[Book review] The Top 100 Drugs Clinical pharmacology and practical prescribing 2E

The Top 100 Drugs

Clinical pharmacology and practical prescribing

Second Edition

By A. Hitchings, D. Lonsdale, D. Burrage, E. Baker.

2019

Link: First edition

After ruining my copy of the first edition of this book, I decided to treat myself to the second edition. Although the list still contains 100 drugs (plus 5 fluids), the selection of featured drugs has been revised. 11 drugs were added, so 11 drugs were removed.

The top 100 drugs

The top 100 drugs listed by indication

The top 100 drugs listed by system

Pharmacological treatment of heart failure with reduced ejection fraction

Topic: Heart failure

• Mineralocorticoid antagonists (MRAs)
• Angiotensin receptor blockers (ARBs)
• Angiotensin-converting enzyme inhibitors (ACE-I) 
• Angiotensin receptor–neprilysin inhibitors (ARNIs)
• Sacubitril/valsartan
• Beta-blockers
• Digoxin
• Diuretics, loop
• I_f  channel blockers
• Ivabradine
• Omega-3 polyunsaturated fatty acids (N-3PUFAs) 
• Vasodilators
• Hydralazine
• Isosorbide dinitrate

References

1. Piotr Ponikowski, Adriaan A Voors, Stefan D Anker, Héctor Bueno, John G F Cleland, Andrew J S Coats, Volkmar Falk, José Ramón González-Juanatey, Veli-Pekka Harjola, Ewa A Jankowska, Mariell Jessup, Cecilia Linde, Petros Nihoyannopoulos, John T Parissis, Burkert Pieske, Jillian P Riley, Giuseppe M C Rosano, Luis M Ruilope, Frank Ruschitzka, Frans H Rutten, Peter van der Meer, ESC Scientific Document Group, 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)
   Developed with the special contribution of the Heart Failure Association (HFA) of the ESC, European Heart Journal, Volume 37, Issue 27, 14 July 2016, Pages 2129–2200, https://doi.org/10.1093/eurheartj/ehw128

[Clinical pharmacology] Introduction

Clinical pharmacologists specialise in the use of pharmaceutical drugs & therapeutics. They promote safe and effective prescribing.

 

Etymology

Ancient Greek φάρμακον (pharmakon) = drug, poison, spell
Ancient Greek λογία (logia) = study

Pharmacology = the study of drugs

 

Subspecialties

• Hypertension pharmacology
• Medical toxicology 
• Clinical trial pharmacology
• Pharmacology research

Lithium

Also known as

• Lithium compounds
• Lithium salts

Lithium is mood stabilising drug used most commonly prophylatically 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.

 

Common indications

• Used in the treatment of manic depressive psychosis and for prophylaxis in bipolar disorder.

 

Mechanisms of action

 not fully understood, two theories:

• interferes with inositol triphosphate formation
• interferes with cAMP formation

 

Important adverse effects

• nausea/vomiting, diarrhoea
• fine tremor
• nephrotoxicity: polyuria, secondary to nephrogenic diabetes insipidus
• thyroid enlargement, may lead to hypothyroidism
• ECG: T wave flattening/inversion
• weight gain
• idiopathic intracranial hypertension

 

Warnings

 

Important interactions

 

Monitoring

• Range = 0.4 - 1.0 mmol/l
• Take 12 hrs post-dose
• Lithium testing

• inadequate monitoring of patients taking lithium is common - NICE and the National Patient Safety Agency (NPSA) have issued guidance to try and address this. As a result it is often an exam hot topic
• after starting lithium levels should be performed weekly and after each dose change until concentrations are stable
• once established, lithium blood level should 'normally' be checked every 3 months. Levels should be taken 12 hours post-dose
• thyroid and renal function should be checked every 6 months
• patients should be issued with an information booklet, alert card and record book

Ciclosporin

Common indications

• Severe acute ulcerative colitis refractory to corticosteroid treatment
• Severe active rheumatoid arthritis (administered on expert advice)
• Severe active rheumatoid arthritis [in combination with low-dose methotrexate, when methotrexate monotherapy has been ineffective] (administered on expert advice)
• Short-term treatment of severe atopic dermatitis where conventional therapy ineffective or inappropriate (administered on expert advice 
• Short-term treatment of very severe atopic dermatitis where conventional therapy ineffective or inappropriate (administered on expert advice)
• Severe psoriasis where conventional therapy ineffective or inappropriate (administered on expert advice)
• Organ transplantation (used alone) 
• Bone-marrow transplantation, Prevention and treatment of graft-versus-host disease
• Nephrotic syndrome

 

Mechanisms of action

• Ciclosporin inhibits production and release of lymphokines, thereby suppressing cell-mediated immune response.

