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
