MRCPCH—PHARMA

bronchospasm in asthmatic patients

Salmeterol is a long-acting b2-agonist, and is used as a bronchodilator. However, it is associated with paradoxical bronchoconstriction, which is more common with the MDI formulation. Indometacin, a cyclo-oxygenase inhibitor, can lead to bronchoconstriction is susceptible patients . Atenolol, although a cardio-selective b-blocker, can still cause bronchospasm, while captopril and other ACE inhibitors can lead to bronchospasm probably through an increase in kinin levels.

 acute aspirin overdose

Overdose of aspirin leads to the following symptoms: tinnitus, vertigo and vomiting occur in moderately severe overdose. In more severe cases, this progresses to hypoglycaemia, hyperkalaemia, and hyperthermia. Hyperventilation leads to respiratory alkalosis, which is then followed by metabolic acidosis. In the most severe cases, coma, cardiovascular collapse and renal failure may develop. Deafness is not seen in acute cases.

Photosensitivity has been reported with terbinafine, amiodarone, demeclocycline (a common feature of all tetracyclines) and sulphamethoxazole (a common feature of sulphonamides). Amiloride has not been implicated in photosensitivity. Other drugs known to cause photosensitivity include antimicrobials (ciprofloxacin, griseofulvin and quinine), NSAIDs (azapropazone, piroxicam, tiaprofenic acid), thiazide diuretics and psychotropic agents (chlorpromazine, thioridazine, imipramine).

For most adolescents and young women, side-effects of the pill are minor. Common unwanted side-effects include bloating, breast tenderness, headaches (including migraine), acne, loss of sex drive and mild vaginal discharge. The pill does increase the risks of DVT, myocardial infarction and stroke, although the risk of thrombotic events for most pill users is still very low. The risk of stroke is increased in women with certain types of migraine. There may be a small increase in the risk of breast cancer (balanced by a reduction in risk for endometrial and ovarian malignancies). Menstrual irregularity and increased bleeding are common adverse effects with progestogen-only pills, but combined pills are associated with a lower risk of dysmenorrhoea and bleeding and are often used to control menstrual symptoms.

chloroquine

Side effects include:More common: Diarrhoea;  difficulty in seeing to read ;  headache;  itching;  loss of appetite;  nausea or vomiting;  stomach cramps or pain  Less common: Blurred vision;  change in vision;  eye pain;  loss of vision  Bleaching of hair or increased hair loss;  blue-black discoloration of skin, fingernails, or inside of mouth;  skin rash  Rare: haematemesis, melaena;  haematuria; seizures;  cough;  lightheadedness;  fever;  increased muscle weakness;  lower back or side pain;  mood or other mental changes;  dysuria;  rash; tinnitus;  unusual bleeding or bruising;  unusual tiredness or weakness Symptoms of overdose: Drowsiness;  headache;  increased excitability.

Amphetamines release stores of norepinephrine and dopamine from nerve endings by converting the respective molecular transporters into open channels. Amphetamine also releases stores of serotonin from synaptic vesicles. Like methylphenidate (Ritalin) amphetamines also prevent the monoamine transporters for dopamine and norepinephrine from recycling them which leads to increased amounts of dopamine and norepinephrine in synaptic clefts.Short-term physiological effects include decreased appetite, increased stamina and physical energy, increased sexual drive/response, involuntary bodily movements, increased perspiration, hyperactivity, jitteriness, nausea, itchy, blotchy or greasy skin, increased heart rate, irregular heart rate, and headaches. Long term psychological effects can include insomnia, mental states resembling schizophrenia, aggressiveness, addiction or dependence with accompanying withdrawal symptoms, irritability, confusion, and panic. Chronic and/or extensively continuous use can lead to amphetamine psychosis which causes delusions and paranoia.Short-term effects can include alertness, euphoria, increased concentration, rapid talking, increased confidence, increased social responsiveness, nystagmus, hallucinations, and loss of REM sleep. Long-term use and overdose effects can include tremor, restlessness, changed sleep patterns, poor skin condition, hyperreflexia, tachypnoea, gastrointestinal narrowing, and weakened immune system. Fatigue and depression can follow the excitement stage. Erectile dysfunction, heart problems, stroke, and liver, kidney and lung damage can result from prolonged use.

Sodium valproate is associated with weight gain as a result of increased appetite. It is usually the drug of choice in pregnancy because it is effective at controlling seizures and side effects/teratogenic effects are know. As yet none of the newer anticonvulsants has been convincingly shown to be less teratogenic.

Reversible dementia, Hair loss, Tremor

Alpha adrenergic agonists include Dopamine in the neonatal period, metaraminol, phenylephrine and noradrenaline. Adrenaline is Beta and alpha, isoprenaline and salbutamol are beta. Phosphodiesterase (PDE) type 3 is inhibited by enoximone, amrinone and milrinone leading to systemic vasodilatation. PDE type 5 is inhibited by zaprinast and sildenafil causing pulmonary vasodilatation. ACE increases formation of angiotensin 2 from angiotensin 1.

Class 1 drugs act on the sodium channel, propafenone being in group 1c and mainly used for atrial arrhythmias. Class 2 act on the calcium channel preventing depolarisation and are beta blockers. Class 3 act on the repolarising potassium channel, including sotalol and amiodarone. Class 4 block the AV node including verapamil (calcium channel) and adenosine (potassium channel opener).

