PHARMACOKINETICS: METABOLISM

 Drug metabolism usually involves two types of biochemical reactions – phase I and phase II
reactions
o Phase I reactions: Oxidation, reduction, hydrolysis. Mainly performed by the P450
enzymes but some drugs are metabolized by specific enzymes, for example alcohol
dehydrogenase and xanthine oxidase. Products of phase I reactions are typically more
active and potentially toxic
o Phase II reactions: Conjugation. Products are typically inactive and excreted in urine or
bile. Glucuronyl, acetyl, methyl, sulphate and other groups are typically involved
 Majority of phase I and phase II reactions take place in the liver
 Usually both phase I and II reactions decrease lipid solubility
 First-pass metabolism
o A phenomenon where the concentration of a drug is greatly reduced before it reaches
the systemic circulation due to hepatic metabolism
o As a consequence, much larger doses are need orally than if given by other routes
o Examples:
 Aspirin
 Isosorbide dinitrate
 Glyceryl trinitrate
 Lignocaine
 Propranolol
 Verapamil
 Isoprenaline
 Testosterone
 Hydrocortisone
 Zero-order kinetics/ Saturation pharmacokinetics
o Describes metabolism which is independent of the concentration of the reactant
o This is due to metabolic pathways becoming saturated resulting in a constant amount
of drug being eliminated per unit time  explains why people may fail a breathalyzer
test in the morning if they have been drinking the night before
o Drugs exhibiting zero-order kinetics:
 Phenytoin
 Salicylates (high dose aspirin)
 Heparin
 Ethanol
 Acetylator status – 50% of the UK population are deficient in hepatic N-acetyltransferase
o Drugs affected by acetylator status:
 Isoniazid
 Procainamide
 Hydralazine
 Dapsone
 Sulfasalazine
PHARMACOKINETICS: EXCRETION/ CLEARANCE

 Majority of drugs exhibit ‘first-order’ elimination kinetics i.e. the rate of drug elimination is proportional
to drug concentration
o First-order kinetics are considered as a linear process
o Means that the higher the drug concentration, the higher its elimination rate
o Elimination processes are not saturated and can adapt to the needs of the body, to reduce
accumulation of the drug
 Certain drugs exhibit zero-order kinetics where the rate of excretion is constant despite changes in plasma
concentration – due to saturation of the metabolic process
o Clearance rate depends on an easily saturated enzyme system
o As soon as the system is saturated, the rate of clearance plateaus, and does not vary no matter
how much drug is present  results in a constant rate of elimination predisposing to high levels
of drug and toxicity
o Examples of drugs exhibiting zero-order kinetics: Phenytoin, Salicylates, Alcohol

P450 ENZYME SYSTEM

 Induction usually requires prolonged exposure to the inducing drug, as opposed to P450 inhibitors, where
effects are often seen rapidly
 Induction increases metabolism of the drug itself  auto-induction, thus causing subtherapeutic drug
levels
 Inducers of the P450 system include:
o Antiepileptics: Phenytoin, Carbamazepine
o Barbiturates: Phenobarbitone
o Rifampicin – will therefore increase the metabolism of warfarin, therefore decreasing the INR
(caused decreased INR)
o St John’s Wort
o Chronic alcohol intake
o Griseofulvin
o Smoking (induces CYP1A2 isoenzyme – reducing effectiveness of Aminophylline: reason why
smokers require more aminophylline)
 Inhibitors  causes inhibited liver enzymes  raised INR
 Inhibitors of the P450 system include:
o Antibiotics: Ciprofloxacin, Erythromycin
o Isoniazid – inhibits liver enzymes causing raised INR
o Cimetidine, Omeprazole
o Amiodarone
o Allopurinol
o Imidazoles: Ketoconazole, Fluconazole
o SSRIs: Fluoxetine, Sertraline
o Ritonavir
o Sodium valproate
o Acute alcohol intake
o Quinupristin
ANTIBIOTICS: GROSS MECHANISM OF ACTION

Mechanism of action Subtypes Groups Examples

Inhibits cell wall Peptidoglycan cross- Penicillins
formation linking Cephalosporins
Carbapenems
Peptidoglycan synthesis Glycopeptides Vancomycin, Teicoplanin

Teicoplanin (similar to
Vancomycin) has a
significantly longer
duration of action,
allowing once daily
administration after the
loading dose
Inhibits protein 50S subunit (reversible Macrolides Clarithromycin – good
synthesis (by acting on inhibition of 50S Chloramphenicol gram positive cover and
the ribosome) ribosome subunit) Clindamycin that of atypical
Linezolid organisms
Streptogrammins
30S subunit Aminoglycosides
Tetracyclines
Inhibits DNA synthesis Quinolones Ciprofloxacin
Damages DNA Metronidazole
Inhibits folic acid Sulphonamides
formation Trimethoprim
Co-trimoxazole
Inhibits RNA synthesis Rifampicin

Trimethoprim – works by inhibiting dihydrofolate reductase; Associated with myelosuppression and

neural tube defects
MACROLIDES

 Erythromycin was the first macrolide used clinically; Newer examples include Clarithromycin and
Azithromycin
 Macrolides act by inhibiting bacterial protein synthesis by blocking translocation
 Mechanism of resistance: Post-transcriptional methylation of the 23S bacterial ribosomal RNA
 Used in gastroparesis as it has prokinetic properties = promotes gastric emptying
 Adverse effects:
o Gastrointestinal side-effects are common
 Nausea less common with Clarithromycin then Erythromycin
o Cholestatic jaundice: Risk may be reduced if erythromycin stearate is used
o P450 inhibitor
o Erythromycin may potentially interact with amiodarone, warfarin (P450 inhibitor) and
simvastatin
 Common interactions: Statins should be stopped whilst taking a course of macrolides
o Macrolides inhibit the cytochrome P450 isoenzyme CYP3A4 that metabolises statins
o Taking macrolides concurrently with statins significantly increases the risk of myopathy
and rhabdomyolysis

TACROLIMUS

 A macrolide used as an immunosuppressant to prevent transplant rejection

 Has a very similar action to ciclosporin
 Action of ciclosporin:
o Decreases clonal proliferation of T cells by reducing IL-2 release
o Binds to cyclophilin forming a complex which inhibits calcineurin, a phosphatase that
activates various transcription factors in T cells
 Action of tacrolimus differs in that it binds to a protein called FKBP rather than cyclophilin
 Tacrolimus is more potent than ciclosporin and hence the incidence of organ rejection is less
 However, nephrotoxicity and impaired glucose tolerance is more common

QUINOLONES

 A group of antibiotics which work by inhibiting DNA synthesis

 Bactericidal in nature
 Examples: 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
 Ciprofloxacin may lead to tendinopathy
 Adverse effects:
o Lower seizure threshold in patients with epilepsy
o Tendon damage (including rupture), especially Achilles tendon rupture – well
documented complication of quinolone therapy, with the risk is increased in patients
also taking steroids
 Appears to be an idiosyncratic reaction, with the actual median duration of
treatment being 8 days before problems occur
o Cartilage damage has been demonstrated in animal models – quinolones generally
avoided, but not necessarily contraindicated in children
o Lengthens QT interval
 Contraindications:
o Quinolones should generally be avoided in women who are pregnant or breastfeeding
o Avoid in G6PD

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. diarrhea) or a coincidental rash (e.g.
amoxicillin in patients with infectious mononucleosis)
 Reported penicillin allergy is very common, with up to 10% of patients claiming to be allergic to
penicillin
o However, less than 10% of these people have a true IgE mediated allergy to penicillin
o Symptoms such as an urticarial rash or itching make it more likely that they have an IgE
mediated allergy
 Penicillins, cephalosporins and carbapenems are all members of the beta-lactam group of
antibiotics and share a common beta-lactam ring
o Therefore, a small risk of allergy cross-over between all these antibiotics
o Rates of allergy cross-over are lower with 2nd and 3rd generation cephalosporins than 1st
generation cephalosporins such as Cefalexin
 Around 0.5-6.5% of patients who are allergic to penicillin are also allergic to Cephalosporins
(including Cefalexin)
o Patients with history of immediate hypersensitivity to penicillin should not receive a
cephalosporin
o If a cephalosporin is essential in these patients, then cefixime, cefotaxime, ceftazidime,
ceftriaxone, or cefuroxime can be used with caution
o Cefaclor, cefadroxil, cefalexin, cefradine and ceftaroline fosamil should be avoided
 Types of Penicillin:
o Phenoxymethylpenicillin
 o Benzylpenicillin
o Flucloxacillin
o Amoxicillin
o Ampicillin
o Co-amoxiclav (Augmentin)
o Co-fluampicil (Magnapen)
o Piperacillin with tazobactam (Tazocin)
o Ticarcillin with clavulanic acid (Timentin)

TUBERCULOSIS: DRUG SIDE EFFECTS AND MECHANISM OF ACTION

DRUGS MECHANISM OF ACTION SIDE EFFECTS

Rifampicin Inhibits bacterial DNA Hepatotoxicity
dependent RNA polymerase Orange bodily fluids
preventing transcription of DNA Rash
into mRNA Flu-like symptoms
Potent liver enzyme inducer Drug interactions
Isoniazid Inhibits mycolic acid synthesis Peripheral neuropathy –
prevent with Pyridoxine
Liver enzyme inhibitor (vitamin B6)
Hepatotoxicity
Agranulocytosis
Psychosis
Pyrazinamide Converted by pyrazinamidase Hyperuricemia causing gout
into pyrazinoic acid which in Arthralgia, myalgia
turn inhibits fatty acid synthase Hepatotoxicity
(FA S) I Nausea
Ethambutol Inhibits the enzyme arabinosyl Optic neuritis: Check visual
transferase which polymerizes acuity before and during
arabinose into arabinan treatment
Rash
*Dose needs adjusting in
patients with renal impairment
ANTIARRHYTHMICS: VAUGHAN WILLIAMS CLASSIFICATION

 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

Class Examples Mechanism of action Notes

Ia Quinidine Block sodium channels Quinidine toxicity causes
Procainamide cinchonism (headache, tinnitus,
Disopyramide Increases action potential thrombocytopenia)
duration
Procainamide may cause drug-
induced lupus
Ib Lidocaine Block sodium channels
Mexiletine
Tocainide Decreases action potential
duration
Ic Flecainide Block sodium channels
Encainide
Propafenone No effect on action potential
duration
II Propranolol Beta-adrenoceptor antagonists
Atenolol
Bisoprolol
Metoprolol
III Amiodarone Block potassium channels Amiodarone therapy can result in
Sotalol both corneal opacities and optic
Ibutilide neuritis
Bretylium
IV Verapamil Calcium channel blockers
Diltiazem

