Bradycardia and miosis should be anticipated following the administration of anticholinesterases.

Anticholinesterase agents include the following medications:
– Pyridostigmine, neostigmine, and edrophonium which play a significant role in the diagnosis and the management of myasthenia gravis.
– Rivastigmine, galantamine and donepezil are cholinesterase inhibitors found to be significantly useful in the management of Alzheimer’s disease.

Mechanism of action and pharmacological effects:
Inhibition of cholinesterase increases the level and the duration of action of acetylcholine within the synaptic cleft.

Thus, cholinergic effects such as a reduction in heart rate (bradycardia), miosis (pupillary constriction), increased secretions, increased gastrointestinal motility and reduction in BP may occur with anticholinesterases.

Toxins such as organophosphates and carbamates also are primarily anticholinergic and cause the following typical SLUDGE symptoms:
– Salivation
– Lacrimation
– Urination
– Diaphoresis
– Gastrointestinal upset
– Emesis

The total daily morphine dose is 30 x 2 = 60 mg. Therefore, the breakthrough dose should be one-sixth of this, 10 mg.

Dilation of systemic veins is a beneficial effect of nitro-glycerine.

Administration of nitro-glycerine results in the dilation of systemic veins and decrease of myocardial wall tension and oxygen demand. Dilatation of systemic veins can cause reduced systemic vascular resistance leading to reduced cardiac workload thus reducing anginal symptoms secondary to demand ischemia.

This is accompanied by vasodilation of large and medium-sized coronary arteries with increased coronary blood flow to the sub endocardium.

Tricyclic compounds can’t be cleared by haemodialysis.

Drugs that can be cleared with haemodialysis include: (BLAST)
– Barbiturate
– Lithium
– Alcohol (inc methanol, ethylene glycol)
– Salicylates
– Theophyllines (charcoal hemoperfusion is preferable)

Drugs which cannot be cleared with haemodialysis include:
– Tricyclics
– Benzodiazepines
– Dextropropoxyphene (Co-proxamol)
– Digoxin
– Beta-blockers

Memantine is an antagonist of the NMDA (N-Methyl-D-Aspartate)-receptor subtype of glutamate receptor. It is used to slow the neurotoxicity thought to be involved in Alzheimer’s disease and other neurodegenerative diseases.

Drug interactions:
When given concomitantly with other NMDA-receptor antagonists (e.g., ketamine, amantadine) increase the risk of psychosis.
Dopamine agonists, L-dopa, and anticholinergics enhance effects of memantine.
Antispasmodics (e.g., baclofen)  enhance effects, as memantine has some antispasmodic effects.
Drugs excreted by cationic transporters in the kidney (e.g. quinine, cimetidine, ranitidine) reduce excretion.

Common adverse effects include dizziness, headache, confusion, diarrhoea, and constipation.

Vestibular damage is a neurological side effect of streptomycin.

Streptomycin is an aminoglycoside bactericidal antibiotic. It is used in the treatment of tularaemia and resistant mycobacterial infections.
The most common neurological side-effect is vestibular damage leading to vertigo and vomiting.
Cochlear damage is less frequent and results in deafness.
Other side-effects include rashes, angioneurotic oedema, and nephrotoxicity.

Metabolic acidosis is associated with cocaine overdose.
In overdose, cocaine leads to agitation, tachycardia, hypertension, sweating, hallucinations, and finally convulsions.
Metabolic acidosis, hyperthermia, rhabdomyolysis, and ventricular arrhythmias also occur.
Chronic use may be associated with premature coronary artery disease, dilated cardiomyopathy, and increased risk of cerebral haemorrhage.
There are 3 stages for acute cocaine toxicity:
Stage I: CNS symptoms of headache, vertigo, pseudo hallucinations, hyperthermia, hypertension.
Stage II: increased deep tendon reflexes, tachypnoea, irregular breathing, hypertension.
Stage III: Areflexia, coma, fixed and dilated pupils, hypotension, ventricular fibrillation, apnoea, and respiratory failure.

