PASSMEDICINE TEXT BOOK (DOWNLOADED 28/01/2022)

PHARMACOLOGY

Acute intermittent porphyria: drugs

Acute intermittent porphyria (AIP) is an autosomal dominant condition caused by a defect in porphobilinogen deaminase, an
enzyme involved in the biosynthesis of haem. It characteristically presents with abdominal and neuropsychiatric symptoms in 20-40
year olds. AIP is more common in females (5:1)

Drugs which may precipitate attack

 barbiturates
 halothane
 benzodiazepines
 alcohol
 oral contraceptive pill
 sulphonamides

Drugs considered safe to use

 paracetamol
 aspirin
 codeine
 morphine
  chlorpromazine
 beta-blockers
 penicillin
 metformin

Adrenaline

Adrenaline is a sympathomimetic amine with both alpha and beta adrenergic stimulating properties

Indications

 anaphylaxis
 cardiac arrest

Recommend Adult Life Support (ALS) adrenaline doses

 anaphylaxis: 0.5ml 1:1,000 IM

 cardiac arrest: 10ml 1:10,000 IV or 1ml of 1:1000 IV

Management of accidental injection

 local infiltration of phentolamine

Background

 responsible for the fight or flight response

 released by the adrenal glands
 acts on α 1 and 2, β 1 and 2 receptors
 acts on β 2 receptors in skeletal muscle vessels-causing vasodilation
 increases cardiac output and total peripheral resistance
 causes vasoconstriction in the skin and kidneys causing a narrow pulse pressure

Actions on α adrenergic receptors:

 inhibits insulin secretion by the pancreas

 stimulates glycogenolysis in the liver and muscle
 stimulates glycolysis in muscle

Actions onβ adrenergic receptors:

 stimulates glucagon secretion in the pancreas

 stimulates ACTH
 stimulates lipolysis by adipose tissue
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

Allopurinol

Allopurinol is used in the prevention of gout. It works by inhibiting xanthine oxidase.

Initiating allopurinol prophylaxis

 it has traditionally been taught that urate-lowering therapy (ULT) should not be started until 2 weeks after an acute attack, as starting
too early may precipitate a further attack. The evidence base to support this however looks weak
  in 2017 the BSR updated their guidelines. They still support a delay in starting urate-lowering therapy because it is better for a patient to
make long-term drug decisions whilst not in pain
o the key passage is: 'Commencement of ULT is best delayed until inflammation has settled as ULT is better discussed when the
patient is not in pain'
 initial dose of 100 mg od, with the dose titrated every few weeks to aim for a serum uric acid of < 300 µmol/l. Lower initial doses should
be given if the patient has a reduced eGFR
 colchicine cover should be considered when starting allopurinol. NSAIDs can be used if colchicine cannot be tolerated. The BSR
guidelines suggest this may need to be continued for 6 months

Indications for allopurinol

 the British Society of Rheumatology Guidelines now advocate offering urate-lowering therapy to all patients after their first attack of
gout
 ULT is particularly recommended if:
o >= 2 attacks in 12 months
o tophi
o renal disease
o uric acid renal stones
o prophylaxis if on cytotoxics or diuretics
 patients with Lesch-Nyhan syndrome often take allopurinol for life

Adverse effects

The most significant adverse effects are dermatological and patients should be warned to stop allopurinol immediately if they develop a rash:
  severe cutaneous adverse reaction (SCAR)
 drug reaction with eosinophilia and systemic symptoms (DRESS)
 Stevens-Johnson syndrome

Certain ethnic groups such as the Chinese, Korean and Thai people seem to be at an increased risk of these dermatological reactions.

Patients at a high risk of severe cutaneous adverse reaction should be screened for the HLA-B *5801 allele.