FLECAINIDE

 A Vaughan Williams class 1c antiarrhythmic

 Slows conduction of the action potential by acting as a potent sodium channel blocker – blocks
specifically the Nav1.5 sodium channel in the heart which slowing the upstroke of the cardiac
action potential
 May be reflected by widening of the QRS complex and prolongation of the PR interval
  Shown to increase mortality post myocardial infarction and is therefore contraindicated in the
use to treat asymptomatic or mildly symptomatic premature ventricular complexes (PVCs) post
myocardial infarction
 Indications:
o Atrial fibrillation
o SVT associated with accessory pathway e.g. Wolff-Parkinson-White syndrome
 Adverse effects of Flecainide:
o Negatively inotropic
o Bradycardia
o Proarrhythmic
o Oral paraesthesia
o Visual disturbances

AMIODARONE & THE THYROID GLAND

 Around 1 in 6 patients taking Amiodarone develop thyroid dysfunction

 Amiodarone-induced hypothyroidism
o The pathophysiology of amiodarone-induced hypothyroidism (AIH) is thought to be due
to the high iodine content of amiodarone causing a Wolff-Chaikoff effect – an
autoregulatory phenomenon where thyroxine formation is inhibited due to high levels
of circulating iodide
o Amiodarone may be continued if this is desirable (especially if patient has a history of
ventricular tachycardia so it is unwise to withdraw amiodarone abruptly)
o Also add on Thyroxine for hypothyroidism
 Amiodarone-induced thyrotoxicosis – 2 types:
o Amiodarone should be stopped if possible in patients who develop AIT

AIT type 1 AIT type 2

Pathophysiology Excess iodine-induced thyroid Amiodarone-related destructive
hormone synthesis thyroiditis
Goiter Present Absent
Management Carbimazole or potassium Corticosteroids
perchlorate

OTHER ANTI-ARRHYTHMIC DRUGS

DRUG MECHANISM OF ACTION

Bisoprolol Blocks the stimulation of beta-1 adrenergic receptors found mainly
in the heart muscle, which ultimately leads to decreased adrenergic
tone and stimulation of the heart muscle
Procainamide Works in a similar way to Flecainide; but instead induces a rapid
blocking of the batrachotoxin activated sodium channels rapidly
 Dronedarone Mechanism of action is unclear; but believed to be involved in both
the inhibition of outward potassium channels as well as reduction
of sodium into the cells
Also thought to have an effect of the calcium channels
Ibutilide Works primarily by prolonging the repolarization in atrial and
ventricular myocardium – this effect is caused by blocking IKr, the
rapid component of the cardiac delayed rectifier potassium current
PRESCRIBING IN PATIENTS WITH HEART FAILURE

 Medications which can cause worsening of heart failure: NSAIDs, non-dihydropyridine calcium
channel blockers, non-cardio-selective beta blockers, some arrhythmic agents and alpha-
blockers used for urological problems
 The following medications may exacerbate heart failure:
o Thiazolidinediones: Proglitazone is contraindicated as it causes fluid retention
o Verapamil: Negative inotropic effect
o NSAIDs/ glucocorticoids: Should be used with caution as they cause fluid retention
o Class I antiarrhythmics: Flecainide (negative inotropic and proarrhythmic effect) –
contraindicated in patients with structural heart disease
 Low dose aspirin is an exception – many patients will have coexistent cardiovascular disease and
the benefits of taking aspirin outweigh the risks

ASPIRIN

 Works by blocking the action of both cyclooxygenase-1 and 2 (COX-1 and COX-2) – non-
reversible COX-1 and COX-2 inhibitor
 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 led to the widespread use of low-dose aspirin in cardiovascular disease
 First-line for patients with ischemic heart disease
 Potentiates:
o Oral hypoglycemic
o Warfarin
o Steroids
 Aspirin should not be used in children under 16 due to the risk of Reye’s syndrome
o An exception is Kawasaki disease, where the benefits are thought to outweigh the risks
 NICE now recommend clopidogrel first-line following an ischemic stroke and for peripheral
arterial disease
o However, older NICE guidelines still recommend aspirin + dipyridamole
 In the BNF section ‘prescribing in dental practice’, it advises that patients should continue taking
anti-platelets as normal
ADRENOCEPTOR AGONISTS

CLASS MECHANISM OF PATHWAYS – ALL EXAMPLE OF EXAMPLE OF

ACTION ARE G-PROTEIN AGONISTS ANTAGONISTS
COUPLED
Alpha-1 Vasoconstriction – Activate Phenylephrine Doxazosin
to achieve phospholipase C
decongestant effect  IP3  DAG
Vasopressor
Relaxation of GI
smooth muscle
Salivary secretion
Hepatic
glycogenolysis
Alpha-2 Mainly presynaptic: Inhibit adenylate Clonidine Yohimbine
Inhibition of cyclase
transmitter release
(including
noradrenaline, Ach
from autonomic
nerves)
Inhibits insulin
Platelet aggregation
Beta-1 Mainly located in Stimulate Dobutamine Bisoprolol,
the heart adenylate cyclase Atenolol
Increase heart rate +
force
Beta-2 Vasodilatation Stimulate Salbutamol Phentolamine
Bronchodilation adenylate cyclase
Relaxation of GI
smooth muscle
Beta-3 Lipolysis Stimulate Being developed,
adenylate cyclase may have a role in
preventing obesity
(stimulation causes
lipolysis)
ADRENOCEPTOR ANTAGONISTS

 Alpha antagonists
o Alpha-1: Doxazosin – used in the treatment of hypertension and benign prostatic
hypertrophy
o Alpha-1a: Tamsulosin – acts mainly on urogenital tract
o Alpha-2: Yohimbine
o Non-selective: Phenoxybenzamine (previously used in peripheral arterial disease)
 Beta antagonists
o Beta-1: Atenolol
o Non-selective: Propanolol
 Carvedilol and Labetolol are mixed alpha and beta antagonists

ADRENALINE

 A sympathomimetic amine with both alpha and beta adrenergic stimulating properties
 Responsible for the fight or flight response
 Released by the adrenal glands
 Acts on alpha-1 and 2, beta-1 and 2 receptors
 Acts on beta-2 receptors in skeletal muscle vessels – causing vasodilatation
 Increases cardiac output and total peripheral resistance
 Causes vasoconstriction in the skin and kidneys causing a narrow pulse pressure
 Also causes adrenaline-induced ischemia
 Acts on alpha-adrenergic receptors:
o Inhibits insulin secretion by the pancreas
o Stimulates glycogenolysis in the liver and muscle
o Stimulates glycolysis in muscle
 Actions on beta-adrenergic receptors:
o Stimulates glucagon secretion in the pancreas
o Stimulates ACTH
o Stimulates lipolysis by adipose tissue
 Induces hyperglycemia, hyperlactatemia and hypokalemia
o Insulin secretion is suppressed by alpha adrenergic stimulation, plasma concentration of
insulin remains low
o Hyperglycemia induced by an increase in glucose production caused by an increase in
hepatic glycogenolysis and an increase in gluconeogenesis
o Also marked increase in oxygen consumption
o In skeletal muscle, epinephrine increases glycolysis and glycogenolysis, inducing an
upsurge in lactate  muscular lactate serves as a substrate for hepatic neoglucogenesis
(Cori cycle)
o Epinephrine also increases lipolysis and decreases muscular proteolysis
 Indications:
 o Anaphylaxis
o Cardiac arrest
 10ml of the 1:10,000 preparation contains 1mg of Adrenaline
 Recommend Adult Life Support (ALS) adrenaline doses:
o Anaphylaxis: 0.5ml 1:1000 IM
o Cardiac arrest: 1mg - 10ml 1:10,000 IV or 1ml of 1:1000 IV
 Adrenaline (epinephrine) 1 in 10,000 (100 micrograms/mL) is recommended in a
dose of 1mg (10mL) by intravenous injection repeated every 3-5 minutes if
necessary
 Management of accidental injection  adrenaline-induced ischemia: Local infiltration of
phentolamine
o Phentolamine – a short acting alpha blocker; normally used mainly to control blood
pressure during surgical resection of phaeochromocytoma

DIGOXIN & DIGOXIN TOXICITY

 Digoxin is a cardiac glycoside now mainly used for rate control in the management of atrial
fibrillation
 It has positive inotropic properties – sometimes used for improving symptoms (but not
mortality) in patients with heart failure
 Half-life of digoxin is around 36-48 hours – results in a delay before steady plasma levels are
seen  full effect will not be seen for one week is usually the advice given to patient
 Mechanism of action:
o Decreases conduction through the atrioventricular node which slows the ventricular
rate in atrial fibrillation and flutter
o Increases the force of cardiac muscle contraction due to inhibition of the Na+/K+ ATPase
pump. Also stimulates vagus nerve
o Digoxin has a narrow therapeutic index
 Digoxin toxicity:
o Plasma concentration alone does not determine whether a patient has developed
digoxin toxicity
o BNF advises that the likelihood of toxicity increases progressively from 1.5 to 3mcg/L
o Features:
 Generally unwell, lethargy, nausea & vomiting, anorexia, confusion, yellow-
green vision or xanthopsia
 Arrhythmias (e.g. AV block, bradycardia)
 Gynecomastia
o Precipitating factors:
 Classically: Hypokalemia, which may also worsen digoxin toxicity
 Increasing age
 Renal failure
 Myocardial ischemia
  Hypomagnesemia, hypercalcemia, hypernatremia, acidosis
 Hypoalbuminemia
 Hypothermia
 Hypothyroidism
 Drugs: Amiodarone, quinidine, verapamil, diltiazem, spironolactone (competes
for secretion in distal convoluted tubule therefore reduce excretion), Ciclosporin
 Also drugs which cause hypokalemia – thiazides and loop diuretics
o Management:
 Digibind
 Correct arrhythmias
 Monitor potassium

SIDE-EFFECTS OF COMMON DRUGS: ANTI-ANGINALS

DRUG SIDE-EFFECT
Calcium channel blockers Headache
Flushing
Ankle edema

Verapamil also commonly causes constipation

Beta-blockers Bronchospasm (especially in asthmatics)
Fatigue
Cold peripheries
Sleep disturbances – complaint of having
frequent nightmares with extremely disturbing
and vivid imagery

