Pharmacology Flashcards
Palliative care prescribing pain
NICE guidelines
In 2012 NICE published guidelines on the use of opioids in palliative care. Selected points are listed below. Please see the link for more details.
Starting treatment
when starting treatment, offer patients with advanced and progressive disease regular oral modified-release (MR) or oral immediate-release morphine (depending on patient preference), with oral immediate-release morphine for breakthrough pain
if no comorbidities use 20-30mg of MR a day with 5mg morphine for breakthrough pain. For example, 15mg modified-release morphine tablets twice a day with 5mg of oral morphine solution as required
oral modified-release morphine should be used in preference to transdermal patches
laxatives should be prescribed for all patients initiating strong opioids
patients should be advised that nausea is often transient. If it persists then an antiemetic should be offered
drowsiness is usually transient - if it does not settle then adjustment of the dose should be considered
SIGN guidelines
SIGN issued guidance on the control of pain in adults with cancer in 2008. Selected points
the breakthrough dose of morphine is one-sixth the daily dose of morphine
all patients who receive opioids should be prescribed a laxative
opioids should be used with caution in patients with chronic kidney disease. Alfentanil, buprenorphine and fentanyl are preferred
metastatic bone pain may respond to strong opioids, bisphosphonates or radiotherapy. The assertion that NSAIDs are particularly effective for metastatic bone pain is not supported by studies. Strong opioids have the lowest number needed to treat for relieving the pain and can provide quick relief, in contrast to radiotherapy and bisphosphonates*. All patients, however, should be considered for referral to a clinical oncologist for consideration of further treatments such as radiotherapy
Other points
When increasing the dose of opioids the next dose should be increased by 30-50%.
In addition to strong opioids, bisphosphonates and radiotherapy, denosumab may be used to treat metastatic bone pain.
Opioid side-effects
Usually transient
Usually persistent
Nausea
Drowsiness
Constipation
Tuberculosis: drug side-effects and mechanism of action
Rifampicin
mechanism of action: inhibits bacterial DNA dependent RNA polymerase preventing transcription of DNA into mRNA
potent liver enzyme inducer
hepatitis, orange secretions
flu-like symptoms
Isoniazid
mechanism of action: inhibits mycolic acid synthesis
peripheral neuropathy: prevent with pyridoxine (Vitamin B6)
hepatitis, agranulocytosis
liver enzyme inhibitor
Pyrazinamide
mechanism of action: converted by pyrazinamidase into pyrazinoic acid which in turn inhibits fatty acid synthase (FAS) I
hyperuricaemia causing gout
arthralgia, myalgia
hepatitis
Ethambutol
mechanism of action: inhibits the enzyme arabinosyl transferase which polymerizes arabinose into arabinan
optic neuritis: check visual acuity before and during treatment
dose needs adjusting in patients with renal impairment
Ethambutol is associated with optic neuropathy and development of colour blindness. It should be discontinued if these symptoms develop. In clinical practice pyridoxine (vitamin B6) is given concurrently with ethambutol to try to prevent these side effects.
Quinolones
Quinolones are a group of antibiotics which work by inhibiting DNA synthesis and are bactericidal in nature. Examples include:
ciprofloxacin
levofloxacin
Mechanism of action
inhibit topoisomerase II (DNA gyrase) and topoisomerase IV
Mechanism of resistance
mutations to DNA gyrase, efflux pumps which reduce intracellular quinolone concentration
Adverse effects
lower seizure threshold in patients with epilepsy
tendon damage (including rupture) - the risk is increased in patients also taking steroids
cartilage damage has been demonstrated in animal models and for this reason quinolones are generally avoided (but not necessarily contraindicated) in children
lengthens QT interval
Contraindications
Quinolones should generally be avoided in women who are pregnant or breastfeeding
avoid in G6PD
Mefloquine
Mefloquine (brand name Lariam) is used for both the prophylaxis and treatment of certain types of malaria. There has long been a concern about the neuropsychiatric side-effects of mefloquine. A recent review has however led to ‘strengthened warnings’ about the potential risks.