Treatment:
– Airway, breathing, and circulation to be secured. The patient’s fever should be managed, and one should rule out hypoglycaemia as a cause of the neuropsychiatric symptoms.
– Cardiovascular toxicity and agitation are best-treated first-line with benzodiazepines to decrease CNS sympathetic outflow.
– The mixed beta/alpha blocker labetalol is safe and effective for treating concomitant cocaine-induced hypertension and tachycardia.
– Non-dihydropyridine calcium channels blockers such as diltiazem and verapamil have been shown to reduce hypertension reliably, but not tachycardia.
– Dihydropyridine agents such as nifedipine should be avoided, as reflex tachycardia may occur.
– The alpha-blocker phentolamine has been recommended but only treats alpha-mediated hypertension and not tachycardia.

The use of nitrates and nicorandil concomitantly with sildenafil citrate is contraindicated.

Sildenafil (Viagra) is a phosphodiesterase type V inhibitor used in the treatment of impotence.

Contraindications
– Patients taking nitrates and related drugs such as nicorandil
– Hypotension
– Recent stroke or myocardial infarction (NICE recommend waiting 6 months)

Side-effects:
Visual disturbances e.g. cyanopsia, non-arthritic anterior ischaemic Neuropathy
Nasal congestion
Flushing
Gastrointestinal side-effects
Headache

Carbimazole is used to treat hyperthyroidism. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents thyroid peroxidase enzyme from coupling and iodinating the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones T3 and T4 (thyroxine).

The two statements that fit the characteristics of doxapram are, epilepsy is a contraindication for doxapram use and concurrent use with theophylline may increase agitation.

Doxapram is a central respiratory stimulant. In clinical practice, doxapram is usually used for patients who have an acute exacerbation of chronic obstructive pulmonary disease (COPD) who are unsuitable for admission to the intensive therapy unit for ventilatory support. Doxapram infusion may buy an extra 24 h to allow for recovery.

Contraindications include: ischaemic heart disease, epilepsy, cerebral oedema, acute stroke, asthma, hypertension, hyperthyroidism, and pheochromocytoma.
The infusion may worsen agitation and dyspnoea and lead to hypertension, nausea, vomiting and urinary retention.

Drug interactions:
Concomitant administration of doxapram and aminophylline (theophylline) can cause increased skeletal muscle activity, agitation, and hyperactivity.

Acute dystonic reactions (extrapyramidal symptoms) such as spasmodic torticollis, trismus, and oculogyric crises can occur following the administration of metoclopramide or stemetil and thus, neither is recommended for the treatment of nausea in young women.

Such reactions respond well to treatment with benztropine or procyclidine.
– Benztropine: It is an anticholinergic medication with significant CNS penetration.
A single dose of benztropine 1 to 2 mg IV followed by 1 to 2 mg p.o twice a day for up to 7 days to prevent a recurrence. Subsequently, both the offending agent and those from the same group should be avoided.
– Alternatively, diphenhydramine can be used intravenously (up to a dose of 50mg) or intramuscularly followed by p.o therapy every 6 hours for 1 to 2 to prevent a recurrence.
– Second-line therapy with IV benzodiazepines is reserved for those patients who do not respond to anticholinergics.

1mg Prednisolone = 4mg hydrocortisone, so the actual equivalent daily dose is 7mg.

Carbon monoxide (CO) poisoning, considered as the great imitator of other diseases, as the patients present with a myriad of symptoms. The carbon monoxide diffuses rapidly across the pulmonary capillary membrane binding to the haem molecule with a very high affinity (240 times that of oxygen) forming carboxy-haemoglobin (COHb). Non-smokers have a baseline COHb of ,3% while smokers have a baseline COHb of 10-15%.

Use of Hyperbaric oxygen therapy (HBOT) for treatment of mild to moderate CO poisoning is not routine.
The selection criteria for HBOT in cases of CO poisoning include:
• COHb levels > 20-25%
• COHb levels > 20% in pregnant patient
• Loss of consciousness
• Severe metabolic acidosis (pH <7.1)
• Evidence of end-organ ischemia (e.g., ECG changes, chest pain, or altered mental status)
Principle of HBOT:
Exposing patients to 100 percent oxygen under supra-atmospheric conditions results in a decrease in the half-life (t1/2) of COHb, from , 90 min in atmospheric air to , 30 minutes. The amount of oxygen dissolved in the blood also rises from , 0.3 to 6 mL/dL, increasing the delivery of non-haemoglobin-bound oxygen to the tissues.

