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

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)

Lead can be absorbed through the skin and by inhalation. It is associated with iron deficiency and a microcytic anaemia. The most common gastrointestinal symptoms are abdominal colic and constipation.

The statement that fits the characteristics of doxapram is, epilepsy is a contraindication for doxapram use. Concurrent use with theophylline may increase agitation not relaxation.

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.

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.

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)

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.

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.

Among the above statements, gastric lavage and normal saline IV infusion are the two appropriate interventions for a patient of acute lithium toxicity.

Activated charcoal is not effective after lithium overdose, although gastric lavage should be considered if patients present within 6–8 h.
Where levels are above 3 mmol/l, the use of normal saline to induce diuresis should be considered, although careful monitoring of fluid balance is necessary.
Where levels of lithium are above 4 mmol/l, dialysis is often required. Haemodialysis is preferred, but in a facility where haemodialysis is not possible, peritoneal dialysis may be considered.
Patients should not be discharged until they are asymptomatic and have a serum lithium level less than 1.5 mEq/L.

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.

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

The cause for bone marrow suppression in this patient is most probably mercaptopurine toxicity.
Azathioprine is metabolized to 6-mercaptopurine (6-MP), which itself is metabolized by xanthine oxidase.
Xanthine oxidase inhibition by allopurinol leads to the accumulation of 6-MP which then precipitates bone marrow failure.
This may be potentially fatal if unrecognized.
Clinical presentation:
Toxicity symptoms include gastrointestinal symptoms, bradycardia, hepatotoxicity, myelosuppression.

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.

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.

Desmopressin test (done to differentiate nephrogenic diabetes insipidus from central diabetes insipidus), and serum lithium levels can together confirm a diagnosis of lithium-induced nephrogenic diabetes insipidus.

Bipolar disease is most often managed with mood stabilizers like lithium. This patient develops gastrointestinal symptoms followed by an acute confusional state associated with polyuria and polydipsia. These symptoms are suggestive of diabetes insipidus.

In a case where these symptoms occur in a bipolar patient under treatment, lithium-induced nephrogenic diabetes insipidus should be considered as the most probable cause.

Lithium intoxication can present with symptoms of nausea, vomiting, mental dullness, action tremor, weakness, ataxia, slurred speech, blurred vision, dizziness, especially vertical nystagmus and stupor or coma. Diffuse myoclonic twitching and nephrogenic diabetes insipidus can also occur. Such a clinical syndrome occurs above the serum level of lithium of 1.5–2.0 mEq/L.

Management:
– Correcting electrolyte abnormalities in patients with acute disease is critical and often life-saving.
– Treatment should be initiated with parenteral fluids to replete hypovolemia (normal saline at 200-250 mL/h), followed by administration of hypotonic fluid (0.5% normal saline).
– On the restoration of the volume status of the patient forced diuresis should be initiated by the administration of parenteral furosemide or bumetanide accompanied by continued intravenous hypotonic fluid administration to maintain volume status.
– Polyuria is managed with hydrochlorothiazide combined with amiloride, acetazolamide.

The most probable diagnosis in this patient is serotonin syndrome.

The serotonin syndrome is a cluster of symptoms and signs (range from barely perceptible tremor to life-threatening hyperthermia and shock).
It may occur when SSRIs such as citalopram, escitalopram, fluoxetine, fluoxetine, paroxetine, and sertraline that impair the reuptake of serotonin from the synaptic cleft into the presynaptic neuron are taken in combination with monoamine oxidase inhibitors or tricyclic antidepressants. It has also been reported following an overdose of selective serotonin reuptake inhibitors (SSRIs) alone.

Treatment:
Most cases of serotonin syndrome are mild and will resolve with removal of the offending drug alone.
After stopping all serotonergic drugs, management is largely supportive and aimed at preventing complications.
Patients frequently require sedation, which is best facilitated with benzodiazepines.
Antipsychotics should be avoided because of their anticholinergic properties, which may inhibit sweating and heat dissipation.

Statins are a selective, competitive inhibitor of hydroxymethylglutaryl-CoA (HMG-CoA) reductase, which is the enzyme responsible for the conversion of HMG-CoA to mevalonate in the cholesterol synthesis pathway.
Statins are usually well tolerated with myopathy, rhabdomyolysis, hepatotoxicity, and diabetes mellitus being the most common adverse reactions.
This is the rate-limiting step in cholesterol synthesis, that leads to increased hepatic low-density lipoprotein (LDL) receptors and reduced hepatic VLDL synthesis coupled with increased very-low-density lipoprotein (VLDL) clearance.

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.

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.

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.

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.

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.

Sarin acts by inhibiting acetylcholinesterase.

Sarin gas is a highly toxic synthetic organophosphorus compound which causes inhibition of the enzyme acetylcholinesterase
Sarin gas is a highly toxic synthetic organophosphorus compound which causes inhibition of the enzyme acetylcholinesterase. This results in high levels of acetylcholine (ACh).

The effects of excessive ACh can be remembered by the mnemonic DUMBELLS:
Diarrhoea
Urination
Miosis/muscle weakness
Bronchorrhea/Bradycardia
Emesis
Lacrimation
Salivation/sweating

Organophosphate insecticide poisoning:
One of the effects of organophosphate poisoning is inhibition of acetylcholinesterase
Features can be predicted by the accumulation of acetylcholine (mnemonic = SLUD)
Salivation
Lacrimation
Urination
Defecation/diarrhoea
cardiovascular: hypotension, bradycardia
miosis, muscle fasciculation.

Organophosphate poisoning is treated with the anti-muscarinic atropine.

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 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.

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.

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.

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).

Cefalexin should be avoided in this patient.
This patient is known to have a severe penicillin allergy. None of the above antibiotics are penicillin based. However, 0.5 – 6.5% of patients who are proven to have an IgE mediated penicillin allergy will also be allergic to cephalosporins, including cefalexin.

Penicillin, cephalosporins, and carbapenems are all members of the beta-lactam group of antibiotics and share a common beta-lactam ring. There is, therefore, a small risk of allergy cross-over between all these antibiotics. The rates of allergy cross-over are lower with second and third-generation cephalosporins than first-generation cephalosporins such as cefalexin.

It is important to question the patient carefully to ascertain what symptoms they had on exposure to penicillin. Symptoms such as an urticarial rash or itching make it more likely that they have an IgE mediated allergy.

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)