Clinical Pharma

PASSMEDICINE
NOTES 2023
CLINICAL PHARMACOLOGY AND TOXICOLOGY
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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
Adrenoceptor agonists
Alpha-1 agonists
 phenylephrine
Alpha-2 agonists
 clonidine
Beta-1 agonists
 dobutamine
Beta-2 agonists
 salbutamol
Beta-3 agonists
 being developed, may have a role in preventing obesity (stimulation causes

lipolysis)
Adrenoceptor antagonists
Alpha antagonists
 alpha-1: doxazosin
 alpha-1a: tamsulosin - acts mainly on urogenital tract
 alpha-2: yohimbine
 non-selective: phenoxybenzamine (previously used in peripheral arterial
disease)
Beta antagonists
 beta-1: atenolol
 non-selective: propranolol
Carvedilol and labetalol are mixed alpha and beta antagonists
Adrenoceptors
Alpha-1
 vasoconstriction
 relaxation of GI smooth muscle
 salivary secretion
 hepatic glycogenolysis
Alpha-2
 mainly presynaptic: inhibition of transmitter release (inc NA, Ach from

autonomic nerves)
 inhibits insulin
 platelet aggregation
Beta-1
 mainly located in the heart

 increase heart rate + force
Beta-2
 vasodilation
 bronchodilation
 relaxation of GI smooth muscle
Beta-3
 lipolysis
Pathways
 all are G-protein coupled

 alpha-1:activate phospholipase C → IP3 → DAG
 alpha-2: inhibit adenylate cyclase
 beta-1: stimulate adenylate cyclase
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
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
Excess iodine-induced thyroid hormone Amiodarone-related destructive

Pathophysiology
synthesis thyroiditis
Goitre Present Absent
Management Carbimazole or potassium perchlorate Corticosteroids
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
Anaesthetic agents
The table below summarises some of the more commonly used IV induction agents
Agent Specific features
 GABA receptor agonist

 Rapid onset of anaesthesia
 Pain on IV injection
 Rapidly metabolised with little accumulation of metabolites
Propofol  Proven anti emetic properties
 Moderate myocardial depression
 Widely used especially for maintaining sedation on ITU, total IV
anaesthesia and for daycase surgery
 Extremely rapid onset of action making it the agent of choice for

rapid sequence of induction
 Marked myocardial depression may occur
Sodium
 Metabolites build up quickly
thiopentone
 Unsuitable for maintenance infusion
 Little analgesic effects
 NMDA receptor antagonist

 May be used for induction of anaesthesia
 Has moderate to strong analgesic properties
Ketamine  Produces little myocardial depression making it a suitable agent for
anaesthesia in those who are haemodynamically unstable
 May induce state of dissociative anaesthesia resulting in nightmares
 Has favorable cardiac safety profile with very little haemodynamic

instability
 No analgesic properties
Etomidate  Unsuitable for maintaining sedation as prolonged (and even brief)
use may result in adrenal suppression
 Post operative vomiting is common
Antiarrhythmics: Vaughan Williams classification
The Vaughan Williams classification of antiarrhythmics is still widely used although it

should be noted that a number of common drugs are not included in the
classification e.g. adenosine, atropine, digoxin and magnesium
AP = action potential
Class Examples Mechanism of action Notes
Quinidine toxicity causes cinchonism

(headache, tinnitus,
Quinidine Block sodium channels
thrombocytopaenia)
Ia Procainamide
Disopyramide Increases AP duration
Procainamide may cause drug-
induced lupus
Lidocaine Block sodium channels

Ib Mexiletine
Tocainide Decreases AP duration
Flecainide Block sodium channels

Ic Encainide
Propafenone No effect on AP duration
Propranolol
Atenolol
II Beta-adrenoceptor antagonists
Bisoprolol
Metoprolol
Amiodarone
Sotalol
III Block potassium channels
Ibutilide
Bretylium
Verapamil
IV Calcium channel blockers
Diltiazem
Antibiotics: gross mechanism of action
The diagram and list below summarises the gross mechanism of action of the
commonly used antibiotics. More detailed descriptions are found elsewhere on the
site.
Diagram showing the gross mechanism of action of the commonly used antibiotics
Inhibits cell wall formation
 peptidoglycan cross-linking: penicillins, cephalosporins, carbopenems

 peptidoglycan synthesis: glycopeptides (e.g. vancomycin)
Inhibits protein synthesis (by acting on the ribosome)
 50S
subunit: macrolides, chloramphenicol, clindamycin, linezolid, streptogrammins
 30S subunit: aminoglycosides, tetracyclines
Inhibits DNA synthesis
 quinolones (e.g. ciprofloxacin)
Damages DNA
 metronidazole
Inhibits folic acid formation
 sulphonamides
 trimethoprim
Inhibits RNA synthesis
 rifampicin
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'
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
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
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.
Side-effects and
Examples Indications & notes
cautions
Angina, hypertension, arrhythmias

Heart failure,
Constipation
Highly negatively inotropic
Verapamil Hypotension,
Bradycardia,
Should not be given with beta-blockers as may
Flushing
cause heart block
Angina, hypertension
Hypotension
Less negatively inotropic than verapamil Bradycardia
Diltiazem
but caution should still be exercised when Heart failure
patients have heart failure or are taking beta- Ankle swelling
blockers
Hypertension, angina, Raynaud's
Affects the peripheral vascular smooth muscle

Nifedipine, more than the myocardium and therefore do not
Flushing
amlodipine, result in worsening of heart failure but may
Headache
felodipine therefore cause ankle swelling
Ankle swelling
(dihydropyridines)
Shorter acting dihydropyridines (e.g. nifedipine)
cause peripheral vasodilation which may result
in reflex tachycardia
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
Caustic substance ingestion
Caustic (corrosive) substance ingestion is a common emergency department

presentation in adults and children. The majority of cases are accidental exposures to
household products: these are usually of little clinical consequence. Conversely,
significant morbidity can occur when the substance is consumed in larger quantities
with the intention of deliberate self-harm.
Types of substance* - vital to obtain bottle/label if possible
 Oxidising agents, e.g. hydrogen peroxide, sodium hypochlorite (found in

household bleach)
 Strong alkali, e.g. sodium hydroxide, potassium hydroxide (found in
dishwasher cleaner, industrial cleaners) -> liquefactive necrosis, more
commonly resulting in oesophageal injury
 Strong acid, e.g. hydrochloric, nitric acid (found in car batteries, WC cleaner) -
> coagulative necrosis, more commonly resulting in gastric injury
Acute management 1 - (general principles, local guidance on timing of endoscopy

and PPI may vary)
 ABCDE approach, particular caution to airway swelling and compromise, look

for peri-oral oedema
 Urgent upper GI surgical referral if signs of perforation present (surgical
emphysema, mediastinal widening on chest x-ray)
 Neutralisation of ingested substance (e.g. with milk) should be avoided as the
resulting exothermic reaction will release heat and may cause further injury
 High dose IV PPI
 Symptomatic ingestion (drooling, vomiting, dysphagia, odynophagia, chest
pain) requires urgent assessment with upper GI endoscopy to assess the
degree of ulceration (Zargar classification). Extensive injury on endoscopy
should prompt consideration of urgent surgical exploration
 Asymptomatic ingestion can usually be discharged after a trial of oral fluid
and a period of observation
Complications
Acute
 Upper GI ulceration, perforation