The cytochrome p450 3A4 enzyme system in the liver is affected by grapefruit juice.

Patients taking antihistamines should be advised to avoid drinking grapefruit juice. This is because constituents of grapefruit juice such as naringin and bergamottin inhibit CYP3A4 in the liver, particularly at high doses, leading to decreased drug elimination via hepatic metabolism and can increase potential drug toxicities.

Inhibition of this enzyme system leads to reduced metabolism of antihistamines leading to an increased incidence of side effects like excessive drowsiness and nausea as in this patient.

Cyanide poisoning:
Aetiology:
Smoke inhalation, suicidal ingestion, and industrial exposure (specific industrial processes involving cyanide include metal cleaning, reclaiming, or hardening; fumigation; electroplating; and photo processing) are the most frequent sources of cyanide poisoning. Treatment with sodium nitroprusside or long-term consumption of cyanide-containing foods is a possible source.
Cyanide exposure most often occurs via inhalation or ingestion, but liquid cyanide can be absorbed through the skin or eyes. Once absorbed, cyanide enters the blood stream and is distributed rapidly to all organs and tissues in the body. 

Pathophysiology:
Inside cells, cyanide attaches itself to ubiquitous metalloenzymes, rendering them inactive. Its principal toxicity results from inactivation of cytochrome oxidase (at cytochrome a3), thus uncoupling mitochondrial oxidative phosphorylation and inhibiting cellular respiration, even in the presence of adequate oxygen stores.

Presentation:
• ‘Classical’ features: brick-red skin, smell of bitter almonds
• Acute: hypoxia, hypotension, headache, confusion
• Chronic: ataxia, peripheral neuropathy, dermatitis

Management:
• Supportive measures: 100% oxygen, ventilatory assistance in the form of intubation if required.
• Definitive: Hydroxocobalamin (iv) is considered the drug of choice and is approved by the FDA for treating known or suspected cyanide poisoning.
• Coadministration of sodium thiosulfate (through a separate line or sequentially) has been suggested to have a synergistic effect on detoxification.
Mechanism of action of hydroxocobalamin:
• Hydroxocobalamin combines with cyanide to form cyanocobalamin (vitamin B-12), which is renally cleared.
• Alternatively, cyanocobalamin may dissociate from cyanide at a slow enough rate to allow for cyanide detoxification by the mitochondrial enzyme rhodanese.

The cardiovascular effects of β-adrenoceptor block result from reduction of the sympathetic drive which includes reduced heart rate (automaticity) and reduced myocardial contractility (rate of rise of pressure in the ventricle). This will lead to reduced cardiac output and an overall fall in oxygen consumption.

Among the give options, reactivation of tuberculosis may occur in a patient under treatment with etanercept.
Etanercept is a biological TNF inhibit commonly used to control ankylosing spondylitis, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, and rheumatoid arthritis.
Etanercept is a soluble receptor that binds both TNF-alpha and TNF-beta to inhibit the inflammatory response in joints and skin that is characteristic of these autoimmune disorders.
The most common adverse effects include infections (viral, bacterial, and fungal – mostly upper respiratory tract infections) and injection site reaction (erythema, itching, pain, swelling, bleeding, bruising).
Rarely it can also cause, reactivation of hepatitis B and TB, pneumocystis pneumonia, congestive cardiac failure, Steven-Johnson syndrome, toxic epidermal necrolysis, etc.

