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.

Confusion and pink mucosae are typical features of CO poisoning.
The patient often presents, most commonly with headaches, and other symptoms like malaise, nausea, and dizziness.

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%.

Features of carbon monoxide toxicity
– Headache: 90% of cases
– Nausea and vomiting: 50%
– Vertigo: 50%
– Confusion: 30%
– Subjective weakness: 20%
– Severe toxicity: ‘pink’ skin and mucosae, hyperpyrexia, arrhythmias, extrapyramidal features, coma, death

Treatment:
Use of Hyperbaric oxygen therapy (HBOT) for treating 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)

Blue tinge of vision/cyanopsia is caused due to the intake of sildenafil citrate.

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.

Note: Xanthopsia (yellow-green vision) may occur secondary to treatment with digoxin.

Loss of vision after consumption of antifreeze is a characteristic presentation of methanol poisoning.

Pathophysiology of methanol toxicity:
When ingested, methanol is absorbed rapidly via the gastrointestinal tract in less than 10 minutes. Methanol is not protein-bound and is absorbed directly into the total body water compartment.
Metabolism occurs mainly in the liver through serial oxidation via alcohol dehydrogenase and aldehyde dehydrogenase but begins with alcohol dehydrogenase present in the gastric mucosa.
Alcohol dehydrogenase oxidizes methanol to formaldehyde, and aldehyde dehydrogenase subsequently oxidizes formaldehyde to formic acid.
Formic acid is the primary toxic metabolite that accounts for the associated anion gap metabolic acidosis and end-organ damage.

Clinical presentation:
Patients who present within the first 12 to 24 hours following ingestion may appear normal, and this is described as the latent period.
Nausea, vomiting, and abdominal pain subsequently ensue, followed by CNS depression and hyperventilation due to metabolic acidosis.
Ocular symptoms associated with retinal toxicity are often evident in the form of blurry vision, decreased visual acuity, photophobia, and “halo vision.”

Treatment:
Treatment options for methanol toxicity include supportive care, fomepizole (Antizole, 4-Methylpyrazole or 4MP), ethanol, dialysis, and folate.

Among the options provided, hypothermia is not a symptom of opioid withdrawal.

Symptoms of opioid withdrawal include dysphoric mood, yawning, insomnia, muscle aches, lacrimation/rhinorrhoea, papillary dilatation, piloerection, fever, sweating, nausea/vomiting, diarrhoea.
If the patient is having an opioid withdrawal reaction, then give 10 mg of methadone syrup and wait about 60 min to determine its effect.

COWS (Clinical Opioid Withdrawal Scale) assessment for opioid withdrawal is commonly used to determine the severity of opioid withdrawal.

The most likely cause for these results is delayed paracetamol nephrotoxicity.

The blood investigations of this patient are highly suggestive of acute kidney injury.
Paracetamol overdose is well known to cause hepatotoxicity, but not for its delayed nephrotoxicity, especially in significant overdose. Appropriate monitoring of a patient’s blood tests is important.

Management:
NAC (N-Acetyl cysteine) has a clear role in preventing acetaminophen-induced liver necrosis. Although NAC has not been proven to be harmful to the kidney, its role in patients without hepatoxicity and only isolated renal dysfunction is uncertain.

Other options:
-There are no features in the history that are suggestive of dehydration and pre-renal AKI presenting in this manner in a 25-year-old would be very unusual.
– Minimal change nephropathy typically presents with a nephrotic picture of kidney injury.
– Berger’s more commonly presents with isolated haematuria.

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.

Among the given anti-epileptics the best drug that can be given in this patient is lamotrigine.
Topiramate, carbamazepine, phenytoin, and phenobarbital are all hepatic enzyme inducers and are associated with decreased effectiveness of the oral contraceptive (OCP) due to acceleration of the metabolism of oestrogens and progestogens.
If she is planning on pregnancy then registry studies suggest that lamotrigine would also be the best choice.
Other hepatic enzyme inducers include rifampicin, spironolactone, griseofulvin, etc.

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.

Initiation of allopurinol treatment during an attack can exacerbate and prolong the episode. Thus treatment should be delayed until the attack resolves.

Mechanism of action of low molecular weight heparin (LMWH):
It inhibits coagulation by activating antithrombin III. Antithrombin III binds to and inhibits factor Xa. In doing so it prevents activation of the final common path; Xa inactivation means that prothrombin is not activated to thrombin, thereby not converting fibrinogen into fibrin for the formation of a clot.

LMHW is a small fragment of a larger mucopolysaccharide, heparin. Heparin works similarly, by binding antithrombin III and activating it. Heparin also has a binding site for thrombin, so thrombin can interact with antithrombin III and heparin, thus inhibiting coagulation.
Heparin has a faster onset of anticoagulant action as it will inhibit not only Xa but also thrombin, while LMWH acts only on Xa inhibition.

Compared to heparin, LMWHs have a longer half-life, so dosing is more predictable and can be less frequent, most commonly once per day.

Dosage and uses:
LMWH is administered via subcutaneous injection. This has long-term implications on the choice of anticoagulant for prophylaxis, for example, in orthopaedic patients recovering from joint replacement surgery, or in the treatment of DVT/PE.

Adverse effects:
The main risk of LMWH will be bleeding. The specific antidote for heparin-induced bleeding is protamine sulphate.
Less commonly it can cause:
Heparin-induced thrombocytopenia (HIT)
Osteoporosis and spontaneous fractures
Hypoaldosteronism
Hypersensitivity reactions

The principal action of organophosphates is the inhibition of acetylcholinesterase’s, therefore leading to the accumulation of acetylcholine at muscarinic receptors (miosis, hypersalivation, sweating, diarrhoea, excessive bronchial secretions), nicotinic receptors (muscle fasciculations and tremor) and in the central nervous system (anxiety, loss of memory, headache, coma).