 Upper airway injury and compromise
 Aspiration pneumonitis
 Infection
 Electrolyte disturbance (e.g. hypocalcaemia in hydrofluoric acid ingestion)
Chronic
 Strictures, fistulae, gastric outlet obstruction

 Upper GI carcinoma (estimated 1000-3000 fold increased risk)
*Please refer to National Poisons Information/toxbase for specific management
References
1. Bonnici, K., Wood, D. and Dargan, P. (2014). Should computerised tomography
replace endoscopy in the evaluation of symptomatic ingestion of corrosive
substances?. Clinical Toxicology, 52(9), pp.911-925.
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
Combined oral contraceptive pill:
advantages/disadvantages
Advantages of combined oral contraceptive pill
 highly effective (failure rate < 1 per 100 woman years)

 doesn't interfere with sex
 contraceptive effects reversible upon stopping
 usually makes periods regular, lighter and less painful
 reduced risk of ovarian, endometrial - this effect may last for several
decades after cessation
 reduced risk of colorectal cancer
 may protect against pelvic inflammatory disease
 may reduce ovarian cysts, benign breast disease, acne vulgaris
Disadvantages of combined oral contraceptive pill
 people may forget to take it

 offers no protection against sexually transmitted infections
 increased risk of venous thromboembolic disease
 increased risk of breast and cervical cancer
 increased risk of stroke and ischaemic heart disease (especially in smokers)
 temporary side-effects such as headache, nausea, breast tenderness may be
seen
Whilst some users report weight gain whilst taking the combined oral contraceptive
pill a Cochrane review did not support a causal relationship.
Combined oral contraceptive pill: contraindications
The decision of whether to start a women on the combined oral contraceptive pill is
now guided by the UK Medical Eligibility Criteria (UKMEC). This scale categorises the
potential cautions and contraindications according to a four point scale, as detailed
below:
 UKMEC 1: a condition for which there is no restriction for the use of the
contraceptive method
 UKMEC 2: advantages generally outweigh the disadvantages
 UKMEC 3: disadvantages generally outweigh the advantages
 UKMEC 4: represents an unacceptable health risk
Examples of UKMEC 3 conditions include
 more than 35 years old and smoking less than 15 cigarettes/day

 BMI > 35 kg/m^2*
 family history of thromboembolic disease in first degree relatives < 45 years
 controlled hypertension
 immobility e.g. wheel chair use
 carrier of known gene mutations associated with breast cancer (e.g.
BRCA1/BRCA2)
 current gallbladder disease
Examples of UKMEC 4 conditions include
 more than 35 years old and smoking more than 15 cigarettes/day

 migraine with aura
 history of thromboembolic disease or thrombogenic mutation
 history of stroke or ischaemic heart disease
 breast feeding < 6 weeks post-partum
 uncontrolled hypertension
 current breast cancer
 major surgery with prolonged immobilisation
 positive antiphospholipid antibodies (e.g. in SLE)
Diabetes mellitus diagnosed > 20 years ago is classified as UKMEC 3 or 4 depending
on severity
Changes in 2016
 breast feeding 6 weeks - 6 months postpartum was changed from UKMEC 3 →

2
Combined oral contraceptive pill: counselling
Women who are considering taking the combined oral contraceptive pill (COC)
should be counselled in a number of areas:
Potential harms and benefits, including
 the COC is > 99% effective if taken correctly

 small risk of blood clots
 very small risk of heart attacks and strokes
 increased risk of breast cancer and cervical cancer
Advice on taking the pill, including
 if the COC is started within the first 5 days of the cycle then there is no need
for additional contraception. If it is started at any other point in the cycle then
alternative contraception should be used (e.g. condoms) for the first 7 days
 should be taken at the same time every day
 the COCP is conventionally taken for 21 days then stopped for 7 days - similar
uterine bleeding to menstruation. However, there was a major change
following the 2019 guidelines. 'Tailored' regimes should now be discussed
with women. This is because there is no medical benefit from having a
withdrawal bleed. Options include never having a pill-free interval or
'tricycling' - taking three 21 day packs back-to-back before having a 4 or 7
day break
 advice that intercourse during the pill-free period is only safe if the next pack
is started on time
Discussion on situations where efficacy may be reduced*
 if vomiting within 2 hours of taking COC pill

 medication that induce diarrhoea or vomiting may reduce effectiveness of oral
contraception (for example orlistat)
 if taking liver enzyme-inducing drugs
Other information
 discussion on STIs
*Concurrent antibiotic use
 for many years doctors in the UK have advised that the concurrent use of
antibiotics may interfere with the enterohepatic circulation of oestrogen and
thus make the combined oral contraceptive pill ineffective - 'extra-
precautions' were advised for the duration of antibiotic treatment and for 7
days afterwards
 no such precautions are taken in the US or the majority of mainland Europe
 in 2011 the Faculty of Sexual & Reproductive Healthcare produced new
guidelines abandoning this approach. The latest edition of the BNF has been
updated in line with this guidance
 precautions should still be taken with enzyme inducing antibiotics such as
rifampicin
Combined oral contraceptive pill: special situations
Concurrent antibiotic use
 for many years doctors in the UK have advised that the concurrent use of
antibiotics may interfere with the enterohepatic circulation of oestrogen and
thus make the combined oral contraceptive pill ineffective - 'extra-
precautions' were advised for the duration of antibiotic treatment and for 7
days afterwards
 no such precautions are taken in the US or the majority of mainland Europe
 in 2011 the Faculty of Sexual & Reproductive Healthcare produced new
guidelines abandoning this approach. The latest edition of the BNF has been
updated in line with this guidance
 precautions should still be taken with enzyme inducing antibiotics such as
rifampicin
Switching combined oral contraceptive pills
 the BNF and Faculty of Sexual & Reproductive Healthcare (FSRH) appear to
give contradictory advice. The Clinical Effectiveness Unit of the FSRH have
stated in the Combined Oral Contraception guidelines that the pill free
interval does not need to be omitted (please see link). The BNF however
advises missing the pill free interval if the progesterone changes. Given the
uncertainty it is best to follow the BNF
Cyanide poisoning
Cyanide may be used in insecticides, photograph development and the production

of certain metals. Cyanide inhibits the enzyme cytochrome c oxidase, resulting in
cessation of the mitochondrial electron transfer chain.
Presentation
 'classical' features: brick-red skin, smell of bitter almonds

 acute: hypoxia, hypotension, headache, confusion
 chronic: ataxia, peripheral neuropathy, dermatitis
Management
 supportive measures: 100% oxygen

 definitive: hydroxocobalamin (intravenously), also combination of amyl nitrite
(inhaled), sodium nitrite (intravenously), and sodium thiosulfate (intravenously)
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
Dopamine receptor agonists
Indications
 Parkinson's disease
 prolactinoma/galactorrhoea
 cyclical breast disease
 acromegaly
Currently accepted practice in the management of patients with Parkinson's disease

is to delay treatment until the onset of disabling symptoms and then to introduce a
dopamine receptor agonist. If the patient is elderly, L-dopa is sometimes used as an
initial treatment
Overview
 e.g. bromocriptine, ropinirole, cabergoline, apomorphine