The presence of tinnitus, fever and hyperventilation are clues for aspirin (salicylate) toxicity.
Clinical Presentation of salicylate toxicity can include:
• Pulmonary manifestations include: Hyperventilation, hyperpnea, severe dyspnoea due to noncardiogenic pulmonary oedema, fever and dyspnoea due to aspiration pneumonitis
• Auditory symptoms caused by the ototoxicity of salicylate poisoning include: Hard of hearing and deafness, and tinnitus (commonly encountered when serum salicylate concentrations exceed 30 mg/dL).
• Cardiovascular manifestations include: Tachycardia, hypotension, dysrhythmias – E.g., ventricular tachycardia, ventricular fibrillation, multiple premature ventricular contractions, asystole – with severe intoxication, Electrocardiogram (ECG) abnormalities – E.g., U waves, flattened T waves, QT prolongation may reflect hypokalaemia.
• Neurologic manifestations include: CNS depression, with manifestations ranging from somnolence and lethargy to seizures and coma, tremors, blurring of vision, seizures, cerebral oedema – With severe intoxication, encephalopathy
• GI manifestations include: Nausea and vomiting, which are very common with acute toxicity, epigastric pain, GI haemorrhage – More common with chronic intoxication, intestinal perforation, pancreatitis, hepatitis – Generally in chronic toxicity; rare in acute toxicity, Oesophageal strictures – Reported as a very rare delayed complication
• Genitourinary manifestations include: Acute kidney injury (NSAID induced Nephropathy) is an uncommon complication of salicylate toxicity, renal failure may be secondary to multisystem organ failure.
• Hematologic effects may include prolongation of the prothrombin and bleeding times and decreased platelet adhesiveness. Disseminated intravascular coagulation (DIC) may be noted with multisystem organ failure in association with chronic salicylate toxicity.
• Electrolyte imbalances like: Dehydration, hypocalcaemia, acidaemia, Syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypokalaemia
Management of these patients should be done in the following manner:
• Secure Airway, Breathing, and Circulation
• Supportive therapy
• GI decontamination
• Urinary excretion and alkalization
• Haemodialysis

The most probable diagnosis for this patient is delirium tremens due to alcohol withdrawal, which should be treated as a medical emergency. 
Delirium tremens is a hyperadrenergic state and is often associated with tachycardia, hyperthermia, hypertension, tachypnoea, tremor, and mydriasis.
Treatment:
– The most common and validated treatment for alcohol withdrawal is benzodiazepine: first-line treatment includes oral lorazepam.
– If the symptoms persist, or the medication is refused, parenteral lorazepam, haloperidol or olanzapine should be given.
– Central-acting, alpha-2 agonists such as clonidine and dexmedetomidine should not be used alone for the treatment of alcohol withdrawal.
– It is also recommended to avoid using alcohol, antipsychotics, anticonvulsants, beta-adrenergic receptor blockers, and baclofen for the treatment of alcohol withdrawal as there are not enough studies to support the safety of these.

The best treatment for the patient in question would be methylene blue.
The most probable diagnosis in this patient is methemoglobinemia due to the ingestion of amyl nitrate.

Amyl nitrate promotes the formation of methaemoglobin, which avidly conserves oxygen and leads to decreased tissue oxygen saturations.

Treatment of choice includes methylene blue and vitamin C.

Adverse effects:
Benign side effects include green or blue discoloration of urine and patients should be forewarned.
Significant side effects are based on methylene blue, itself, being an oxidizing agent and an inhibitor of monoamine oxidase A (MAO-A).
As an oxidizing agent, methylene blue can actually precipitate methemoglobinemia or haemolysis in high doses or when ineffectively reduced.
Methylene blue administration in a patient taking a serotonergic agents may predispose to serotonin syndrome.

Note: Although methylene blue administration is controversial in the setting of G6PD-deficiency due to reduced levels of NADPH, it is not contraindicated and should be administered cautiously and judiciously.

Among the following hypertensives, lisinopril (an ACE inhibitor) is contraindicated in patients who are planning for pregnancy.

Per the NICE guidelines, when treating the woman in question, she should be treated as if she were pregnant given the absence of effective contraception.
ACE inhibitors such as lisinopril are known teratogens and most be avoided.

Drugs contraindicated in pregnancy:
Antibiotics
Tetracyclines
Aminoglycosides
Sulphonamides and trimethoprim
Quinolones

Other drugs:
ACE inhibitors, angiotensin II receptor antagonists
Statins
Warfarin
Sulfonylureas
Retinoids (including topical)
Cytotoxic agents
The majority of antiepileptics including valproate, carbamazepine, and phenytoin are known to be potentially harmful.

The most likely complaint of this patient would be hot flushes.

Alopecia and cataracts are listed in the BNF as possible side-effects. They are however not as prevalent as hot flushes, which are very common in pre-menopausal women.