Sotalol has both class 2 and class 3 actions

Adenosine terminates SVT because it is a potassium channel opener

Flecainide is used for prophylaxis of SVT because of its 1c action on blocking the sodium channel

Erythropoietin is used to treat the anaemia of chronic renal failure, to increase the yield of blood in normal individuals, and to shorten the period of anaemia in patients receiving cytotoxic chemotherapy. Epoietin beta is also used for the prevention of anaemia in premature infants.

Pyrimethamine and methotrexate (dihydrofolate reductase inhibition) interfere with folate metabolism. Tetracycline interferes with calcium metabolism, ibuprofen with platelets and vitamin B12 is necessary when giving folate supplements to prevent deficiency.

These are all recognised therapies for pulmonary hypertension. Magnesium sulphate is a co-factor in endogenous nitric oxide production and sildenafil inhibits cyclic GMP breakdown. Iloprost and prostacyclin enhance cAMP formation. Tolazoline is no longer used due to its side effects of bleeding.

There are many side effects of ciclosporin including gingival hypertrophy, renal (dose dependent), hypertension and hypertrichosis, but it is virtually free of myelotoxicity. Erythromycin decreases ciclosporin metabolism.

Cimetidine increases metabolism of phenytoin, inhibits metabolism of metronidazole, warfarin and ciclosporin but has no known effect on gentamicin

All the anthracyclines cause cardiomyopathy which depends on the total dose. Any immunosuppressant agent may lead to oral ulceration and busulphan can cause irreversible rare progressive fibrosis. Vincristine causes peripheral or autonomic neuropathy.

paracetamol overdose

The most sensitive prognostic marker is prothrombin time (PT). Approximately 50% of patients with a PT of 36s at 36h after ingestion will develop ALF. Acute renal failure is usually caused by either hepatorenal syndrome or multi-system organ failure. Acute renal failure may however also be the primary clinical manifestation of toxicity. Pancreatitis is rare.

There is no known specific antidote to carbamazepine. Evacuate the stomach, with an emetic or by gastric lavage, then administer activated charcoal. The use of N-acetyl-cysteine, is useful in paracetamol poisoning. Hypokalaemia and metabolic acidosis are also features of theophylline and salbutamol overdosage.

Erythromycin administered together with theophylline can lead to elevated blood levels of theophylline. Theophylline passes into breast milk and may be toxic to nursing infants. Overdose can cause agitation, restlessness, dilated pupils, sinus tachycardia, and hyperglycaemia.

Metabolism of theophylline is inhibited by erythromycin (increased plasma concentration). Plasma concentration of phenobarbitone are increased by valproate. Metabolism of oestrogens accelerated by phenytoin (reduced contraceptive effect). 

 Many drugs can potentially be transferred in breast milk. A in a few breast feeding is contraindicated. In many cases the individual case must be considered (e.g. is there an alternative, how likely is a reaction, what dose is the mother taking etc.)

Lead poisoning is due to the ingestion of lead-containing compounds (deliberate (pica) or inadvertent), contaminated water from old lead water-pipes and certain traditional remedies such as ayurvedic medicines. Typically, acute effects of lead toxicity occur above concentrations of 450 µg/l and include nausea, abdominal pain, constipation and neurological and haematological effects. Chronic low-grade exposure (< 450 µg/l) can be associated with mild neurodevelopmental delays. Abdominal X-rays are essential to see if there is any unabsorbed lead present, which can be removed by whole-bowel irrigation. Oral DMSA (dimercaptosuccinic acid), which is used in the treatment of lead toxicity, will increase the absorption of any lead from the gastrointestinal tract. Absorption is also increased in patients with iron-deficiency anaemia. Hypocalcaemia is associated with increased lead deposition in bones, leading to an increased half-life of lead. Management includes complete gut decontamination; chelation therapy with oral DMSA or intravenous EDTA (ethylenediaminetetraacetic acid) should then be considered for patients with blood lead concentrations over 450 µg/l or signs of severe toxicity.Chronic moderate poisoning (450–600 µg/l) is associated with motor neuropathies

Carbon monoxide is the commonest cause of poisoning-associated death in the United Kingdom. Patients with pre-existing vascular disease are at an increased risk of morbidity and mortality from carbon monoxide poisoning. Carboxyhaemoglobin concentrations are typically below 5% in healthy patients, but may be as high as 10% in heavy smokers. Cerebellar signs are the most reliable sign of significant neurological toxicity. Treatment consists of removing the patient from the source of the carbon monoxide, giving high-flow oxygen (12 l/min) via a tight-fitting mask without a re-breathing circuit and consideration of hyperbaric oxygen therapy. Indications for this include any history of unconsciousness, carboxyhaemoglobin concentrations over 40% at any time, pregnancy, documented neurological signs and ECG changes. There are some relative contraindications: patients with arrhythmias that may require cardioversion, since this is not possible within the hyperbaric chamber; and patients with asthma or COPD due to the increased risk of pneumothorax. Although sodium bicarbonate can correct any metabolic acidosis, it can also decrease oxygen release to the tissues.