Bisoprolol can cause constipation, but not as

commonly as Verapamil
Nitrates Headache
Postural hypotension
Tachycardia
Nicorandil Headache
Flushing
Anal ulceration

CALCIUM CHANNEL BLOCKERS

 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
 Examples Indications and notes Side-effects and cautions
Verapamil Angina, hypertension, Heart failure, constipation,
arrhythmias hypotension, bradycardia,
flushing
Highly negative inotropic

Should not be given with beta-

blockers as may cause heart
block
Diltiazem Angina, hypertension Hypotension, bradycardia, heart
failure, ankle swelling
Less negatively inotropic than
verapamil, but caution should
still be exercised when patients
have heart failure or are taking
beta-blockers
Nifedipine, amlodipine, Hypertension, angina, Flushing, headache, ankle
Felodipine (dihydropyridines) Raynaud’s swelling

Affects the peripheral vascular

smooth muscle more than the
myocardium, therefore do not
result in worsening of heart
failure

PHOSPHODIESTERASE TYPE V INHIBITORS

 Used in the treatment of erectile dysfunction

 Also used in the management of pulmonary hypertension
 Examples:
o Sildenafil (Viagra) – this was the first phosphodiesterase type V inhibitor
o Tadalafil (Cialis)
o Vardenafil (Levitra)
 Contraindications:
o Patients taking nitrates and related drugs such as nicorandil
o Hypotension
o Recent stroke or myocardial infarction (NICE recommend waiting 6 months)
o BNF recommends avoiding alpha-blockers for 4 hours after Sildenafil
 Side effects:
o Visual disturbances e.g. blue discolouration, non-arteritic anterior ischemic neuropathy
o Nasal congestion
o Flushing
 o Gastrointestinal side effects
o Headache

DOPAMINE RECEPTOR AGONISTS

 Examples: Bromocriptine, Ropinirole, Cabergoline, Apomorphine

 Indications:
o Parkinson’s disease
o Prolactinoma/ galactorrhea
o Cyclical breast disease
o 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
o If the patient is elderly, L-dopa is sometimes used as an initial treatment
 Ergot-derived dopamine receptor agonists (Bromocriptine, carbegoline, pergolide) have been
associated with pulmonary, retroperitoneal and cardiac fibrosis
o ESR, creatinine and chest x-ray should be obtained prior to treatment and patients
should be closely monitored
 Adverse effects of dopamine receptor agonists:
o Nausea/ vomiting
o Postural hypotension
o Hallucinations
o Daytime somnolence

DRUGS WHICH ACT ON SEROTONIN RECEPTORS

 Act via modulation of the serotonin (5-HT) system

 5-HT receptor agonists are used in the acute treatment of migraine whilst 5-HT receptor
antagonists are used in prophylaxis
 Agonists:
o Sumatriptan is a 5-HT1D receptor agonist which is used in the acute treatment of
migraine
o Ergotamine is a partial agonist of 5-HT1 receptors
 Antagonists:
o Pizotifen is a 5-HT2 receptor antagonists used in the prophylaxis of migraine attacks
o Methysergide is another antagonist of the 5-HT2, but rarely used due to the risk of
retroperitoneal fibrosis
 o Cyproheptadine is a 5-HT2 receptor antagonist which is used to control diarrhea in
patients with carcinoid syndrome
o Ondansetron is a 5-HT3 receptor antagonist and is used as an antiemetic

PHENYTOIN

 Half-life of phenytoin has an average of 14 hours

o Drugs with long half-lives are more likely to accumulate and often need therapeutic drug
monitoring
o Half-life is essential to decide on the appropriate dosing interval
 Phenytoin is metabolized by the liver and excreted in bile as an inactive metabolite
o Phenytoin is minimally renal excreted
o Dose modification is not required for renal dysfunction, even if severe

TAMOXIFEN

 Tamoxifen is a Selective Estrogen Receptor Modulator (SERM) which acts as an estrogen

receptor antagonist and partial agonist
 Used in the management of estrogen receptor positive breast cancer
 Typically used for 5 years following removal of the tumor
 Adverse effects:
o Menstrual disturbance: Vaginal bleeding, amenorrhea
o Hot flushes – 3% of patients stop taking Tamoxifen due to climacteric side-effects
o Venous thromboembolism
o Endometrial cancer
 Although Tamoxifen is antagonistic with respects to breast tissue, may serve as an agonist at
other sites, therefore risk of endometrial cancer is increased
 Raloxifene is a pure estrogen receptor antagonist, and carries a lower risk of endometrial cancer

OCTREOTIDE

 Long-acting analogue of somatostatin

 Somatostatin is released from D cells of pancreas and inhibits the release of growth hormone,
glucagon and insulin
 Known to inhibit hepatic bile secretion and gallbladder emptying leading to biliary stasis and
subsequently an increased risk of developing gallstones
  Potent inhibitor of gastrointestinal secretions, hence it is a first line treatment for carcinoid
syndrome
 Also a potent inhibitor of growth hormone, glucagon and insulin
 Uses:
o Acute treatment of variceal hemorrhage
o Acromegaly
o Carcinoid syndrome
o Prevent complications following pancreatic surgery
o VIPomas
o Refractory diarrhea
 Adverse effects: Gallstones (secondary to biliary stasis)

METFORMIN

 A biguanide used mainly in the treatment of type 2 diabetes mellitus

 It has a number of actions which improves glucose tolerance
 Unlike sulphonylureas, it does not cause hypoglycemia and weight gain and is therefore first-
line, particularly if the patient is overweight
 Also used in polycystic ovarian syndrome and non-alcoholic fatty liver disease
 Mechanism of action:
o Acts by activation of the AMP-activated protein kinase (AMPK) – AMPK is a major
cellular regulator of lipid and glucose metabolism
 Pharmacological activation of AMPK promotes glucose uptake, fatty acid
oxidation, and insulin sensitivity, and also inhibits gluconeogenesis
o Increases insulin sensitivity
o Decreases hepatic gluconeogenesis
o May also reduce gastrointestinal absorption of carbohydrates
 Adverse effects:
o Gastrointestinal upsets are common (nausea, anorexia, diarrhea, bloating), intolerable
in 20%. If patients develop unacceptable side effects then modified-release metformin
should be considered
o Reduced vitamin B12 absorption – rarely a clinical problem
o Lactic acidosis with severe liver disease or renal failure
o Should be stopped following myocardial infarction due to the risk of lactic acidosis; may
be introduced at a later date
 If metformin is not tolerated due to GI side-effects, try a modified-release formulation before
switching to a second-line agent
o Sulphonylurea, Pioglitazone, Sitagliptin could be considered as a second-line agent if
metformin is not tolerated
 Sulphonylureas have the property of increasing endogenous insulin secretion
 Contraindications:
 o Chronic kidney disease: NICE recommend that the dose should be reviewed if the
creatinine is >130 micromol/L (or eGFR <45 ml/min) and stopped if the creatinine is
>150 micromol/L (or eGFR <30 ml/min)
o 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
o 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
o Alcohol abuse is a relative contraindication
 Starting metformin: Should be titrated up slowly to reduce incidence of gastrointestinal side
effects, leave at least 1 week before increasing dose (e.g. Metformin 500mg OD with food for
14 days, then Metformin 500mg BD for 14 days then review)
 If patient is intolerant to standard metformin, then modified-release preparations should be
tried – produce fewer gastrointestinal side-effects in patients intolerant of standard-release
metformin

 Hypoglycemia can occur with use of other diabetic medications, including sulphonylurea and
insulin
 Urinary tract infections and thrush are more common with SGLT2 inhibitors which increase
excretion of glucose in urine
 Swelling of the feet and ankles can occur with thiazolidinediones

OTHER DIABETIC MEDICATIONS

DRUGS MECHANISM OF ACTION

Sulphonylureas (e.g. Act by closing ATP-sensitive K-channels in pancreatic beta cells 
Gliclazide) causes increased insulin secretion
Thiazolidinediones (e.g. PPARγ (gamma) agonists  cause increased insulin sensitivity
Pioglitazone)
Sitagliptin Dipeptidyl peptidase-4 (DPP-4) inhibitor
This enzyme breaks down the incretins GLP-1 and GIP; By preventing
GLP-1 and GIP inactivation, increased insulin is secreted by the
pancreas
Gliflozin (e.g. Dapagliflozin) Inhibits SGLT2 in the kidneys  results in decreased reabsorption of
glucose
SIDE-EFFECTS OF DIABETIC DRUGS

DRUG SIDE EFFECT

Metformin Gastrointestinal side effects
Lactic acidosis
Sulphonylureas – have the property of increasing Hypoglycemic episodes
endogenous insulin secretion Increased appetite and weight gain
Syndrome of inappropriate ADH secretion
(Sulphonylureas, particulary long-acting ones
such as chlorpropamide are well-established
causes of SIADH)
Liver dysfunction (cholestatic)
Glitazones Weight gain
Fluid retention
Decompensation of pre-existing heart failure
Liver dysfunction
Fractures
Gliptins Pancreatitis

HYPERLIPIDEMIA: MECHANISM OF ACTION AND ADVERSE EFFECTS

Concomitant prescription of fibrates with statins causes side-effects in relation to muscle toxicity

DRUGS MECHANISM OF ACTION ADVERSE EFFECTS

Statins HMG CoA reductase inhibitors Myositis, deranged LFTs
Ezetimibe Decreases cholesterol Headache
absorption in the small intestine
Nicotinic acid Decreases hepatic VLDL Flushing, myositis
secretion
Fibrates Agonist of PPAR-alpha therefore Myositis (presents with
increases lipoprotein lipase myalgia), pruritus, cholestasis
expression
Cholestyramine Decreases bile acid GI side-effects
reabsorption in the small
intestinte
Upregulating the amount of
cholesterol that is converted to
bile acid
HEPARIN

 2 main types of heparin – unfractioned, ‘standard’ heparin or low molecular weight heparin
(LMWH)
 Heparins generally act by activating antithrombin III
 Unfractioned 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

