An agonist is a molecule with intrinsic efficacy and affinity for a receptor. The ability of a drug-receptor interaction to produce a maximal response is referred to as intrinsic efficacy or activity. Efficacy also refers to a drug’s ability to have a therapeutic or beneficial effect. Although the potencies of morphine and fentanyl differ, they both have the same intrinsic efficacy.

The amount of drug required to produce a given effect is referred to as potency. If drug X is effective in a dose of 100 mcg, its potency is greater than if drug Y is effective in a dose of 10 mg.

The therapeutic index, also known as the margin of safety, is a ratio of the lethal or serious side effect dose of a drug divided by the therapeutic dose of the same drug.

The term bioavailability refers to the ability of a substance to be absorbed. The area under a curve (AUC) of a graphic plot of plasma concentration and time is used to calculate oral bioavailability. It’s used to figure out how much of a drug to take and when to take it.

Barbituric acid is the barbiturates’ pharmacologically inactive precursor. A pyrimidine heterocyclic nucleus is formed by the condensation of urea and malonic acid. Its pharmacological activity can be influenced by minor structural changes (structure function relationship).

The duration of action and potency as a sedative are influenced by the length of the side chains at C5. Barbiturates with three carbon atoms in their chain last longer than those with two. Anticonvulsant properties are enhanced by branched chains.

The addition of a methyl group at N1 causes a faster onset/offset of action, but it also causes excitatory phenomena (twitching/lower convulsive threshold).

The addition of oxygen and sulphur to C2 increases the molecule’s lipid solubility and thus its potency. Thiopentone (thiobarbiturate) has sulphur groups at C2, making it 20-200 times more lipid soluble than oxybarbiturates.

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

According to the 2015 National Institute for Health and Care Excellence (NICE) Guidelines, antibiotic prophylaxis against infective endocarditis (IE) is not recommended routinely for people with any cardiac defect (corrected or uncorrected) due to lack of sufficient evidence regarding its benefits. Instead, antibiotic prophylaxis is recommended for those who are at risk of developing IE, such as those with acquired valvular heart disease with stenosis or regurgitation; hypertrophic cardiomyopathy; valve replacement; and previous IE.

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.

Vecuronium is used as a part of general anaesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. It is a monoquaternary aminosteroid (not quaternary) non- depolarising neuromuscular blocking drug.

It has a structure similar to both rocuronium and pancuronium. The only difference is the substitution of specific groups on the steroid structure.

Vecuronium is not associated with the release of norepinephrine from sympathetic nerve endings. However, Pancuronium has norepinephrine releasing the property.

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.

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.

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.

Oxytocin is secreted by the posterior pituitary along with Antidiuretic Hormone (ADH). It increases the contraction of the upper segment (fundus and body) of the uterus whereas the lower segment is relaxed facilitating the expulsion of the foetus.

Oxytocin acts through G protein-coupled receptor and phosphoinositide-calcium second messenger system to contract uterine smooth muscle.

It has 0.5 to 1 % ADH activity introducing possibilities of water intoxication when used in high doses.

The sensitivity of the uterus to oxytocin increases as the pregnancy progresses.

It is used for induction of labour in post maturity and uterine inertia.

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%

To begin, one must determine the child’s approximate weight. There are a variety of formulas to choose from. It is acceptable to use the advanced paediatric life support formula:

(Age + 4) 2 = Weight

A 5-year-old child will weigh around 18 kilogrammes.

10 mcg/kg (0.1 ml/kg of 1 in 10 000 adrenaline) = 180 mcg is the appropriate dose of intravenous or intraosseous adrenaline.

The correct energy level to deliver is 4 J/kg, which equals 72 joules.

The pad size that is appropriate for this patient is 8-12 cm. For an infant, a 4.5 cm pad is appropriate.

To allow adequate separation in infants and small children, the pads should be placed anteriorly and posteriorly on the chest.

When using a bag and mask to ventilate, take two breaths for every 15 chest compressions. If chest compressions are being applied intubated and without interruption, a ventilation rate of 10-20 breaths per minute should be given.

Chest compressions should be done at a rate of 100-120 per minute, the same as an adult.

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.

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.

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.

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

The ideal gas equation makes the following assumptions:

The gas particles have a small volume in comparison to the volume occupied by the gas.
Between the gas particles, there are no forces of interaction.
Individual gas particle collisions, as well as gas particle collisions with container walls, are elastic, meaning momentum is conserved.
PV = nRT
Where:

P = pressure
V = volume
n = moles of gas
T = temperature
R = universal gas constant

Helium is a monoatomic gas with a small helium atom. The attractive forces between helium atoms are small because the helium atom is spherical and has no dipole moment. Because helium atoms are spherical, collisions between them approach the ideal state of elasticity.

Most real gases behave qualitatively like ideal gases at standard temperatures and pressures. When intermolecular forces and molecular size become important, the ideal gas model tends to fail at lower temperatures or higher pressures. It also fails to work with the majority of heavy gases.