Drug Teratogenic effectAndrogens Cardiac deformitiesAlcohol Fetal alcohol syndrome Carbamazepine MicrocephalyDiethylstilbestrol Vaginal carcinomaLithium CretinismPhenobarbital Cleft palate Sodium valproate Neural tube defects

Thalidomide PhocomeliaWarfarin Chondrodysplasia punctata

Following overdoses of most NSAIDs, the main effects are mild gastrointestinal upset with epigastric tenderness, nausea, vomiting and diarrhoea. These effects are mainly due to the inhibition of cyclo-oxygenase. However, 10–20% of patients will have convulsions following an NSAID overdose. This is more common in patients who have ingested mefenamic acid. Large overdoses can present with an acidosis, renal impairment, gastrointestinal haemorrhage and CNS effects (drowsiness, coma, cerebellar signs). Management of NSAID overdose is with activated charcoal in patients presenting within the first hour, and supportive care. Oral H2-histamine blockers and proton-pump inhibitors may reduce the symptoms of gastrointestinal toxicity. There is no indication for the use of multi-dose activated charcoal.

Vigabatrin is the drug of choice for infantile spasms. It may cause aggression, alopecia, retinal atrophy and reduced peripheral vision. Tiagabine is useful in partial secondary generalised tonic–clonic seizures and is not prescribed for infantile spasms. It also reduces peripheral vision. The other drugs are not associated with visual field defects.

Isotretinoin is a highly effective treatment for acne. It is also highly teratogenic. Women must have a negative pregnancy test before treatment and be on effective contraception for at least a month before the course begins, during the course, and for a month after it finishes. Congenital deafness and CNS and heart defects may occur in children exposed to isotretinoin in utero. The other drugs, although useful in the treatment of acne, are less effective and not so teratogenic.

The commonest drugs used to control seizures in children are sodium valproate and carbamazepine. Phenytoin causes serious side-effects including, gingival hypertrophy, hirsutism, cerebellar signs, rickets and pseudolymphomas – all of which are undesirable in a child. Lamotrigine is commonly used as an adjunctive drug, although it is being used infrequently as monotherapy. Topiramate is also used quite rarely, primarily for intractable seizures or for ones that are difficult to control on common drugs. Phenobarbital can cause folate deficiency, osteomalacia, neuropathy and excitement in children.

theophylline overdose

An acute overdose occurs with the ingestion of a single large dose. These patients usually present with gastrointestinal symptoms and cardiovascular manifestations. Seizure risk is not as great as in a chronic overdose.

A chronic overdose occurs in people who have ingested repeated doses over time that are greater than their ability to clear the medication. These patients are more likely to have seizures.

Cardiovascular effects include hypotension and arrhythmias. Gastrointestinal effects include nausea, vomiting, diarrhoea, and abdominal pain or cramping. Metabolic effects include hypokalaemia, hyperglycemia, hypercalcemia, rhabdomyolysis, and acidosis. Neurological effects include headaches, restlessness, tremors, disorientation, hallucinations, insomnia, and seizures.

Steroid withdrawal symptoms include weakness, fatigue, decreased appetite, weight loss, nausea, vomiting, diarrhoea (which can lead to fluid and electrolyte abnormalities), and abdominal pain. Hypotension can result leading to dizziness or fainting. Blood sugar levels may drop. 

Amiodarone

Due to the iodine content of the agent (37.3% by weight), abnormalities in thyroid function are common. Amiodarone is structurally similar to thyroxine (a thyroid hormone), which contributes to the effects of amiodarone on thyroid function. The incidence of hypothyroidism is about 6%, while the incidence of hyperthyroidism is about 2%. Amiodarone is fat-soluble, and tends to concentrate in tissues including fat, muscle, liver, lungs, and skin. This confers a high volume of distribution (5000 liters in a 70kg adult) and a long half-life. Amiodarone decreases the peripheral deiodination of thyroxine to triiodothyronine.

AZT (Azidothymidine

The anti-retrovirus AZT is a selective, competitive inhibitor of HIV protease.  Its role is to slow down both the process in which the HIV virus reproduces and also the formation of infectious virus.  Maturation of the virus is blocked by interfering with the formation of essential proteins and enzymes.  In combination with other drugs, AZT may lower HIV viral load titre, increase CD4 cell (T-cell) count, increase immunity and reduce likelihood of developing complications. AZT is contra-indicated with abnormally low neutrophil counts or haemoglobin values and in neonates with hyperbilirubinaemia requiring treatment other than phototherapy.

Odour Toxin/poisonGarlic Arsenic, seleniumBitter almonds CyanideRotten eggs Hydrogen sulphide, mercaptans Wintergreen MethylsalicylateMothballs NaphthaleneBeta agonists and angiotensin II augment proto-oncogene expression, stimulate protein synthesis and induce the synthesis of fetal forms of actin and myosin, leading to hypertrophy of smooth muscle. Thyroxine acts directly via nuclear receptors to regulate myosin heavy-chain gene transcription. The other drugs have no effect on proto-oncogenes.

Acetazolamide is an inhibitor of carbonic anhydrase. It is used in post-haemorrhagic hydrocephalus (often with furosemide) and for reducing intraocular pressure. It causes metabolic acidosis, due to bicarbonate loss in the proximal and distal tubules, by inhibiting reabsorption. Acute interstitial nephritis (AIN) is a complication of acetazolamide therapy. Administration of acetazolamide may cause agranulocytosis and thrombocytopenia. Macrocytic hypochromic anaemia is not a feature.