Interactions

Azathioprine

 metabolised to active compound 6-mercaptopurine

 xanthine oxidase is responsible for the oxidation of 6-mercaptopurine to 6-thiouric acid
 allopurinol can therefore lead to high levels of 6-mercaptopurine
 a much reduced dose (e.g. 25%) must therefore be used if the combination cannot be avoided

Cyclophosphamide

 allopurinol reduces renal clearance, therefore may cause marrow toxicity

Theophylline
  allopurinol causes an increase in plasma concentration of theophylline by inhibiting its breakdown

Alpha blockers

Alpha blockers are used in the management of benign prostatic hyperplasia and hypertension. Examples include doxazosin and
tamsulosin.

Side-effects

 postural hypotension
 drowsiness
 dyspnoea
 cough

Caution should be exercised in patients who are having cataract surgery due to the risk of intra-operative floppy iris syndrome

Amiodarone and the thyroid gland

Around 1 in 6 patients taking amiodarone develop thyroid dysfunction

Amiodarone-induced hypothyroidism

The pathophysiology of amiodarone-induced hypothyroidism (AIH) is thought to be due to the high iodine content of amiodarone causing a
Wolff-Chaikoff effect*

Amiodarone may be continued if this is desirable

Amiodarone-induced thyrotoxicosis

Amiodarone-induced thyrotoxicosis (AIT) may be divided into two types:

AIT type 1 AIT type 2

Pathophysiology Excess iodine-induced Amiodarone-related

thyroid hormone synthesis destructive thyroiditis

Goitre Present Absent

Management Carbimazole or potassium Corticosteroids

perchlorate

Unlike in AIH, amiodarone should be stopped if possible in patients who develop AIT

*an autoregulatory phenomenon where thyroxine formation is inhibited due to high levels of circulating iodide

Amiodarone: adverse effects

Adverse effects of amiodarone use

  thyroid dysfunction: both hypothyroidism and hyper-thyroidism
 corneal deposits
 pulmonary fibrosis/pneumonitis
 liver fibrosis/hepatitis
 peripheral neuropathy, myopathy
 photosensitivity
 'slate-grey' appearance
 thrombophlebitis and injection site reactions
 bradycardia
 lengths QT interval

Important drug interactions of amiodarone include:

 decreased metabolism of warfarin, therefore increased INR

 increased digoxin levels

Aspirin

Aspirin works by blocking the action of both cyclooxygenase-1 and 2. Cyclooxygenase is responsible for prostaglandin, prostacyclin
and thromboxane synthesis. The blocking of thromboxane A2 formation in platelets reduces the ability of platelets to aggregate
which has lead to the widespread use of low-dose aspirin in cardiovascular disease. Until recent guidelines changed all patients with
established cardiovascular disease took aspirin if there was no contraindication. Following the 2010 technology appraisal of
clopidogrel this is no longer the case*.

Two recent trials (the Aspirin for Asymptomatic Atherosclerosis and the Antithrombotic Trialists Collaboration) have cast doubt on
the use of aspirin in primary prevention of cardiovascular disease. Guidelines have not yet changed to reflect this. However the
Medicines and Healthcare products Regulatory Agency (MHRA) issued a drug safety update in January 2010 reminding prescribers
that aspirin is not licensed for primary prevention.

What do the current guidelines recommend?

 first-line for patients with ischaemic heart disease

Potentiates

 oral hypoglycaemics
 warfarin
 steroids

Aspirin should not be used in children under 16 due to the risk of Reye's syndrome. An exception is Kawasaki disease, where the
benefits are thought to outweigh the risks.

*NICE now recommend clopidogrel first-line following an ischaemic stroke and for peripheral arterial disease. For TIAs the situation
is more complex. Recent Royal College of Physician (RCP) guidelines support the use of clopidogrel in TIAs. However the older NICE
guidelines still recommend aspirin + dipyridamole - a position the RCP state is 'illogical'

Botulinum toxin
As well as the well-publicised cosmetic uses of Botulinum toxin ('Botox') there are also a number of licensed indications:

 blepharospasm
 hemifacial spasm
 focal spasticity including cerebral palsy patients, hand and wrist disability associated with stroke
 spasmodic torticollis
 severe hyperhidrosis of the axillae
 achalasia

British National Formulary symbols

The list below explains the meanings of the main symbols used in the BNF:

Denotes a preparation that is less suitable to prescribe

Newly licensed medicines

Not prescribable on the NHS

Prescription-only medicine

Controlled drug

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.