Removal from the source of the organophosphate, adequate decontamination, supplemental oxygen and atropine are the initial treatment measures. Pralidoxime, an activator of cholinesterase, should be given to all symptomatic patients.

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.

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.

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 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).

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.

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.

Drug metabolism can be broadly classified into:
Phase I (functionalization) reactions: also termed non-synthetic reactions, they include oxidation, reduction, hydrolysis, cyclization and de-cyclization. The most common and vital reactions are oxidation reactions. (Of the given enzymes only Alcohol dehydrogenase is involved in phase I drug metabolism. Succinate dehydrogenase, is a vital enzyme involved in the Kreb’s cycle and the mitochondrial electron transport chain). They are mainly catalysed by Cytochrome P-450 enzyme.

Phase II (conjugation) reactions: occur following phase I reactions, they include reactions: glucuronidation and sulphate conjugation, etc. They are mostly catalysed by UDP-glucuronosyltransferase enzyme. Other phase II enzymes include: sulfotransferases, N-acetyltransferases, glutathione S-transferases and methyltransferases.

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

Activated charcoal is useful if given within one hour of the paracetamol overdose. Liver function tests, INR and prothrombin time will be normal, as liver damage may not manifest until 24 hours or more after ingestion.

The antidote of choice is intravenous N-acetylcysteine, which provides complete protection against toxicity if given within 10 hours of the overdose.

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.

The farmer has most likely ingested an organophosphate insecticide.
Organophosphorus compounds are used widely as:
• Insecticides – Malathion, parathion, diazinon, dichlorvos
• Nerve gases – Soman, sarin, tabun, VX
• Ophthalmic agents – Echothiophate
• Antihelmintics – Trichlorfon
• Herbicides – merphos
• Industrial chemical (plasticizer) – Tricresyl phosphate
Signs and symptoms of Organophosphorus Poisoning (OPP) can be classified as:
• Muscarinic effects:
o Cardiovascular – Bradycardia, hypotension
o Respiratory – Rhinorrhoea, bronchorrhea, bronchospasm, cough, severe respiratory distress
o Gastrointestinal – Hypersalivation, nausea and vomiting, abdominal pain, diarrhoea, faecal incontinence
o Genitourinary – Incontinence
o Ocular – Blurred vision, miosis
o Glands – Increased lacrimation, diaphoresis
• Nicotinic effects:
o Muscle fasciculation, weakness, cramping, diaphragmatic failure, and autonomic side effects include: hypertension, tachycardia, and mydriasis.
• Central nervous system (CNS) effects:
o Anxiety, emotional lability, restlessness, confusion, ataxia, tremors, seizures, coma, apnoea
Mainstay Treatment:
• Decontamination
• Securing Airway, Breathing and Circulation
• Atropine
• Pralidoxime
• Benzodiazepines

Hormone replacement therapy (HRT) involves the use of a small dose of oestrogen, combined with a progestogen (in women with a uterus), to help alleviate menopausal symptoms. The main indication is the control of vasomotor symptoms. The other indications, such as reversal of vaginal atrophy and prevention of osteoporosis, should be treated with other agents as first-line therapies.

Lidocaine is an example of class IB antiarrhythmics.

The Vaughan-Williams classification of antiarrhythmics
I: Membrane stabilizing agents
IA: Quinidine, Procainamide, Disopyramide
IB: Lidocaine, Mexiletine
IC: Propafenone, Flecainide
II: β blockers – Propranolol, Esmolol
III: Agents widening AP – Amiodarone, Dronedarone, Dofetilide, Ibutilide, Sotalol
IV: Calcium channel blockers – Verapamil, Diltiazem
V: Miscellaneous – Digoxin, adenosine, magnesium

Digoxin acts by inhibiting the Na+/K+ ATPase pump.
Digoxin is a cardiac glycoside now mainly used for rate control in the management of atrial fibrillation. As it has positive inotropic properties it is sometimes used for improving symptoms (but not mortality) in patients with heart failure.

Mechanism of action:
It decreases the conduction through the atrioventricular node which slows the ventricular rate in atrial fibrillation and atrial flutter.
It increases the force of cardiac muscle contraction due to inhibition of the Na+/K+ ATPase pump. It also stimulates the vagus nerve.

Digoxin toxicity:
Plasma concentration alone does not determine whether a patient has developed digoxin toxicity. The likelihood of toxicity increases progressively from 1.5 to 3 mcg/l.
Clinical feature of digoxin toxicity include a general feeling of unwell, lethargy, nausea & vomiting, anorexia, confusion, xanthopsia, arrhythmias (e.g. AV block, bradycardia), and gynaecomastia

Precipitating factors:
Hypokalaemia
Increasing age
Renal failure
Myocardial ischemia
Hypomagnesaemia, hypercalcemia, hypernatremia, acidosis
Hypoalbuminemia
Hypothermia
Hypothyroidism
Drugs: amiodarone, quinidine, verapamil, diltiazem, spironolactone (competes for secretion in the distal convoluted tubule, therefore, reduce excretion), ciclosporin. Also, drugs that cause hypokalaemia e.g. thiazides and loop diuretics.

Management of digoxin toxicity:
Digibind
Correct arrhythmias
Monitor and maintain potassium levels within the normal limits.

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.

Spironolactone is an aldosterone antagonist which acts in the distal convoluted tubule. It is a potassium-sparing diuretic that prevents the body from absorbing too much salt and keeps the potassium levels from getting too low. Spironolactone is used to treat heart failure, high blood pressure (hypertension), or hypokalaemia (low potassium levels in the blood).

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.

Proton pump inhibitors can reduce gastric acid secretion by up to 99%. Acid production resumes following the normal renewal of gastric parietal cells.