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.

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.

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

The fall in plasma concentration of a drug with time decreases exponentially in a single compartment pharmacokinetic model (wash-out curve).

A straight line is produced when the logarithm (ln) of a drug’s plasma concentration is plotted against time because a constant proportion of the drug is removed from the plasma per unit time. The line’s gradient or slope can be expressed mathematically as k. (the rate constant). The gradient is related to the half life (T1/2) because it can be used to predict a drug’s plasma concentration at any time.

According to the following formula, clearance (CL), volume of distribution (Vd), and elimination rate constant (k) are mathematically related.

CL = Vd x k

For drug A, CL = 1 x 0.1 = 0.1units per minute

For drug B, Cl = 2 x 0.2 = 0.4 units per minute

Hence, it is proved that Drug A has a lower clearance than drug B.

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 ?-2 adrenoceptor has three subtypes (2a, 2b and 2c). The receptors are generally presynaptic, meaning they prevent noradrenaline from being released at nerve endings. Both the central and peripheral nerve systems are affected by the ?-2 agonists. ?-2 agonists cause drowsiness, analgesia, and euphoria centrally in the locus coeruleus (in the brainstem), lower the MAC of volatile anaesthetic drugs, and are used to treat acute withdrawal symptoms in chronic opioid addicts.

The most common impact of ?-2 agonists on heart rate is bradycardia. The adrenoreceptors ?-1 and ?-2 are blocked by phenoxybenzamine.

Clonidine is a selective agonist for the ? -2 receptor, having a 200:1 affinity ratio for the ?-2: ?-1 receptors, respectively.

Tizanidine is similar to clonidine but has a few key variances. It has the same sedative, anxiolytic, and analgesic characteristics as clonidine, although for a shorter period of time and with less effect on heart rate and blood pressure.

Dexmedetomidine, like clonidine, is a highly selective ?-2 adrenoreceptor agonist having a higher affinity for the ?-2 receptor. In the case of ?-2: ?-1 receptors, the affinity ratio is 1620:1. It has a biphasic blood pressure impact and induces a brief rise in blood pressure and reflex bradycardia (activation of ?-2b subtypes of receptors in vascular smooth muscles), followed by a reduction in sympathetic outflow from the brainstem and hypotension/bradycardia.

A prodrug is methyldopa. It blocks the enzyme dopa-decarboxylase, which converts L-dopa to dopamine (a precursor of noradrenaline and adrenaline). It is also converted to alpha-methyl noradrenaline, a centrally active agonist of the ?-2 adrenoreceptor. These two processes contribute to its blood pressure-lowering effect. Without a rise in heart rate, cardiac output is generally maintained. The heart rate of certain patients is slowed.

Phentolamine is a short-acting antagonist of peripheral ?-1 and ?-2 receptors that causes peripheral vascular resistance to reduce and vasodilation to increase. It’s used to treat hypertensive situations that aren’t life threatening (e.g. hypertension from phaeochromocytoma).

A baroreceptor reflex commonly causes reflex tachycardia when systemic vascular resistance drops.

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.

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

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

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

The 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.

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.

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.

Caudal analgesia using bupivacaine is a widely employed technique for achieving both intraoperative and early postoperative pain relief. 0.5 ml/kg of 0.25% plain bupivacaine is favoured by many practitioners who employ this fixed scheme for procedures involving sacral dermatomes (circumcision, hypospadias repair) as well as lower thoracic dermatomes (orchidopexy). However, there are other dosing regimens for caudal blocks with variable analgesic success rates: These include 0.75 ml/kg, 1.0 ml/kg and 1.25 ml/kg.

A study indicated that plain bupivacaine 0.25% at a dose of 0.75 ml/kg compared to a dose of 0.5 ml/kg when administered for herniotomies provided improved quality of caudal analgesia with a low side effects profile. There were consistently more patients with favourable objective pain scale (OPS) scores at all timelines, increased the time to the analgesic request with similar postoperative consumption of paracetamol in the group of patients who received 0.75 ml/kg of 0.25% bupivacaine.

Metronidazole is a nitroimidazole antiprotozoal drug that is selectively absorbed by anaerobic bacteria and sensitive protozoa. Once taken up be anaerobes, it is nonenzymatically reduced by reacting with reduced ferredoxin. This reduction results in products that accumulate in and are toxic to anaerobic cells. The metabolites of metronidazole are taken up into bacterial DNA, forming unstable molecules. This action occurs only when metronidazole is partially reduced, and, because this reduction usually happens only in anaerobic cells, it has relatively little effect on human cells or aerobic bacteria.

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.

Ciprofloxacin belongs to the quinolone group of antibiotics, and doxycycline and minocycline are tetracyclines. So, they are not affected by beta-lactamase.
However, amoxicillin is a beta-lactam antibiotic and beta-lactamase cleaves the beta-lactam ring present in amoxicillin. This results in the breakdown of the antibiotic and thus the area of erythema dramatically increased.
Co-amoxiclav contains amoxicillin and clavulanic acid which protects amoxicillin from beta-lactamase.

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.

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.