STANDARD HEPARIN LOW MOLECULAR WEIGHT

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

 Adverse effects of heparins:

o Bleeding
o Thrombocytopenia
o Osteoporosis and increased risk of fractures
o Hyperkalemia – thought to be caused by inhibition of aldosterone secretion
 Heparin-induced thrombocytopenia (HIT)
o Immune-mediated – antibodies form against complexes of platelet factor 4 (PF4) and
heparin
o These antibodies bind to the PF4-heparin complexes on the platelet surface and induce
platelet activation by cross-linking FcyIIA receptors
o Usually does not develop until after 5-10 days of treatment
o It is actually a prothrombotic condition
o Features: Greater than 50% reduction in platelets, thrombosis and skin allergy
o Treatment: Alternative anticoagulants such as Lepirudin and Danaparoid
o Heparin overdose may be reversed by protamine sulphate, although this only partially
reverses the effect of LMWH
 Current NICE guidelines state that unfractionated heparin (UFH) is the anticoagulant of choice
in patients with severe chronic kidney disease
 o Low molecular weight heparins (LMWHs) have been studied to accumulate in the case
of severe renal impairment
o Warfarin is used for the treatment of venous thromboembolism (VTE), but is not
currently fist line for prophylaxis
o TED stockings should not be used in peripheral arterial disease when the ABPI is less
than 0.8 (or more than 1.3)
o Apixaban is currently licensed for use in VTE prophylaxis following hip/ knee
replacement surgery, however, is recommended to be avoided in eGFR <15ml/min

ALLOPURINOL

 Used in the prevention of gout

 Works by inhibiting xanthine oxidase
o Xanthine oxidase is responsible for the oxidation of 6-mercaptopurine to 6-thiouric acid
 Initiating allopurinol prophylaxis:
o Allopurinol should not be started until 2 weeks after an acute attack has settled
o Initial dose of 100mg OD, with the dose titrated every few weeks to aim for a serum uric acid
of <300 micromol/L
o NSAID or colchicine cover should be used when starting allopurinol
 Indications for allopurinol:
o Recurrent attacks – in uncomplicated gout, uric acid lowering drug therapy should be started
if a second attack, or further attacks occur within 1 year
o Tophi
o Renal disease
o Uric acid renal stones
o Prophylaxis if on cytotoxics or diuretics
o Patients receiving CHOP for non-Hodgkin’s lymphoma are at particular risk of tumor lysis
syndrome and associated gout secondary to hyperuricemia  co-prescribe allopurinol to
reduce risk
o Patients with Lesch-Nyhan syndrome often take allopurinol for life
 Allopurinol should be avoided in patients with mild to moderate chronic kidney disease
 Risk factors for high risk of allopurinol sensitivity: Diuretic use, ethnicity, chronic kidney disease
 Adverse effects – most significant are dermatological:
o Severe cutaneous adverse reaction (SCAR)
o Drug reaction with eosinophilia and systemic symptoms (DRESS)  can result in kidney
failure and death
o 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 allopurinol-induced severe cutaneous adverse reaction
should be screened for the HLA-B *5801 allele
 Interactions:
o Azathioprine
 Metabolized 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
o Cyclophosphamide
 Allopurinol reduces renal clearance, therefore may cause marrow toxicity
o Theophylline
 Allopurinol causes an increase in plasma concentration of theophylline by inhibiting
its breakdown

FINASTERIDE

 An inhibitor of 5 alpha-reductase, an enzyme which metabolises testosterone into

dihydrotestosterone
 Indications:
o Benign prostate hyperplasia
o Male-pattern baldness
 Adverse effects:
o Impotence
o Decrease libido
o Ejaculation disorders
o Gynecomastia and breast tenderness
 Also causes decreased levels of serum prostate specific antigen

ST JOHN’S WORT

 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:
o Profile in trials similar to placebo
o Can cause serotonin syndrome
o Inducer of P450 system – decreased levels of drugs such as warfarin, ciclosporin. The
effectiveness of the combined oral contraceptive pill may also be reduced

MONOCLONAL ANTIBODIES
 Manufactured by a technique called somatic cell hybridization – 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 constant region of the antibody is human in origin
 Main limitation is that mouse antibodies are immunogenic leading to the formation of human
anti-mouse antibodies (HAMAs) – overcome by combining the variable region from the mouse
body with the constant region from an human antibody
 Clinical examples:
o Infliximab (anti-TNF): used in rheumatoid arthritis and Crohn’s
o Rituximab (anti-CD20): used in non-Hodgkin’s lymphoma and rheumatoid arthritis
o Cetuximab (epidermal growth factor receptor antagonist): used in metastatic colorectal
cancer and head and neck cancer
 Example of EGFR inhibitor used in lung cancer would be Erlotinib (Tarceva)
o VEGF inhibitors are vascular endothelial growth factor inhibitors – example:
Bevacizumab – which is used in colorectal cancer
o Trastuzumab (HER2/ neu receptor antagonist): Used in metastatic breast cancer
o Alemtuzumab (anti-CD52): used in chronic lymphocytic leukemia
o Abciximab (glycoprotein IIb/ IIIa receptor antagonist): Prevention of ischemic events in
patients undergoing percutaneous coronary interventions
o OKT3 (anti-CD3): used to prevent organ rejection
o Cedelizumab (anti-CD4 antibody)
o Nivolumab (PD-1 inhibitor) and Ipilimumab (CTLA-4 inhibitor) are checkpoint inhibitors
which are used in the treatment of metastatic melanoma, shows encouraging results in
patients with stage 4 metastatic melanoma and lymphoma
 Effects on the endocrine system are being increasingly reported with prolonged
therapy (hypophysitis and hypothyroidism) – important to assess patient
carefully who present with symptoms of hypothyroidism whilst on these drugs
 PD-1 receptors are found on the surface of T cells. When a T cell is alerted to a
cancer cell, the cancer cell can express the PD-L1 protein – a ligand which binds
to the T cell receptor and deactivates it. It is therefore a mechanism cancer cells
use to evade the immune system and disable T cells
o ALK-1 inhibitors are drugs that act on anaplastic lymphoma kinase (a tyrosine kinase) –
example: Crizotinib
o CTLA-4 (cytotoxic T-lymphocyte associated protein 4) is another immune checkpoint
which down-regulates T cell responses. Blocking this with inhibitors such as Ipilimumab
again activates the immune system against cancer
o Heparin – activates anti-thrombin III
o Prasugel – P2Y12 ADP inhibitor
o Abciximab – glycoprotein IIb/ IIIa inhibitor
o Dabigatran – direct thrombin inhibitor
o Rivaroxaban – direct factor X inhibitor
 Monoclonal antibody also used for:
o Medical imaging when combined with a radioisotope
 o Identification of cell surface markers in biopsied tissue
o Diagnosis of viral infections

TRASTUZUMAB (HERCEPTIN)

 A monoclonal antibody directed against the HER2/neu receptor

 This drug exerts anti-tumor effects by binding to HER2 receptor stopping the activation of
tyrosine kinases
 2 main cancers which overexpress HER2 include breast and gastric adenocarcinoma – up to 30%
of breast cancers and 20% of gastric cancers will overexpress HER2
 Used mainly in metastatic breast cancer, although some patients with early disease are now also
given trastuzumab
 NICE state Trastuzumab in combination with cisplatin and capecitabine or 5-fluorouracil is a
recommended option for HER2 positive metastatic adenocarcinoma of the stomach
 Adverse effects:
o Flu-like symptoms and diarrhea are common
o Cardiotoxicity: more common when anthracyclines have also been used. An echo
usually performed before starting treatment

 VEGFR – A receptor which stimulates angiogenesis; Bevacizumab is a monoclonal antibody

which inhibits this receptor
 Cetuximab – A monoclonal antibody which blocks activations of the HER1 receptor
o Mutations in HER1 (also known as epidermal growth factor receptor/ EGFR) are
associated with colorectal and squamous cell cancers
 Imatinib and Dasatinib – used in the treatment of leukemias; Inhibit PDFGR along with other
receptors
 Overexpression of HER3 – associated with many malignancies including ovarian, breast,
colorectal, squamous cell carcinomas and more

CICLOSPORIN
 Mechanism of action: Decreases IL-2 release by inhibiting calcineurin
 An immunosuppressant which decreases clonal proliferation of T cells by reducing IL-2 release
 Acts by binding to cyclophilin forming a complex which inhibits calcineurin, a phosphatase that
activates various transcription factors in T cells
 Ciclosporin + Tacrolimus: Inhibit calcineurin, thus decreasing IL-2
 Blood pressure monitoring is important in ciclosporin therapy
 Adverse effects of ciclosporin – increase in all: Fluid, BP, K+, hair, gums, glucose
o Nephrotoxicity, hepatotoxicity
o Fluid retention
o Hypertension
o Hyperkalemia
o Hypertrichosis
o Gingival hyperplasia
o Tremor
o Impaired glucose tolerance
o Hyperlipidemia
o Increased susceptibility to severe infection
 Fluconazole inhibits metabolism of ciclosporin which increases the risk of ciclosporin
nephrotoxicity
 For an immunosuppressant, ciclosporin is noted by the BNF to be ‘virtually non-myelotoxic’
 Indications:
o Following organ transplantation
o Rheumatoid arthritis
o Psoriasis (has a direct effect on keratinocytes and modulating T cell function)
o Ulcerative colitis
o Pure red cell aplasia
 Drug monitoring: Trough levels immediately before dose

 Mycophenolate mofetil – inhibits inosine monophosphate dehydrogenase

 Azathioprine – metabolized to the active compound mercaptopurine, a purine analogue that
inhibits DNA synthesis
 Methotrexate – an antimetabolite which inhibits dihydrofolate reductase

 Blood pressure measurement is important in Ciclosporin therapy

 Urinalysis is required for gold and penicillamine (for protein due to the risk of membranous
glomerulonephritis) and cyclophosphamide (for blood due to the risk of hemorrhagic cystitis and
bladder cancer)
 Penicillamine can cause drug-induced lupus
  Therapeutic levels are required for calcineurin inhibitors ciclosporin and tacrolimus

IMMUNOGLOBULINS: THERAPEUTICS

 Uses:
o Primary and secondary immunodeficiency
o Idiopathic thrombocytopenic purpura
 Management of thrombotic thrombocytopenic purpura involves steroids and
immunosuppressants, plasma exchange is also commonly used
o Myasthenia gravis
o Guillain-Barre syndrome
o Kawasaki disease
o Toxic epidermal necrolysis
o Pneumonitis induced by CMV following transplantation
o Low serum IgG levels following hematopoietic stem cell transplant for malignancy
o Dermatomyositis
o Chronic inflammatory demyelinating polyradiculopathy
 Basics:
o Formed from large pool of donors (e.g. 5000)
o IgG molecules with a subclass distribution similar to that of normal blood
o Half-life of 3 weeks