Indications &
Examples notes Side-effects and cautions

Verapamil Angina, Heart

hypertension, failure, constipation, hypotension, bradyc
arrhythmias ardia, flushing
 Indications &
Examples notes Side-effects and cautions

Highly
negatively
inotropic

Should not be
given with
beta-blockers
as may
cause heart
block

Diltiazem Angina, Hypotension, bradycardia, heart

hypertension failure, ankle swelling

Less
negatively
inotropic than
verapamil
but caution sh
ould still be
exercised
when patients
have heart
failure or are
taking beta-
blockers

Nifedipine, Hypertension, Flushing, headache, ankle swelling

amlodipine, angina,
 Indications &
Examples notes Side-effects and cautions

felodipine Raynaud's
(dihydropyrid
ines) Affects the
peripheral
vascular
smooth
muscle more
than the
myocardium
and therefore
do not result
in worsening
of heart
failure but ma
y therefore
cause ankle
swelling
Flow chart showing the management of hypertension as per current NICE guideliness

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
 o < 3% non-smokers
o < 10% smokers
o 10 - 30% symptomatic: headache, vomiting
o > 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
o from a physiological perspective, this decreases the half-life of carboxyhemoglobin (COHb)
o should be administered as soon as possible, with treatment continuing for a minimum of six hours
o target oxygen saturations are 100%
o treatment is generally continued until all symptoms have resolved, rather than monitoring CO levels
 hyperbaric oxygen
o 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
o therefore, discussion with a specialist should be considered for more severe cases (e.g. levels > 25%)
o 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

Ciclosporin
Ciclosporin is an immunosuppressant which decreases clonal proliferation of T cells by reducing IL-2 release. It acts by binding to
cyclophilin forming a complex which inhibits calcineurin, a phosphatase that activates various transcription factors in T cells

Adverse effects of ciclosporin (note how everything is increased - fluid, BP, K +, hair, gums, glucose)

 nephrotoxicity
 hepatotoxicity
 fluid retention
 hypertension
 hyperkalaemia
 hypertrichosis
 gingival hyperplasia
 tremor
 impaired glucose tolerance
 hyperlipidaemia
 increased susceptibility to severe infection

Interestingly for an immunosuppressant, ciclosporin is noted by the BNF to be 'virtually non-myelotoxic'.

Indications

 following organ transplantation

 rheumatoid arthritis
 psoriasis (has a direct effect on keratinocytes as well as modulating T cell function)
 ulcerative colitis
  pure red cell aplasia

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 include:

 coronary artery spasm → myocardial ischaemia/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

Delayed prescribing

Delayed prescribing has come in and out of fashion for many years. NICE currently advocate it as a strategy to reduce antibiotic
prescriptions for a respiratory tract infections. There is however still some debate about how effective this is and whether patients
find it acceptable.

Cochrane published a review in 2013 of 10 studies looking at the delayed prescription of antibiotics for acute respiratory tract
infections. Findings included:

 delayed prescribing reduced antibiotic use from 93% to 32%

 the method of delayed prescribing (e.g. post-dated script, same-day script but with advice to use after 48 hours etc) did not
significantly effect whether antibiotics were used
 patient satisfaction levels were not significantly affected

Critics of delayed prescribing point to the other findings of the study suggesting that patient satisfaction levels were just as high for
patients who were refused antibiotics.
Diclofenac

The MHRA updated it's guidance on diclofenac in June 2013 after a Europe-wide of review of cardiovascular safety.

Whilst it has long been known that NSAIDs may be linked to an increased risk of cardiovascular events the evidence base has now
become much clearer. Diclofenac appears to be associated with a significantly increased risk of cardiovascular events compared
with other NSAIDs.