 ergot-derived dopamine receptor agonists (bromocriptine, cabergoline,
pergolide*) have been associated with pulmonary, retroperitoneal and cardiac
fibrosis. The Committee on Safety of Medicines advice that an ESR, creatinine
and chest x-ray should be obtained prior to treatment and patients should be
closely monitored
Adverse effects
 nausea/vomiting
 postural hypotension
 hallucinations
 daytime somnolence
*pergolide was withdrawn from the US market in March 2007 due to concern
regarding increased incidence of valvular dysfunction
DRESS syndrome
DRESS is an unexpected, severe reaction to medication. Several organs are

commonly affected including the skin, liver, kidneys, lungs and heart. Not all of these
organs may be affected at any one time.
Classically patients develop a morbilliform skin rash in 80% cases which often leads
to an exfoliative dermatitis, high fever, and inflammation of one or more organs.
Vesicles and bullae may be seen. Erythroderma can occur in 10% of cases, mucosal
involvement in 25% and facial swelling in 30%. The reaction usually occurs 2-8 weeks
after commencing the offending drug.
Patients may develop systematic symptoms which can include haematological

abnormalities (raised and low white count, eosinophilia (in 30% this is > 2.0 * 109 /L,
thrombocytopaenia, anaemia, atypical lymphocytes), enlarged lymph nodes (75%),
10% develop kidney disease which is usually mild (interstitial nephritis is common,
renal failure is rare), myocarditis, pericarditis, liver enlargement, hepatitis and rarely
hepatic necrosis with liver failure (abnormal liver function tests are found in 70-90%
in particularly raised transaminases), lung disease (pneumonitis, pleuritis,
pneumonia), neurological involvement which may lead to meningitis and
encephalitis, gastrointestinal symptoms, in severe cases, acute colitis and pancreatitis
can occur, and endocrine abnormalities may include thyroiditis and diabetes.
Diagnosis can be very difficult and it may also be difficult to determine the exact
drug causing the hypersensitivity as first exposure may have started 8 weeks prior.
Common drugs causing DRESS include allopurinol, anti-epileptics, antibiotics,
immunosuppresants, HIV treatment and NSAIDS. A careful drug history should be
taken.
The diagnosis should be suspected when there is presence of the triad of extensive
skin rash, high fever, and organ involvement, supported by a finding of eosinophilia
and abnormal liver function tests. RegiSCAR has proposed a diagnostic criteria and
patients require at least 3 of the following:
 Hospitalisation
 Reaction suspected to be drug related
 Acute skin rash
 Fever about 38ºC
 Enlarged lymph nodes at two sites
 Involvement of at least one internal organ
 Blood count abnormalities such as low platelets, raised eosinophils or
abnormal lymphocyte count.
Skin biopsy can help to confirm the diagnosis. This may show inflammatory infiltrate
in particularly eosinophils, extravasated erythrocytes and oedema. Regular blood
tests including FBC, clotting, liver and renal function, CK, viral screen, glucose and
thyroid function tests should be taken. Investigations looking for complications
should be undertaken including ECG, CXR, echocardiogram, and urinalysis.
DRESS syndrome treatment requires all medications that are a possible culprits to be
stopped and supportive care started. Antihistamines, topical steroids and emollients
can be used to help control the rash. Careful fluid balance is necessary and clinicians
should be aware of the patients nutritional status. Skin should be regularly checked
and secondary infections should be treated with antibiotics. Systemic steroids may
be started in severe cases where exfoliative dermatitis / pneumonitis / hepatitis is
present. Occasionally immunosuppressants, intravenous immunoglobulin and
plasmapheresis may be started. Potential culprit drugs should not be restarted again.
The mortality is around 8%.
Drug causes of agranulocytosis
Common drugs that cause agranulocytosis:
 Antithyroid drugs - carbimazole, propylthiouracil

 Antipsychotics - atypical antipsychotics (CLOZAPINE)
 Antiepileptics - carbamazepine
 Antibiotics - penicillin, chloramphenicol, co-trimoxazole
 Antidepressant - mirtazapine
 Cytotoxic drugs - methotrexate
Drug causes of urticaria
The following drugs commonly cause urticaria:
 aspirin
 penicillins
 NSAIDs
 opiates
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
Drug Main monitoring parameters Details of monitoring
Statins LFT LFTs at baseline, 3 months and 12 months
U&E prior to treatment

ACE inhibitors U&E U&E after increasing dose
U&E at least annually
TFT, LFT, U&E, CXR prior to treatment

Amiodarone TFT, LFT
TFT, LFT every 6 months
Rheumatology drugs
Main
Drug monitoring Details of monitoring
parameters
The Committee on Safety of Medicines recommend 'FBC and

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

Azathioprine FBC, LFT FBC weekly for the first 4 weeks
FBC, LFT every 3 months
Neuropsychiatric drugs
Main monitoring
Drug Details of monitoring
parameters
TFT, U&E prior to treatment

Lithium levels weekly until stabilised then every 3
Lithium Lithium level, TFT, U&E
months
TFT, U&E every 6 months
Sodium LFT, FBC before treatment

LFT
valproate LFT 'periodically' during first 6 months
Endocrine drugs
Drug Main monitoring parameters Details of monitoring
LFT before treatment

Glitazones LFT
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 e.g. antipsychotics, antihistamines
 opioids
 NSAIDs
 disopyramide
Drugs acting on common receptors
The table below lists the common receptors and gives examples of both agonists and
antagonists. It is not comprehensive and is intended to give examples of each.
Receptor Agonist Antagonist

Alpha-1: Decongestants (e.g.
Benign prostatic hyperplasia (e.g.
phenylephrine/oxymetazoline)
Alpha tamsulosin)
Alpha-2: Glaucoma (e.g. topical
Hypertension (e.g. doxazosin)
brimonidine)
Non-selective & selective beta-blockers
Beta-1 Inotropes (e.g. dobutamine)
(e.g. atenolol, bisoprolol)
Non-selective beta-blockers (e.g.
Beta-2 Bronchodilators (e.g. salbutamol)
propranolol, labetalol)
Schizophrenia (antipsychotics e.g.
Parkinson's disease (e.g. ropinirole) haloperidol)
Dopamine
Prolactinoma Anti-emetics (e.g.
metoclopramide/domperidone)
Benzodiazepines
GABA Flumazenil
Baclofen
Histamine-1 Antihistamines (e.g. loratadine)
Histamine-2 Antacids (e.g. ranitidine)
Atropine (e.g. for bradycardia)

Bronchodilator (e.g. ipratropium bromide,
Muscarinic Glaucoma (e.g. pilocarpine)
tiotropium)
Urge incontinence (e.g. oxybutynin)
Nicotine
Varenicline (used for smoking
Non-depolarising muscle relaxants (e.g.
Nicotinic cessation)
atracurium)
Depolarising muscle relaxant (e.g.
suxamethonium)
Oxytocin Inducing labour (e.g. Syntocinon) Tocolysis (e.g. atosiban)

Triptans (for acute migraine, e.g.
Serotonin Anti-emetics (e.g. ondansetron)
zolmitriptan)
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
Drugs causing photosensitivity
Causes of drug-induced photosensitivity
 thiazides
 tetracyclines, sulphonamides, ciprofloxacin
 amiodarone
 NSAIDs e.g. piroxicam
 psoralens
 sulphonylureas
Drugs which act on serotonin receptors