The following advice is therefore given:
certain side-effects such nightmares or anxiety may be ‘prodromal’ of a more serious neuropsychiatric event
suicide and deliberate self harm have been reported in patients taking mefloquine
adverse reactions may continue for several months due to the long half-life or mefloquine
mefloquine should not be used in patients with a history of anxiety, depression schizophrenia or other psychiatric disorders
patients who experience neuropsychiatric sife-effects should stop mefloquine and seek medical advice
Antibiotics
Nitrofurantoin is a relatively old and unique antibiotic which has enjoyed a new lease of life with increasing antibiotic resistance. It is actually an inactive pro-drug which is reduced in vivo to active forms by the bacterial flavoprotein nitrofuran reductase, and it is these reduced forms of the drug which exert their antibiotic properties by damaging bacterial proteins. In order to be effective at treating urinary tract infections, nitrofurantoin needs to be concentrated in the urine and an adequate glomerular filtration is required for this to occur. An eGFR of less than 40-60ml/min means that the drug is wholly ineffective as a bactericidal agent and is not recommended in patients with CKD stage 3 or worse due to the likelihood of treatment failure. Coupled with this is the risk of drug toxicity in the patient. Without adequate renal filtration, the drug is likely to accumulate. Although bacterial flavoproteins activate nitrofurantoin more readily, human enzymes can reduce this drug to generate many highly active radical species, which can cause side effects including peripheral neuropathy, which may not be reversible, hepatotoxicity and acute and chronic pulmonary reactions and fibrosis.
Patients taking nitrofurantoin should be advised that this drug will discolour the urine. It is also a safe drug to use in pregnancy except at full term when there is a risk of haemolysis in the neonate.
Amoxicillin and co-amoxiclav are widely used antibiotics in the treatment of urinary tract infections and are relatively safe in renal impairment. Dose reduction is recommended in severe chronic renal disease, i.e. an eGFR <15-30ml/min to avoid the risk of crystalluria. Similarly, a reduction in dose is necessary for ciprofloxacin in CKD to avoid crystalluria although this is recommended from an eGFR of 30-60ml/min.
Trimethoprim is an antibiotic which is entirely safe to use in all but the most severe forms of chronic kidney disease where a modest dose adjustment is required. It should be noted however that use of trimethoprim is likely to affect the results of renal function tests since the drug inhibits tubular secretion of creatinine leading to a rise in serum levels in all patients, including those with previously normal renal function. This is without any effect on the glomerular filtration rate.
Prescribing in patients with renal failure
Questions regarding which drugs to avoid in renal failure are common
Drugs to avoid in renal failure
antibiotics: tetracycline, nitrofurantoin
NSAIDs
lithium
metformin
Drugs likely to accumulate in chronic kidney disease - need dose adjustment
most antibiotics including penicillins, cephalosporins, vancomycin, gentamicin, streptomycin
digoxin, atenolol
methotrexate
sulphonylureas
furosemide
opioids
Drugs relatively safe - can sometimes use normal dose depending on the degree of chronic kidney disease
antibiotics: erythromycin, rifampicin
diazepam
warfarin
Side-effects of common drugs: antibiotics
The table below summarises characteristic (if not necessarily the most common) side-effects of drugs used antibiotics
Drug
Side-effect
Amoxicillin
Rash with infectious mononucleosis
Co-amoxiclav
Cholestasis
Flucloxacillin
Cholestasis (usually develops several weeks after use)
Erythromycin
Gastrointestinal upset
Prolongs QT interval
Ciprofloxacin
Lowers seizure threshold
Tendonitis
Metronidazole
Reaction following alcohol ingestion
Doxycycline
Photosensitivity
Trimethoprim
Rashes, including photosensitivity
Pruritus
Suppression of haematopoiesis
All tetracyclines should be avoided in pregnancy.
It should be noted that the above prescriptions are not necessarily the recommended first-line treatments
Prescribing in pregnant patients
Very few drugs are known to be completely safe in pregnancy. The list below largely comprises of those known to be harmful. Some countries have developed a grading system - see the link.
Antibiotics
tetracyclines
aminoglycosides
sulphonamides and trimethoprim
quinolones: the BNF advises to avoid due to arthropathy in some animal studies
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. The decision to stop such treatments however is difficult as uncontrolled epilepsy is also a risk
Digoxin and digoxin toxicity
Digoxin is a cardiac glycoside now mainly used for rate control in the management of atrial fibrillation. As it has positive inotropic properties it is sometimes used for improving symptoms (but not mortality) in patients with heart failure.