It is therefore advised that diclofenac is contraindicated in patients with the following:

 ischaemic heart disease

 peripheral arterial disease
 cerebrovascular disease
 congestive heart failure (New York Heart Association classification II-IV)

Patients should be switched from diclofenac to other NSAIDs such as naproxen or ibuprofen. This advice does not apply to topical
diclofenac.

Studies have shown that naproxen and low-dose ibuprofen have the best cardiovascular risk profiles of the NSAIDs.

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
o 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

Drug causes of urticaria

The following drugs commonly cause urticaria:

 aspirin
 penicillins
 NSAIDs
 opiates

Drug dose calculations

Questions requiring you to calculate drug doses are increasingly common due to concerns about the frequency of prescription errors. There
have been several high profile cases where such calculations have been incorrect by a factor of 10 resulting in serious patient harm.

Whilst the calculations themselves are relatively simple it easy to make a mistake.

Many calculations involve drugs given either as solutions or infusions. These require you first to work out the correct dose for the patients
weight, e.g.

Paracetamol for a child: 20mg/kg, every 6-8 hours

The child weighs 18kg therefore 18 * 20 = 360mg.

Paracetamol oral suspension is available as 120mg/5ml

Therefore we divide 360 by the 'top' figure - 120 = 3 and times this by the 'bottom' figure - 5

i.e. 360mg / 120mg = 3 * 5ml = 15 ml of paracetamol oral suspension 120mg/5ml should be given every 6-8 hours
Drug monitoring

The tables below show the monitoring requirements of common drugs. It should be noted these are basic guidelines and do not relate to
monitoring effectiveness of treatment (e.g. Checking lipids for patients taking a statin)

Cardiovascular drugs

Main monitoring
Drug parameters Details of monitoring

Statins LFT LFTs at baseline, 3 months and

12 months

ACE U&E U&E prior to treatment

inhibitors U&E after increasing dose
U&E at least annually

Amiodarone TFT, LFT TFT, LFT, U&E, CXR prior to

treatment
TFT, LFT every 6 months

Rheumatology drugs
 Main
monitoring
Drug parameters Details of monitoring

Methotrexate FBC, LFT, U&E The Committee on Safety of Medicines

recommend 'FBC and renal and LFTs
before starting treatment and repeated
weekly until therapy stabilised, thereafter
patients should be monitored every 2-3
months'

Azathioprine FBC, LFT FBC, LFT before treatment

FBC weekly for the first 4 weeks
FBC, LFT every 3 months

Neuropsychiatric drugs

Main monitoring
Drug parameters Details of monitoring

Lithium Lithium level, TFT, TFT, U&E prior to treatment

U&E Lithium levels weekly until stabilised
then every 3 months
TFT, U&E every 6 months

Sodium LFT LFT, FBC before treatment

valproate LFT 'periodically' during first 6
months
Endocrine drugs

Main monitoring
Drug parameters Details of monitoring

Glitazones LFT LFT before treatment

LFT 'regularly' during
treatment

Drug-induced impaired glucose tolerance

Drugs which are known to cause impaired glucose tolerance include:

 thiazides, furosemide (less common)

 steroids
 tacrolimus, ciclosporin
 interferon-alpha
 nicotinic acid
 antipsychotics

Beta-blockers cause a slight impairment of glucose tolerance. They should also be used with caution in diabetics as they
can interfere with the metabolic and autonomic responses to hypoglycaemia
Drug-induced thrombocytopenia

Drug-induced thrombocytopenia (probable immune-mediated)

 quinine
 abciximab
 NSAIDs
 diuretics: furosemide
 antibiotics: penicillins, sulphonamides, rifampicin
 anticonvulsants: carbamazepine, valproate
 heparin

Drug-induced urinary retention

The following drugs may cause urinary retention:

 tricyclic antidepressants e.g. amitriptyline

 anticholinergics
 opioids
 NSAIDs
 disopyramide

Drugs causing lung fibrosis

Causes

 amiodarone
 cytotoxic agents: busulphan, bleomycin
 anti-rheumatoid drugs: methotrexate, sulfasalazine
 nitrofurantoin
 ergot-derived dopamine receptor agonists (bromocriptine, cabergoline, pergolide)