Below is a summary of drugs which are known to act via modulation of the serotonin
(5-HT) system. It should be noted that 5-HT receptor agonists are used in the acute
treatment of migraine whilst 5-HT receptor antagonists are used in prophylaxis
Agonists
 sumatriptan is a 5-HT1D receptor agonist which is used in the acute treatment

of migraine
 ergotamine is a partial agonist of 5-HT1 receptors
Antagonists
 pizotifen is a 5-HT2 receptor antagonist used in the prophylaxis of migraine

attacks. Methysergide is another antagonist of the 5-HT2 receptor but is rarely
used due to the risk of retroperitoneal fibrosis
 cyproheptadine is a 5-HT2 receptor antagonist which is used to control
diarrhoea in patients with carcinoid syndrome
 ondansetron is a 5-HT3 receptor antagonist and is used as an antiemetic
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
Ethylene glycol toxicity
Ethylene glycol is a type of alcohol used as a coolant or antifreeze
Features of toxicity are divided into 3 stages:
 Stage 1: symptoms similar to alcohol intoxication: confusion, slurred speech,

dizziness
 Stage 2: metabolic acidosis with high anion gap and high osmolar gap. Also
tachycardia, hypertension
 Stage 3: acute kidney injury
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 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
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
Flecainide
Flecainide is a Vaughan Williams class 1c antiarrhythmic. It slows conduction of the

action potential by acting as a potent sodium channel blocker (specifically the Nav1.5
sodium channels). This may be reflected by widening of the QRS complex and
prolongation of the PR interval.
The Cardiac Arrhythmia Suppression Trial (CAST, 1989) investigated the use of agents
to treat asymptomatic or mildly symptomatic premature ventricular complexes
(PVCs) post myocardial infarction. The hypothesis was that this would reduce deaths
from ventricular arrhythmias. Flecainide was actually shown to increase mortality
post-myocardial infarction and is, therefore, contraindicated in this situation.
Indications
 atrial fibrillation
 SVT associated with accessory pathway e.g. Wolf-Parkinson-White syndrome
Contraindications
 post myocardial infarction

 structural heart disease: e.g. heart failure
 sinus node dysfunction; second-degree or greater AV block
 atrial flutter
Adverse effects
 negatively inotropic
 bradycardia
 proarrhythmic
 oral paraesthesia
 visual disturbances
Gentamicin
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
o due to auditory or vestibular nerve damage
o irreversible
 nephrotoxicity
o accumulates in renal failure
o the toxicity is secondary to acute tubular necrosis
o concomitant use of furosemide increases the risk
o 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
Haemodialysis in overdose
Drugs that can be cleared with haemodialysis - mnemonic: BLAST
 Barbiturate
 Lithium
 Alcohol (inc methanol, ethylene glycol)
 Salicylates
 Theophyllines (charcoal haemoperfusion is preferable)
Drugs which cannot be cleared with haemodialysis include
 tricyclics
 benzodiazepines
 dextropropoxyphene (Co-proxamol)
 digoxin
 beta-blockers
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
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.
The table below shows the differences between standard heparin and LMWH:
Low molecular weight heparin

Standard heparin
(LMWH)
Administration Intravenous Subcutaneous
Duration of
Short Long
action
Activates antithrombin III. Forms a

Mechanism of Activates antithrombin III. Forms a
complex that inhibits thrombin, factors
action complex that inhibits factor Xa
Xa, IXa, Xia and XIIa
Bleeding Bleeding
Heparin-induced thrombocytopaenia
Side-effects
(HIT) Lower risk of HIT and osteoporosis
Osteoporosis with LMWH
Activated partial thromboplastin time Anti-Factor Xa (although routine

Monitoring
(APTT) monitoring is not required)
Useful in situations where there is a Now standard in the management

high risk of bleeding as of venous thromboembolism
Notes
anticoagulation can be terminated treatment and prophylaxis and
rapidly. Also useful in renal failure acute coronary syndromes
Hyperlipidaemia: mechanism of action and adverse effects
The following table compares the side-effects of drugs used in hyperlipidaemia:
Adverse
Drugs Mechanism of action
effects
Myositis,
Statins HMG CoA reductase inhibitors deranged
LFTs
Ezetimibe Decreases cholesterol absorption in the small intestine Headache
Flushing,
Nicotinic acid Decreases hepatic VLDL secretion
myositis
Myositis,
Agonist of PPAR-alpha therefore increases lipoprotein lipase
Fibrates pruritus,
expression
cholestasis
Decreases bile acid reabsorption in the small intestine,

GI side-
Cholestyramine upregulating the amount of cholesterol that is converted to bile
effects
acid
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
Immunoglobulins: therapeutics
The Department of Health issued guidelines on the use of intravenous

immunoglobulins in May 2008
Uses
 primary and secondary immunodeficiency

 idiopathic thrombocytopenic purpura
 myasthenia gravis
 Guillain-Barre syndrome
 Kawasaki disease
 toxic epidermal necrolysis
 pneumonitis induced by CMV following transplantation
 low serum IgG levels following haematopoietic stem cell transplant for
malignancy
 dermatomyositis
 chronic inflammatory demyelinating polyradiculopathy
Basics
 formed from large pool of donors (e.g. 5,000)

 IgG molecules with a subclass distribution similar to that of normal blood
 half-life of 3 weeks
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
Local anaesthetic agents
Lidocaine
 An amide
 Local anaesthetic and a less commonly used antiarrhythmic (affects Na
channels in the axon)
 Hepatic metabolism, protein bound, renally excreted
 Toxicity: due to IV or excess administration. Increased risk if liver dysfunction
or low protein states. Note acidosis causes lidocaine to detach from protein
binding. Local anesthetic toxicity can be treated with IV 20% lipid emulsion
 Drug interactions: Beta blockers, ciprofloxacin, phenytoin
 Features of toxicity: Initial CNS over activity then depression as lidocaine
initially blocks inhibitory pathways then blocks both inhibitory and activating
pathways. Cardiac arrhythmias.
 Increased doses may be used when combined with adrenaline to limit
systemic absorption.
Cocaine
 Pure cocaine is a salt, usually cocaine hydrochloride. It is supplied for local

anaesthetic purposes as a paste.
 It is supplied for clinical use in concentrations of 4 and 10%. It may be applied
topically to the nasal mucosa. It has a rapid onset of action and has the
additional advantage of causing marked vasoconstriction.
 It is lipophillic and will readily cross the blood brain barrier. Its systemic effects
also include cardiac arrhythmias and tachycardia.
 Apart from its limited use in ENT surgery it is otherwise used rarely in
mainstream surgical practice.
Bupivacaine
 Bupivacaine binds to the intracellular portion of sodium channels and blocks

sodium influx into nerve cells, which prevents depolarization.
 It has a much longer duration of action than lignocaine and this is of use in
that it may be used for topical wound infiltration at the conclusion of surgical
procedures with long duration analgesic effect.
 It is cardiotoxic and is therefore contra indicated in regional blockage in case
the tourniquet fails.
 Levobupivicaine (Chirocaine) is less cardiotoxic and causes less vasodilation.
Prilocaine
 Similar mechanism of action to other local anaesthetic agents. However, it is

far less cardiotoxic and is therefore the agent of choice for intravenous
regional anaesthesia e.g. Biers Block.
All local anaesthetic agents dissociate in tissues and this contributes to their
therapeutic effect. The dissociation constant shifts in tissues that are acidic e.g. where
an abscess is present, and this reduces the efficacy.
Doses of local anaesthetics
Agent Dose plain Dose with adrenaline
Lignocaine 3mg/Kg 7mg/Kg
Bupivacaine 2mg/Kg 2mg/Kg
Prilocaine 6mg/Kg 9mg/Kg
These are a guide only as actual doses depend on site of administration, tissue
vascularity and co-morbidities.
Maximum total local anaesthetic doses
 Lignocaine 1% plain - 3mg/ Kg - 200mg (20ml)