Mechanism of action
decreases conduction through the atrioventricular node which slows the ventricular rate in atrial fibrillation and flutter
increases the force of cardiac muscle contraction due to inhibition of the Na+/K+ ATPase pump. Also stimulates vagus nerve
digoxin has a narrow therapeutic index
Monitoring
digoxin level is not monitored routinely, except in suspected toxicity
if toxicity is suspected, digoxin concentrations should be measured within 8 to 12 hours of the last dose
Digoxin toxicity
Plasma concentration alone does not determine whether a patient has developed digoxin toxicity. Toxicity may occur even when the concentration is within the therapeutic range. The BNF advises that the likelihood of toxicity increases progressively from 1.5 to 3 mcg/l.
Features
generally unwell, lethargy, nausea & vomiting, anorexia, confusion, yellow-green vision
arrhythmias (e.g. AV block, bradycardia)
gynaecomastia
Precipitating factors
classically: hypokalaemia
digoxin normally binds to the ATPase pump on the same site as potassium. Hypokalaemia → digoxin more easily bind to the ATPase pump → increased inhibitory effects
increasing age
renal failure
myocardial ischaemia
hypomagnesaemia, hypercalcaemia, hypernatraemia, acidosis
hypoalbuminaemia
hypothermia
hypothyroidism
drugs: amiodarone, quinidine, verapamil, diltiazem, spironolactone (competes for secretion in distal convoluted tubule therefore reduce excretion), ciclosporin. Also drugs which cause hypokalaemia e.g. thiazides and loop diuretics
Management
Digibind
correct arrhythmias
monitor potassium
Calcium channel blockers
Calcium channel blockers are primarily used in the management of cardiovascular disease. Voltage-gated calcium channels are present in myocardial cells, cells of the conduction system and those of the vascular smooth muscle. The various types of calcium channel blockers have varying effects on these three areas and it is therefore important to differentiate their uses and actions.
Examples
Indications & notes
Side-effects and cautions
Verapamil
Angina, hypertension, arrhythmias
Highly negatively inotropic
Should not be given with beta-blockers as may cause heart block
Heart failure, constipation, hypotension, bradycardia, flushing
Diltiazem
Angina, hypertension
Less negatively inotropic than verapamil but caution should still be exercised when patients have heart failure or are taking beta-blockers
Hypotension, bradycardia, heart failure, ankle swelling
Nifedipine, amlodipine, felodipine
(dihydropyridines)
Hypertension, angina, Raynaud’s
Affects the peripheral vascular smooth muscle more than the myocardium and therefore do not result in worsening of heart failure
Flushing, headache, ankle swelling
Metformin
Metformin is a biguanide used mainly in the treatment of type 2 diabetes mellitus. It has a number of actions which improves glucose tolerance (see below). Unlike sulphonylureas it does not cause hypoglycaemia and weight gain and is therefore first-line, particularly if the patient is overweight. Metformin is also used in polycystic ovarian syndrome and non-alcoholic fatty liver disease
Mechanism of action
acts by activation of the AMP-activated protein kinase (AMPK)
increases insulin sensitivity
decreases hepatic gluconeogenesis
may also reduce gastrointestinal absorption of carbohydrates
Adverse effects
gastrointestinal upsets are common (nausea, anorexia, diarrhoea), intolerable in 20%
reduced vitamin B12 absorption - rarely a clinical problem
lactic acidosis* with severe liver disease or renal failure
Contraindications
chronic kidney disease: NICE recommend that the dose should be reviewed if the creatinine is > 130 µmol/l (or eGFR < 45 ml/min) and stopped if the creatinine is > 150 µmol/l (or eGFR < 30 ml/min)