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

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

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

Heparin
There are two main types of heparin - unfractionated, 'standard' heparin or low molecular weight heparin (LMWH). Heparins
generally act by activating antithrombin III. Unfractionated heparin forms a complex which inhibits thrombin, factors Xa, IXa, XIa and
XIIa. LMWH however only increases the action of antithrombin III on factor Xa

Adverse effects of heparins include:

 bleeding
 thrombocytopenia - see below
 osteoporosis and an increased risk of fractures
 hyperkalaemia - this is thought to be caused by inhibition of aldosterone secretion

The table below shows the differences between standard heparin and LMWH:

Low molecular weight

Standard heparin heparin (LMWH)
Administration Intravenous Subcutaneous
Duration of Short Long
action
Mechanism of Activates antithrombin III. Activates antithrombin
action Forms a complex that III. Forms a complex that
inhibits thrombin, factors inhibits factor Xa
Xa, IXa, Xia and XIIa
Side-effects Bleeding Bleeding
Heparin-induced
thrombocytopaenia (HIT) Lower risk of HIT and
Osteoporosis osteoporosis with LMWH
Monitoring Activated partial Anti-Factor Xa (although

Standard heparin
thromboplastin time
(APTT)
Notes Useful in situations where
there is a high risk of
bleeding as anticoagulation
can be terminated rapidly.
Also useful in renal failure
Low molecular weight
heparin (LMWH)
routine monitoring is not
required)
Now standard in the
management of venous
thromboembolism
treatment and prophylaxis
and acute coronary
syndromes

Heparin-induced thrombocytopaenia (HIT)

 immune mediated - antibodies form against complexes of platelet factor 4 (PF4) and heparin
 these antibodies bind to the PF4-heparin complexes on the platelet surface and induce platelet activation by cross-linking
FcγIIA receptors
 usually does not develop until after 5-10 days of treatment
 despite being associated with low platelets HIT is actually a prothrombotic condition
 features include a greater than 50% reduction in platelets, thrombosis and skin allergy
 address need for ongoing anticoagulation:
o direct thrombin inhibitor e.g. argatroban
o danaparoid

Heparin overdose may be reversed by protamine sulphate, although this only partially reverses the effect of LMWH.

Hormone replacement therapy: indications and types

Hormone replacement therapy (HRT) involves the use of a small dose of oestrogen, combined with a progestogen (in women with a uterus), to
help alleviate menopausal symptoms.

The indications for HRT have changed significantly over the past ten years as the long-term risks became apparent, primarily as a result of the
Women's Health Initiative (WHI) study.

Indications

 vasomotor symptoms such as flushing, insomnia and headaches

o this is considered the most important factor in choosing whether to start HRT, rather than other possible health benefits such as
increased bone mineral density
o other indications such as reversal of vaginal atrophy should be treated with other agents as first-line therapies
 premature menopause
o should be continued until the age of 50 years
o the most important reason in giving HRT to younger women is preventing the development of osteoporosis

Other benefits include a reduced incidence of colorectal cancer.

Types of HRT

HRT generally consists of an oestrogenic compound, which replaces the diminished levels that occur in the perimenopausal period. This is
normally combined with a progestogen if a woman has a uterus to reduce the risk of endometrial cancer.

