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.

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.

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.

The maximum safe amount of bupivacaine is 2mg/kg. Addition of adrenaline slows down absorption of the local anaesthetic and allows a maximum dose of 2.5mg/kg to be used.

The maximum safe dose of bupivacaine for this patient is 125 mg.

A 0.125% solution will contain 0.125g/100mL or 125mg/100 mL.

The maximum volume of local anaesthetic is approximately 80-100 mL.

Tranylcypromine is a monoamine oxidase inhibitor that binds irreversibly to target enzyme.

Monoamine oxidase inhibitors are responsible for blocking the monoamine oxidase enzyme. The monoamine oxidase enzyme breaks down different types of neurotransmitters from the brain: norepinephrine, serotonin, dopamine, and tyramine. MAOIs inhibit the breakdown of these neurotransmitters thus, increasing their levels and allowing them to continue to influence the cells that have been affected by depression.

There are two types of monoamine oxidase, A and B. The MAO A is mostly distributed in the placenta, gut, and liver, but MAO B is present in the brain, liver, and platelets. Serotonin and noradrenaline are substrates of MAO A, but phenylethylamine, methylhistamine, and tryptamine are substrates of MAO B. Dopamine and tyramine are metabolized by both MAO A and B. Selegiline and rasagiline are irreversible and selective inhibitors of MAO type B, but safinamide is a reversible and selective MAO B inhibitor.

MAOIs prevent the breakdown of tyramine found in the body and certain foods, drinks, and other medications. Patients that take MAOIs and consume tyramine-containing foods or drinks will exhibit high serum tyramine level. A high level of tyramine can cause a sudden increase in blood pressure, called the tyramine pressor response. Even though it is rare, a high tyramine level can trigger a cerebral haemorrhage, which can even result in death.

Eating foods with high tyramine can trigger a reaction that can have serious consequences. Patients should know that tyramine can increase with the aging of food; they should be encouraged to have fresh foods instead of leftovers or food prepared hours earlier. Examples of high levels of tyramine in food are types of fish and types of meat, including sausage, turkey, liver, and salami. Also, certain fruits can contain tyramine, like overripe fruits, avocados, bananas, raisins, or figs. Further examples are cheeses, alcohol, and fava beans; all of these should be avoided even after two weeks of stopping MAOIs. Anyone taking MAOIs is at risk for an adverse hypertensive reaction, with accompanying morbidity. Patients taking reversible MAOIs have fewer dietary restrictions.

Amitriptyline is a tricyclic antidepressant, and citalopram and escitalopram are selective serotonin reuptake inhibitors.

Noradrenaline has a short half-life of about 2 minutes. It is rapidly cleared from plasma by a combination of cellular reuptake and metabolism.

It acts as sympathomimetics by acting on ?1 receptors and also on ? receptors.

It decreases renal and hepatic blood flow.

Norepinephrine is metabolized by the enzymes monoamine oxidase and catechol-O-methyltransferase to 3-methoxy-4-hydroxymandelic acid and 3-methoxy-4-hydroxyphenylglycol (MHPG).

Natural catecholamines are Adrenaline, Noradrenaline, and Dopamine

Low molecular weight heparin (LMWH) creates a complex by binding to antithrombin. This complex binds with and inactivates factor Xa.

There is less risk of bleeding with LMWH because it binds less to platelets, endothelium and von Willebrand factor.

LMW binds Xa more readily. The shorter chains are less likely to bind both antithrombin and thrombin.

There is need for monitoring in renal impairment because LMHW is excreted in the urine (and partly by hepatic metabolism)

LMWH have been shown to be as efficacious as unfractionated heparin. It is also safer and have improved inpatient stay and reduced hospital cost.

Nitroglycerine is rapidly denitrated enzymatically in the smooth muscle cell to release the free radical nitric oxide (NO).