metformin may cause lactic acidosis if taken during a period where there is tissue hypoxia. Examples include a recent myocardial infarction, sepsis, acute kidney injury and severe dehydration
iodine-containing x-ray contrast media: examples include peripheral arterial angiography, coronary angiography, intravenous pyelography (IVP); there is an increasing risk of provoking renal impairment due to contrast nephropathy; metformin should be discontinued on the day of the procedure and for 48 hours thereafter
alcohol abuse is a relative contraindication
Starting metformin
metformin should be titrated up slowly to reduce the incidence of gastrointestinal side-effects
if patients develop unacceptable side-effects then modified-release metformin should be considered
*it is now increasingly recognised that lactic acidosis secondary to metformin is rare, although it remains important in the context of exams
Side-effects of common drugs: diabetes drugs
The table below summarises characteristic (if not necessarily the most common) side-effects of drugs used to treat diabetes mellitus
Drug
Side-effect
Metformin
Gastrointestinal side-effects
Lactic acidosis
Sulfonylureas
Hypoglycaemic episodes
Increased appetite and weight gain
Syndrome of inappropriate ADH secretion
Liver dysfunction (cholestatic)
Glitazones
Weight gain
Fluid retention
Liver dysfunction
Fractures
Gliptins
Pancreatitis
NICE recommend that the dose of metformin should be reviewed if the creatinine is > 130 micromol/l (or eGFR < 45 ml/min) and stopped if the creatinine is > 150 micromol/l (or eGFR < 30 ml/min)
Important for meLess important
Metformin is the drug that needs to be stopped in this case. NICE recommendations on the use of metformin in the treatment of diabetes mellitus specify that:
A review of the dose of metformin be undertaken if the serum creatinine exceeds 130 micromol/litre or the estimated glomerular filtration rate (eGFR) is below 45 ml/minute/1.73m²
Stop Metformin if the serum creatinine exceeds 150 micromol/litre or the eGFR is below 30 ml/minute/1.73m²
St John’s Wort
Overview
shown to be as effective as tricyclic antidepressants in the treatment of mild-moderate depression
mechanism: thought to be similar to SSRIs (although noradrenaline uptake inhibition has also been demonstrated)
NICE advise ‘may be of benefit in mild or moderate depression, but its use should not be prescribed or advised because of uncertainty about appropriate doses, variation in the nature of preparations, and potential serious interactions with other drugs’
Adverse effects
profile in trials similar to placebo
can cause serotonin syndrome
inducer of P450 system, therefore decreased levels of drugs such as warfarin, ciclosporin. The effectiveness of the combined oral contraceptive pill may also be reduced
Gentamicin
Aminoglycosides are nephrotoxic
Importance: 50
is an amino glycoside antibiotic with excellent cover of gram negative bacteria. It is used for severe infections, and is particularly useful for severe infections of the urinary tract and within the abdomen.
A common complication associated with gentamicin usage is nephrotoxicity.
This is because of the narrow therapeutic window required to achieve a therapeutic dose. If we go above this index we risk nephrotoxicity.
Another common complication is ototoxicity and this is often examined in final exams.
More on Gentamicin - http://qjmed.oxfordjournals.org/content/102/12/873
Gentamicin is a type of aminoglycoside antibiotic. It is poorly lipid-soluble and is therefore given parentally (e.g. for infective endocarditis) or topically (e.g. for otitis externa).