Tamoxifen is a Selective Oestrogen Receptor Modulator (SERM) which acts as an oestrogen receptor antagonist and partial agonist. It is used in the management of oestrogen receptor-positive breast cancer

Adverse effects:
Menstrual disturbance: vaginal bleeding, amenorrhoea
Hot flushes – 3% of patients stop taking tamoxifen due to climacteric side-effects.
Venous thromboembolism.
Endometrial cancer
Tamoxifen is typically used for 5 years following the removal of the tumour.

Raloxifene is a pure oestrogen receptor antagonist and carries a lower risk of endometrial cancer.

Although antagonistic with respects to breast tissue tamoxifen may serve as an agonist at other sites. Therefore the risk of endometrial cancer is increased cancer.

Carbon monoxide (CO) poisoning:
It is considered as the great imitator of other diseases as the patients present with a myriad of symptoms. The carbon monoxide diffuses rapidly across the pulmonary capillary membrane binding to the haem molecule with a very high affinity (240 times that of oxygen) forming carboxy-haemoglobin (COHb). Non-smokers have a baseline COHb of ,3% while smokers have a baseline COHb of 10-15%.

Clinical features of carbon monoxide toxicity:
Headache: 90% of cases (most common clinical feature)
Nausea and vomiting: 50%
Vertigo: 50%
Confusion: 30%
Subjective weakness: 20%
Severe toxicity: ‘pink’ skin and mucosa, hyperpyrexia, arrhythmias, extrapyramidal features, coma, death
Cherry red skin is a sign of severe toxicity and is usually a post-mortem finding.
Management
• 100% oxygen
• Hyperbaric oxygen therapy (HBOT)

The use of Hyperbaric oxygen therapy (HBOT) for treatment mild to moderate CO poisoning is not routine.
The selection criteria for HBOT in cases of CO poisoning include:
• COHb levels > 20-25%
• COHb levels > 20% in pregnant patient
• Loss of consciousness
• Severe metabolic acidosis (pH <7.1)
• Evidence of end-organ ischemia (e.g., ECG changes, chest pain, or altered mental status)

Among the given options the most appropriate management in this patient would be ethanol and haemodialysis.

Ethanol competes with ethylene glycol for alcohol dehydrogenase and thus, helps manage a patient with ethylene glycol toxicity.

Ethylene glycol is a type of alcohol used as a coolant or antifreeze
Features of toxicity are divided into 3 stages:
Stage 1: (30 min to 12 hours after exposure) Symptoms similar to alcohol intoxication: confusion, slurred speech, dizziness (CNS depression)
Stage 2: (12 – 48 hours after exposure) Metabolic acidosis with a high anion gap and high osmolar gap. Also tachycardia, hypertension
Stage 3: (24 – 72 hours after exposure) Acute renal failure

Management has changed in recent times:
Fomepizole, an inhibitor of alcohol dehydrogenase, is now used first-line in preference to ethanol.
Ethanol has been used for many years works by competing with ethylene glycol for the enzyme alcohol dehydrogenase this limits the formation of toxic metabolites (e.g. glycolaldehyde and glycolic acid) which are responsible for the hemodynamic/metabolic features of poisoning.
Haemodialysis has a role in refractory cases.

The rationale behind the use of sodium bicarbonate is that it increases the alkalinity of the urine promoting lithium excretion. The preferred treatment in severe cases would be haemodialysis.

Lithium is a mood-stabilizing drug used most commonly prophylactically in bipolar disorder but also as an adjunct in refractory depression. It has a very narrow therapeutic range (0.4-1.0 mmol/L) and a long plasma half-life being excreted primarily by the kidneys. Lithium toxicity generally occurs following concentrations > 1.5 mmol/L.

Toxicity may be precipitated by dehydration, renal failure, diuretics (especially Bendroflumethiazide), ACE inhibitors, NSAIDs and metronidazole.

Features of toxicity
Coarse tremor (a fine tremor is seen in therapeutic levels)
Hyperreflexia
Acute confusion
Seizure
Coma

Management
Mild-moderate toxicity may respond to volume resuscitation with normal saline
Haemodialysis may be needed in severe toxicity
Sodium bicarbonate is sometimes used but there is limited evidence to support this. By increasing the alkalinity of the urine it promotes lithium excretion.

