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.

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.

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.

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.

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)

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.

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.

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

Before the initiation of trastuzumab, an echocardiography is a must to rule out any pre-existing cardiac abnormalities as trastuzumab is cardiotoxic.

Trastuzumab (Herceptin) is a monoclonal antibody directed against the HER2/neu receptor. It is used mainly in metastatic breast cancer although some patients with early disease are now also given trastuzumab.

Adverse effects include:
Flu-like symptoms and diarrhoea are common.
Cardiotoxicity:
– Risk increases when anthracyclines are used concomitantly.
– Trastuzumab-induced cardiac dysfunctions are regarded as less severe and largely reversible because primary cardiomyocyte do not show ultrastructure changes unlike those associated with anthracycline-induced cardiotoxicity.
– Primary myocyte injury does not occur in patients who were treated with trastuzumab.

Carbon monoxide has high affinity for haemoglobin and myoglobin resulting in a left-shift of the oxygen dissociation curve and tissue hypoxia. There are approximately 50 deaths per year from accidental carbon monoxide poisoning in the UK. In these circumstances, antidotal therapy to block alcohol dehydrogenase with ethanol or 4-MP alone is insufficient to treat the poisoning. Data suggest that a severe lactic acidosis needs initial correction and in this patient the most appropriate treatment would be IV fluids with bicarbonate to correct the metabolic acidosis. Haemodialysis may be required thereafter.

The given clinical scenario is suggestive of myo-neuropathy and is most likely to be caused by colchicine toxicity.
It gives rise to subacute proximal muscle weakness and on occasions can lead to an acute necrotizing myopathy. Creatine phosphokinase may be normal or may be elevated.
Weakness resolves when the drug is discontinued but the neuropathic features remain.
Death is usually a result of respiratory depression and cardiovascular collapse.
Treatment is symptomatic and supportive, and the treatment for colchicine poisoning includes lavage and measures to prevent shock.

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.

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.

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.

Ezetimibe is a cholesterol-lowering agent that acts to prevent cholesterol absorption by directly inhibiting cholesterol receptors on enterocytes.
It does not affect the absorption of drugs (e.g. digoxin, thyroxine) or fat-soluble vitamins (A, D and K) as the anion-exchange resins do. It does not affect the cytochrome P450 enzyme system.
The increased risk of myositis associated with the statins is not seen with ezetimibe.
The most common adverse effects include headache, runny nose, and sore throat.
Less common reactions include body aches, back pain, chest pain, diarrhoea, joint pain, fatigue, and weakness.

N-acetylcysteine depletes glutathione reserves by providing cysteine, which is an essential precursor in glutathione production.

Glutathione within the liver can normally detoxify these minuscule quantities of NAPQI and prevent tissue damage.
N-acetylcysteine (NAC) is the mainstay of therapy for acetaminophen toxicity.

Paracetamol overdose:
The liver normally conjugates paracetamol with glucuronic acid/sulphate. During an overdose, the conjugation system becomes saturated leading to oxidation by cytochrome P450 (predominately CYP2E1) mixed-function oxidases. This produces a toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI).

Normally glutathione acts as a defence mechanism by conjugating with the toxin forming the non-toxic mercapturic acid. If glutathione stores run-out, the toxin forms covalent bonds with cell proteins, denaturing them and leading to cell death.

Other uses: In COPD, cystic fibrosis, and other lung conditions, nebulized NAC has mucolytic, anti-inflammatory, and antioxidant properties.

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.

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

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.

Tumour lysis syndrome (TLS) occurs most notably in patients with haematological malignancies including, Non-Hodgkin’s Lymphoma (NHL) and Acute Lymphocytic Leukaemia (ALL).
Risk factors for TLS include:
• Large tumour burden
• Sensitivity of the tumour to chemotherapy
• Rapid tumour growth rate
TLS is characterized by:
• Hyperuricemia
• Hyperkalaemia
• Hyperphosphatemia
• Hypocalcaemia
Treatment of TLS:
• Allopurinol: It is a xanthine oxidase inhibitor, it reduces the conversion of nucleic acid by-products to uric acid. Thus, it prevents urate nephropathy and subsequent oliguric renal failure. Note: dose reduction is essential in renal failure or if given along with mercaptopurine or azathioprine.
Alternatives to Allopurinol: Febuxostat; Rasburicase are useful in patients with hyperuricemia.
• Hydration
• Diuresis: Should be considered in well hydrated patients with insufficient urine output. Furosemide to be considered in normo-volemic patients with hyperkalaemia. Urine alkalization can be considered for promoting alkaline diuresis.
• Treatment of electrolyte imbalances including hyperkalaemia, hyperphosphatemia, and hypocalcaemia.
• Dialysis can be considered in refractory cases.