BOTULINUM TOXIN

 As well as the well publicised cosmetic uses of Botulinum toxin (Botox), there are also a number of
licensed indications:
o Blepharospasm – abnormal, involuntary blinking or spasm of the eyelids
o Hemifacial spasm
o Focal spasticity including cerebral palsy patients, hand and wrist disability associated with stroke
o Spasmodic torticollis
o Severe hyperhidrosis of the axillae
o Achalasia
 Botulinum toxin is used therapeutically in achalasia, often in cases where the patient is
not suitable for surgical intervention (for example in some elderly patients)
Botulinum causes flaccid paralysis and is not used in diverticular disease, hemorrhoids, irritable bowel syndrome
or Crohn’s disease

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: Hyoscine > Cyclizine > Promethazine
o BNF recommends hyoscine (e.g. transdermal patch) as being the most effective treatment; Use is
limited due to side-effects
o Non-sedating antihistamines such as cyclizine or cinnarizine are recommended in preference to
sedating preparations such as promethazine

DRUG OVERDOSE/ SUBSTANCE ABUSE

THERAPEUTIC DRUG MONITORING

 Lithium:
o Range = 0.4 – 1.0 mmo/L
o Take 12 hours post dose
 Ciclosporin: Trough levels immediately before dose
 Digoxin: At least 6 hours post dose
 Phenytoin levels:
o Do not need to be monitored routinely
o But trough levels, immediately before dose should be checked if:
 Adjustment of phenytoin dose
 Suspected toxicity
 Detection of non-adherence to the prescribed medication

 Opiates and benzodiazepines are more likely to cause respiratory acidosis through respiratory
depression
o Flumazenil used in benzodiazepine overdose
o Naloxone used in opiate overdose
 Causes of raised anion gap:
o Lactic acidosis
o Ketoacidosis
o Renal failure (high urate)
o Toxins: Methanol, ethylene glycol, salicylates
OVERDOSE AND POISONING: MAIN MANAGEMENT

TOXIN PRESENTATION TREATMENT

Paracetamol  Activated charcoal if ingested <1
hour ago
 N-acetylcysteine (NAC)
 Liver transplantation
Salicylate  Urinary alkalinization is now rarely
used – contraindicated in cerebral
and pulmonary edema with most
units now proceeding straight to
hemodialysis in case of severe
poisoning
 Hemodialysis
Ibuprofen Overdose might present with 
abdominal pain, nausea,
vomiting, drowsiness,
dizziness, headache, ear
ringing and nystagmus
Opioid/ opiates Naloxone
Benzodiazepines Flumazenil

Majority of overdoses are managed with

supportive care only due to the risk of
seizures with flumazenil. Generally only
used with severe or iatrogenic overdoses
Tricyclic  IV bicarbonate may reduce the risk
antidepressants – e.g. of seizure and arrhythmias in
Amitriptylline severe toxicity
(Tricyclic overdose =  Arrhythmias: class 1a (e.g.
dilated pupils + history Quinidine) and class 1c
of depression) antiarrhythmics (e.g. Flecainide)
are contraindicated as they prolong
depolarization
 Class III drugs (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
Lithium  Mild-moderate toxicity may
respond to volume resuscitation
 with normal saline
 Hemodialysis may be needed in
severe toxicity
 Sodium bicarbonate sometimes
used – by increasing alkalinity of
urine, it promotes lithium excretion
Warfarin Vitamin K, prothrombin complex
Heparin Protamine sulphate
Beta-blockers  If bradycardic – Atropine
 In resistant cases – Glucagon
(intravenous) may be used
Ethylene glycol Typically presents with  Ethanol
nausea and vomiting,  Fomepizole
headaches and intoxication  Hemodialysis also has a role in
before seizures refractory cases
Methanol poisoning  Fomepizole or ethanol
 Hemodialysis
Organophosphate  Atropine
insecticides  Role of pralidoxime is still unclear –
meta-analyses to date have failed
to show any clear benefit
Digoxin Digoxin-specific antibody fragments
Iron Desferrioxamine, a chelating agent
Lead More typically presents with Dimercaprol (Used in heavy metal
abdominal pain, constipation poisoning), calcium edetate
and headaches
Carbon monoxide Typically presents with 100% oxygen, Hyperbaric oxygen
headache, dizziness,
weakness, vomiting, chest
pain and confusion
Cyanide Hydroxocobalamin
Also combination of amyl nitrite, sodium
nitrite, and sodium thiosulfate

PARACETAMOL OVERDOSE: METABOLIC PATHWAYS

 Liver normally conjugates paracetamol with glucuronic acid/ sulphate

 During an overdose, the conjugation system becomes saturated leading to oxidation by P450
mixed function oxidases  produces a toxic metabolite (N-acetyl-P-benzoquinone imine)
 Normally glutathione acts as a defence mechanism by conjugating with the toxin forming the
non-toxic mercapturic acid
o If glutathione stores run-out, the toxin forms covalent bonds with cell proteins,
denaturing them and leading to cell death
 o This occurs not only in hepatocytes but also in the renal tubules
 Mechanism:
o The highly toxic metabolite is NAPQI (N-acetyl-p-benzoquinoneimine)
o Methionine can be converted to homocysteine to cysteine and subsequently converted
to glutathione under enzyme action
o In the liver, glutathione conjugates this toxic metabolite to cysteine and mercaptate
compounds which are then excreted in the urine
o When excess paracetamol is ingested, it is metabolized to N-acetyl-P-
benzoquinoneimine which can deplete glutathione
o When glutathione levels are depleted, this NAPQI builds up in the system causing mainly
fulminant liver failure potentially leading to death
 N-acetyl cysteine (antidote to paracetamol overdose) is used in the management of
paracetamol overdose as it is a precursor of glutathione and hence can increase hepatic
glutathione production, thus restoring levels of glutathione
 There is a lower threshold for treating patients who take P450 inducing medications e.g.
phenytoin or rifampicin
 Depletion of glutathione stores occurs in paracetamol toxicity
 Paracetamol overdose well known to cause hepatotoxicity and delayed nephrotoxicity
(especially in significant overdose)

PARACETAMOL OVERDOSE: MANAGEMENT

 Based on 2012 Commision on Human Medicines (CHM) review of paracetamol overdose

management
 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:
o There is a staggered ingestion of a potentially toxic dose of paracetamol (>75mg/kg) (all
tablets were not taken within 1 hour) or there is doubt over the time of paracetamol
ingestion, regardless of the plasma paracetamol concentration
o Plasma paracetamol concentration is on or above a single treatment line joining points
of 100mg/dL at 4 hours and 15mg/L at 15 hours, regardless of risk factors of
hepatotoxicity
 Acetylcysteine should be infused over 1 hour (rather than 15 minutes) to reduce the number of
adverse effects
 Acetylcysteine commonly causes an anaphylactoid reaction (non-IgE mediated mast cell release)
o Anaphylactoid reactions to IV Acetylcysteine are generally treated by stopping the
infusion, then restarting at a slower rate
 If respiratory depression or hypoxia present, justifies use of Naloxone
 King’s College Hospital criteria for liver transplantation (paracetamol liver failure) and markers
of poor prognosis:
o Arterial pH <7.3, 24 hours after ingestion
o Or all of the following:
  Prothrombin time >100 seconds
 Creatinine >300 micromol/L
 Grade III or IV encephalopathy

SALICYLATE OVERDOSE

 Salicylate overdose leads to a mixed respiratory alkalosis and metabolic acidosis – occurs in a
sweaty, confused patient
 Early stimulation of the respiratory centre leads to 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
 Salicylates cause the uncoupling of oxidative phosphorylation leading to decreased adenosine
triphosphate production, increased oxygen consumption and increased carbon dioxide and heat
production = feature of pyrexia
 Features:
o Hyperventilation (centrally stimulates respiration)
o Tinnitus
o Lethargy
o Sweating, pyrexia
o Nausea/vomiting
o Hyperglycemia and hypoglycemia
o Seizures
o Coma
 Treatment:
o General (ABC, charcoal)
o Urinary alkalinization with intravenous sodium bicarbonate – enhances elimination of
aspirin in the urine
o Hemodialysis
 Management:
o Activated charcoal Can bind to aspirin decreasing the absorption – used first-line in
patients who have ingested the drug within one hour
o Alkalinization with sodium bicarbonate increases the urine pH to >7.5 which in turn
increases the excretion of aspirin through this route – commonly used in the treatment
and would likely be used in this case but after activated charcoal is given
o Gastric lavage is rarely used nowadays and only used in specific emergency life-
threatening situations; complications include pulmonary aspiration and laryngospasm
 o Aspirin toxicity can cause dysregulation of glucose – any patients with altered mental
status and low sugars should be given dextrose
o Hemodialysis may be used in the treatment of salicylate poisoning
 Indications for hemodialysis in salicylate overdose:
o Serum concentration >700 mg/L
o Metabolic acidosis resistant to treatment
o Acute renal failure
o Pulmonary edema – suggests severe poisoning  indication for hemodialysis
o Seizures
o Coma

METHANOL POISONING

 Causes both the effects associated with alcohol (intoxication, nausea etc.) and also specific
visual disturbance, including blindness
 These effects are thought to be secondary to the accumulation of formic acid
 Actual pathophysiology of methanol-associated visual loss not fully understood but it is thought
to be caused by a form of optic neuropathy – accumulation of formic acid in the optic nerve
causing visual disturbance and eventually blindness
 Causes raised anion-gap metabolic acidosis – the other differential diagnosis is ethylene glycol
poisoning, also causes a very similar biochemical and clinical picture
 Finding of eye signs (macular oedema and poor pupillary responses) in the context of a drowsy
patient with raised anion gap metabolic acidosis is strongly suggestive that methanol is the
culprit
o In exams, cases involving methanol toxicity often involve patients not meeting your gaze
or asking for the lights to be switched on, as well as the more traditional visual acuity
results
o Indicated by symptoms of reduced vision and poorly reactive pupils
o Alcohol and eythlene glycol would not produce the visual changes
 Management:
o Fomepizole or ethanol
 Fomepizole is a competitive inhibitor of the enzyme alcohol dehydrogenase
and can be used to treat methanol and ethylene glycol toxicity
o Hemodialysis