Choice of hormone
  oestrogens
o 'natural' oestrogens such as estradiol, estrone and conjugated oestrogen are generally used rather than synthetic oestrogens
such as ethinylestradiol (which is used in the combined oral contraceptive pill)
 progestogens
o 'synthetic' progestogens such as medroxyprogesterone, norethisterone, levonorgestrel, and drospirenone are usually used
o a levonorgestrel-releasing intrauterine system (e.g. Mirena) may be used as the progestogen component of HRT, i.e. a woman
could take an oral oestrogen and have endometrial protection using a Mirena coil
 tibolone
o synthetic compound with both oestrogenic, progestogenic, and androgenic activity

Route

 HRT can be taken orally or transdermally (via a patch or gel)

 transdermal is preferred if the woman is at risk of venous thromboembolism (VTE), as the rates of VTE do not appear to rise with
transdermal preparations

Hypomagnesaemia

Cause of low magnesium

 drugs
o diuretics
o proton pump inhibitors
 total parenteral nutrition
 diarrhoea
o may occur with acute or chronic diarrhoea
  alcohol
 hypokalaemia
 hypercalcaemia
o e.g. secondary to hyperparathyroidism
o calcium and magnesium functionally compete for transport in the thick ascending limb of the loop of Henle
 metabolic disorders
o Gitleman's and Bartter's

Features may be similar to hypocalcaemia:

 paraesthesia
 tetany
 seizures
 arrhythmias
 decreased PTH secretion → hypocalcaemia
 ECG features similar to those of hypokalaemia
 exacerbates digoxin toxicity

Treatment

<0.4 mmol/L or tetany, arrhythmias, or seizures

 intravenous magnesium replacement is commonly given.

 an example regime would be 40 mmol of magnesium sulphate over 24 hours
>0.4 mmol/l

 oral magnesium salts (10-20 mmol orally per day in divided doses)
 diarrhoea can occur with oral magnesium salts

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
 polyuria
  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

Macrolides

Erythromycin was the first macrolide used clinically. Newer examples include clarithromycin and azithromycin.

Macrolides act by inhibiting bacterial protein synthesis by blocking translocation. If pushed to give an answer they are bacteriostatic
in nature, but in reality this depends on the dose and type of organism being treated.

Mechanism of resistance

 post-transcriptional methylation of the 23S bacterial ribosomal RNA

Adverse effects
  prolongation of the QT interval
 gastrointestinal side-effects are common. Nausea is less common with clarithromycin than erythromycin
 cholestatic jaundice: risk may be reduced if erythromycin stearate is used
 P450 inhibitor (see below)
 azithromycin is associated with hearing loss and tinnitus

Common interactions

 statins should be stopped whilst taking a course of macrolides. Macrolides inhibit the cytochrome P450 isoenzyme CYP3A4
that metabolises statins. Taking macrolides concurrently with statins significantly increases the risk of myopathy and
rhabdomyolysis.

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

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
o it is now increasingly recognised that lactic acidosis secondary to metformin is rare, although it remains important in
the context of exams
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

Motion sickness

Motion sickness describes the nausea and vomiting which occurs when an apparent discrepancy exists between visually perceived
movement and the vestibular systems sense of movement

Management
  the BNF recommends hyoscine (e.g. transdermal patch) as being the most effective treatment. Use is limited due to side-
effects
 non-sedating antihistamines such as cyclizine or cinnarizine are recommended in preference to sedating preparation such as
promethazine

Oculogyric crisis

An oculogyric crisis is a dystonic reaction to certain drugs or medical conditions

Features

 restlessness, agitation
 involuntary upward deviation of the eyes

Causes

 antipsychotics
 metoclopramide
 postencephalitic Parkinson's disease

Management

 intravenous antimuscarinic: benztropine or procyclidine

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

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

Over-the-counter treatments

Cough and cold remedies

In 2009 the Medicines and Healthcare products Regulatory Agency (MHRA) / Commission on Human Medicines (CHM) announced a major
change in the regulation of over-the-counter (OTC) preparations aimed at children with coughs/colds (e.g. Tixylix, Medised etc)
This affected medicines containing a wide range of ingredients:

 cough suppressants: dextromethorphan and pholcodine

 expectorants: guaifenesin and ipecacuanha
 nasal decongestants: ephedrine, oxymetazoline, phenylephrine, pseudoephedrine and xylometazoline
 antihistamines: brompheniramine, chlorphenamine, diphenhydramine, doxylamine, promethazine and triprolidine

Products with these ingredients should therefore be avoided in children under the age of 6 years. Products aimed at children aged 6-12 years
which contain these ingredients will only be available after discussion with a pharmacist, i.e. Not on the shelves.