Adverse effects
ototoxicity
due to auditory or vestibular nerve damage
irreversible
nephrotoxicity
accumulates in renal failure
the toxicity is secondary to acute tubular necrosis
concomitant use of furosemide increases the risk
lower doses and more frequent monitoring is required
Contraindications
myasthenia gravis
Dosing
due to the significant ototoxic and nephrotoxic potential of gentamicin it is important to monitor plasma concentrations
both peak (1 hour after administration) and trough levels (just before the next dose) are measured
if the trough (pre-dose) level is high the interval between the doses should be increased
if the peak (post-dose) level is high the dose should be decreased
P450 enzyme system
Induction usually requires prolonged exposure to the inducing drug, as opposed to P450 inhibitors, where effects are often seen rapidly
Inducers of the P450 system include
antiepileptics: phenytoin, carbamazepine
barbiturates: phenobarbitone
rifampicin
St John’s Wort
chronic alcohol intake
griseofulvin
smoking (affects CYP1A2, reason why smokers require more aminophylline)
Inhibitors of the P450 system include
antibiotics: ciprofloxacin, erythromycin
isoniazid
cimetidine,omeprazole
amiodarone
allopurinol
imidazoles: ketoconazole, fluconazole
SSRIs: fluoxetine, sertraline
ritonavir
sodium valproate
acute alcohol intake
quinupristin
Sulfasalazine can cause lung fibrosis
Drugs causing lung fibrosis
Causes
amiodarone
cytotoxic agents: busulphan, bleomycin
anti-rheumatoid drugs: methotrexate, sulfasalazine
nitrofurantoin
ergot-derived dopamine receptor agonists (bromocriptine, cabergoline, pergolide)
Side-effects of common drugs: anti-hypertensives
The table below summarises characteristic (if not necessarily the most common) side-effects of drugs used to treat hypertension
Drug
Side-effect
ACE inhibitors
Cough
Hyperkalaemia
Bendroflumethiazide
Gout
Hypokalaemia
Hyponatraemia
Impaired glucose tolerance
Calcium channel blockers
Headache
Flushing
Ankle oedema
Beta-blockers
Bronchospasm (especially in asthmatics)
Fatigue
Cold peripheries
Doxazosin
Postural hypotension
Lithium toxicity
Lithium is a mood stabilising drug used most commonly prophylactically in bipolar disorder but also as an adjunct in refractory depression. It has a very narrow therapeutic range (0.4-1.0 mmol/L) and a long plasma half-life being excreted primarily by the kidneys. Lithium toxicity generally occurs following concentrations > 1.5 mmol/L.
Toxicity may be precipitated by:
dehydration
renal failure
drugs: diuretics (especially thiazides), ACE inhibitors/angiotensin II receptor blockers, NSAIDs and metronidazole.
Features of toxicity
coarse tremor (a fine tremor is seen in therapeutic levels)
hyperreflexia
acute confusion
seizure
coma
Management
mild-moderate toxicity may respond to volume resuscitation with normal saline
haemodialysis may be needed in severe toxicity
sodium bicarbonate is sometimes used but there is limited evidence to support this. By increasing the alkalinity of the urine it promotes lithium excretion
Ecstasy poisoning
Ecstasy (MDMA, 3,4-Methylenedioxymethamphetamine) use became popular in the 1990’s during the emergence of dance music culture
Clinical features
neurological: agitation, anxiety, confusion, ataxia
cardiovascular: tachycardia, hypertension
hyponatraemia
hyperthermia
rhabdomyolysis
Management
supportive
dantrolene may be used for hyperthermia if simple measures fail
Drug-induced urinary retention
The following drugs may cause urinary retention:
tricyclic antidepressants
anticholinergics
opioids
NSAIDs
disopyramide
The BNF advises avoiding quinolones in pregnancy due to arthropathy in animal studies.
There have been some reports of an increased risk of necrotizing enterocolitis following the use of co-amoxiclav in pregnancy. The evidence is however inconclusive and the BNF states that co-amoxiclav is ‘not known to be harmful’. A link is provided both to the BNF and the UK teratology information service.
Prescribing in pregnant patients
Very few drugs are known to be completely safe in pregnancy. The list below largely comprises of those known to be harmful. Some countries have developed a grading system - see the link.
Antibiotics
tetracyclines
aminoglycosides
sulphonamides and trimethoprim
quinolones: the BNF advises to avoid due to arthropathy in some animal studies
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. The decision to stop such treatments however is difficult as uncontrolled epilepsy is also a risk
Finasteride
Finasteride is an inhibitor of 5 alpha-reductase, an enzyme which metabolises testosterone into dihydrotestosterone.
Indications
benign prostatic hyperplasia
male-pattern baldness
Adverse effects
impotence
decrease libido
ejaculation disorders
gynaecomastia and breast tenderness
Finasteride causes decreased levels of serum prostate-specific antigen
Finasteride is a 5 alpha reductase inhibitor which converts testosterone into DHT
Importance: 65
Finasteride is a 5-alpha reductase inhibitor given to patients suffering from benign prostatic hyperplasia. By blocking 5-alpha reductase it stops the conversion of testosterone to dihydrotestosterone, thereby reducing the size of the prostate.
Trimethoprim works by binding to dihydrofolate reductase, therefore, interfering with bacterial DNA synthesis.