ETHYLENE GLYCOL TOXICITY

 Ethylene glycol is a type of alcohol used as a coolant or antifreeze

 Features of toxicity are divided into 3 stages:
 o Stage 1: Symptoms similar to alcohol intoxication – confusion, slurred speech, dizziness
o Stage 2: Metabolic acidosis with high anion gap and high osmolar gap, tachycardia,
hypertension
o Stage 3: Acute renal failure
 Management:
o Ethanol (oral or parenteral) – works by competing with ethylene glycol for the enzyme
alcohol dehydrogenase, also limits formation of toxic metabolites (glycoaldehyde and
glycolic acid) which are responsible for the hemodynamic/ metabolic features of
poisoning
o Fomepizole – an inhibitor of alcohol dehydrogenase, is now used first-line in preference
to ethanol
o Hemodialysis also has a role in refractory cases

LITHIUM TOXICITY

 Lithium is mood stabilizing drug used most commonly prophylactic in bipolar disorder, also as an
adjunct in refractory depression
 Has a very narrow therapeutic range (0.4 – 1.0 mmol/L) and a long plasma half-life bring
excreted primarily by the kidneys
 Lithium toxicity generally occurs following concentrations >1.5 mmol/L
 Toxicity may be precipitated by dehydration, renal failure, diuretics (especially
bendroflumethiazide), ACE inhibitors (Ramipril), angiotensin II receptor antagonists, NSAIDs
and metronidazole
o BNF advises that neurotoxicity may be increased when lithium is given with diltiazem or
verapamil, but there is no significant interaction with Amlodipine
 Lithium: Fine tremor in chronic treatment; Coarse tremor in acute toxicity
 Features of toxicity:
o Coarse tremor (a fine tremor seen in therapeutic levels)
o Hyperreflexia
o Acute confusion
o Seizure
o Coma
 Management:
o Mild-moderate toxicity (non-specific signs of toxicity, such as apathy and restlessness)
may respond to volume resuscitation with intravenous 0.9% normal saline
o Hemodialysis may be needed in severe toxicity
o Sodium bicarbonate sometimes used but there is limited evidence to support this – by
increasing the alkalinity of the urine, it promotes lithium excretion (alone it would not
be used in this case without the ultimate management step which is hemodialysis)
 Both sodium bicarbonate and aminophylline may reduce plasma concentrations of lithium;
Sodium valproate not listed in the BNF as interacting with lithium
ORGANOPHOSPHATE INSECTICIDE POISONING

 One of the effects 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
o Sarin gas is a highly toxic synthetic organophosphorus compound which causes
inhibition of the enzyme acetylcholinesterase – results in high levels of acetylcholine
(ACh)
 Features can be predicted by the accumulation of acetylcholine (mnemonic = DUMBELLS):
o Defecation/ diarrhea
o Urination
o Miosis/ muscle weakness
o Bronchorrhea/ Bradycardia
o Emesis
o Lacrimation
o Salivation
o Cardiovascular: hypotension, bradycardia
 Management:
o Atropine (anti-muscarinic)
o The role of Pralidoxime is still unclear – meta-analyses to date have failed to show any
clear benefit

NOVEL PSYCHOACTIVE SUBSTANCES

 The medical term for the many new substances which are chemically related to established
recreational drugs such as MDMA and cannabis
1. Stimulants
 Similar to MDMA, amphetamines and cocaine
 Resulting in increased levels of serotonin, dopamine and noradrenaline, resulting in a
‘high’ and feeling of euphoria
 Common example: Stimulant NPS – Mephedrone (‘bath salts’, ‘M-CAT’, ‘meow meow’),
a cathinone and structurally similar to khat, a plant found in East Africa
 Another example: Benzylpiperazine (‘Exodus’, ‘Legal X’, ‘Legal E’)
 Typically swallowed as a pill/ powder (‘bombing’) or snorted
 Adverse effect similar to MDMA/ cocaine, with risk of serotonin syndrome
2. 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
3. Hallucinogens
 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
4. Depressant
 Can be either opioid or benzodiazepine-based
 Usually taken as a pill or powder
 Often structurally very similar to the original drug class, hence adverse effects are
similar
 Benzodiazepines NPS often have a significantly longer half-life
5. Other substances include:
 Gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL): ‘G’, ‘Geebs’ or
‘Liquid Ecstasy’
 GHB causes respiratory depression
o When taken with other respiratory depressants, most commonly alcohol, this
can be potentially life threatening
 Nitrous oxide: ‘Hippie crack’

ECSTASY POISONING

 Ecstasy (MDMA, 3,4-Methylenedioxymethamphetamine) use became popular in the 1990’s

during the emergence of dance music culture
 Presents similarly to cocaine, with increased psychomotor agitation, palpitations and
hyperthermia
 Additionally, teeth grinding (bruxism) is noted frequently
 Clinical features:
o Neurological: agitation, anxiety, confusion, ataxia
o Cardiovascular: Tachycardia, hypertension
o Hyponatremia – Ecstasy is thought to stimulate the production of anti-diuretic
hormone, thus users of ecstasy also commonly drink too much water in the (mistaken)
belief that this will protect them from the adverse effects
o Hyperthermia
o Rhabdomyolysis
 Management – Supportive; Dantrolene may be used for hyperthermia if simple measures fail

COCAINE
 Cocaine is an alkaloid derived from the coca plant
 It is widely used as a recreational stimulant
 Mechanism of action: Cocaine blocks the uptake of dopamine, noradrenaline and serotonin 
produces sympathetic effects – agitation, restlessness, increased heart rate and blood pressure
 Adverse effects:
1. Cardiovascular effects
 Myocardial infarction
 Both tachycardia and bradycardia may occur
 Hypertension
 QRS widening and QT prolongation
 Aortic dissection
2. Neurological effects
 Seizures
 Mydriasis
 Hypertonia
 Hyperreflexia
3. Psychiatric effects
 Agitation
 Psychosis
 Hallucinations
4. Others:
 Ischemic colitis is recognized in patients following cocaine ingestion – should
be considered if patients complain of abdominal pain or rectal bleeding
 Hyperthermia
 Metabolic acidosis
 Rhabdomyolysis
5. Can induce preterm labour
 Cocaine is a sympathomimetic drug; Its use during pregnancy can result in pre-
term labour (<37 weeks gestation), congenital anomalies, and intrauterine
growth retardation (IUGR)
 Cocaine can initiate uterine contractions, and therefore the most likely agent to
predispose to pre-term labour
 In severe toxicity, hyperthermia and rhabdomyolysis may occur
 Will not cause reduced GCS or altered QRS duration on ECG
 Management of cocaine toxicity:
o In general, benzodiazepines are generally first-line for most cocaine related problems
o Chest pain: Benzodiazepines + glyceryl trinitrate; Benzodiazepines thought to temper
the systemic effects of cocaine
 If myocardial infarction develops then primary percutaneous coronary
intervention
o Hypertension: Benzodiazepines + sodium nitroprusside
o 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)
TRICYCLIC OVERDOSE

 Overdose of tricyclic antidepressants is a common presentation to emergency departments

 Amitriptyline and dosulepin (dothiepin) are particularly dangerous in overdose
 Main effect of tricyclic antidepressant (TCAs) is to increase serotonin and noradrenaline in the
brain by slowing re-uptake, they also block histamine, cholinergic and alpha-1 receptors
 Early features relate to anticholinergic properties: dry mouth, dilated pupils, agitation, sinus
tachycardia, urinary retention, blurred vision
 Divergent pupils are common finding in tricyclic overdose
 TCAs are also cardiotoxic by inactivating sodium channels in the heart leading to a potential
prolongation of the QTc interval and a widened QRS complex  potentially lead to ventricular
arrhythmias
 Features of severe poisoning include:
o Arrhythmias
o Seizures
o Metabolic acidosis
o Coma
 ECG changes include:
o Sinus tachycardia
o Widening of QRS
 Widening of QRS >100ms is associated with an increased risk of seizures
 QRS >160ms is associated with ventricular arrhythmias
o Prolongation of QT interval
 Management:
o IV bicarbonate – may reduce the risk of seizures and arrhythmias in severe toxicity;
Standard initial therapy for patients who develop cardiotoxicity (usually a QRS >
100ms or a ventricular arrhythmia) as a result of tricyclic antidepressant (TCA)
overdose
o Arrhythmias:
 Class 1a (e.g. Quinidine) and class 1c antiarrhythmics (e.g. Flecainide) are
contraindicated as they prolong depolarization
 Class III drugs such as Amiodarone should also be avoided as they prolong the
QT interval
 Response to Lignocaine is variable
 Should be emphasized that correction of acidosis is the first line in
management of tricyclic induced arrhythmias
o Intravenous lipid emulsion is increasingly used to bind free drug and reduce toxicity – an
emerging therapy for overdose of lipophilic compounds, also have a role in overdoses of
verapamil, beta-blockers and some TCAs
o Intravenous magnesium sulphate can be used as a second-line agent in refractory
arrhythmias
 o Dialysis is ineffective in removing tricyclics

SEROTONIN SYNDROME

 In overdose sertraline (SSRIs) may present with serotonin syndrome

o Combination of 2 or more serotonergic medications greatly increases the risk
 Causes:
o Monoamine oxidase inhibitors
o SSRIs
o Ecstasy
o Amphetamines
 Glasgow coma scale may be reduced, pupils dilated, but skin would not be dry
 Classic feature of serotonin syndrome is hyperreflexia, often with muscle rigidity and tremor
 Features:
o Neuromuscular excitation (e.g. hyperreflexia, myoclonus, rigidity)
o Autonomic nervous system excitation (e.g. hyperthermia)
o Altered mental state
 QTc prolongation is unlikely with selective serotonin reuptake inhibitors (Citalopram is an
exception)
 Management:
o Supportive including IV fluids
o Benzodiazepines
o More severe cases are managed using serotonin antagonists such as cyproheptadine
and chlorpromazine
 Cyproheptadine – an H1 and non-specific 5HT antagonist

SEROTONIN SYNDROME NEUROLEPTIC MALIGNANT SYNDROME

Caused by SSRIs, MAOIs, ecstasy/ novel Caused by antipsychotics
psychoactive stimulants
Faster onset (hours) Slower onset (hours – days)
Increased reflexes, clonus decreased reflexes, ‘lead-pipe’ rigidity
Dilated pupils normal pupils
Management of severe cases: Cyproheptadine, Management of severe cases: Dantrolene
Chlorpromazine
‘Drug’ reaction – often young patients
Tachycardia, increased BP
Pyrexia, diaphoresis
Rigidity, increased CK (both can cause raised CK, tends to be more associated with NMS)
IV fluids, Benzodiazepines
DIAZEPAM INGESTION