Moxonidine and alpha-methyl dopa are centrally acting antihypertensives and modify blood pressure through modifying sympathetic activity.

Other options:
Verapamil is a calcium antagonist.
Minoxidil and hydralazine are both vasodilators.
Phenoxybenzamine is an alpha-blocker.

Adverse effects:
Dry mouth and somnolence were the most frequently reported adverse events, followed by headache, dizziness, nausea and allergic skin reactions.

Hyperthermia (Temperature 39.5 C) points towards the use of ecstasy.

MDMA (3,4 – methylenedioxymethamphetamine), or more commonly known as Molly or Ecstasy, is a synthetic psychoactive substance.
Patients who consumed MDMA may present in a tachycardic, hypertensive, hyperthermic, and agitated state.
Adverse effects, even at minor recreational doses, include increased muscle activity (such as bruxism, restless legs, and jaw clenching), hyperactivity, insomnia, difficulty concentrating and feelings of restlessness.

Treatment of MDMA overdose:
Emphasis should be on maintaining the airway along with the stabilization of breathing and circulation.
Patients may present obtunded due to hyponatremia requiring endotracheal intubation.
For the hyperthermic patient, evaporative cooling along with ice packs to the groin and axilla are beneficial.
Patients who present in severe toxicity within one hour of ingestion can receive activated charcoal PO or via an NG tube.
Antipyretics, such as acetaminophen, should be avoided as they have no role and can worsen an already compromised liver.

Tacrolimus is a calcineurin inhibitor used as an immunosuppressive agent used for prophylaxis of organ rejection post-transplant.

Pharmacology: Calcineurin inhibition leads to reduced T-lymphocyte signal transduction and IL-2 expression. It has a half-life of 12 hours (average).

Other off-label indications for the use of tacrolimus include Crohn disease, graft-versus-host disease (GVHD), myasthenia gravis, rheumatoid arthritis.

Adverse effects of tacrolimus includes:
Cardiovascular: Angina pectoris, cardiac arrhythmias, hypertension
Central nervous system: Abnormal dreams, headaches, insomnia, tremors.
Dermatologic: Acne vulgaris, alopecia, pruritis, rash
Endocrine and metabolic: Decreased serum bicarbonate, decreased serum iron, new-onset diabetes mellitus after transplant (NODAT), electrolyte disturbances.
Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhoea
Genitourinary: Urinary tract infection
Hepatic: Abnormal hepatic function tests
Neuromuscular and skeletal: Arthralgia, muscle cramps
Ophthalmic: Blurred vision, visual disturbance
Otic: Otalgia, otitis media, tinnitus
Renal: Acute renal failure

Other options:
Sirolimus (a macrolide) is an mTOR inhibitor that blocks the response to IL-2 and has a half-life of 12–15 hours.
Azathioprine inhibits purine synthesis, an essential step in the proliferation of white cells and has a half-life of around 5 hours.

Both fibrates and nicotinic acid have been associated with myositis, especially when combined with a statin. However, the Committee on Safety of Medicines has produced guidance which specifically warns about the concomitant prescription of fibrates with statins concerning muscle toxicity.

Bezafibrate: It is a fibric acid derivative (fibrate) that has been used as a class of agents known to decrease triglyceride levels while substantially increasing HDL-C levels.
Pharmacological effects:
– Increases VLDL catabolism by increasing lipoprotein and hepatic triglyceride lipase.
– Decreases triglyceride synthesis by inhibiting acetyl-CoA reductase.
– Decreases cholesterol synthesis by inhibiting HMG-CoA reductase.

Side effects:
– Hypersensitivity
– Primary biliary cirrhosis
– Pre-existing gallbladder disease
– Concurrent use with HMG-CoA inhibitors (statins) can produce myopathy
– Hepatic/renal impairment in a patient warrants dose adjustment as this drug is primarily excreted via the renal mechanism.

Contraindications: Concurrent use of MAO inhibitors, hypersensitivity, pre-existing cholestasis, and pregnancy.