The INR (International Normalised Ratio) is used to monitor the effect of warfarin. Theophylline has a narrow therapeutic window and needs close monitoring of its serum level to avoid toxicity. The maintenance dose for

carbimazole is determined by measuring T4 and TSH levels. Regular full blood counts and urinalysis are used to monitor cyclophosphamide

The main use of ciclosporin is to reduce T-cell immune function in transplant patients and so reduce the chances of rejection (liver, renal, pancreas, heart and bone marrow transplants). Levels are carefully monitored for therapeutic efficacy. Renal toxicity is common with high levels (> 200 ng/ml) and rejection is common with low serum levels. Chronic interstitial nephritis is a major side-effect of ciclosporin therapy. It is markedly nephrotoxic, but virtually non-myelotoxic. Hypertrichosis is a common side-effect of ciclosporin treatment. Stomatitis and urolithiasis are not seen with ciclosporin treatment.

Multi-dose activated charcoal means giving 50 g of activated charcoal every 3–4 hours. It is useful in patients who have taken significant amounts of salicylates, and should be continued until plasma salicylate concentrations have peaked. It is also useful in the management of patients who have taken drugs with significant enterohepatic circulation (carbamazepine, phenobarbital, theophylline and quinine) and sustained-/modified-release preparations. It is contraindicated in patients with signs of bowel obstruction, since activated charcoal can cause constipation and may worsen any underlying obstruction.

Acetylcysteine (NAC) exhibits direct and indirect antioxidant properties. Its free thiol group is capable of interacting with the electrophilic groups. This leads to intermediate formation of NAC thiol, with NAC disulphide as a major end-product . In addition, NAC exerts an indirect antioxidant effect related to its role as a glutathione (GSH) precursor. GSH is a tripeptide made up of glutamic acid, cysteine and glycine. It serves as a central factor in protecting against internal toxic agents (such as cellular aerobic respiration and metabolism of phagocytes) and external agents (such as nitric oxide (NO), sulphur oxide and other components of cigarette smoke, and pollution). The sulphydryl group of cysteine neutralises these agents. Maintaining adequate intracellular levels of GSH is essential to overcoming the harmful effects of toxic agents. GSH synthesis takes place mainly in the liver (which acts as a reservoir) and the lungs.

Reduction of the circulation of toxic metabolites- mode of action of N-acetylcysteine

Anabolic steroids can be taken orally (eg stanozolol) or may have to be injected due to high first-pass metabolism (eg testosterone enantate). Amongst many unwanted effects, they have effects that increase the risk of cardiovascular disease. Blood pressure is elevated. Blood lipid profiles change, with increased LDL-cholesterol and decreased HDL-cholesterol. Haematocrit is increased, leading to a prothrombotic tendency, although there is a protective decrease in plasma fibrinogen concentrations with prolonged use.

This boy most probably has Kallmann’s syndrome, which is a combination of anosmia, obesity and hypogonadotrophic hypogonadism. It is an X-linked recessive disorder causing an isolated deficiency of gonadotrophin-releasing hormone (GnRH). Long-term treatment of males with HCG or testosterone restores pubertal development and secondary sex characteristics. Buserelin and nafarelin acetate are GnRH analogues. Long-term administration results in the suppression of LH/FSH release. Octreotide is a long-acting analogue of

somatostatin and is used in the treatment of acromegaly. It also suppresses the LH response to GnRH. Cyclic oestrogen and progesterone is indicated only if the patient is female.

Cocaine reduces the reuptake of dopamine into neurones by inhibiting the dopamine-reuptake transporter. Overdoses of cocaine are often rapidly fatal. Death may occur in minutes from arrhythmias, seizures or respiratory depression. Cocaine has a powerful vasoconstrictive action that can cause a hypertensive crisis leading to myocardial infarction and strokes. -- A 17-year-old man presents with nausea, vomiting and diaphoresis. His pupils are dilated and his blood pressure is elevated. Misuse of which substance is most likely to have caused this condition?

Opioid overdose causes miosis, slurred speech, disorientation and respiratory depression. Alcohol intoxication produces typical effects of acute sedative–hypnotic drug overdose, vasodilatation, tachycardia and gastrointestinal irritation. Amfetamine overdoses are rarely fatal; they can usually be managed by sedating the patient with benzodiazepines. Lysergic acid diethylamide (LSD) produces a series of somatic, perceptual and psychological effects that overlap each other. Dizziness, weakness and tremors occur, along with blurring of vision, hallucinations, impaired memory, poor judgement and altered mood.

Ampicillin and amoxicillin can cause skin rashes that are not allergic in nature. All the other antibiotics produce a diffuse, papular, non-purpuric rash that may be intensely pruritic.--blotchy, non-pruritic purpuric rash all over his body

Bioequivalence is all about demonstrating similar biological effect. Pharmacodynamics or pharmacokinetics may be useful comparative data, but if each one is considered in isolation it may not necessarily tell the whole story. There may be differences between products in excipients or delivery vehicle, which means the biological effects are different when the products are compared. 

Diethylene glycol is used mainly in polyester resins and polyols, as a humectant in the tobacco industry and as a solvent. It achieved notoriety in 1985 when it was discovered that for a number of years it had been added to some wines. Several pharmaceutical errors have also led to fatalities. Nausea, vomiting and abdominal pain frequently occur, and are followed by the development of jaundice and hepatomegaly, pulmonary oedema, metabolic acidosis, coma and renal failure in most cases. 

Supportive measures to treat the dehydration and to correct the metabolic acidosis should be instituted promptly. Ethanol or fomepizole (4-methylpyrazole) should be administered to block diethylene glycol metabolism, and dialysis should be employed if renal failure supervenes. A loading dose of 50 g of ethanol orally (conveniently given as 125 ml of gin, whisky or vodka) should be administered, followed by an intravenous infusion of 10–12 g ethanol/h to produce a blood ethanol concentration of 0.5–1 g/l. The infusion should be continued until diethylene glycol is no longer detectable in the blood. If dialysis is employed, the rate of ethanol administration will need to be increased to 17–22 g/h.