Overdose and poisoning: management

The table below outlines the main management for common overdoses:

Toxin Treatment
Paracetamol Management

 activated charcoal if ingested < 1 hour

ago
 N-acetylcysteine (NAC)
 liver transplantation

Salicylate Management

 urinary alkalinization with IV

 Toxin Treatment

bicarbonate
 haemodialysis

Opioid/opiates Naloxone
Benzodiazepines Flumazenil
The majority of overdoses are managed with
supportive care only due to the risk of seizures
with flumazenil. It is generally only used with
severe or iatrogenic overdoses.
Tricyclic Management
antidepressants

 IV bicarbonate may reduce the risk of

seizures and arrhythmias in severe
toxicity
 arrhythmias: class 1a (e.g. Quinidine)
and class Ic antiarrhythmics (e.g.
Flecainide) are contraindicated as they
prolong depolarisation. Class III drugs
such as amiodarone should also be
avoided as they prolong the QT
interval. Response to lignocaine is
variable and it should be emphasized
that correction of acidosis is the first
line in management of tricyclic
induced arrhythmias
 dialysis is ineffective in removing
tricyclics
 Toxin Treatment
Lithium 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

Warfarin Vitamin K, prothrombin complex

Heparin Protamine sulphate
Beta-blockers Management

 if bradycardic then atropine

 in resistant cases glucagon may be
used

Ethylene glycol Management has changed in recent times

 ethanol has been used for many years

 works by competing with ethylene
glycol for the enzyme alcohol
dehydrogenase
 this limits the formation of toxic
 Toxin Treatment
metabolites (e.g. Glycoaldehyde and
glycolic acid) which are responsible
for the haemodynamic/metabolic
features of poisoning
 fomepizole, an inhibitor of alcohol
dehydrogenase, is now used first-line
in preference to ethanol
 haemodialysis also has a role in
refractory cases

Methanol Management
poisoning

 fomepizole or ethanol
 haemodialysis

Organophosphate Management
insecticides

 atropine
 the role of pralidoxime is still unclear -
meta-analyses to date have failed to
show any clear benefit

Digoxin Digoxin-specific antibody fragments

Iron Desferrioxamine, a chelating agent
Lead Dimercaprol, calcium edetate
Carbon monoxide Management
 Toxin Treatment

 100% oxygen
 hyperbaric oxygen

Cyanide Hydroxocobalamin; also combination of amyl

nitrite, sodium nitrite, and sodium thiosulfate

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

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)
o this was the first phosphodiesterase type V inhibitor
o short-acting - usually taken 1 hour before sexual activity
 tadalafil (Cialis)
o longer acting than sildenafil, may be taken on a regular basis (e.g. once daily)
 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
o blue discolouration
o non-arteritic anterior ischaemic neuropathy
 nasal congestion
 flushing
 gastrointestinal side-effects
 headache
 priapism

The blue pill, Viagra (sildenafil), causes blue discolouration of vision

Potassium-sparing diuretics

Potassium-sparing diuretics may be divided into the epithelial sodium channel blockers (amiloride and triamterene) and
aldosterone antagonists (spironolactone and eplerenone).
They should be used with caution in patients taking ACE inhibitors as they precipitate hyperkalaemia.