Released NO activated cytosolic guanylyl cyclase which increases cGMP (cyclin guanosine monophosphate) which causes dephosphorylation of myosin light chain kinase (MLCK) through a cGMP-dependent protein kinase.

Reduced availability of phosphorylated (active) MLCK interferes with activation of myosin and in turn, it fails to interact with actin to cause contraction. Consequently, relaxation occurs.

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.

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.

Alpha 1 adrenergic receptor stimulation results in vasoconstriction of peripheral arteries mainly of those of skin, gut and kidney arterioles. This would cause and increase in total peripheral resistance and mean arterial pressure and as a result the perfusion of vital organs i.e. brain, heart and lungs are maintained.

Muscarinic M2 receptor also known as cholinergic receptor are located in heart, where they act to slow the heart rate down to normal sinus rhythm after negative stimulatory actions of parasympathetic nervous system. They also reduce contractile forces of the atrial cardiac muscle, and reduce conduction velocity of AV node. This could worsen the compensation.

Stimulation of beta 2 adrenergic receptor result in dilation of smooth muscle as in bronchodilation.

Beta 3 adrenergic receptors are present on cell surface f both white and brown adipocytes and are responsible for lipolysis, thermogenesis, and relaxation of intestinal smooth muscle.

Alpha 2 adrenergic receptor stimulation results in inhibition of the release of noradrenaline in a form of negative feedback.

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.

The first line of defence against acid-base disorder is buffering. The blood mainly utilizes bicarbonate ion (HCO3-) for its buffering capacity (total of 53%, plasma and red blood cells combined).

Strong acids, when acted upon by a buffer, release H+, which then combines to HCO3- and forms carbonic acid (H2CO3). When acted upon by the enzyme carbonic anhydrase, H2CO3 dissociates into H2O and CO.

The rest are the percentage of utilization for the following buffers:
Haemoglobin (by RBCs) – 35%
Plasma proteins (by plasma) – 7%
Organic phosphates (by RBCs) – 3%
Inorganic phosphates (by plasma) – 2%

Based on the presenting symptoms and clinical examination, it is a case of an adult sinus bradycardia with adverse signs. The first pharmacological treatment for this condition is atropine 500mcg intravenously and if necessary repeat every three to five minutes up to a maximum of 3 mg.

If the bradycardia does not subside even after the administration of atropine, cardiac pacing should be considered. If pacing cannot be achieved promptly, we should consider the use of second-line drugs like adrenaline, dobutamine, or isoprenaline.

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.

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.

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.

Propofol infusion syndrome (PRIS) is characterized by lactic acidosis, bradyarrhythmia, rhabdomyolysis, cardiac and renal failure, and often leads to death. So, lactate monitoring is advised in patients with propofol infusion syndrome.

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.

Sucralfate is an octasulfate of glucose to which Al(OH)3 has been added. It undergoes extensive cross-linking in an acidic environment and forms a polymer which adheres to the ulcer base for up to 6 hours and protects it from further erosion. Since it is not systemically absorbed it is virtually devoid of side effects. However, it may cause constipation in about 2% of cases due to the Aluminium component in it.

Sucralfate does not have antibacterial action against Helicobacter pylori. However, Bismuth has antibacterial action due to its oligodynamic effect.

The temperature above which a gas cannot be liquefied no matter how much pressure is applied is its critical temperature. The critical temperature of nitrous oxide is 36.5°C

The minimum pressure that causes liquefaction is the critical pressure of that gas.

The Poynting effect refers to the phenomenon where mixing of liquid nitrous oxide at low pressure with oxygen at high pressure (in Entonox) leads to formation of gas of nitrous oxide.

There is no relevance of molecular weight to this question. it does not change with phase of a substance.

Drug interactions can be seen in the following examples:

Additive interaction (summation).

Additive effects are described for intravenous drug combinations such as ketamine and thiopentone or ketamine and midazolam. Different mechanisms of action are used by them. Thiopentone and midazolam are GABAA receptor agonists, whereas ketamine is an NMDA receptor antagonist. Nitrous oxide and halothane are two other examples.