Any dose of paracetamol above 150 mg/kg (as in this case) is associated with the possibility of serious liver damage.

Amiodarone is a class III antiarrhythmic drug. Class III antiarrhythmics are potassium channel blockers, they prolong duration of action potential with resulting prolongation of effective refractory period. Other Class III antiarrhythmics are sotalol, disopyramide and bretylium.

Aminoglycosides, quinoline antimicrobial drugs, aztreonam and ceftazidime are least active against anaerobic bacteria. These drugs are included in antimicrobial regimes for treating mixed infections, though their role is clearly to suppress the facultative Gram-negative organisms.

Warfarin competitively inhibits carboxylation of vitamin K-dependent factors. Vitamin K-dependent factors include factors II, VII, IX and X (reverse the year 1972) and protein C. The half-life of warfarin is approximately 44 hours. The level of warfarin in breast milk is too low to be of any clinical significance. Autoimmune thrombocytopenia and osteoporosis are side-effects associated with heparin rather than warfarin.

Vancomycin is bactericidal against several species of Gram-positive cocci but it is less effective against Gram-negative cocci. It acts on multiplying organisms by inhibiting formation of the peptidoglycan component of the cell wall. Vancomycin is poorly absorbed from the gut and it is eliminated by the kidney. Its main side-effect is damage to the auditory portion of the VIIIth cranial nerve.

Acetazolamide (a carbonic anhydrase inhibitor) inhibits proximal tubule bicarbonate resorption in a similar fashion to type 2 renal tubular acidosis (RTA). Amiloride acts by inhibiting the sodium channel in the collecting duct, which inhibits renal acid secretion or bicarbonate resorption. All diuretics that promote sodium chloride loss and cause volume depletion are more likely to produce a picture of metabolic acidosis.

Given the history it appears most likely that this patient has an overdose of beta-blockers. Management of choice for profound hypotension as in this case is with iv glucagon, bolus followed by infusion. Glucagon exerts an inotropic effect independent of beta-receptor activation by raising myocardial cAMP levels. Predominant bradycardia is managed with atropine +/– isoprenaline infusion. Patients who fail to respond to these two measures may require installation of a temporary pacing wire. Hypoglycaemia may also occur in association with beta-blocker overdose, bolus doses of iv 50% dextrose followed by 10% dextrose infusion is the management of choice.

There is no evidence that oral administration of zidovudine at the time of conception reduces the risk of HIV transmission. Oral zidovudine from 28 weeks’ gestation onwards has been used to reduce the risk of transmission. There is also no evidence that intravenous zidovudine during labour is of any benefit. Zidovudine is effective in reducing the risk of HIV transmission from mother to neonate by 8.3% - 18%. The ideal treatment regimen is to commence zidovudine as an intravenous infusion at the onset of labour and continue it until the baby is 6 weeks of age. Breast-feeding increases the risk of HIV transmission. Elective Caesarean section may reduce the risk compared to

vaginal delivery. Shortening the second stage by operative delivery increases the risk of transmission.

Tetracycline is used to treat a Coxiella burnetii infection and psittacosis. Rifampicin therapy is given in legionella infection and in severe cases of Mycoplasma pneumoniae. Penicillin is used commonly in pneumococcal infection. Clarithromycin is preferred for mycoplasma infections, while co-trimoxazole is given in Pneumocystis carinii (also known as Pneumocystis jiroveci) infection.

HCO3– levels are very low, w ith severe acidosis and base deficit. In this

situation the next immediate treatment is with sodium bicarbonate, the 8.4% concentration should be given via central line over 30–40 min. It is almost as important to begin treatment for inhibition of alcohol dehydrogenase as soon as possible. Fomepizole or alcohol may be given as inhibitors of alcohol dehydrogenase. Fomepizole has the advantage of not decreasing conscious level. It is likely that haemodialysis will be required; in patients requiring haemodialysis either the alcohol infusion rate or dose interval between doses of fomepizole requires alteration. As little as 30 ml of ethylene glycol may be fatal in adults, plasma levels of >500 mg/l indicate a severe overdose, and degree of acidosis is predictive of outcome.

Amphetamine overdose is associated with mydriasis, hypertension, tachycardia, skin pallor, hyperexcitability and, in the initial stages, agitation and increased talkativeness. Poor prognostic features associated with amphetamine overdose include hyperpyrexia, rhabdomyolysis, acute renal failure and acute liver failure. Complications include intracerebral haemorrhage, which may occur after a single amphetamine dose. Any patients who show focal signs or decreased conscious level should raise suspicion of the possibility of intracerebral haemorrhage. Hypertension should be controlled with beta blockade, and agitated patients may be sedated with benzodiazepines.

Ecstasy is an amfetamine derivative (methylenedioxymethamfetamine, MDMA) and its effect is to cause stimulation of the sympathetic nervous system. The effects of ecstasy usually occur within 1 hour and typically last for 4–6 hours, although in large ingestions they can last for up to 48 hours. Unwanted effects include cardiac arrhythmias (the principal cause of MDMA-associated deaths), hyponatraemia, hypertension and hyperthermia. Hyponatraemia can occur either because of an excessive fluid intake or because of SIADHS (syndrome of inappropriate antidiuretic hormone secretion). Treatment of hyperthermia includes giving cold intravenous fluids if the core temperature is over 39 °C: if this is ineffective, it should be followed by iv dantrolene and/or paralysis and ventilation.

