Agonists activate the receptor as a direct result of binding to it with a characteristic affinity. Moreover, intrinsic activity of an agonist to its receptor determines the ability to create a maximal response.

Responses to low doses of a drug usually increase in direct proportion to dose. As doses increase, however, the response increment diminishes; finally, doses may be reached at which no further increase in response can be achieved. The relationship formed between the dose and response when plotted graphically is hyperbolic. This also shows that even at low receptor occupancy, a maximal response may be produced.

Antagonists bind to receptors in the same affinity as agonists, but they have no intrinsic efficacy. They do not activate generation of signal. Instead, they interfere with the ability of the agonist to activate the receptor.

Partial agonists are similar to full agonists in that they have similar affinity to the target receptor, but they produce a lower response than full agonists.

Using a lean body weight metric encompasses a more scientific approach to weight-based dosing. Lean body weight reflects the weight of all ‘non-fat’ body components, including muscle and vascular organs such as the liver and kidneys. As lean body weight contributes to approximately 99% of a drug’s clearance, it is useful for guiding dosing in obesity.

This metric has undergone a number of transformations. The most commonly cited formula derived by Cheymol is not optimal for dosing across body compositions and can even produce a negative result. A new formula has been developed that appears stable across different body sizes, in particular the obese to morbidly obese.

A practical downfall of the calculation of lean body weight (and other body size descriptors) is the numerical complexity, which may not be palatable to a busy clinician. Often limited time is available for prescribing and an immediate calculation is required. Lean body weight calculators are available online, for example in the Therapeutic Guidelines.

Using total body weight assumes that the pharmacokinetics of the drug are linearly scalable from normal-weight patients to those who are obese. This is inaccurate. For example, we cannot assume that a 150 kg patient eliminates a drug twice as fast as a 75 kg patient and therefore double the dose. Clinicians are alert to toxicities with higher doses, for example nephro- and neurotoxicity with some antibiotics and chemotherapeutics, and bleeding with anticoagulants. Arbitrary dose reductions or ‘caps’ are used to avoid these toxicities, but if too low can result in sub-therapeutic exposure and treatment failure.

Body surface area is traditionally used to dose chemotherapeutics. It is a function of weight and height and has been shown to correlate with cardiac output, blood volume and renal function. However, it is controversial in patients at extremes of size because it does not account for varying body compositions. As a consequence, some older drugs such as cyclophosphamide, paclitaxel and doxorubicin were ‘capped’ (commonly at 2 m^2) potentially resulting in sub-therapeutic treatment. Recent guidelines suggest that unless there is a justifiable reason to reduce the dose (e.g. renal disease), total body weight should be used in the calculation of body surface area, until further research is done. Little research into dosing based on body surface area has been conducted for other medicines.

Ideal body weight was developed for insurance purposes not for drug dosing. It is a function of height and gender only and, like body surface area, does not take into account body composition. Using ideal body weight, all patients of the same height and sex would receive the same dose, which is inadequate and generally results in under-dosing. For example a male who has a total body weight of 150 kg and a height of 170 cm will have the same ideal body weight as a male who is 80 kg and 170 cm tall. Both could potentially receive a mg/kg dose based on 65 kg (ideal body weight).

Nitrous oxide increases cerebral blood flow by direct cerebral stimulation and tends to elevate intracranial pressure (ICP)

It increases the cerebral metabolic rate of oxygen consumption (CMRO2)

It is not an NMDA agonist as it antagonizes NMDA receptors.

Cerebral autoregulation is impaired with the use of nitrous oxide but when used with propofol, it is maintained.

Carbon dioxide reactivity is not affected by it.

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.

Propofol is cleared at the fastest rate at the rate of 60ml/kg/min.

Clearance rate of other drugs are as follows:
– Thiopental: 3.5 ml/kg/min
– Methohexitone: 11 ml/kg/min
– Ketamine: 17 ml/kg/min
– Etomidate: 10-20 ml/kg/min

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

Drug A is a pure agonist for the receptor, with high intrinsic efficacy and affinity, according to the log-dose response curve.

Drug B, on the other hand, works as a competitive antagonist. It binds to the receptor but has no inherent efficacy. Drug A’s efficacy will not change, but its potency will be reduced.

A partial agonist is a drug with partial intrinsic efficacy and affinity for the receptor. Giving a partial agonist after a pure agonist will not increase receptor occupancy or decrease receptor activity, and thus will not affect drug A’s efficacy. The inverse agonist flumazenil can reverse all benzodiazepines.

An inverse agonist is a drug that binds to the receptor but has the opposite pharmacological effect.

A non-competitive antagonist is a drug that has affinity for a receptor but has different pharmacological effects and reduces the efficacy of an agonist for that receptor.

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.

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.

