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.

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.

Because enflurane is much less soluble in blood and has a blood: gas partition coefficient of 1.8, both wash-in and wash-out should be faster.

Sevoflurane’s sweet-smelling, non-irritant nature, combined with a low blood: gas partition coefficient, would result in similar offset and onset characteristics.

Isoflurane and enflurane have a molecular weight of 184.

The oil: gas partition coefficient on a volatile agent is a measure of lipid solubility, potency, and thus MAC. Halothane has an oil: gas partition coefficient of 220 and a MAC of 0.74. One would expect the MAC to be higher with an oil gas partition coefficient of 180 (less lipid soluble).

The conversion of halothane (20%) to trifluoroacetic acid via oxidative metabolism has been linked to the development of hepatitis.

P450 2E1 converts sevoflurane to hexafluoroisopropanol, which results in the release of inorganic fluoride ions. It’s the only fluorinated volatile anaesthetic that doesn’t break down into trifluoracetic acid.

Desflurane is likely to cause airway irritation, which can lead to coughing, apnoea, and laryngospasm, despite its low blood:gas partition coefficient (0.42).

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

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

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

Dopamine (DA) is a dopaminergic (D1 and D2) as well as adrenergic α and β1 (but not β2 ) 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 cyclic adenosine monophosphate).

Moderately high doses produce a positive inotropic (direct β1 and D1 action + that due to NA release), but the little chronotropic effect on the heart.

Vasoconstriction (α1 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 α and β receptors; does not penetrate the blood-brain barrier€”no Central nervous system effects.

Dopamine is less arrhythmogenic than adrenaline

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

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 inpatients with propofol infusion syndrome.

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.

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.

Lidocaine 1% is formulated either as 1000 mg/100 mL or 100 mg/1mL.

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.

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.

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.

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

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.

Ketamine is usually used as a racemic mixture, i.e. (R/S)-ketamine. For over 20 years, use of the more potent (S)-enantiomer by anaesthesiologists has become a preferred option due to the assumption of increased anaesthetic and analgesic properties, a more suitable control of anaesthesia, and of an improved recovery from anaesthesia.

The use of ketamine in anaesthesia and psychiatry may be accompanied by the manifestation of somatic and especially psychomimetic symptoms such as perceptual disturbances, experiences of dissociation, euphoria, and anxiety.

Ketamine is a phencyclidine (hallucinogenic) derivative that is administered in a dose of 2 mg/kg and acts by blocking NMDA (N-methyl-D-aspartate) receptors of glutamate.

It is a powerful bronchodilator agent and is, therefore, an intravenous anaesthetic of choice in bronchial asthma (halothane is an inhalational anaesthetic agent of choice for bronchial asthma). It is also used in the management of refractory status epilepticus.

It is an acid solution with an elimination half-life of three hours.

It has S (+) enantiomer and R (-) enantiomer. the S(+) enantiomer is two to four times more potent than the R(-) and is less likely to produce hallucinations.

Its use is contraindicated in patients with ischaemic heart disease because it increased sympathetic outflow leading to tachycardia and increased cardiac output which in turn increases the myocardial oxygen demand.

The neuromuscular blocking agent is likely to be filtered and not reabsorbed by the renal tubules due to an exclusion process.

Neuromuscular blocking agents that contain one or more quaternary nitrogen atoms are polar and ionised. As a result, the molecules have low lipid solubility, low membrane diffusion capacity, and low distribution volume.

It’s unlikely that a compound with three quaternary nitrogen atoms is an ester. Its high polarity would prevent molecules from moving quickly into tissues.

When drugs have a low hepatic extraction ratio (0.3), the venous and arterial drug concentrations are nearly identical. The liver is not the primary site of drug metabolism.

Therefore:

Changes in liver blood flow have no effect on clearance.
Protein binding, intrinsic metabolism, and excretion are all very sensitive to changes in clearance.
When taken orally, there is no first-pass metabolism.

There is no reason for the lungs to eliminate any neuromuscular blocking agent.

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.

Phenytoin, Carbamazepine, and Valproate act by inhibiting the sodium channels when these are open. These drugs also prolong the inactivated stage of these channels (Sodium channels are refractory to stimulation till these reach the closed/ resting phase from inactivated phase)

Carbamazepine is the drug of choice for partial seizures and trigeminal neuralgia

It can have neurotoxic side effects. Major neurotoxic effects include dizziness, headache, ataxia, vertigo, and diplopia

The half-life of carbamazepine is about 13-17 years.

It is metabolized in liver into active metabolite, carbamazepine-10,11-epoxide.

Cephalosporin belongs to a family of beta-lactam antibiotics. All β-lactam antibiotics interfere with the synthesis of the bacterial cell walls. The β-lactam antibiotics inhibit the transpeptidases so that cross-linking (which maintains the close-knit structure of the cell wall) does not take place i.e. they inhibit bacterial cell wall formation.

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

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

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

Glyceryl trinitrate (GTN) has a significant first pass metabolism. About 90% of a dose of GTN is metabolised in the liver by the enzyme glutathione organic nitrate reductase.

An INSIGNIFICANT amount of metabolism occurs in the intestinal mucosa.

There is approximately 1% bioavailability after oral administration and 38% after sublingual administration.

GTN does NOT cause gastric irritation and it is well absorbed in the gastrointestinal tract.

The volume of distribution of GTN is 2.1 to 4.5 L/kg. This is HIGH.

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

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.

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.

Nausea and vomiting occur commonly due to Chemoreceptor Trigger Zone (CTZ) stimulation by dopamine (Domperidone but not metoclopramide can be used for the treatment of this vomiting)

Dopamine itself cannot cross the blood-brain barrier (BBB) but its precursor levodopa can cross BBB.

Dopamine can modulate extrapyramidal symptoms like acute dyskinesia, tardive dyskinesia, Parkinsonism, and Neuroleptic malignant syndrome.

Dopamine inhibits the secretion of prolactin from the pituitary gland.

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.

It is well known that atropine will cross the placenta and that maternal administration results in an increase in fetal heart rate.

Atropine is highly selective for muscarinic receptors. Its potency at nicotinic receptors is much lower, and actions at non-muscarinic receptors are generally undetectable clinically. Atropine does not distinguish among the M1, M2, and M3 subgroups of muscarinic receptors. In contrast, other antimuscarinic drugs are moderately selective for one or another of these subgroups. Most synthetic antimuscarinic drugs are considerably less selective than atropine in interactions with nonmuscarinic receptors.

A study on glycopyrrolate, a quaternary ammonium salt, was found to have a fetal: maternal serum concentration ratio of 0.4 indicating partial transfer.

Heparin, suxamethonium, and vecuronium do not cross the placenta.