 

Ecstasy (3,4-methylenedioxymethamfetamine, MDMA) stimulates the central nervous system. Poisoning with this drug is usually the result of its recreational use rather than a single massive dose.

Gastric lavage should be considered if a substantial overdose has been ingested in the preceding 1 hour. The dehydration should be corrected. All patients should be transferred to A&E and observed and monitored for at least 6 hours for the electrocardiogram (ECG) and electrolyte balance. Diazepam should be given if the patient convulses. Cooling measures (fan, sponging, ice packs, cool iv fluids) should be instigated if the rectal temperature rises above

39 °C. If this is unsuccessful, the patient will need to be paralysed and ventilated. 

b-Adrenoceptor blocking drugs will antagonise the peripheral sympathomimetic actions of amfetamines. These drugs cause increased alertness and self-confidence, euphoria, extrovert behaviour, increased talkativeness with rapid speech, lack of desire to eat or sleep, tremor, dilated pupils, tachycardia and hypertension.

Generic medicines are produced by companies who are subject to the same tight controls as those who make branded products. In fact, the same company often makes branded and generic medicines. Generic medicines contain the same active ingredients, are of the same dosage form and are identical in strength to the original medicine. They have to be therapeutically equivalent to their branded product, which means that the maximum concentration (Cmax), the area under the curve (AUC) and the time of maximum concentration (tmax) must be comparable to the already registered drug. This means that they work in the same way in the body and are associated with the same risks and benefits of the original medicine. Different generic forms of the same medicine will not differ in their safety and clinical actions from each other or their branded equivalent.

 

A pharmaceutical company wants to bring generic ranitidine to the market after the patent has expired.

What kind of study is needed to obtain approval to market the drug?

Phase-I bioequivalence study

Glucocorticoids include cortisone and hydrocortisone, which have a low mineralocorticoid activity, along with prednisolone, betamethasone and dexamethasone. For replacement therapy, hydrocortisone in combination with fludrocortisone is used; this latter drug has little anti-inflammatory activity.

The strength of the anti-inflammatory effects of 5 mg prednisolone =

Betamethasone 750 µg Cortisone acetate 25 mg Deflazacort 6 mg Dexamethasone 750 µg Hydrocortisone 20 mg Methylprednisolone 4 mg

Antacids tend to alkalinise the urine, leading to increased urinary aspirin clearance, whereas metoclopramide enhances its absorption. Aspirin diminishes the actions of uricosuric agents such as probenicid and sulfinpyrazone.

The following are first-line treatments for the other conditions:

Rheumatic fever: phenyloxymethylpenicillin Meningococcal meningitis: rifampicin (ciprofloxacin for pregnant women and young

children) Haemophilus influenzae type B: rifampicin.

NSAIDs are disease-modifying drugs. They decrease the antihypertensive effect of angiotensin-converting enzyme inhibitors and therefore increase the risk of renal failure and hyperkalaemia. They antagonise the effects of ß-blockers and inhibit cyclo-oxygenase. Many of the renal side-effects arise from the prostaglandin-inhibiting properties of NSAIDs. In the kidney NSAIDs cause vasoconstriction, a decreased glomerular filtration rate and sodium and water retention, oppose the action of loop diuretics, augment the action of antidiuretic hormone (water retention) and cause hypernatraemia, hyperaldosteronism and hyperkalaemia. Side-effects of using NSAIDs include interstitial nephritis and nephrotic proteinuria but not nephritic syndrome. Eosinophilic infiltrates are often found on biopsy. Other complications include nausea and rashes.

This drug is a class 3 antiarrhythmic drug. It is a vasodilator of both the peripheral and the central circulation, and is a negative chronotrope. It has a half-life of 7–8 weeks and needs a loading dose. It acts to prolong the action potential in the refractory period. It also prolongs the QT and QRS complexes and is a sodium channel blocker. It directly decreases the automaticity of the sinus and the autonomic nervous system, and has a a- and ß-blocking properties.

What is this drug?

Amiodarone has the above properties, successfully suppresses an arrhythmia and does not cause mortality. It was used in the Basal Antiarrhythmic Study of Infarction Survey (BASIS) and found to be of benefit. It decreased all arrhythmias compared with a placebo and other antiarrhythmic medication. The study did, however, conclude that ß-blockers were still the best medication for a post-myocardial infarct.

Amiodarone potentiates digoxin, as it competes with it at digoxin-binding sites, warfarin, other antiarrhythmics and iodine content. It may therefore potentiate hyperthyroidism and may subsequently inhibit the conversion of thyroxine to active T3 and cause hypothyroidism. Other side-effects include reversible corneal microdeposits, optic neuritis, slate-grey skin syndrome, photosensitivity, pulmonary fibrosis, alveolitis, hepatitis, peripheral neuropathy, myopathy, hyperthyroidism, hypothyroidism (10%), heart block, dermatitis, tremor, gastrointestinal disturbance, lung amiodarone pulmonary disease, bradycardia, raised intracranial pressure, vasculitis and thrombocytopenia. It may be well tolerated in low doses and is effective in the prevention and cardioversion of atrial flutter and fibrillation.