 Could cause reduced GCS due to sedative effects

 Would not generally affect pupil size, heart rate or ECG
 Associated with respiratory depression

CYANIDE POISONING

 Cyanide may be used in insecticides, photograph development and the production of certain
metals
 Fires involving the burning of plastics can result in cyanide toxicity
 Cyanide ions inhibit mitochondrial cytochrome oxidase, preventing aerobic respiration. This
manifests in normal oxygen saturations, a high pO2 and flushing (or ‘brick red’ skin) brought on
by the excess oxygenation of venous blood
 Inhibits the enzyme cytochrome c oxidase – resulting in cessation of the mitochondrial electron
transfer chain, causing histotoxic hypoxia because the cells of an organism are unable to create
ATP
 Presentation:
o ‘classical’ features: Brick-red skin, smell of bitter almonds
o Acute: hypoxia, hypotension, headache, confusion
o Chronic: ataxia, peripheral neuropathy, dermatitis
 Blood gas shows increased anion gap, with high venous PO2 consistent with high lactate
(generated by anaerobic respiration due to inability to use available oxygen)
 Management:
o Supportive measures: 100% oxygen
o Definitive: Hydroxocobalamin (intravenously) – has the best side effect profile and
speed of onset, also combination of amyl nitrate (inhaled), sodium nitrite
(intravenously), and sodium thiosulfate (intravenously)
o The other recommended treatment for moderate cyanide toxicity in the UK: Sodium
thiosulfate, Dicobalt edetate

CARBON MONOXIDE POISONING

 Carbon monoxide has high affinity for hemoglobin 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
  Questions may hint at badly maintained housing e.g. student houses
 Cherry red skin is a sign of severe toxicity and is usually seen post-mortem
 Features of carbon monoxide toxicity:
o Headache: 90% of cases (most common presentation)
o Nausea and vomiting: 50%
o Vertigo: 50%
o Confusion: 30%
o Subjective weakness: 20%
o Severe toxicity: ‘pink’ skin and mucosa, hyperpyrexia, arrhythmias, extrapyramidal
features, coma, death
 Carboxyhemoglobinemia is a feature of carbon monoxide poisoning – Exposure to small
concentrations of CO hinder the ability of Hb to deliver oxygen to the body, because
carboxyhemoglobin forms more readily than oxygemoglobin
 Typical carboxyhemoglobin levels:
o <3% non-smokers
o <10% smokers
 Heavy smokers may have carboxyhemoglobin concentration of 10-15%
o 10-30% symptomatic: Headache, vomiting
o >30% severe toxicity
 Management:
o 100% oxygen
o Hyperbaric oxygen – Indications:
 Loss of consciousness at any point
 Neurological signs other than headache, extrapyramidal features
 Myocardial ischemia or arrhythmia
 Pregnancy

MERCURY POISONING

 Commonest cause of mercury poisoning is ingestion via foodstuffs – in particular fish and whale
 Can cause visual field defects, hearing loss and paraesthesia
 Features:
o Paraesthesia
o Visual field defects
o Hearing loss
o Irritability
o Renal tubular acidosis

CAUSTIC SUBSTANCE INGESTION

 Caustic (corrosive) substance ingestion is a common emergency department presentation in
adults and children
 Majority of cases are accidental exposures to household products
 Significant morbidity can occur when the substance is consumed in larger quantities with
intention of deliberate self-harm
 Types of substance – vital to obtain bottle/label if possible:
o Oxidizing agents e.g., hydrogen peroxide, sodium hypochlorite (found in household
bleach)
o Strong alkali e.g., sodium hydroxide, potassium hydroxide (found in dishwasher cleaner,
industrial cleaners)  liquefactive necrosis, more commonly resulting in esophageal
injury
o Strong acid, e.g., hydrochloric, nitric acid (found in car batteries, WC cleaner) 
coagulative necrosis, more commonly resulting in gastric injury
 Acute management:
o ABCDE approach, particular caution to airway swelling and compromised, look for peri-
oral edema
o Urgent upper GI surgical referral if signs of perforation present (surgical emphysema,
mediastinal widening on chest x-ray)
o Neutralization of ingested substance (e.g. with milk) should be avoided as the resulting
exothermic reaction will release heat and may cause further injury
o High dose IV PPI
o 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
 Early endoscopy, ideally within 12 hours (sometimes 24 hours dependent on
local guidance)
 However, most guidelines advocate avoiding endoscopy between days 5 and 15
post ingestion when esophageal strength is at its lowest
o Asymptomatic ingestion can usually be discharged after a trial of oral fluid and a period
of observation
o Nasogastric tube insertion involves potential re-exposure of the upper GI tract to the
substance and is therefore not advisable
 Complications:
o Acute:
 Upper GI ulceration, perforation
 Upper airway injury and compromise
 Aspiration pneumonitis
 Infection
 Electrolyte disturbance (e.g. hypocalcemia in hydrofluoric acid ingestion)
o Chronic:
 Strictures, fistulae, gastric outlet obstruction
 Upper GI carcinoma (estimated 1000-3000 fold increased risk)
ALCOHOL – PROBLEM DRINKING: MANAGEMENT

 Ethanol – Reduces the calcium-dependent secretion of anti-diuretic hormone (ADH) by blocking

channels in the neurohypophyseal nerve terminal
 Nausea associated with hangovers is mainly due to vagal stimulation to the vomiting centre
 Following a particular severe episode of alcohol excess people may experience tremors – due to
increased glutamate production by neurons to compensate for the previous inhibition by
ethanol
 Nutritional support – SIGN recommends alcoholic patient should receive oral thiamine if their
‘diet may be deficient’
 Drugs used:
o Benzodiazepines – for acute withdrawal
o 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,
food, mouthwashes) can produce severe symptoms
 Contraindications include ischemic heart disease and psychosis
o Acamprosate: Reduces craving, known to be a weak antagonist of NMDA receptors,
improves abstinence in placebo controlled trials

BETA-BLOCKER OVERDOSE

 Features:
o Bradycardia
o Hypotension
o Heart failure
o Syncope
 Management:
o If bradycardic, then Atropine
o In resistant cases, Glucagon may be used – Glucagon has a positive inotropic action on
the heart and decreases renal vascular resistance
o Cardiac pacing should be reserved for patients unresponsive to pharmacological therapy
 Hemodialysis is not effective in beta-blocker overdose
PRESCRIBING IN PATIENTS WITH RENAL FAILURE

 Drugs to avoid in renal failure

o Antibiotics: Tetracycline, Nitrofurantoin
o NSAIDs
o Lithium
o Metformin
 Drugs likely to accumulate in chronic kidney disease – need dose adjustment
o Most antibiotics including penicillins, cephalosporins, vancomycin, gentamicin,
streptomycin
o Digoxin, atenolol
o Methotrexate
o Sulphonylureas
o Furosemide
o Opioids
 Active metabolites of morphine accumulate in renal failure which means that long-term use is
contraindicated in patients with moderate/severe renal failure
o These toxic metabolites can accumulate causing toxicity and risk overdose
o Oxycodone – main metabolized in the liver, thus safer to use in patients with
moderate to end-stage renal failure with dose reductions
 Drugs relatively safe – can sometimes use normal drugs depending on the degree of chronic
kidney disease
o Antibiotics: Erythromycin, Rifampicin
o Diazepam
o Warfarin

HEMODIALYSIS IN OVERDOSE

 Drugs that can be cleared with hemodialysis – mnemonic: BLAST

o Barbiturate
o Lithium
 o Alcohol (including methanol, ethylene glycol)
o Salicylates
o Theophyllines (charcoal hemoperfusion is preferable)
 Drugs which cannot be cleared with hemodialysis include:
o Tricyclics
o Benzodiazepines
o Dextropropoxyphene (Co-proxamol)
o Digoxin
o Beta-blockers

PRESCRIBING IN PREGNANT PATIENTS

 Antibiotics:
o Tetracyclines
o Aminoglycosides
o Sulphonamides and trimethoprim
o Quinolones: BNF advises to avoid due to arthropathy in some animal studies
 Other drugs:
o ACE inhibitors – e.g. Lisinopril (are known teratogens), angiotensin II receptor
antagonists
o Statins – Simvastatin contraindicated in pregnancy and must be stopped immediately
o Warfarin
o Sulfonylureas
o Retinoids (including topical)
o Cytotoxic agents
 Majority of antiepileptics including valproate, carbamazepine and phenytoin are known to be
potentially harmful; difficult to stop these medications as uncontrolled epilepsy is also at risk

COMBINED ORAL CONTRACEPTIVE PILLS: CONTRAINDICATIONS

 Decision whether to start a woman 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
o UKMEC 1: A condition for which there is no restriction for the use of the contraceptive
method
o UKMEC 2: Advantages generally outweigh the disadvantages
o UKMEC 3: Disadvantages generally outweigh the advantages
o UKMEC 4: Represents an unacceptable health risk
 Examples of UKMEC 3 conditions:
o More than 35 years old and smoking less than 15 cigarettes/ day
o BMI >35 kg/m2
o Family history of thromboembolic disease in first degree relatives <45 years
 o Controlled hypertension
o Immobility e.g. wheelchair use
o Carrier of known gene mutations associated with breast cancer (e.g. BRCA1/ BRCA2)
 Examples of UKMEC 4 conditions:
o More than 35 years old and smoking more than 15 cigarettes/ day
o Migraine with aura
o History of thromboembolic disease or thrombogenic mutation
o History of stroke or ischemic heart disease
o Breast feeding <6 weeks post-partum
o Uncontrolled hypertension
o Current breast cancer
o Major surgery with prolonged immobilization
 Diabetes mellitus diagnosed >20 years ago is classified as UKMEC 3 or 4 depending on severity
 Changes in 2016: Breastfeeding 6 weeks – 6 months postpartum was changed from UKMEC 32