Tamsulosin is an alpha blocker which selectively blocks the alpha 1 receptors in the bladder neck and prostate causing a relaxation of the smooth muscle.
Oxybutynin has a direct spasmolytic effect on the bladder smooth muscle by competitively antagonising the muscarinic receptors on the bladder.
Finally sildenafil inhibits cGMP specific phosphodiesterase type 5 therefore helping to improve blood flow to the penis to help with erectile dysfunction.
Finasteride
Finasteride is an inhibitor of 5 alpha-reductase, an enzyme which metabolises testosterone into dihydrotestosterone.
Indications
benign prostatic hyperplasia
male-pattern baldness
Adverse effects
impotence
decrease libido
ejaculation disorders
gynaecomastia and breast tenderness
Finasteride causes decreased levels of serum prostate-specific antigen
Tamoxifen
Tamoxifen is a Selective oEstrogen Receptor Modulator (SERM) which acts as an oestrogen receptor antagonist and partial agonist. It is used in the management of oestrogen receptor positive breast cancer
Adverse effects
menstrual disturbance: vaginal bleeding, amenorrhoea
hot flushes - 3% of patients stop taking tamoxifen due to climateric side-effects
venous thromboembolism
endometrial cancer
osteoporosis
Tamoxifen is typically used for 5 years following removal of the tumour.
Raloxifene is a pure oestrogen receptor antagonist, and carries a lower risk of endometrial cancer
Drugs causing ocular problems
Cataracts
steroids
Corneal opacities
amiodarone
indomethacin
Optic neuritis
ethambutol
amiodarone
metronidazole
Retinopathy
chloroquine, quinine
Sildenafil can cause both blue discolouration and non-arteritic anterior ischaemic neuropathy
There are a number of causes of gynaecomastia in males and it is important to rule out sinister ones such as kidney failure, endocrine disturbances, liver failure or malignancy.
Another key cause is medication related, in this case the finasteride taken by this patient can cause gynaecomastia.
Finasteride works by blocking 5-alpha-reductase inhibitors those reducing the production of dihydrotestosterone and therefore shrinking the prostate, however side effects can include gynaecomastia and sexual dysfunction.
Carbon monoxide poisoning
Carbon monoxide has a high affinity for haemoglobin and myoglobin resulting in a left-shift of the oxygen dissociation curve and tissue hypoxia. There are approximately 50 per year deaths from accidental carbon monoxide poisoning in the UK.
Pathophysiology
in carbon monoxide poisoning the oxygen saturation of haemoglobin decreases leading to an early plateau in the oxygen dissociation curve
Questions may hint at badly maintained housing e.g. student houses.
Features of carbon monoxide toxicity
headache: 90% of cases
nausea and vomiting: 50%
vertigo: 50%
confusion: 30%
subjective weakness: 20%
severe toxicity: ‘pink’ skin and mucosae, hyperpyrexia, arrhythmias, extrapyramidal features, coma, death
Investigations
pulse oximetry may be falsely high due to similarities between oxyhaemoglobin and carboxyhaemoglobin
therefore a venous or arterial blood gas should be taken
typical carboxyhaemoglobin levels
< 3% non-smokers
< 10% smokers
10 - 30% symptomatic: headache, vomiting
> 30% severe toxicity
an ECG is a useful supplementary investgation to look for cardiac ischaemia
Management
patients with suspected carbon monoxide poisoning should be assessed in the emergency department
100% high-flow oxygen via a non-rebreather mask
from a physiological perspective, this decreases the half-life of carboxyhemoglobin (COHb)
should be administered as soon as possible, with treatment continuing for a minimum of six hours
target oxygen saturations are 100%
treatment is generally continued until all symptoms have resolved, rather than monitoring CO levels
hyperbaric oxygen
due to the small number of cases the evidence base is limited, but there is some evidence that long-term outcomes may be better than standard oxygen therapy for more severe cases
therefore, discussion with a specialist should be considered for more severe cases (e.g. levels > 25%)
in 2008, the Department of Health publication ‘Recognising Carbon Monoxide Poisoning’ also listed loss of consciousness at any point, neurological signs other than headache, myocardial ischaemia or arrhythmia and pregnancy as indications for hyperbaric oxygen
Paracetamol overdose: management
The following is based on 2012 Commission on Human Medicines (CHM) review of paracetamol overdose management. The big change in these guidelines was the removal of the ‘high-risk’ treatment line on the normogram. All patients are therefore treated the same regardless of risk factors for hepatotoxicity. The National Poisons Information Service/TOXBASE should always be consulted for situations outside of the normal parameters.