Use: It can be used to treat Barth syndrome (characterized by dilated cardiomyopathy, neutropenia (presenting with recurrent infections), skeletal myopathy and short stature)

Different Oral Hypoglycaemic Agents (OHAs) and their respective mechanism(s) of action include:
• Sulfonylureas (such as, glipizide, gliclazide, glimepiride) – bind to ATP sensitive Potassium channels (K – ATP channels) in the ? cells of the islets of the pancreas. Inhibition of these channels lead to an altered resting membrane potential in these cells causing an influx of calcium which increases insulin secretion.
• Meglitinides (like Repaglinide) through a different receptor, they similarly regulate K – ATP channels thereby causing an increase in insulin secretion.
• Biguanides (e.g., Metformin) increase the hepatic AMP-activated protein kinase activity leading to reduced gluconeogenesis and lipogenesis and increased insulin-mediated uptake of glucose in muscles. (it doesn’t increase insulin secretion)
• Thiazolidinediones (rosiglitazone, pioglitazone) bind to PPAR-? and increase peripheral uptake of glucose and decrease hepatic glucose production.
• α-Glucosidase inhibitors (such as acarbose, miglitol, voglibose) competitively inhibit α-glucosidase enzymes in the intestine that digest the dietary starch thus, inhibiting the polysaccharide reabsorption as well as metabolism of sucrose to glucose and fructose.
• DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin) prolong the action of glucagon-like peptide. This leads to inhibition of glucagon release, increase in insulin secretion and a decrease in gastric emptying leading to a decrease in blood glucose levels.
• SGLT2 inhibitors (dapagliflozin and canagliflozin) inhibit glucose reabsorption in the proximal tubules of the renal glomeruli leading to glycosuria which in-turn reduces blood glucose levels.
Note: Side effects of pioglitazone are weight gain, pedal oedema, bone loss and precipitation of congestive cardiac failure.

The blood gas analysis provided above is suggestive of a mixed respiratory alkalosis and metabolic acidosis characteristic of salicylate overdose.

Pathophysiology:
The direct stimulation of the cerebral medulla causes hyperventilation and respiratory alkalosis.
As it is metabolized, it causes an uncoupling of oxidative phosphorylation in the mitochondria.
Lactate levels then increase due to the increase in anaerobic metabolism. This, along with a slight contribution from the salicylate metabolites result in metabolic acidosis.

Tinnitus is characteristic and salicylate ototoxicity may produce deafness. Other neurological sequelae include encephalopathy and agitation, seizures and CNS depression and coma. Cardiovascular complications include tachycardia, hypotension, and dysrhythmias (VT, VF, and asystole).

The symptoms of ataxia, slurred speech and blurred vision are all suggestive of phenytoin toxicity. Cimetidine increases the efficacy of phenytoin by reducing its hepatic metabolism.

Phenytoin has a narrow therapeutic index (10-20 mg/L) and its levels are monitored by measuring the total phenytoin concentration.
Cimetidine is an H2 receptor antagonist used in the treatment of peptic ulcers. It acts by decreasing gastric acid secretion.
Cimetidine also has an inhibitory effect on several isoforms of the cytochrome enzyme system including the CYP450 enzymatic pathway. Phenytoin is metabolized by the same cytochrome P450 enzyme system in the liver.
Thus, the simultaneous administration of both these medications leads to an inhibition of phenytoin metabolism and thus increases its circulating levels leading to phenytoin toxicity.

The blood investigations in this patient reveal hyponatremia as well as hypokalaemia. Among the options provided, Bendroflumethiazide therapy can cause the above presentation with the electrolyte disturbances.
Note:
– Spironolactone is a potassium-sparing diuretic that is associated with hyperkalaemia.
– Enalapril therapy can cause side effects of dizziness, hypotension, cough, and rarely a rash.
– Felodipine therapy can cause side effects of dizziness, headache, cough, and palpitations.

All the above side-effects, with the exception of alopecia, may be seen in patients taking lithium.

Common lithium side effects may include:
– dizziness, drowsiness;
– tremors in your hands;
– trouble walking;
– dry mouth, increased thirst or urination;
– nausea, vomiting, loss of appetite, stomach pain;
– cold feeling or discoloration in your fingers or toes;
– rash; or.
– blurred vision.

The patient (known case of acromegaly) seems to have developed cholelithiasis (presenting with right upper quadrant pain) probably due to octreotide.

It is a long-acting analogue of somatostatin which is released from D cells of the pancreas and inhibits the release of growth hormone, glucagon, and insulin.