Ketamine is the substance in question. Its structure and pharmacodynamic effects make it a one-of-a-kind intravenous induction agent. The molecule is made up of two cyclohexanone rings (2-(O-chlorophenyl)-2-methylamino cyclohexanone and 2-(O-chlorophenyl)-2-methylamino cyclohexanone). Ketamine has local anaesthetic properties and acts primarily on the brain and spinal cord.

It affects Ca2+ channels as a non-competitive antagonist for the N-D-methyl-aspartate (NMDA) receptor. It also acts as a local anaesthetic by interfering with neuronal Na+ channels.

Ketamine causes profound dissociative anaesthesia (profound amnesia and analgesia) as well as sedation.

Phenoxybenzamine, an alpha-1 adrenoreceptor antagonist, is an example of an irreversible competitive antagonist. It forms a covalent bond with the calcium influx receptor.

Benzodiazepines are GABAA receptor agonists that affect chloride influx.

Flumazenil is an inverse agonist that affects GABAA receptor chloride influx.

Ketamine is a cyclohexanone derivative that acts as a non-competitive Ca2+ channel antagonist.

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.

The first line of treatment in case of hypotension is fluid resuscitation.

Activated charcoal can be used within one hour of tricyclic antidepressant ingestion but an intact and secure airway must be checked before intervention. The risk of aspiration should be assessed.

Vasopressors are indicated for the treatment of hypotension following (Tricyclic Antidepressant) TCA overdose when patients fail to respond to fluids and bicarbonate.

Epoprostenol has a half-life of only 42 seconds and has rapid offset. It is used for the treatment of pulmonary hypertension.

Aspirin inhibits the COX enzyme irreversibly. It inhibits thromboxane synthesis but does not inhibit the enzyme thromboxane synthetase.

Ticlopidine, clopidogrel and prasugrel act as irreversible antagonists of P2 Y12 receptor of Adenosine Diphosphate (ADP). These drugs interfere with the activation of platelets by ADP and fibrinogen. Both aspirin and clopidogrel act irreversibly so they are not correct.

Paclitaxel is a long-acting antiproliferative agent used for the prevention of restenosis (recurrent narrowing) of coronary and peripheral stents and is not the correct answer.

Tirofiban has the next shortest duration of action after epoprostenol. If epoprostenol is not given in the question, it would be the best answer.

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.

An intercostal nerve block is used for therapeutic and diagnostic purposes. Intercostal nerve blocks manage acute and chronic pain in the chest area. Common indications are chest wall surgery and shingles or postherpetic neuralgia.

An intercostal nerve block is also an effective option for the management of pain associated with chest trauma and rib fractures. These blocks have been shown to improve oxygenation and respiratory mechanics, and offer pain relief that is comparable to that of epidural analgesia.

This technique, however, is limited by the relatively large doses of local anaesthetic required, and relatively high intravascular uptake from the intercostal space, increasing risk of local anaesthetic toxicity.

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.

Thiopental is a new British Approved Name for thiopentone and is thio-barbiturate.
Methohexitone is an oxy- barbiturate. Both thiopental and methohexitone are intravenous induction agents.

Ketamine cannot cause loss of consciousness in less than 30 seconds. At least 30 seconds is needed to cause loss of consciousness following intravenous administration.

Etomidate is an imidazole but it is not used in the Intensive Care unit for sedation because it has an antidepressant effect on the steroid axis.

Prednisolone 5 mg is the same as 20 mg hydrocortisone.

Prednisolone 40 mg is the same as 8 x 20 mg or 160 mg of prednisolone.

Mineralocorticoid effects and variations in action duration are not taken into account in these comparisons.

5 mg of prednisolone is the same as Dexamethasone 750 mcg, Hydrocortisone 20 mg, Methylprednisolone 4 mg, and Cortisone acetate 25 mg.

Insulin is secreted from the ? cells of the pancreas. It consists of 51 amino acids arranged in two chains. It interacts with cell surface receptors (not the nuclear receptors and thus mechanism of action is not similar to steroids).
Since insulin can pass from plasma to interstitium and lymphatics, it can be measured in lymph but the concentrations here can be up to 30% less than that of plasma.

It decreases blood glucose by stimulating the entry of glucose in muscle and fat (by increasing the synthesis of Glucose transporters)

Ketamine, a phencyclidine derivative, is an antagonist at the NMDA receptor. It causes depression of the CNS that is dose dependent and induces a dissociative anaesthetic state with profound analgesia and amnesia.

Ketamine has a chiral centre usually presented as a racemic mixture with two optical isomers, S (+) and R (-) forms. These isomers are in equal proportions. The S (+) isomer is about three times more potent than the R (-) form. The S (+) form is less likely to cause emergence delirium and hallucinations.

Ketamine is extensively metabolised by hepatic microsomal cytochrome P450 enzymes producing norketamine as its main metabolite. Norketamine has a one third to one fifth as potency as its parent compound.
It increases the CMRO2, cerebral blood flow and potentially increase intracranial pressure.

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.

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.

Anticholinergic agents are a group of drugs that blocks the action of the neurotransmitter called acetylcholine at synapses in the central and peripheral nervous system.

