative volumes of these compartments are different in young children when compared to adults.

Kataria, therefore, is the correct option as described above.

The Maitre model is a three-compartmental model for alfentanil TCI.

The Marsh model describes a propofol TCI model for adults

The Minto model applies to TCI remifentanil.

The Schnider model is also an adult model for propofol that incorporates age and lean body mass as covariates.

Dabigatran template is a prodrug and its active metabolite is a direct thrombin inhibitor. It is a synthetic, reversible, non-peptide thrombin inhibitor. This inhibition of thrombin results in a decrease of fibrin and reduces platelet aggregation.

Drugs like warfarin act by inhibiting the activation of vitamin K-dependent clotting factors. These factors are synthesized by the liver and activated by gamma-carboxylation of glutamate residues with the help of vitamin K. Hydroquinone form of vitamin K is converted to epoxide form in this reaction and regeneration of hydroquinone form by enzyme vitamin K epoxide reductase (VKOR) is required for this activity. Oral anticoagulants prevent this regeneration by inhibiting VKOR, thus vitamin K-dependent factors are not activated. These factors include clotting factors II, VII, IX, and X as well as anti-clotting proteins, protein C and protein S.

Selegiline is a monoamine oxidase inhibitor. Inhibition of monoamine oxidase leads to increased levels of norepinephrine and serotonin in the central nervous system.

Pethidine, also known as meperidine, is a strong agonist at the mu and kappa receptors. It inhibits pain neurotransmission and blocks muscarinic-specific actions.

Administering opioid analgesic is relatively contraindicated to individuals taking monoamine oxidase inhibitors. This is because of the high incidence of serotonin syndrome, which is characterized by fever, agitation, tremor, clonus, hyperreflexia and diaphoresis. Onset of symptoms is within hours, and the treatment is mainly through sedation, paralysis, intubation and ventilation.

The clinical findings are more consistent with Serotonin syndrome rather than exacerbation of Parkinson’s. Parkinson’s Disease (PD) exacerbations are defined as patient-reported or caregiver-reported episodes of subacute worsening of PD motor function in 1 or more domains (bradykinesia, tremor, rigidity, or PD-related postural instability/gait disturbance) that caused a decline in functional status, developed over a period of < 2 months, did not fluctuate with medication timing, and are not caused by intentional adjustments of PD medications by the treating neurologist. Malignant hyperthermia usually occurs within minutes of administration of a volatile anaesthetic, such as halothane, or succinylcholine. There is massive release of calcium from the sarcoplasmic reticulum, leading to fever, acidosis, rhabdomyolysis, trismus, clonus, and hypertension. In sepsis, it more common for patients to present with hypotension rather than hypertension.

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.

Bupivacaine is used to decrease sensation in a specific area. It is injected around a nerve that supplies the area, or into the spinal canal’s epidural space.

The maximum volume of 0.5% bupivacaine that should be administered to a 10kg child is 5 ml

Ondansetron is a serotonin antagonist at the 5HT3 receptor. 5HT3 receptors in the gastrointestinal tract and in the vomiting centre of the medulla participate in the vomiting reflex. They are particularly important in vomiting caused by chemical triggers such as cancer chemotherapy drugs.

The nucleus solitarius is the recipient of all visceral afferents, and an essential part of the regulatory centres of the internal homeostasis, through its multiple projections with cardiorespiratory and gastrointestinal regulatory centres. It participates in the reflexes of the nerves innervating the nucleus, so it mediates cough reflex, carotid sinus reflex, gag reflex, and vomiting reflex.

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.

Fentanyl is a pethidine congener, 80–100 times more potent than morphine, both in analgesia and respiratory depression. Fentanyl is ten times more potent than alfentanil.

Alfentanil has a more rapid onset than fentanyl even if fentanyl is more lipid-soluble because both are basic compounds and alfentanil has lower pKa, so a greater proportion of alfentanil is unionized and is more available to cross membranes.

Elimination of alfentanil is higher than fentanyl due to its lower volume of distribution.