 Lignocaine 1% with 1 in 200,000 adrenaline - 7mg/Kg - 500mg (50ml)
 Bupivicaine 0.5% - 2mg/kg- 150mg (30ml)
Maximum doses are based on ideal body weight
Effects of adrenaline
Adrenaline may be added to local anaesthetic drugs. It prolongs the duration of
action at the site of injection and permits usage of higher doses (see above). It is
contra indicated in patients taking MAOI's or tricyclic antidepressants. The toxicity of
bupivacaine is related to protein binding and addition of adrenaline to this drug
does not permit increases in the total dose of bupivacaine, in contrast to the
situation with lignocaine.
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.
Mercury poisoning
Features
 paraesthesia
 visual field defects
 hearing loss
 irritability
 renal tubular acidosis
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
Methanol poisoning
Methanol poisoning causes both the effects associated with alcohol (intoxication,
nausea etc) and also specific visual problems, including blindness. These effects are
thought to be secondary to the accumulation of formic acid. The actual
pathophysiology of methanol-associated visual loss is not fully understood but it is
thought to be caused by a form of optic neuropathy
Management
 fomepizole (competitive inhibitor of alcohol dehydrogenase) or ethanol

 haemodialysis
 cofactor therapy with folinic acid to reduce ophthalmological complications
Monoclonal antibodies
Monoclonal antibodies have an increasing role in medicine. They are manufactured

by a technique called somatic cell hybridization. This involves the fusion of myeloma
cells with spleen cells from a mouse that has been immunized with the desired
antigen. The resulting fused cells are termed a hybridoma and act as a 'factory' for
producing monoclonal antibodies.
The main limitation to this is that mouse antibodies are immunogenic leading to the
formation of human anti-mouse antibodies. This problem is overcome by a process
known as humanising. One method involves combining the variable region from the
mouse body with the constant region from a human antibody.
Clinical examples of monoclonal antibodies:
 infliximab (anti-TNF): used in rheumatoid arthritis and Crohn's

 rituximab (anti-CD20): used in non-Hodgkin's lymphoma and rheumatoid
arthritis
 cetuximab (epidermal growth factor receptor antagonist): used in metastatic
colorectal cancer and head and neck cancer
 trastuzumab (HER2/neu receptor antagonist): used in metastatic breast cancer
 alemtuzumab (anti-CD52): used in chronic lymphocytic leukaemia
 abciximab (glycoprotein IIb/IIIa receptor antagonist): prevention of ischaemic
events in patients undergoing percutaneous coronary interventions
 OKT3 (anti-CD3): used to prevent organ rejection
Monoclonal antibodies are also used for:
 medical imaging when combined with a radioisotope

 identification of cell surface markers in biopsied tissue
 diagnosis of viral infections
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
Muscle relaxants
 Depolarising neuromuscular blocker

 Inhibits action of acetylcholine at the neuromuscular junction
 Degraded by plasma cholinesterase and acetylcholinesterase
 Fastest onset and shortest duration of action of all muscle relaxants
Suxamethonium
 Produces generalised muscular contraction prior to paralysis
 Adverse effects include hyperkalaemia, malignant hyperthermia and
lack of acetylcholinesterase
 Non depolarising neuromuscular blocking drug

 Duration of action usually 30-45 minutes
 Generalised histamine release on administration may produce facial
Atracurium flushing, tachycardia and hypotension
 Not excreted by liver or kidney, broken down in tissues by hydrolysis
 Reversed by neostigmine
 Non depolarising neuromuscular blocking drug

 Duration of action approximately 30 - 40 minutes
 Degraded by liver and kidney and effects prolonged in organ
Vecuronium
dysfunction
 Effects may be reversed by neostigmine
 Non depolarising neuromuscular blocker

 Onset of action approximately 2-3 minutes
Pancuronium  Duration of action up to 2 hours
 Effects may be partially reversed with drugs such as neostigmine
Novel psychoactive substances
Novel psychoactive substances is the medical term for the many new substances
which are chemically related to established recreational drugs such as MDMA and
cannabis. They are often referred to as 'legal highs' although this is a misnomer in
the UK, as their distribution and sale have been illegal since 2016.
The information below describes some of the common types:
Stimulants
 similar to MDMA, amphetamines and cocaine, resulting in increased levels of

serotonin, dopamine and noradrenaline, resulting in a 'high' and feeling of
euphoria
 a common example is a stimulant NPS is mephedrone ('bath salts','M-
CAT'.'meow meow'). It is a cathinone and structurally similar to khat, a plant
found in East Africa
 another example is benzylpiperazine ('Exodus', 'Legal X', 'Legal E')
 typically swallowed as a pill/powder ('bombing') or snorted
 adverse effect profile similar to MDMA/cocaine, with the risk of serotonin
syndrome
Cannabinoids
 termed synthetic cannabinoid receptor agonists

 commonly referred to as 'spice'
 typically sprayed on to herbal mixtures which are then smoked. Also available
in liquid form which is then inhaled using e-cigarettes
 similar adverse effects to cannabis
Hallucinogenics
 can be either dissociatives and psychedelics

 dissociatives produce a similar effect to ketamine, with a sense of not being
connected to the physical body or time. A common dissociative NPS is
methoxetamine ('mexxy')
 psychedelics have a similar effect to LSD although NPS versions may also be a
stimulant
Depressant
 can be either opioid or benzodiazepine-based

 usually taken as a pill or a powder
 often structurally very similar to the original drug class, hence the adverse
effects are similar
 benzodiazepine NPS often have a significantly longer half-life
Other substances include:
 Gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL): 'G',

'Geebs' or 'Liquid Ecstasy'
 GHB causes respiratory depression. When taken with other respiratory
depressants, most commonly alcohol, this can be potentially life threatening
 Nitrous oxide: 'Hippie crack'
For a more detailed overview please see the excellent review in BMJ 2017;356:i6848
Octreotide
Overview
 long-acting analogue of somatostatin

 somatostatin is released from D cells of pancreas and inhibits the release of
growth hormone, glucagon and insulin
Uses
 acute treatment of variceal haemorrhage

 acromegaly
 carcinoid syndrome
 prevent complications following pancreatic surgery
 VIPomas
 refractory diarrhoea
Adverse effects
 gallstones (secondary to biliary stasis)
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
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
Overdose and poisoning: management
The table below outlines the main management for common overdoses:
Toxin Treatment
Management
 activated charcoal if ingested < 1 hour ago