Hyoscine, atropine, and glycopyrrolate are anticholinergic which acts at muscarinic receptors with little activity at the nicotinic receptors.

Hyoscine and atropine are naturally occurring esters. Since Glycopyrrolate is a synthetic quaternary amine, it does not cross the blood brain barrier. Noteworthy, hyoscine, butylbromide also does not cross the blood brain barrier significantly.

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.

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause bronchospasm, rhinorrhoea, and nasal obstruction in some asthma patients.

The inhibition of cyclooxygenase-1 (Cox-1) appears to be the cause of NSAID-induced reactions. This activates the lipoxygenase pathway, which increases the release of cysteinyl leukotrienes (Cys-LTs), which causes bronchospasm and nasal obstruction.

The following changes in arachidonic acid (AA) metabolism have been observed in NSAID-intolerant asthmatic patients:

Prostaglandin E2 production is low, possibly due to a lack of Cox-2 regulation.
An increase in leukotriene-C4 synthase expression and
A decrease in the production of metabolites (lipoxins) released by AA’s transcellular metabolism.

Phospholipase A produces membrane phospholipids, which are converted to arachidonic acid.

TXA2 causes vasoconstriction as well as platelet aggregation and adhesion.

PGI2 causes vasodilation and a reduction in platelet adhesion.

PGE2 is involved in parturition initiation and maintenance, as well as thermoregulation.

Lorazepam is an intermediate-acting benzodiazepine that binds to the GABA-A receptor subunit to increase the frequency of chloride channel opening and facilitate membrane hyperpolarization. It is the preferred treatment for status epilepticus, although Diazepam can also be used as an alternative.

Lorazepam has a longer duration of action than Diazepam, and binds with greater affinity to the GABA-A receptor subunit.

Phenobarbital is a barbiturate that acts on the GABA-A receptor site to increase the duration of chloride channel opening. Barbiturates, particularly phenobarbital, is considered the drug of choice for seizures in infants.

Phenytoin is a sodium-channel blocker that is given for generalized tonic-clonic seizures, partial seizures, and status epilepticus. Phenytoin is preferred in prolonged therapy for status epilepticus because it is less sedating.

Propofol or thiopentone is preferred when airway protection is required.

Tramadol is weak agonist at the mu receptor. It inhibits the neuronal reuptake of serotonin and norepinephrine, and inhibits pain neurotransmission. It is given for moderate pain, chronic pain syndromes, and neuropathic pain.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI). It inhibits the neuronal reuptake of serotonin by inhibiting the serotonin transporter (SERT). It is the drug of choice for major depressive disorder, and is given for other psychiatric disorders such as anxiety, obsessive-compulsive, post-traumatic stress, and phobias.

When tramadol is given with SSRIs, serotonin syndrome may occur. Serotonin syndrome is characterized by fever, agitation, tremors, clonus, hyperreflexia and diaphoresis. The onset of symptoms may occur within a few hours, and the first-line treatment is sedation, paralysis, intubation and ventilation.

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.

Elimination of phenytoin from the body follows first-order kinetics. This means that the rate of elimination is proportional to plasma concentration.

The rate of elimination can be described by the equation:

C = C0·e-kt

Where:

C = drug concentration
C0 = drug concentration at time zero (extrapolated)
k = Rate constant
t = Time

Enzyme systems become saturated when phenytoin concentrations exceed the normal range and elimination of the drug becomes zero-order. At this point, the drug is metabolised at a fixed rate and metabolism is independent of plasma concentration.

Aspirin and ethyl alcohol are other drugs that behave this way.

The usual method of calculating the dose of a drug to be given to patients of normal weight is to use total body weight (TBW). This is because the lean body weight (LBW) and ideal body weight (IBW) dosing scalars are similar in these patients.

Because the LBW and fat mass do not increase in proportion in patients with morbid obesity, this is not the case. Drugs that are lipid soluble, such as propofol or thiopentone, can cause a relative overdose. Lean body mass is a better scalar in these situations.

Suxamethonium has a small volume of distribution, so the dose is best calculated using the TBW to ensure optimal and deep intubating conditions. The higher dose was justified because these patients’ plasma cholinesterase activity was elevated.

Other scalars include:

The dose of highly lipid soluble drugs like benzodiazepines, thiopentone, and propofol can be calculated using lean body weight (LBW). The formula LBW = IBW + 20% can be used on occasion.

Fentanyl, rocuronium, atracurium, vecuronium, morphine, paracetamol, bupivacaine, and lidocaine are all administered with LBW.

Formulas can be used to calculate the ideal body weight (IBW). There are a number of drawbacks, including the fact that patients of the same height receive the same dose, and the formulae do not account for changes in body composition associated with obesity. Because IBW is typically lower than LBW, administering a drug based on IBW may result in underdosing. The body mass index (BMI) isn’t used to calculate drug dosage directly.