Midazolam is the benzodiazepine in question. It’s the only benzodiazepine that undergoes tautomeric transformation (dynamic isomerism). The molecule is ionised and water soluble at pH 3.5, but when injected into the body at pH 7.4, it becomes unionised and lipid soluble, allowing it to easily pass through the blood brain barrier.

The half-life of midazolam is only 2-4 hours.

It is a GABAA receptor agonist because it is a benzodiazepine. GABAA receptors are found in abundance throughout the central nervous system, particularly in the cerebral cortex, hippocampus, thalamus, basal ganglia, and limbic system. GABAA receptors are ligand-gated ion channels, with the inhibitory neurotransmitter gamma-aminobutyric acid as the endogenous agonist. It is a pentameric protein (2, 2 and one subunit) that spans the cell membrane, and when the agonist interacts with the alpha subunit, a conformational change occurs, allowing chloride ions to enter the cell, resulting in neuronal hyperpolarization.

For status epilepticus, midazolam is not the drug of choice. Lorazepam is the benzodiazepine of choice for status epilepticus.

Lesser the potency of the drug, the higher the dose required to produce maximal receptor occupation. So, the least potent drug will have a log dose-response curve furthest to the right on X-axis.

Based on the option given, tramadol is the least potent drug and thus higher dose is required to produce maximal opioid receptor occupation.

Thus, Tramadol is the least potent opioid with a log dose-response curve furthest to the right on X-axis.

Note, Fentanyl is the most potent opioid with a log dose-response curve furthest to the left on the X-axis.

Doxycycline belongs to the family of tetracyclines and inhibits protein synthesis through reversible binding to bacterial 30s ribosomal subunits, which prevent binding of new incoming amino acids (aminoacyl-tRNA) and thus interfere with peptide growth.

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

Alfentanil is less lipid-soluble than fentanyl and thus is less permeable to the membrane making it less potent.

Alfentanil is a phenylpiperidine opioid analgesic with rapid onset and shorter duration of action.

Alfentanil has less volume of distribution due to its high plasma protein binding (92%)

It can cause respiratory depression and can cause sedation

The drug of choice for the treatment of anaphylaxis is adrenaline. It has an intravenous route of administration. Since the patient already has intravenous access, the intramuscular route is not appropriate.

Second-line pharmacological intervention includes the use of chlorpheniramine 10mg intravenous, Hydrocortisone 200mg.

Dose response curves are plotted as % response to drug against Logarithm of drug concentration. The graph is usually sigmoid shaped.

Any drug that has high affinity and high intrinsic activity is likely an agonist. A drug with high affinity but no intrinsic activity will act as an antagonist. Displacement of an agonist also depends on the relative concentrations of the two drugs at the receptor sites.

Maximal response may be achieved by activation of a small proportion of receptor sites.

Therapy with gabapentin requires dose adjustment with renal diseases. However, plasma monitoring of the drug is not necessary.

Gabapentin is not a liver enzyme inducer unlike other anticonvulsants like phenytoin and phenobarbitone

Gabapentin has not been shown to be associated with visual disturbances.

Gabapentin is used for add-on therapy in partial or generalized seizures and used in the management of chronic pain conditions but is of no use in petit mal.

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.

Rifampicin is a potent inducer of liver cytochrome enzymes. Other enzyme inducers are:
Carbamazepine
Sodium valproate
Phenytoin
Phenobarbitone

Sevoflurane is highly fluorinated methyl isopropyl ether widely used as an inhalational anaesthetic. It is suggested that sevoflurane preconditioning occurs via the opening of mitochondrial Potassium ATP dependent channel similar to that of Ischemic Preconditioning protection.

Therapeutic index is a measure which relates the dose of a drug required to produce a desired effect to that which produces an undesired effect.

In humans, it is usually defined as the ratio of the toxic dose for 50% of the population (TD50) to the minimum effective dose for 50% of the population (ED50) for some therapeutically relevant effect. In animal studies, the therapeutic index can be defined as the ratio of the median lethal dose (LD50) to the ED50.

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

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.