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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 3040 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 46 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 (C
max
), the area under the curve (AUC) and the time of maximum concentration
(t
max
) 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 g
Cortisone acetate 25 mg
Deflazacort 6 mg
Dexamethasone 750 g
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 -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 78 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 -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 -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 T
3
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 mol/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 -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:
3500 mg/l is mild
500750 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.
Atomoxetine
Dexamfetamine sulphate
Methylphenidate
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 childs 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
Dystonia
Akathisia
Dyskinesia
Parkinsonian 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 400500 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 bloodbrain barrier, thereby
increasing CNS toxicity.
antihistamine
Desloratadine is a long-acting H
1
-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.