Paracetamol
 N-acetylcysteine (NAC)
 liver transplantation
Management
Salicylate
 urinary alkalinization with IV bicarbonate
 haemodialysis
Opioid/opiates Naloxone
Flumazenil
The majority of overdoses are managed with supportive care only due to
Benzodiazepines
the risk of seizures with flumazenil. It is generally only used with severe or
iatrogenic overdoses.
Management
 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.
Tricyclic
Flecainide) are contraindicated as they prolong depolarisation. Class
antidepressants
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
Management
 mild-moderate toxicity may respond to volume resuscitation with

normal saline
Lithium
 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
Management
Beta-blockers
 if bradycardic then atropine
 in resistant cases glucagon may be used
Management has changed in recent times
 ethanol has been used for many years

 works by competing with ethylene glycol for the enzyme alcohol
dehydrogenase
Ethylene glycol  this limits the formation of toxic 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
Management
Methanol
poisoning  fomepizole or ethanol
 haemodialysis
Management
Organophosphate  atropine
insecticides  the role of pralidoxime is still unclear - meta-analyses to date have
failed to show any clear benefit
Toxin Treatment
Digoxin Digoxin-specific antibody fragments
Iron Desferrioxamine, a chelating agent
Lead Dimercaprol, calcium edetate
Management
Carbon monoxide
 100% oxygen
 hyperbaric oxygen
Hydroxocobalamin; also combination of amyl nitrite, sodium nitrite, and

Cyanide
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
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:
 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
 there is a staggered overdose* or there is doubt over the time of paracetamol
ingestion, regardless of the plasma paracetamol concentration; or
 patients who present 8-24 hours after ingestion of an acute overdose of more
than 150 mg/kg of paracetamol even if the plasma-paracetamol concentration
is not yet available
 patients who present > 24 hours if they are clearly jaundiced or have hepatic
tenderness, their ALT is above the upper limit of normal
o acetylcysteine should be continued if the paracetamol concentration or
ALT remains elevated whilst seeking specialist advice
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.
King's College Hospital criteria for liver transplantation (paracetamol liver failure)
Arterial pH < 7.3, 24 hours after ingestion
or all of the following:
 prothrombin time > 100 seconds

 creatinine > 300 µmol/l
 grade III or IV encephalopathy
*an overdose is considered staggered if all the tablets were not taken within 1 hour
Paracetamol overdose: metabolic pathways
The liver normally conjugates paracetamol with glucuronic acid/sulphate. During an

overdose the conjugation system becomes saturated leading to oxidation by P450
mixed function oxidases*. This produces a toxic metabolite (N-acetyl-B-
benzoquinone imine)
Normally glutathione acts as a defence mechanism by conjugating with the toxin

forming the non-toxic mercapturic acid. If glutathione stores run-out, the toxin forms
covalent bonds with cell proteins, denaturing them and leading to cell death. This
occurs not only in hepatocytes but also in the renal tubules
N-acetyl cysteine is used in the management of paracetamol overdose as it is

a precursor of glutathione and hence can increase hepatic glutathione production
*this explains why there is a lower threshold for treating patients who take P450
inducing medications e.g. phenytoin or rifampicin
Paracetamol overdose: risk factors
The following groups of patients are at an increased risk of developing

hepatotoxicity following a paracetamol overdose:
 patients taking liver enzyme-inducing drugs (rifampicin, phenytoin,

carbamazepine, chronic alcohol excess, St John's Wort)
 malnourished patients (e.g. anorexia nervosa) or patients who have not eaten
for a few days
Interestingly, acute alcohol intake, as opposed to chronic alcohol excess, is not

associated with an increased risk of developing hepatotoxicity and may actually be
protective.
Penicillin allergy
Allergy to penicillin based antibiotics is common although many patients who report
an allergy may be describing an intolerance/side-effects (e.g. diarrhoea) or a
coincidental rash (e.g. amoxicillin in patients with infectious mononucleosis).
Around 0.5-6.5% of patients who are allergic to penicillin are also allergy to
cephalosporins. The BNF states the following:
The principal side-effect of the cephalosporins is hypersensitivity and about 0.5-6.5% of

penicillin-sensitive patients will also be allergic to the cephalosporins. Patients with a
history of immediate hypersensitivity to penicillin should not receive a cephalosporin. If
a cephalosporin is essential in these patients because a suitable alternative
antibacterial is not available, then cefixime, cefotaxime, ceftazidime, ceftriaxone, or
cefuroxime can be used with caution; cefaclor, cefadroxil, cefalexin, cefradine, and
ceftaroline fosamil should be avoided.
It is important to be aware of other types of penicillin and their trade names to avoid
accidental prescription.
Types of penicillin:
 phenoxymethylpenicillin
 benzylpenicillin
 flucloxacillin
 amoxicillin
 ampicillin
 co-amoxiclav (Augmentin)
 co-fluampicil (Magnapen)
 piperacillin with tazobactam (Tazocin)
 ticarcillin with clavulanic acid (Timentin)
Pharmacodynamics
Pharmacodynamics is often considered to be 'what the drugs do to the body' (in

contrast to pharmacokinetics which is concerned with 'what the body does to the
drugs'). It is obviously a vast topic, so the text below is an introduction to some key
concepts.
Classically drugs exert their effect via interaction with a target, commonly (but not
always) a protein. Targets may be intracellular or extracellular and can be a cellular
receptor on the cell membrane, an intracellular receptor exerting an effect on the
nucleus, an enzyme, transport proteins or even a specific nucleic acid sequence.
Within the cellular targets, there are 4 main types:
 Ion channels- These are the simplest form of receptor, once the drug binds to
a receptor on this target the channel is either opened or closed dependent
upon the action of the drug and whether it is an agonist or antagonist (see
below). Examples of drugs working on ion channels include most local
anaesthetics (e.g. lidocaine) that work on voltage-gated sodium channels.
 G-protein coupled receptors (GPCRs)- These are more complex than ion
channels. When the drug binds to the target, it causes a sequence of events
within the G-protein subunits which then leads to production of a secondary
messenger such as cyclic AMP or a protein phosphorylation cascade. These
second messengers are actually responsible for causing the
effect. Adrenoreceptors are an example of G-protein coupled receptors.
 Tyrosine kinase receptors- these receptors are different in their mechanism to
both ion channels and GPCRs. When a drug activates a tyrosine kinase
receptor it leads to a series of steps within the cell, normally
involving phosphorylation of targets, then causing effects which often include
cell growth and differentiation. Insulin is a commonly used drug (as well as
endogenous hormone!) that works via a tyrosine kinase receptor.
 Nuclear receptors- As the name suggests these receptors are located within
the nucleus of the cell and activation or inhibition of these receptors typically
causes increased or decreased gene transcription. Drugs interacting with these
receptors must obviously be lipid-soluble in order to penetrate the cell
membrane, after which it forms a complex with a receptor protein before
exerting an effect. Commonly used drugs that work via this route are steroids
such as prednisolone and other hormone replacements such as levothyroxine.
With all different receptor targets, it is also important to consider whether the drug
has a 'positive' or 'negative' impact on the receptor.
 Agonists are drugs which activates the receptor.