Amiloride

 blocks the epithelial sodium channel in the distal convoluted tubule

 weak diuretic, usually given with thiazides or loop diuretics as an alternative to potassium supplementation (remember that
thiazides and loop diuretics often cause hypokalaemia)

Aldosterone antagonists e.g. spironolactone

 acts in the cortical collecting duct

 indications
o ascites: patients with cirrhosis develop a secondary hyperaldosteronism. Relatively large doses such as 100 or 200mg
are often used
o heart failure
o nephrotic syndrome
o Conn's syndrome

Prescribing guidance

The BNF issues guidance on good practice when prescribing, selected points include:
  drugs should generally be prescribed by their generic name, except for certain preparations where the clinical effect may
differ - please see the list below
 when writing numbers unnecessary decimal points should be avoided e.g. 250 ml not 0.25 l
 it is a legal requirement for children under the age of 12 that their age is specified on the prescription

Drugs which should be prescribed by brand

 modified release calcium channel blockers

 antiepileptics
 ciclosporin and tacrolimus
 mesalazine
 lithium
 aminophylline and theophylline
 methylphenidate
 CFC-free formulations of beclometasone
 dry powder inhaler devices

Prescribing in patients with epilepsy

The following drugs may worsen seizure control in patients with epilepsy:

 alcohol, cocaine, amphetamines

 ciprofloxacin, levofloxacin
 aminophylline, theophylline
  bupropion
 methylphenidate (used in ADHD)
 mefenamic acid

Some medications such as benzodiazepines, baclofen and hydroxyzine may provoke seizures whilst they are being withdrawn.

Other medications may worsen seizure control by interfering with the metabolism of anti-epileptic drugs (i.e. P450
inducers/inhibitors).

Prescribing in patients with heart failure

The following medications may exacerbate heart failure:

 thiazolidinediones
o pioglitazone is contraindicated as it causes fluid retention
 verapamil
o negative inotropic effect
 NSAIDs/glucocorticoids
o should be used with caution as they cause fluid retention
o low-dose aspirin is an exception - many patients will have coexistent cardiovascular disease and the benefits of taking
aspirin easily outweigh the risks
 class I antiarrhythmics
o flecainide (negative inotropic and proarrhythmic effect)

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
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
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

Serotonin syndrome

Causes

 monoamine oxidase inhibitors

 SSRIs
o St John's Wort, often taken over the counter for depression, can interact with SSRIs to cause serotonin syndrome
 ecstasy
 amphetamines

Features

 neuromuscular excitation
o hyperreflexia
o myoclonus
o rigidity
  autonomic nervous system excitation
o hyperthermia
o sweating
 altered mental state
o confusion

Management

 supportive including IV fluids

 benzodiazepines
 more severe cases are managed using serotonin antagonists such as cyproheptadine and chlorpromazine
Venn diagram showing contrasting serotonin syndrome with neuroleptic malignant syndrome. Note that both conditions can cause a raised creatine kinase
(CK) but it tends to be more associated with NMS.

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

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

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

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

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 climacteric side-effects
 venous thromboembolism
 endometrial cancer

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
Therapeutic drug monitoring

Lithium

 range = 0.4 - 1.0 mmol/l

 take 12 hrs post-dose

Ciclosporin

 trough levels immediately before dose

Digoxin

 at least 6 hrs post-dose

Phenytoin levels do not need to be monitored routinely but trough levels, immediately before dose should be checked if:

 adjustment of phenytoin dose

 suspected toxicity
 detection of non-adherence to the prescribed medication
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

Yellow Card scheme

The Yellow Card scheme has become the standard way to report adverse reactions to medications. It is run by the Medicines and
Healthcare products Regulatory Agency (MHRA).

The following should be reported (taken from the MHRA website)

 all suspected adverse drug reactions for new medicines (identified by the black triangle symbol) should be reported
 all suspected adverse drug reactions occurring in children, even if a medicine

has been used off-label

 all serious* suspected adverse drug reactions for established vaccines and

medicines, including unlicensed medicines, herbal remedies, and medicines used off-label

Other information
  Yellow Cards are found at the back of the BNF or reports can be completed online (www.yellowcard.gov.uk)
 any suspected reactions (not just confirmed) should be reported
 patients can report adverse events
 Yellow Cards are sent to the MHRA who in collate and assess the information. In turn the MHRA may consult with the
Commission on Human Medicines (CHM), an independent scientific advisory body on medicines safety

*reactions which are fatal, life-threatening, disabling or incapacitating, result in or

prolong hospitalisation, or medically significant are considered serious.