Uses
– Acute treatment of variceal haemorrhage
– Acromegaly
– Carcinoid syndrome
– Prevent complications following pancreatic surgery
– VIPomas
– Refractory diarrhoea

Adverse effects
Gallstones (secondary to biliary stasis)

Other options:
– Bromocriptine – a dopamine agonist with side effects arising from its stimulation of the brain vomiting centre.
– Desmopressin – predominantly used in patients with diabetes insipidus by increasing the presence of aquaporin channels in the distal collecting duct to increase water reabsorption from the kidneys. The main side effects include headache and facial flushing due to hypertension.
– Metformin – mainly reduces hepatic gluconeogenesis in patients with type 2 diabetes, common side effects include diarrhoea, vomiting, and lactic acidosis
– Levothyroxine – synthetic thyroxine used in patients with hypothyroidism, common side effects result from incorrect dosing and mimic the symptoms of hyperthyroidism.

Tiotropium is a specific long-acting antimuscarinic agent indicated as maintenance therapy for patients with COPD (chronic obstructive pulmonary disease).
It should be used cautiously in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder neck obstruction.
The most frequently encountered adverse effects of tiotropium include pharyngitis, bronchitis, sinusitis, dry mouth, cough, and headaches. Paradoxical bronchospasm may also occur as a rare side-effect.
Dry mouth occurs in up to 14% of patients taking tiotropium, in keeping with its anticholinergic profile.
Rarer side-effects include tachycardia, blurred vision, urinary retention, and constipation.

Androgen deprivation therapy (ADT) for prostate cancer:

Goserelin (Zoladex) is a synthetic gonadotropin-releasing hormone (GnRH) analogue; chronic stimulation of goserelin results in suppression of LH, FSH serum levels thereby preventing a rise in testosterone.

Dosage form: 3.6 mg/10.8mg implants.

Adverse effects include flushing, sweating, diarrhoea, erectile dysfunction, less commonly, rash, depression, hypersensitivity, etc.

Agitation, hypomania and suicidal intent within a few days after initiating corticosteroid therapy is highly suggestive of a diagnosis of corticosteroid-induced psychosis.

In some patients corticosteroid related psychosis has been diagnosed up to 12 weeks or more after commencing therapy.

Euphoria and hypomania are considered to be the most common psychiatric symptoms reported during short courses of steroids.
During long-term treatment, depressive symptoms were the most common.
Higher steroid doses appear to carry an increased risk for such adverse effects; however, there is no significant relationship between dose and time to onset, duration, and severity of symptoms.

Management: Reduction or cessation of corticosteroids is the mainstay of treatment for steroid psychosis. For those patients who cannot tolerate this reduction/cessation of steroids, mood stabilizers may be of some benefit.

Renal elimination of a drug has no role in altering the bioavailability of a drug.
The bioavailability of a drug is the proportion of the drug which reaches systemic circulation.
Mathematically, bioavailability is the AUCoral/AUCiv x 100%, where AUC = area under the concentration-time curve following a single (oral or iv) dose.

Other options are true:
By definition, the bioavailability of a drug given intravenously is 100%.
Drugs given orally that undergo high pre-systemic (first-pass) metabolism in the liver or gut wall have a low bioavailability e.g. lidocaine.
Bioavailability is also affected by the degree of absorption from the gut and this can change depending on gut motility and administration of other drugs.

Sildenafil citrate (Viagra) is the first oral drug to be widely approved for the treatment of erectile dysfunction.
It is a potent and selective inhibitor of type-V phosphodiesterase, the primary form of the enzyme found in human penile erectile tissue, thereby preventing the breakdown of cyclic guanosine monophosphate (cGMP), the intracellular second messenger of nitric oxide.

Uses:
It is used for the treatment of erectile dysfunction, idiopathic pulmonary hypertension, premature ejaculation, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, and lower urinary tract symptoms.

Adverse effects:
Mild headache, flushing, dyspepsia, cyanopsia, back pain, and myalgias – due to a high concentration of PDE11 enzyme in skeletal muscle, which shows significant cross-reactivity with the use of tadalafil.
It can also cause hypotension, dizziness, and rhinitis.