Synergism is a supra-additive interaction.

Refers to the administration of two drugs with similar pharmacological properties and closely related sites of action, resulting in a combined effect that is greater than the sum of the contributions of each component. The construction of an isobologram can be used to interpret and understand these. The best example is the hypnotic effect of benzodiazepines and intravenous induction agents like propofol. As part of a co-induction technique, midazolam is frequently given before propofol.

Potentiation

In a dose-dependent manner, volatile agents enhance the effects of neuromuscular blocking agents. Electrolyte disturbance (hypomagnesaemia), Penicillin, and probenecid can all increase the effects of neuromuscular blocking agents (the latter has no similar pharmacological activity).

Infra-additive interaction (antagonism).

This can be subdivided into the following categories:

-Pharmacokinetic interference occurs when one drug affects the absorption of another through the gastrointestinal tract or when hepatic microsomal enzyme induction influences metabolism.
-Heparin and protamine, for example, or heavy metals and chelating agents, are examples of chemical antagonists.
-Competitive reversible antagonistic antagonism of receptors, such as opioids and naloxone, and irreversible antagonistic antagonism of receptors

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.

The following are the appropriate doses of the drugs listed above:

Gentamicin (once daily) – 5-7 mg/kg = 90-126 mg and subsequent dose modified according to plasma levels
Ondansetron – 0.1 mg/kg, but a maximum of 4 mg as a single dose = 1.8 mg
Codeine should be administered orally at a dose of 1 mg/kg rather than intravenously, as the latter can cause ‘dangerous’ hypotension due to histamine release.
15 mg/kg paracetamol = 270 mg orally or intravenously (a loading dose of 20 mg/kg, or 360 mg, is sometimes recommended, which is not far short of the doses listed above).
Cefuroxime – the initial intravenous dose is 20 mg/kg (360 mg) depending on the indication (again, similar to the dose given in the answer options above).

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.

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.

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 Dopamine 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 less arrhythmogenic than adrenaline

Regarding dopamine part of the dose is converted to Noradrenaline in sympathetic nerve terminals.

Choosing an appropriate dose of local anaesthetic to reduce the chance of toxicity is the most important safety aspect in performing a caudal block.

The caudal will have to be inserted following induction of anaesthesia as performing it in an awake child is not a viable option.

The patient is placed in the lateral position and the sacral hiatus is identified. Under strict asepsis, a needle ( usually a 21-23FG needle) is advanced at an angle of approximately 55-65° to the coronal plane at the apex of the sacrococcygeal membrane. When there is loss of resistance, thats the endpoint. The needle must first be aspirated before anaesthetic agent is injected because there is a risk (1 in 2000) of perforating the dura or vascular puncture.

Alternatively, a 22-gauge plastic cannula can be used. Following perforation of the sacrococcygeal membrane, the stilette is removed and only the blunter plastic cannula is advanced. This reduces the risk of intravascular perforation.

Eliciting an appropriate end motor response at an appropriate current strength when the caudal and epidural spaces are stimulated helps in improving the efficacy and safety of neural blockade. A 22G insulated needle is advanced in the caudal canal until a pop is felt. If the needle is placed correctly, an anal sphincter contractions (S2 to S4) is seen when an electrical stimulation of 1-10 mA is applied.

The application of ultrasound guidance in identification of the caudal epidural space has been shown to prevent inadvertent dural puncture and to increase the safety and efficacy of the block in children.

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

Gentamicin is a broad-spectrum antibiotic whose mechanism of action involves inhibition of protein synthesis by binding to 30s ribosomes. Its major adverse effect is nephrotoxicity and ototoxicity

Aminoglycoside bind to 30s subunit of ribosome causing misreading of mRNA

Tetracyclines inhibit 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.

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%