This antiepileptic medication is used to enhance the action of -aminobutyric acid, which is a major inhibitory neurotransmitter. It is used in absence attacks, temporal lobe epilepsy and myoclonic-type epilepsy. It inhibits liver enzymes and may enhance the function of other antiepileptic agents such as phenytoin, causing toxicity.

What is this medication?

Sodium valproate has many dose-related side effects, including thrombocytopenia, tremor, appetite stimulation, alopecia, ataxia, fatal hepatitis, gastric irritation, pancreatitis, menstrual irregularities, encephalopathy, hyperammonaemia (20%) and hepatotoxicity (1 in 20,000). Plasma levels are required to determine the efficacy of the clinical response. Sodium valproate is not used for infantile spasms (nitrazepam, adrenocorticotrophic hormone or prednisolone are used instead) or status epilepticus (lorazepam and phenytoin).

A teenager presents unconscious in the emergency department. Her parents give a history that she had been drinking the night before. During the night, she complained of a high fever and sweating with severe abdominal pain. She also intermittently complained of dizziness, tinnitus and deafness. The girl became very irritable and therefore went to bed thinking that this was due to alcohol toxicity. Next morning, she was found unconscious.

Investigations have revealed the following results: sodium 130 mmol/l, potassium 2.9 mmol/l, urea 9.4 mmol/l, creatinine 115 µmol/l, hypoprothrombinaemia and a normal bleeding time on clotting analysis, blood glucose 2.1 mmol/l, urinalysis test positive and blood gases showing a compensated metabolic acidosis. She has also presented with bruising.

What is the diagnosis?

This girl has presented in a compensated metabolic acidosis due to the accumulation of organic acid secondary to salicylate poisoning. All her symptoms are those found in the acute phase of the condition, and loss of consciousness is found in the late phase. Other presenting features and complications include hyperventilation, hyperpyrexia, dehydration, pulmonary oedema, acute renal failure and irritability.

Physiologically, as there is an increase in initial respiratory alkalosis, bicarbonate is released in the urine, causing hyponatraemia and hypokalaemia, and water is released in the urine. This therefore causes a compensatory metabolic acidosis, promoting the accumulation of lactate pyruvate. A stimulation of fat catabolism leads to ketone and ß-hydroxybutyrate production, an increase in protein catabolism and aminoaciduria.

Treatment includes emesis and gastric lavage with activated charcoal. Electrolytes and renal function need to be corrected, and a forced alkaline diuresis with 0.9% saline, 5% dextrose and 1.26% bicarbonate solution is required to keep the pH of the urine between 7.5 and 8.5. The initial hyperventilation in the acute phase causes the respiratory alkalosis and thus the compensatory metabolic acidosis, which in turn causes the ketonuria. With regard to the significance of the serum dose levels at 6 hours, the following should be remembered:

3–500 mg/l is mild 500–750 mg/l is moderate >750 mg/l is severe.

Complications of tricyclic overdose include cardiovascular complications (Sinus tachycardia; Prolonged PR/QRS/QT; ST/T wave changes; Heart block; Vasodilatation; Hypotension; Cardiogenic shock; Ventricular fibrillation/tachycardia; Asystole), central nervous system complications

(Drowsiness; Coma; Convulsions; Pyramidal signs; Rigidity; Delirium; Respiratory depression; Ophthalmoplegia) and anticholinergic effects (Dry mouth; Blurred vision; Dilated pupils; Urinary retention; Absent bowel sounds; Pyrexia; Myoclonic twitching).

This patient has features of attention deficit hyperactivity disorder. According to the clinical evidence, (BMJ), clonidine is of unknown effectiveness, the others are likely to be beneficial. AtomoxetineDexamfetamine sulphateMethylphenidate Methylphenidate plus psychological behavioural treatment

The child has symptoms of atropine poisoning. Atropine is a cycloplegic sometimes used in the eye hospital to paralyse a young child’s accommodation to reveal their full refractive error as the accommodation will no longer effect the results. The fatal dose for a child is only 10mg. 100mg will kill an adult. CNS effects occur only in advanced stages of atropine poisoning, milder effects occur at an earlier stage, so the patient will be thirsty, hot and dry, have a dry mouth, and they will have an increased heart rate.

A child presents with sudden onset pain, photophobia, lacrimation, blurred vision, circumcorneal redness and a small pupil.  What is often used in combination with atropine to prevent worsening of this condition?  Phenylephrine 2.5% The child has symptoms of anterior uveitis and needs to be treated with phenylephrine to prevent posterior synechiae. 

Topical cycloplegic agents are used to dilate the pupil and to relax the ciliary muscle for ocular examination Drugs of choice vary with opinions but 1% cylopentolate would be a suitable choice of cycloplegic in this situation. Cycloplegics paralyse accommodation and therefore reveal an individual's full refractive error without the effects of accommodation altering the prescription. If a prescription is found it is prescribed if it can control or relieve the squint. Tropicamide is a weak mydriatic but will not paralyse ciliary musculature sufficiently to prevent accommodation. Atropine has a longer duration of action than cyclopentolate. Amethocaine is a local anaesthetic.Drugs of choice vary with opinion but 1% Atropine sulphate would be the preferred agent for an individual with darkly pigmented irises. Tropicamide may be used where pupil dilatation alone is required (e.g. to facilitate fundoscopy). In many ophthalmology clinics 1% cyclopentolate is the preferred agent for cycloplegia. Atropine performs better than cyclopentolate in children with dark irises which tend to be more resistant to mydriasis. Drops may need to be instilled some hours before examination in some of these individuals.