The minority of patients who present within 1 hour may benefit from activated charcoal to reduce absorption of the drug.
Acetylcysteine should be given if:
there is a staggered overdose* or there is doubt over the time of paracetamol ingestion, regardless of the plasma paracetamol concentration; or
the plasma paracetamol concentration is on or above a single treatment line joining points of 100 mg/L at 4 hours and 15 mg/L at 15 hours, regardless of risk factors of hepatotoxicity
Acetylcysteine is now infused over 1 hour (rather than the previous 15 minutes) to reduce the number of adverse effects. Acetylcysteine commonly causes an anaphylactoid reaction (non-IgE mediated mast cell release). Anaphylactoid reactions to IV acetylcysteine are generally treated by stopping the infusion, then restarting at a slower rate.
Cocaine
Cocaine is an alkaloid derived from the coca plant. It is widely used as a recreational stimulant. The price of cocaine has fallen sharply in the past decade resulting in cocaine toxicity becoming a much more frequent clinical problem. This increase has made cocaine a favourite topic of question writers.
Mechanism of action
cocaine blocks the uptake of dopamine, noradrenaline and serotonin
The use of cocaine is associated with a wide variety of adverse effects:
Cardiovascular effects
myocardial infarction
both tachycardia and bradycardia may occur
hypertension
QRS widening and QT prolongation
aortic dissection
Neurological effects
seizures
mydriasis
hypertonia
hyperreflexia
Psychiatric effects
agitation
psychosis
hallucinations
Others
ischaemic colitis is recognised in patients following cocaine ingestion. This should be considered if patients complain of abdominal pain or rectal bleeding
hyperthermia
metabolic acidosis
rhabdomyolysis
Management of cocaine toxicity
in general, benzodiazepines are generally first-line for most cocaine-related problems
chest pain: benzodiazepines + glyceryl trinitrate. If myocardial infarction develops then primary percutaneous coronary intervention
hypertension: benzodiazepines + sodium nitroprusside
the use of beta-blockers in cocaine-induced cardiovascular problems is a controversial issue. The American Heart Association issued a statement in 2008 warning against the use of beta-blockers (due to the risk of unopposed alpha-mediated coronary vasospasm) but many cardiologists since have questioned whether this is valid. If a reasonable alternative is given in an exam it is probably wise to choose it
Organophosphate insecticide poisoning
One of the effects of organophosphate poisoning is inhibition of acetylcholinesterase leading to upregulation of nicotinic and muscarinic cholinergic neurotransmission. In warfare, sarin gas is a highly toxic synthetic organophosphorus compound that has similar effects.
Features can be predicted by the accumulation of acetylcholine (mnemonic = SLUD)
Salivation
Lacrimation
Urination
Defecation/diarrhoea
cardiovascular: hypotension, bradycardia
also: small pupils, muscle fasciculation
Management
atropine
the role of pralidoxime is still unclear - meta-analyses to date have failed to show any clear benefit
Alcohol - problem drinking: management
Nutritional support
SIGN recommends alcoholic patients should receive oral thiamine if their ‘diet may be deficient’
Drugs used
benzodiazepines for acute withdrawal
disulfram: promotes abstinence - alcohol intake causes severe reaction due to inhibition of acetaldehyde dehydrogenase. Patients should be aware that even small amounts of alcohol (e.g. In perfumes, foods, mouthwashes) can produce severe symptoms. Contraindications include ischaemic heart disease and psychosis
acamprosate: reduces craving, known to be a weak antagonist of NMDA receptors, improves abstinence in placebo controlled trials
Plasma paracetamol levels obtained less than 4 hours since ingestion cannot be interpreted
Importance: 91
A plasma paracetamol level taken less than four hours since ingestion can underestimate the total ingestion of paracetamol, as the drug is still being absorbed from the gastrointestinal tract at this point. Therefore, it is important to wait until this point to take a blood sample, which can then be plotted on the treatment nomogram.