 Antagonists are those which block a receptor preventing activation, it is
important to note they do not deactivate a receptor.
Antagonists may be competitive or non-competitive. A competitive antagonist binds

at the same site as an agonist, thereby occupying it and preventing an agonist
occupying the site. A non-competitive antagonist occupies another site which often
causes a conformational change in the binding site where an agonist would
otherwise bind.
 'Binding affinity' is a concept of how readily a drug will bind to the specific
receptor, in most cases the more receptors that are occupied by a drug, the
greater the effect produced.
 'Efficacy' is the measure of how able an agonist is to produce a response once
it has bound to the receptor.
 'Potency' is related to the concentration at which a drug is effective.
 'Therapeutic Index' is the ratio of the dose of a drug resulting in an undesired
effect compared to that at which it produces the desired effect. Calculation of
a therapeutic index is complex, however, it is sufficient to be aware of certain
drugs with a 'narrow therapeutic index', such as the antibiotic gentamicin
which whilst effective, requires close monitoring to avoid adverse effects.
Dose-response relationship
The relationship between the amount of drug given (dose) and the impact it has on
the patient (response) is very rarely entirely linear. Often drugs that work by
occupying a certain receptor may 'saturate' the available receptors and so further
increased doses will not cause any more response. Many drugs do not start to have a
significant impact below a certain dose and so are considered to be 'sub-therapeutic'
below such a dose. The relationship between dose and response can be well
illustrated on dose-response graphs with the dose on the x-axis and response on the
y-axis; such graphs allow easy comparison of the characteristics of different drugs. It
is, of course, important to remember that dose-response also varies between
individuals.
Pharmacokinetics: excretion
Clearance
 majority of drugs exhibit 'first-order' elimination kinetics i.e. the rate of drug
elimination is proportional to drug concentration
 certain drugs exhibit zero-order kinetics where the rate of excretion is
constant despite changes in plasma concentration, this is due to saturation of
the metabolic process
 examples of drugs exhibiting zero-order kinetics include phenytoin and
salicylates
Pharmacokinetics: metabolism
Drug metabolism usually involves two types of biochemical reactions - phase I and
phase II reactions
 phase I reactions: oxidation, reduction, hydrolysis. Mainly performed by the

P450 enzymes but some drugs are metabolised by specific enzymes, for
example alcohol dehydrogenase and xanthine oxidase. Products of phase I
reactions are typically more active and potentially toxic
 phase II reactions: conjugation. Products are typically inactive and excreted in
urine or bile. Glucuronyl, acetyl, methyl, sulphate and other groups are
typically involved
The majority of phase I and phase II reactions take place in the liver
First-pass metabolism
This is a phenomenon where the concentration of a drug is greatly reduced before it

reaches the systemic circulation due to hepatic metabolism. As a consequence much
larger doses are need orally than if given by other routes. This effect is seen in many
drugs, including:
 aspirin
 isosorbide dinitrate
 glyceryl trinitrate
 lignocaine
 propranolol
 verapamil
 isoprenaline
 testosterone
 hydrocortisone
Questions concerning zero-order kinetics and acetylator status are also common in
the exam
Zero-order kinetics
Zero-order kinetics describes metabolism which is independent of the concentration

of the reactant. This is due to metabolic pathways becoming saturated resulting in a
constant amount of drug being eliminated per unit time. This explains why people
may fail a breathalyser test in the morning if they have been drinking the night
before
Drugs exhibiting zero-order kinetics
 phenytoin
 salicylates (e.g. high-dose aspirin)
 heparin
 ethanol
Acetylator status
50% of the UK population are deficient in hepatic N-acetyltransferase
Drugs affected by acetylator status
 isoniazid
 procainamide
 hydralazine
 dapsone
 sulfasalazine
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
Post operative fluid management
Composition of commonly used intravenous fluids mmol-1
Na K Cl Bicarbonate Lactate
Plasma 137-147 4-5.5 95-105 22-25 -
0.9% Saline 153 - 153 - -
Dextrose / saline 30.6 - 30.6 - -
Hartmans 130 4 110 - 28
Post operative fluid management
In the UK the GIFTASUP guidelines (see reference below) were devised to try and
provide some consensus guidance as to how intravenous fluids should be
administered. A decade ago it was a commonly held belief that little harm would
occur as a result of excessive administration of normal saline and many oliguric
postoperative patients received enormous quantities of IV fluids. As a result, they
developed hyperchloraemic acidosis. With a greater understanding of this potential
complication, the use of electrolyte balanced solutions (Ringers lactate/ Hartmans) is
now favoured over normal saline. In addition to this, solutions of 5% dextrose and
dextrose/saline combinations are now generally not recommended for surgical
patients. The other guidance includes:
 Fluids given should be documented clearly and easily available

 Assess the patient's fluid status when they leave theatre
 If a patient is haemodynamically stable and euvolaemic, aim to restart oral
fluid intake as soon as possible
 Review patients whose urinary sodium is < 20
 If a patient is oedematous, hypovolaemia if present should be treated first.
This should then be followed by a negative balance of sodium and water,
monitored using urine Na excretion levels.
 Solutions such as Dextran 70 should be used in caution in patients with sepsis
as there is a risk of developing acute renal injury.
References
British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients
GIFTASUP (2009)
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 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
Progestogen only pill: advantages/disadvantages
Advantages
 highly effective (failure rate = 1 per 100 woman years)

 doesn't interfere with sex
 contraceptive effects reversible upon stopping
 can be used whilst breast-feeding
 can be used in situations where the combined oral contraceptive pill is
contraindicated e.g. in smokers > 35 years of age and women with a history of
venous thromboembolic disease
Disadvantages
 irregular periods: some users may not have periods whilst others may have
irregular or light periods. This is the most common adverse effect
 doesn't protect against sexually transmitted infections
 increased incidence of functional ovarian cysts
 common side-effects include breast tenderness, weight gain, acne and
headaches. These symptoms generally subside after the first few months
Quinine toxicity (cinchonism)
Quinine is a remarkably toxic drug; something which is not so readily acknowledged.

It is used as an antimalarial drug and also as a prophylactic agent against leg cramps,
although both uses are increasingly falling from vogue due to the availability of
better, safer agents. Quinine toxicity, known as cinchonism, may be fatal, usually by
cardiac arrhythmia or flash pulmonary oedema in the short term, although incipient
renal failure may be fatal more long-term.
Cardiac arrhythmia is a common finding in cinchonism due to blockade of sodium

and potassium channels prolonging QRS and QT intervals respectively and these
rhythms may degenerate into ventricular tachyarrhythmias or fibrillation causing
death. Hypoglycaemia is also a common finding in cinchonism since quinine
stimulates pancreatic insulin secretion and this should be corrected rapidly if present.
Unlike in the above case, flash pulmonary oedema may develop causing hypoxia and
necessitating positive pressure ventilation. Classical hallmarks of cinchonism are
tinnitus, visual blurring, flushed and dry skin and abdominal pain.
Clinically, quinine toxicity is difficult to distinguish from aspirin poisoning and so

measurement of serum salicylate levels is important when this clinical picture is seen.
In terms of management however, whereas aspirin can be cleared from overdose
victims by haemofiltration, quinine cannot be extracted easily by extracorporeal
methods. Central nervous symptoms such as tinnitus, deafness and visual defects
which may occur with aspirin are usually transient whereas quinine leaves permanent
neural damage, if the patient survives.
Management of quinine poisoning is largely supportive with fluids, inotropes and

bicarbonate as needed as well as positive pressure ventilation for pulmonary
oedema.
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
Salicylate overdose
A key concept for the exam is to understand that salicylate overdose leads to a mixed
respiratory alkalosis and metabolic acidosis. Early stimulation of the respiratory
centre leads to a respiratory alkalosis whilst later the direct acid effects of salicylates
(combined with acute renal failure) may lead to an acidosis. In children metabolic
acidosis tends to predominate.
Features
 hyperventilation (centrally stimulates respiration)