Extrapyramidal side effects include:

Parkinsonian symptoms DystoniaAkathisiaDyskinesiaParkinsonian symptoms may be suppressed by the administration of antimuscarinic drugs such as procyclidine. Tardive dyskinesia may be irreversible. It may even occur after withdrawal of the drug. The symptoms cannot be predicted accurately, but depend on dose, type of drug and individual susceptibility.

Extrapyramidal side effects are caused by piperazine derivatives (fluphenazine, perphenazine, prochlorperazine, and trifluoperazine), the butyrophenones (haloperidol and benperidol)and the depot preparations. Ondansetron is a 5HT3 antagonist. Procyclidine is used to treat extrapyramidal symptoms.

Methaemoglobinaemia is caused by uncoupling of oxidative phosphorylation and any of the nitrates, local anaesthetics or dapsone may be responsible. Treatment is with methylene blue.

Side effects of theophylline toxicity are also agitation, restlessness, dilated pupils, hyperglycaemia and ventricular arrhythmias. Elimination is increased by oral administration of activated charcoal.

Rifampicin and doxorubicin turn urine a red colour. Desferrioxamine turns urine a reddish-brown. None of the other drugs has any significant effect.

Opioid poisoning is classically associated with pinpoint pupils, reduced respiratory rate, bradycardia, drowsiness and coma. Hypothermia is a feature of barbiturate poisoning, while sweating and lacrimation are seen in cases of opiate withdrawal.

Symptoms following salicylate ingestion include nausea, vomiting, flushing, hyperventilation and sweating. Tinnitus typically occurs at plasma salicylate concentrations above 400–500 mg/l. Hypoglycaemia following salicylate ingestion is commonly seen in children but not in adults. Severe toxic effects are CNS effects, including confusion, coma and fits. Initially there is a respiratory alkalosis due to the direct stimulation of the respiratory centre and hyperventilation; then a metabolic acidosis occurs due to uncoupling of oxidative phosphorylation and the build up of lactic acid and fatty acid metabolites. The metabolic acidosis can increase the transfer of salicylates across the blood–brain barrier, thereby increasing CNS toxicity.

antihistamine

Desloratadine is a long-acting H1-receptor antagonist and has poor penetration into the central nervous system. It does not interact with antibiotics or other co-administered medications. Cetirizine, desloratadine and fexofenadine are prescribed for allergic rhinitis (hay fever) and all three are equally effective. However, cetirizine and fexofenadine interact with erythromycin and other

macrolides. Chlorphenamine maleate and terfenadine cause drowsiness and also interact with erythromycin.

The penicillins are relatively safe in breast-feeding. In contrast, ciprofloxacin and ofloxacin are quite lipophilic and are therefore secreted in significant quantities in breast milk. Clarithromycin is not recommended by the manufacturer unless the benefits of treatment outweigh the risk. Fluconazole is also not recommended for use by the manufacturer in patients who are breast-feeding. It is important to note that significant changes in cytochrome P450 metabolism take place during the first few months of life, so that safety in a parent or adult population is no guarantee of safety in the neonate.

Of the choices given, only amoxicillin and rifampicin induce the hepatic enzymes to the extent of reducing the activity of a number of drugs that are metabolised by the liver, including oral contraceptive pills. However, amoxicillin is more likely to have been prescribed for the ear infection than rifampicin in this case. Rifampicin is usually prescribed for tuberculosis.

Carbamazepine is a good first-line anticonvulsant. Plasma levels are easily monitored if control is not achieved. Carbamazepine is not as hepatotoxic as sodium valproate, and is less cardiotoxic than phenytoin (which also has zero-order kinetics, making dose titration difficult). Diazepam as needed is not a realistic treatment because the aim is to prevent seizures – not to treat them when they happen.

ACE inhibitors are beneficial for both post-nephritic and renal hypertension but must be used with caution in patients with renal impairment. They are contraindicated for use in hypertension in pregnancy as they have teratogenic effects such as renal agenesis and hypoplasia, neonatal hypotension, cleft lip and palate deformities, and cardiac malformations. They must not be used to treat heart failure caused by aortic stenosis as there is an increased incidence of sudden death due to the precipitation of profound hypotension. Side-effects include cough, rash and angioneurotic oedema. Captopril and not enalapril causes dysquesia (loss or altered taste). ACE inhibitors do not cause gout or flushes.

Enalapril is used to treat hypertension and heart failure. It inactivates bradykinin in the conversion of angiotensin (AT) I to AT II in the lung epithelium. It therefore reduces the effects of AT II on aldosterone to cause hypotension in nephritic patients. It is a pro-drug that is converted to the active metabolite enalaprilat in the liver. It has a long half-life and is finally excreted via the kidneys. This metabolite is increased in the kidney in renal failure and therefore must be used with caution. Side-effects include hypotension, decreased renal function, neutropenia, angioneurotic oedema, non-productive cough and headaches but not flushing.

Chronic alcohol consumption results in dilated cardiomyopathy due to its toxic effects on the myocardium. Thiamine deficiency causes dilated cardiomyopathy as a result of a poor diet rather than directly because of the alcohol. Other cardiogenic effects include persistent chronic paroxysmal tachycardia and atrial fibrillation (not atrial flutter). There is a reported

increased incidence of haemorrhagic and embolic stroke due to left atrial standstill, which may in turn precipitate the embolic phenomenon.