Anticholinergic syndrome occurs following overdose with drugs that have prominent anticholinergic activity including tricyclic antidepressants, antihistamines and atropine. Features include dry, warm, flushed skin, urinary retention, tachycardia, mydriasis (dilated pupils) and agitation.

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 true statement among the given options is that she will still be protected against pregnancy if she takes amoxicillin for a lower respiratory tract infection while on the combined pill.

Other than enzyme-inducing antibiotics such as rifampicin, antibiotics do not reduce the efficacy of the combined oral contraceptive pill.

It was previously advised that barrier methods of contraception should be used if taking an antibiotic while using the contraceptive pill, due to concerns that antibiotics might reduce the absorption of the pill. This is now known to be untrue. However, if the absorptive ability of the gut is compromised for another reason, such as severe diarrhoea or vomiting, or bowel disease, this may affect the efficacy of the pill.

The exception to the antibiotic rule is that hepatic enzyme-inducing antibiotics such as rifampicin and rifaximin do reduce the efficacy of the pill. Other enzyme-inducing drugs, such as phenytoin, phenobarbital, carbamazepine or St John’s Wort can also reduce the effectiveness of the pill.

Other options:
The combined pill is often prescribed for women with heavy periods as it can make them lighter and less painful.
There is no evidence that women on the combined pill put on any significant weight, although they may experience bloating at certain times in the course.
Women on the pill require monitoring of their blood pressure.
There are multiple different types of combined pills.

The most appropriate intervention in this patient is intravenous hydroxocobalamin.
The clinical scenario provided is suggestive of acute cyanide toxicity secondary to burning plastics in the house fire.
Cyanide ions inhibit mitochondrial cytochrome oxidase, preventing aerobic respiration. This manifests in normal oxygen saturations, a high pO2 and flushing (or ‘brick red’ skin) brought on by the excess oxygenation of venous blood. In the question above it is important to note that the blood gas sample given is venous rather than arterial. His blood gas also demonstrates an increased anion gap, consistent with his high lactate (generated by anaerobic respiration due to the inability to use available oxygen).

The recommended treatment for moderate cyanide toxicity in the UK is one of three options: sodium thiosulfate, hydroxocobalamin or dicobalt edetate.

Among the options given is hydroxocobalamin and this is, therefore, the correct answer. Hydroxocobalamin additionally has the best side-effect profile and speed of onset compared with other treatments for cyanide poisoning.

Other options:
– Intubation would be appropriate treatment in the context of airway burns but this patient has no evidence of these, although close monitoring would be advised.
– High-flow oxygen is the treatment for carbon monoxide poisoning – a sensible differential, but this man’s very high lactate and high venous pO2 fit better with cyanide toxicity. Intravenous dexamethasone would be another treatment for airway oedema once an endotracheal tube had been placed.
– Intravenous sodium nitroprusside is a treatment for high blood pressure that can cause cyanide poisoning, and would, therefore, be inappropriate.

Note:

Cyanide may be used in insecticides, photograph development and the production of certain metals. Toxicity results from reversible inhibition of cellular oxidizing enzymes
Clinical presentation:
Classical features: brick-red skin, the smell of bitter almonds
Acute: hypoxia, hypotension, headache, confusion
Chronic: ataxia, peripheral neuropathy, dermatitis

Management:
Supportive measures: 100% oxygen
Definitive: hydroxocobalamin (intravenously), also a combination of amyl nitrite (inhaled), sodium nitrite (intravenously), and sodium thiosulfate (intravenously).

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

Sodium cromoglycate principally acts by inhibiting the degranulation of mast cells triggered by the interaction of antigen and IgE.
The inhibitory effect on mast cells appears to be cell-type specific since cromoglycate has little inhibitory effect on mediator release from human basophils.
Thus, it inhibits the release of histamine, leukotrienes, and slow-reacting substance of anaphylaxis from mast cells by inhibiting degranulation following exposure to reactive antigens.

Adverse effects include cough, flushing, palpitation, chest pain, nasal congestion, nausea, fatigue, migraine, etc.

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.

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.

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.