 tinnitus
 lethargy
 sweating, pyrexia*
 nausea/vomiting
 hyperglycaemia and hypoglycaemia
 seizures
 coma
Treatment
 general (ABC, charcoal)

 urinary alkalinization with intravenous sodium bicarbonate - enhances
elimination of aspirin in the urine
 haemodialysis
Indications for haemodialysis in salicylate overdose
 serum concentration > 700mg/L

 metabolic acidosis resistant to treatment
 acute renal failure
 pulmonary oedema
 seizures
 coma
*salicylates cause the uncoupling of oxidative phosphorylation leading to decreased

adenosine triphosphate production, increased oxygen consumption and increased
carbon dioxide and heat production
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
o tramadol may also interact with SSRIs
 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-anginals
The table below summarises characteristic (if not necessarily the most common) side-
effects of drugs used to treat angina
Drug Side-effect
• Headache
• Flushing
Calcium channel blockers • Ankle oedema
Verapamil also commonly causes constipation

• Bronchospasm (especially in asthmatics)
• Fatigue
Beta-blockers
• Cold peripheries
• Sleep disturbances
• Headache
Nitrates • Postural hypotension
• Tachycardia
• Headache
Nicorandil • Flushing
• Anal ulceration
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
Gastrointestinal side-effects
Metformin
Lactic acidosis
Hypoglycaemic episodes
Increased appetite and weight gain
Sulfonylureas
Syndrome of inappropriate ADH secretion
Liver dysfunction (cholestatic)
Weight gain
Fluid retention
Glitazones
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
Tacrolimus
Tacrolimus is a calcineurin inhibitor used as an immunosuppressant to prevent

transplant rejection. It has a very similar action to ciclosporin.
Mechanism of action
 decreases clonal proliferation of T cells by reducing IL-2 release

 binds to FKBP forming a complex which inhibits calcineurin, a phosphotase
that activates various transcription factors in T cells
o this contrasts with ciclosporin, which binds to cyclophilin rather than
FKBP
Tacrolimus is more potent than ciclosporin and hence the incidence of organ
rejection is less. However, nephrotoxicity and impaired glucose tolerance is more
common
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
Teratogens
The following table includes some of the drugs and medical conditions that may
harm a developing fetus:
Drug/condition Effect
Renal dysgenesis
ACE inhibitors
Craniofacial abnormalities
Alcohol Craniofacial abnormalities
Aminoglycosides Ototoxicity
Neural tube defects

Carbamazepine
Chloramphenicol 'Grey baby' syndrome
Intrauterine growth retardation

Cocaine
Preterm labour
Diethylstilbesterol Vaginal clear cell adenocarcinoma
Lithium Ebstein's anomaly (atrialized right ventricle)
Macrosomia
Neural tube defects
Maternal diabetes mellitus Polyhydramnios
Preterm labour
Caudal regression syndrome
Preterm labour
Smoking
Intrauterine growth retardation
Tetracyclines Discoloured teeth
Thalidomide Limb reduction defects
Neural tube defects

Valproate
Warfarin Craniofacial abnormalities
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
Trastuzumab
Trastuzumab (Herceptin) is a monoclonal antibody directed against the HER2/neu

receptor. It is used mainly in metastatic breast cancer although some patients with
early disease are now also given trastuzumab.
Adverse effects
 flu-like symptoms and diarrhoea are common

 cardiotoxicity
o more common when anthracyclines have also been used
o an echo is usually performed before starting treatment
Tricyclic overdose
Overdose of tricyclic antidepressants is a common presentation to emergency
departments. Amitriptyline and dosulepin (dothiepin) are particularly dangerous in
overdose.
Early features relate to anticholinergic properties: dry mouth, dilated pupils, agitation,
sinus tachycardia, blurred vision.
Features of severe poisoning include:
 arrhythmias
 seizures
 metabolic acidosis
 coma
ECG changes include:
 sinus tachycardia
 widening of QRS
 prolongation of QT interval
Widening of QRS > 100ms is associated with an increased risk of seizures whilst QRS
> 160ms is associated with ventricular arrhythmias
Management
 IV bicarbonate
o first-line therapy for hypotension or arrhythmias
o indications include widening of the QRS interval >100 msec or a
ventricular arrhythmia
 other drugs for 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
 intravenous lipid emulsion is increasingly used to bind free drug and reduce
toxicity
 dialysis is ineffective in removing tricyclics
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

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PASSMEDICINE

Drugs which may precipitate attack

Drugs considered safe to use

Recommend Adult Life Support (ALS) adrenaline doses

 anaphylaxis: 0.5ml 1:1,000 IM

Management of accidental injection

 local infiltration of phentolamine

 responsible for the fight or flight response

Actions on α adrenergic receptors:

 inhibits insulin secretion by the pancreas

Actions onβ adrenergic receptors:

 stimulates glucagon secretion in the pancreas

 being developed, may have a role in preventing obesity (stimulation causes

Carvedilol and labetalol are mixed alpha and beta antagonists

 mainly presynaptic: inhibition of transmitter release (inc NA, Ach from

 mainly located in the heart

 all are G-protein coupled

 benzodiazepines for acute withdrawal

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

Initiating allopurinol prophylaxis

Indications for allopurinol

 the British Society of Rheumatology Guidelines now advocate offering urate-

 severe cutaneous adverse reaction (SCAR)

 metabolised to active compound 6-mercaptopurine

 allopurinol reduces renal clearance, therefore may cause marrow toxicity

 allopurinol causes an increase in plasma concentration of theophylline by

Around 1 in 6 patients taking amiodarone develop thyroid dysfunction

The pathophysiology of amiodarone-induced hypothyroidism (AIH) is thought to be due to

Amiodarone may be continued if this is desirable

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

AIT type 1 AIT type 2

Excess iodine-induced thyroid hormone Amiodarone-related destructive

Goitre Present Absent

Management Carbimazole or potassium perchlorate Corticosteroids

Agent Specific features

 GABA receptor agonist

 Extremely rapid onset of action making it the agent of choice for

 NMDA receptor antagonist

 Has favorable cardiac safety profile with very little haemodynamic

The Vaughan Williams classification of antiarrhythmics is still widely used although it

Class Examples Mechanism of action Notes

Quinidine toxicity causes cinchonism

Lidocaine Block sodium channels

Flecainide Block sodium channels

 peptidoglycan cross-linking: penicillins, cephalosporins, carbopenems

Inhibits protein synthesis (by acting on the ribosome)

Inhibits DNA synthesis

 quinolones (e.g. ciprofloxacin)

Inhibits folic acid formation

Inhibits RNA synthesis

Aspirin works by blocking the action of both cyclooxygenase-1 and 2.

What do the current guidelines recommend?

 first-line for patients with ischaemic heart disease

 if bradycardic then atropine

Haemodialysis is not effective in beta-blocker overdose

Calcium channel blockers are primarily used in the management of cardiovascular

Angina, hypertension, arrhythmias

Hypertension, angina, Raynaud's

Affects the peripheral vascular smooth muscle

 in carbon monoxide poisoning the oxygen saturation of haemoglobin