COMBINED ORAL CONTRACEPTIVE PILL: ADVANTAGES/ DISADVANTAGES

 Advantages of combined oral contraceptive pill:

o Highly effective (failure rate <1 per 100 woman years)
o Does not interfere with sex
o Contraceptive effects reversible upon stopping
o Usually makes periods regular, lighter and less painful
o Reduced risk of ovarian, endometrial cancer – this effect may last for several decades
after cessation
o Reduced risk of colorectal cancer
o May protect against pelvic inflammatory disease
o May reduce ovarian cysts, benign breast disease, acne vulgaris
 Disadvantages of combined OCP:
o People may forget to take it
o Offers no protection against sexually transmitted infections
o Increased risk of venous thromboembolic disease
o Increased risk of breast and cervical cancer
 In women with known breast cancer mutations such as BRCA1, the risk may
exceed the benefit, and women with current breast cancer should not take the
combined oral contraceptive pill
 There is a small increase in cervical cancer risk after 5 years of use of the
combined oral contraceptive pill and this increase to a 2-fold risk after 10 years
o Increased risk of stroke and ischemic heart disease (especially in smokers)
o Temporary side effects may be seen: Headache, nausea, breast tenderness

COMBINED ORAL CONTRACEPTIVE PILL: SPECIAL SITUATIONS

  Concurrent antibiotic use:
o Concurrent use of antibiotics may interfere with the enterohepatic circulation of
estrogen and thus make the combined oral contraceptive pill ineffective – ‘extra-
precautions’ were advised for the duration of antibiotic treatment and for 7 days
afterwards
o If the absorptive ability of the gut is compromised for reasons such as severe diarrhea or
vomiting, or bowel disease, this may affect the efficacy of the pill
o Precautions should still be taken with enzyme-inducing antibiotics such as Rifampicin,
Rifaximin, Phenytoin, Phenobarbital, Carbamazepine, or St John’s Wort
 Switching combined oral contraceptive pills:
o BNF and Faculty of Sexual and Reproductive Healthcare (FSRH) appear to give
contradictory advice
o BNF advises missing the pill free interval if the progesterone changes
 Others:
o Combined pill often prescribed for women with heavy periods as it can make them
lighter and less painful
o No evidence that women on combined pill put on any significant weight, although they
may experience bloating at certain times in the course
o Women on pill require monitoring of their blood pressure
o There are multiple different types of combined pill

PROGESTOGEN ONLY PILL: ADVANTAGES/ DISADVANTAGES

 Advantages:
o Highly effective (failure rate = 1 per 100 woman years)
o Does not interfere with sex
o Contraceptive effects reversible upon stopping
o Can be used whilst breastfeeding
o 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:
o Irregular periods: Some users may not have periods whilst others may have irregular or
light periods. This is the most common adverse effect
o Does not protect against sexually transmitted infections
o Increased incidence of functional ovarian cysts
o Common side-effects: Breast tenderness, weight gain, acne and headaches – these
symptoms generally subside after the first few months
 ADVERSE EFFECTS OF MEDICATIONS

DRUG CAUSES OF URTICARIA

 Penicillin – the most common antibiotic that can cause urticarial

 Aspirin
 NSAIDs
 Opiates

DRUGS CAUSING PHOTOSENSITIVITY

Causes of drug-induced photosensitivity – rash on forearms and the face:

 Thiazides (Furosemide does not usually cause photosensitivity)

 Tetracyclines, sulphonamides, ciprofloxacin
 Amiodarone
 NSAIDs e.g. Piroxicam
 Psoralens
 Sulphonylureas

DRUG-INDUCED THROMBOCYTOPENIA (probably immune mediated)

 Quinine
 Abciximab
 NSAIDs e.g. Ibuprofen
  Diuretics: Furosemide
 Antibiotics: Penicillins, sulphonamides, Rifampicin
 Anticonvulsants: Carbamazepine, Valproate
 Heparin

DRUG CAUSES OF AGRANULOCYTOSIS

 Antithyroid drugs – Carbimazole, Propylthiouracil

 Antipsychotics – atypical antipsychotics (CLOZAPINE)
 Antiepileptics – Carbamazepine
 Antibiotics – Penicillin, Chloramphenicol, Co-trimoxazole
 Antidepressant – Mirtazapine
 Cytotoxic drugs - Methotrexate

OCULOGYRIC CRISIS

 A dystonic reaction to certain drugs or medical conditions, in particular neuroleptics and

dopaminergic medications (classically metoclopramide and haloperidol)
 Features:
o Restlessness, agitation
o Prolonged involuntary upward deviation of the eyes (bilateral elevation of the visual
gaze) of the eyes
 Causes:
o Antipsychotics
o Metoclopramide
o Postencephalitic Parkinson’s disease
 Management: Intravenous antimuscarinic – Procyclidine (Benztropine and Diphenhydramine are
alternative options)

DRUGS CAUSING OCULAR PROBLEMS

 Cataracts: Steroids
 Corneal opacities:
o Amiodarone
o Indomethacin
 Optic neuritis:
o Ethambutol – can cause optic neuritis, but corneal opacification is unusual
 o Amiodarone – known to cause corneal opacification
o Metronidazole
 Retinopathy: Chloroquine, Quinine
o Patients on long-term hydroxychloroquine require annual eye assessments as there is a
risk of retinopathy
o Other important drug causes of retinopathy: Ethambutol, Vigabatrin, Amiodarone
 Sildenafil can cause both blue-tinted vision/ cyanopsia and non-arteritic anterior ischemic
neuropathy
 Yellow-green vision: Digoxin

HYPOMAGNESEMIA

 Cause of low magnesium:

o Diuretics – e.g. Frusemide
 Both loop and thiazide diuretics inhibit resorption of magnesium in the kidney
 Potassium-sparing diuretics such as Spironolactone are not associated with
hypomagnesemia
o Total parenteral nutrition
o Diarrhea
o Alcohol
o Hypokalemia, hypocalcemia
o Conditions causing diarrhea: Crohn’s, ulcerative colitis
o Metabolic disorders: Gittleman’s and Bartter’s
o Protein pump inhibitors such as Omeprazole are associated with low magnesium levels
when taken in conjunction with loop or thiazide diuretics but are not independently
associated with hypomagnesemia

 Features:
o Paraesthesia, tetany
o Seizures
o Arrhythmias
o Decreased PTH secretion  hypocalcemia
o ECG features: QT prolongation (similar to those of hypokalemia)
o Exacerbates digoxin toxicity
 Treatment:
o <0.4 mmol/L: Intravenous replacement commonly given. An example regime would be
40mmol of magnesium sulphate over 24 hours
o >0.4 mmol/L:
 Oral magnesium salts (10-20 mmol orally per day)
 Diarrhea can occur with oral magnesium salts
  Magnesium salts can be given as laxatives
 Other uses: Polymorphic ventricular tachycardia (torsade de pointes),
acute asthma, prevention/ treatment of seizures in pre-eclampsia

DRUG-INDUCED IMPAIRED GLUCOSE TOLERANCE

 Drugs which are known to cause impaired glucose tolerance include:

o Thiazides, furosemide (less common)
o Steroids
o Tacrolimus, ciclosporin
o Interferon-alpha
o Nicotinic acid
o Antipsychotics
 Beta-blockers cause a slight impairment of glucose tolerance
o They should also be used with caution in diabetics as they can interfere with the
metabolic and autonomic responses to hypoglycemia

ECG CHANGES – CAUSES

 QT prolongation: Hypomagnesemia, Sotalol, Amiodarone, Tricyclic antidepressants, Chloroquine

 QT shortening: Hypercalcemia, congenital QT syndrome, Digoxin
 T- wave inversion: More typically seen with coronary ischemia or left ventricular hypertrophy
 Peaked T-waves: More typically seen with hypercalcemia

DRUGS CAUSING LUNG FIBROSIS

 Causes:
o Amiodarone
o Cytotoxic agents: Busulphan, Bleomycin
o Anti-rheumatoid drugs: Methotrexate, Sulfasalazine, Gold
o Nitrofurantoin
o Ergot-derived dopamine receptor agonists: Bromocriptine, Cabergoline, Pergolide

NITROFURANTOIN-INDUCED PNEUMONITIS
  Can be split into acute, subacute, and or chronic
 Chronic nitrofurantoin-induced pneumonitis tends to be suffered by the elderly
 Patients need to be monitored for pulmonary complications with the antibiotic, and if present,
discontinue use if deterioration arises
 Other drugs that can cause pulmonary fibrosis: Bleomyxin, Cyclophosphamide, Amiodarone,
Penicillamine

DRUG-INDUCED URINARY RETENTION

 The following drugs may cause urinary retention:

o Tricyclic antidepressants
o Anticholinergics – e.g. Amitriptyline – causes urinary retention through its
anticholinergic activity
o Opioids
o NSAIDs
o Disopyramide

ACUTE INTERMITTENT PORPHYRIA – DRUGS

 Acute intermittent porphyria is an autosomal dominant condition caused by a defect in

porphobilinogen deaminase, an enzyme involved in the biosynthesis of haem
 Characteristically presents with abdominal and neuropsychiatric symptoms in 20-40 year old
 AIP more common in females (5:1)
 Drugs which may precipitate attack:
o Barbiturates – e.g. Thiopentone, Phenobarbitone, Primidone
o Halothane
o Benzodiazepines e.g. Diazepam
o Chloral hydrate
o Alcohol
o Oral contraceptive pill
o Sulphonamides
 Drugs considered safe to use:
o Paracetamol
o Aspirin, codeine
o Morphine
 o Chlorpromazine – safe to use as sedative drug in patients presented with acute
psychosis
o Beta-blockers
o Penicillin
o Metformin

TERATOGENS

 Cocaine is a sympathomimetic drug – its use in pregnancy can result in pre-term labour (<37
weeks gestation), congenital anomalies, and intrauterine growth retardation (IUGR)
o Can initiate uterine contractions, therefore most likely agent to predispose to pre-term
labour

Drug/condition Effect
ACE inhibitors Renal dysgenesis
Craniofacial abnormalities
Alcohol Craniofacial abnormalities
Aminoglycosides Ototoxicity
Carbamazepine Neural tube defects
Craniofacial abnormalities
Chloramphenicol ‘Grey baby’ syndrome
Cocaine Intrauterine growth retardation
Preterm labour
Diethylstilbesterol Vaginal clear cell adenocarcinoma
Lithium Ebstein’s anomaly (atrialized right ventricle)
Maternal diabetes mellitus Macrosomia
Neural tube defects
Polyhydramnios
Preterm labour
Caudal regression syndrome
Smoking Preterm labour
Intrauterine growth retardation
Tetracyclines Discoloured teeth
Thalidomide Limb reduction defects
Valproate Neural tube defects
Craniofacial abnormalities
Warfarin Craniofacial abnormalities