Patients who present within one hour of ingestion may benefit from activated charcoal to reduce absorption of the drug. However, a paracetamol level at this stage is of limited value.
Patients who have an unknown ingestion time or who present having taken a staggered overdose might be started on acetylcysteine regardless of their paracetamol level. A staggered overdose refers to an overdose where the tablets are taken over a period of greater than an hour.
Opioid misuse
Opioids are substances which bind to opioid receptors. This includes both naturally occurring opiates such as morphine and synthetic opioids such as buprenorphine and methadone.
Features of opioid misuse
rhinorrhoea
needle track marks
pinpoint pupils
drowsiness
watering eyes
yawning
Complications of opioid misuse
viral infection secondary to sharing needles: HIV, hepatitis B & C
bacterial infection secondary to injection: infective endocarditis, septic arthritis, septicaemia, necrotising fasciitis
venous thromboembolism
overdose may lead to respiratory depression and death
psychological problems: craving
social problems: crime, prostitution, homelessness
Emergency management of opioid overdose
IV or IM naloxone: has a rapid onset and relatively short duration of action
Harm reduction interventions may include
needle exchange
offering testing for HIV, hepatitis B & C
Management of opioid dependence
patients are usually managed by specialist drug dependence clinics although some GPs with a specialist interest offer similar services
patients may be offered maintenance therapy or detoxification
NICE recommend methadone or buprenorphine as the first-line treatment in opioid detoxification
compliance is monitored using urinalysis
detoxification should normally last up to 4 weeks in an inpatient/residential setting and up to 12 weeks in the community
Beta-blocker overdose
Features
bradycardia
hypotension
heart failure
syncope
Management
if bradycardic then atropine
in resistant cases glucagon may be used
Haemodialysis is not effective in beta-blocker overdose
For each of the following drugs select the most appropriate monitoring tests once treatment has commenced
P450 enzyme system
Induction usually requires prolonged exposure to the inducing drug, as opposed to P450 inhibitors, where effects are often seen rapidly
Inducers of the P450 system include
antiepileptics: phenytoin, carbamazepine
barbiturates: phenobarbitone
rifampicin
St John’s Wort
chronic alcohol intake
griseofulvin
smoking (affects CYP1A2, reason why smokers require more aminophylline)
Inhibitors of the P450 system include
antibiotics: ciprofloxacin, erythromycin
isoniazid
cimetidine,omeprazole
amiodarone
allopurinol
imidazoles: ketoconazole, fluconazole
SSRIs: fluoxetine, sertraline
ritonavir
sodium valproate
acute alcohol intake
quinupristin
Sodium valproate is an P450 inhibitor
Prescribing in patients with renal failure
Questions regarding which drugs to avoid in renal failure are common
Drugs to avoid in renal failure
antibiotics: tetracycline, nitrofurantoin
NSAIDs
lithium
metformin
Drugs likely to accumulate in chronic kidney disease - need dose adjustment
most antibiotics including penicillins, cephalosporins, vancomycin, gentamicin, streptomycin
digoxin, atenolol
methotrexate
sulphonylureas
furosemide
opioids
Drugs relatively safe - can sometimes use normal dose depending on the degree of chronic kidney disease
antibiotics: erythromycin, rifampicin
diazepam
warfarin
Phosphodiesterase type V inhibitors
Phosphodiesterase type V (PDE5) inhibitors are used in the treatment of erectile dysfunction. They are also used in the management of pulmonary hypertension. PDE5 inhibitors cause vasodilation through an increase in cGMP leading to smooth muscle relaxation in blood vessels supplying the corpus cavernosum.
Examples
sildenafil (Viagra) - this was the first phosphodiesterase type V inhibitor
tadalafil (Cialis)
vardenafil (Levitra)
Contraindications
patients taking nitrates and related drugs such as nicorandil
hypotension
recent stroke or myocardial infarction (NICE recommend waiting 6 months)
Side-effects
visual disturbances e.g. blue discolouration, non-arteritic anterior ischaemic neuropathy
nasal congestion
flushing
gastrointestinal side-effects
headache
The blue pill, Viagra (sildenafil), causes blue discolouration of vision