Barbiturates are derived from barbituric acid, which itself is nondepressant, but appropriate side-chain substitutions result in CNS depressant activity that varies in potency and duration with carbon chain length, branching, and saturation.

Oxybarbiturates retain an oxygen atom on number 2-carbon atom of the barbituric acid ring.

Thiobarbiturates replace this oxygen atom with a sulphur atom, which confers greater lipid solubility. Generally speaking, a substitution such as sulphuration that increases lipid solubility is associated with greater hypnotic potency and more rapid onset, but shorter duration of action.

Addition of a methyl group to the nitrogen atom of the barbituric acid ring, as with oxybarbiturate methohexital, also results in a compound with a short duration of action.

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

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

ID = Cpss × CL

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

ID = Cpss × 20

Therefore,

Cpss = 100 mg/20000 ml

Cpss = 0.005 mg/mL or 5 mcg/mL

Adrenaline acts on ?1, ?2,?1, and ?2 receptors and also on dopamine receptors (D1, D2) and have sympathomimetic effects.

Natural catecholamines are Adrenaline, Noradrenaline, and Dopamine

Adrenaline is a sympathomimetic amine with both alpha and beta-adrenergic stimulating properties.
Adrenaline is the drug of choice for anaphylactic shock
Adrenaline is also used in patients with cardiac arrest. The preferred route is i.v. followed by the intra-osseous and endotracheal route.

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

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 action of class 1 anti-arrhythmic is sodium channel blockade. Subclasses of this action reflect effects on the action potential duration (APD) and the kinetics of sodium channel blockade.

Drugs with class 1A prolong the APD and refractory period, and dissociate from the channel with intermediate kinetics.

Drugs with class 1B action shorten the APD in some tissues of the heart, shorten the refractory period, and dissociate from the channel with rapid kinetics.

Drugs with class 1C action have minimal effects on the APD and the refractory period, and dissociate from the channel with slow kinetics.

With a history of drug abuse, the patient is likely dependent on and tolerant to opioids. He is also likely to experience significant pain from his injuries. Providing adequate pain relief with regular paracetamol and NSAIDs in combination with a pure opioid agonist while at the same time avoiding occurrence of acute withdrawal syndrome is the goal.

Administering a baseline dose of opioid corresponding to the patient’s usual opioid use plus an opioid dose required to address the level of pain the patient experience can help prevent opioid withdrawal. The best approach is by empowering the patient to use patient controlled analgesia (PCA). The infusion rate, bolus dose and lock-out time are adjusted accordingly. Using PCA helps in avoiding staff/patient confrontations about dose and dosing interval.

2.5 mg heroin is equivalent to 3.3 mg morphine. This patient is usually on 200 mg of heroin per 24 hours. The equivalent dose of morphine is 80 × 3.3 =254 mg per 24 hours (11 mg/hour).

Epidural or spinal opioids might be the best choice for providing a systemic dose of opioids when patients are in remission to avoid withdrawal. Lumbar vertebral fractures is a contraindication to this route of analgesia.

The long half life of Oral methadone make titration to response difficult. Also, absorption of methadone by the gastrointestinal tract is variable. It is therefore NOT the best choice for acute pain management.

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

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

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

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

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

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%

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.

Resistance pulmonary arteries constrict in response to alveolar and airway hypoxia, diverting blood to better-oxygenated alveoli.

In atelectasis, pneumonia, asthma, and adult respiratory distress syndrome, hypoxic pulmonary vasoconstriction optimises O2 uptake. Hypoxic pulmonary vasoconstriction helps maintain systemic oxygenation during single-lung anaesthesia.

A redox-based O2 sensor within pulmonary artery smooth muscle cells is involved in hypoxic pulmonary vasoconstriction. The production of reactive oxygen species by smooth muscle cells in the pulmonary artery varies in proportion to PaO2. Hypoxic removal of these redox second messengers inhibits voltage-gated potassium channels, depolarizing smooth muscle cells in the pulmonary artery.

L-type calcium channels are activated by depolarization, which raises cytosolic calcium and causes hypoxic pulmonary vasoconstriction. Some anaesthetics suppress this response, increasing the risk of further deterioration in ventilation perfusion mismatch.

Agents that inhibit HPV are ether, halothane, and desflurane (>1.6 MAC).
Agents with no effect on HPV include thiopentone, fentanyl, desflurane (1MAC), isoflurane (<1.5MAC), sevoflurane(1MAC), and propofol.

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 an ACID, 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 = 4.3 + log ([ionised]/[unionised])
7.4 − 4.3 = log ([ionised]/[unionised])
log 3.1 = 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 = 10, 2 =100, 3 = 1000, and 4 = 10,000.

If you want to find the antilogarithm of 3.1, for a number between 3 and 4, the antilogarithm will return a value between 1000 and 10,000. The ratio is 1:1 if pKa = pH, that is, pH pKa = log 0. (50 percent ionised and unionised).

According to the above value, there is only one unionised molecule for every approximately 1000 (1259) ionised molecules of this drug in plasma, implying that this drug is largely ionised in plasma (99.99 percent ).