Helium, argon, neon, and xenon are noble or inert gases that behave the most like an ideal gas. Xenon is a noble gas with a much larger atomic size than helium.

Approximately 20% of halothane and 0.02% desflurane undergo hepatic biotransformation. Desflurane, halothane, and isoflurane are metabolised in the liver by cytochrome p450 to trifluoroacetate. Through an immunological mechanism involving trifluoroacetyl hapten formation, trifluoroacetate is thought to be responsible for hepatotoxicity.

Potency of inhaled anaesthetic agents is measured using the minimal alveolar concentration (MAC). The MAC of halothane is 0.74% while that of desflurane is 6.3%. The potency can also be compared using the oil: gas partition coefficient (224 and 18.7 for halothane and desflurane respectively).

Onset of action of volatile agents depends on the blood:gas partition coefficient. A lower blood:gas partition coefficient and insolubility in blood means faster onset and offset of action. The blood gas coefficient for halothane is 2.4 while that of desflurane is 0.42. Desflurane is less soluble than halothane in blood. Halothane has a pungent smell that can irritate the airway which limits its use for a gaseous induction especially in paediatric anaesthesia. desflurane is not pungent.

Desfluranes boiling point is only slightly above normal room temperature (22.8°C) making it extremely volatile while the boiling point of halothane is approximately 50.2°C.

Calcium channel blocker (CCB) blocks L-type of voltage-gated calcium channels present in blood vessels and the heart. By inhibiting the calcium channels, these agents decrease the frequency of opening of calcium channels activity of the heart, decrease heart rate, AV conduction, and contractility.

Three groups of CCBs include
1) Phenylalkylamines: Verapamil, Norverapamil
2) Benzothiazepines : Diltiazem
3) Dihydropyridine : Nifedipine, Nicardipine, Nimodipine, Nislodipine, Nitrendipine, Isradipine, Lacidipine, Felodipine and Amlodipine.

Even though verapamil as good absorption from GIT, its oral bioavailability is low due to high first-pass metabolism.

Nimodipine is a Cerebro-selective CCB, used to reverse the compensatory vasoconstriction after sub-arachnoid haemorrhage and is more lipid soluble analogue of nifedipine

Calcium channel antagonist can potentiate the effect of non-depolarising muscle relaxants.

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.

Doxazosin is selective alpha 1 blocker (it causes less tachycardia than a non-selective alpha-blocker) and is the drug of choice for a patient with hypertension and benign hyperplasia of the prostate (BHP).

The major adverse effect of an alpha-blocker is first-dose hypotension.

Atenolol and Labetalol are beta blockers. It works by relaxing blood vessels and slowing heart rate to improve blood flow and decrease blood pressure.

Clonidine is an α2A-adrenergic agonist used to treat high blood pressure, ADHD, drug withdrawal (alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, and certain pain conditions.

Methyldopa is a centrally-acting alpha-2 adrenergic agonist used to manage hypertension alone or in combination with hydrochlorothiazide, and to treat hypertensive crises.

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.

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.

Salmeterol is a long-acting Beta 2 selective agonist. Therefore it is only used for prophylaxis whereas salbutamol is a short-acting Beta 2 agonist and is thus used for the treatment of acute attacks of asthma.

Salmeterol is 15 times more potent than salbutamol at the Beta 2 receptor but 4 times less potent at the Beta 1 receptor.

Tachyphylaxis to the unwanted side effects commonly occurs, but not to bronchodilation.

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.

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.

Mast cell tryptase is a reliable marker of mast cell degranulation. Tryptase is a protease enzyme that acts via widespread protease-activated receptors (PARs).

Based on the presenting symptoms, this is the case of bacterial meningitis. The treatment of choice for bacterial meningitis is a cephalosporin. Cephalosporin acts by inhibiting bacterial cell wall synthesis.

Carbon dioxide absorbs the most infrared (IR) light between the wavelengths of 4.2-4.4m (4.26m is ideal).

Nitrous oxide absorbs infrared light at wavelengths of 4.4-4.6m (very similar to CO2) and less so at 3.9m.

At a frequency of 4.7m, carbon monoxide absorbs the most IR light.

At 3.3 m and throughout the ranges 8-12 m, the volatile agents have strong absorption bands.

Although oxygen does not absorb infrared light, it collides with CO2 molecules, interfering with absorption. The absorption band is widened as a result of this (so called collision or pressure broadening). A drop of 0.5 percent in measured CO2 can be caused by 95% oxygen.

Nitrous oxide causes a greater inaccuracy of 0.1 percent per ten percent of nitrous oxide.

Water vapour absorbs infrared light as well, resulting in absorption band overlap, collision broadening, and partial pressure dilution. Water traps and water permeable tubing are used to reduce inaccuracies.

Collision broadening is compensated for in modern gas multi-gas analysers.

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.