 

Important adverse effects

 

Warnings

 

Important interactions

 

Monitoring

• Trough levels immediately before dose

Rifampicin

Common indications

• Tuberculosis

 

Mechanisms of action

• Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.

 

Important adverse effects

• Orange-red discolouration of bodily fluids (urine, sweat, tears)

 

Warnings

 

Important interactions

• Cytochrome P450 induction: this increases metabolism of some drugs (e.g. warfarin) and reduces their efficacy. 

Potassium, oral

Common indications

• Treatment and prevention of potassium depletion. This is usually evident from a low serum potassium concentration (hypokalaemia). Addition of a drug with potassium-sparing diuretic effects is preferred when potassium losses are due to loop- or thiazide-diuretic therapy. Intravenous potassium chloride is preferred in the initial treatment of hypokalaemia that is severe (<2.5 mmol/L), symptomatic, or causing arrhythmias.

 

Mechanisms of action

• Hypokalaemia is usually, although not always, due to potassium depletion. This may be because of, for example, diarrhoea, vomiting, or secondary hyperaldosteronism. Potassium supplementation may restore normal potassium balance in this scenario. 
• By contrast, if losses are due to loop- or thiazide-diuretic therapy, supplementation is largely ineffective. This is because although the serum potassium concentration is low, intake and output are in balance. Potassium supplementation results simply in increased potassium excretion and only minimal effect on serum concentration. Treatment with a potassium-sparing diuretic (or aldosterone antagonist) is therefore preferred. 
• In redistributive hypokalaemia the total body potassium content is normal, but the serum concentration is low because of redistribution into cells. Drug therapy (e.g. with insulin, salbutamol) is most often the culprit. Management should ideally be to address the underlying cause.

 

Important adverse effects

• Oral potassium preparations are not very well tolerated, mainly because they are unpalatable and cause gastrointestinal disturbance, including nausea, vomiting, pain, diarrhoea and flatulence. 
• Modified-release preparations may be better tolerated, but these can cause gastrointestinal obstruction, ulceration and bleeding. 
• Overtreatment may lead to hyperkalaemia and a resultant risk of arrhythmias.

 

Warnings

• Potassium supplements must be used with caution (lower dose and more intensive monitoring) in patients with renal impairment, due to the greatly increased risk of hyperkalaemia. 
• They should be avoided in severe renal impairment.

 

Important interactions

• Oral potassium supplements have additive effects with other potassium-elevating drugs, including intravenous potassium chloride, aldosterone antagonists, potassium-sparing diuretics, ACE inhibitors and angiotensin receptor blockers.

β2-agonists

Key examples

• Salbutamol
• Salmeterol
• Formoterol
• Terbutaline

 

Common indications

1. Asthma: short-acting β2-agonists are used to relieve breathlessness. Long-acting β2-agonists are used as ‘step 3’ treatment for chronic asthma, but must always be given in combination with inhaled corticosteroids.
2. Chronic obstructive pulmonary disease (COPD): short-acting β2-agonists are used to relieve breathlessness. Long-acting β2-agonists are an option for second-line therapy of COPD.
3. Hyperkalaemia: nebulised salbutamol may be used as an additional treatment (alongside insulin, glucose and calcium gluconate) for the urgent treatment of a high serum potassium concentration.

 

Mechanisms of action

• Beta2-receptors are found in smooth muscle of the bronchi, gastrointestinal tract, uterus and blood vessels. Stimulation of this G protein-coupled receptor activates a signalling cascade that leads to smooth muscle relaxation. This improves airflow in constricted airways, reducing the symptoms of breathlessness. Like insulin, β2-agonists also stimulate Na+/K+-ATPase pumps on cell surface membranes, thereby causing a shift of K+ from the extracellular to intracellular compartment. This makes them a useful adjunct in the treatment of hyperkalaemia, particularly when IV access is difficult. However, their effect is less reliable than other therapies, so they should not be used in isolation.
• Beta2-agonists are classified as short-acting (salbutamol, terbutaline) or long-acting (salmeterol, formoterol) according to their duration of effect.

 

Important adverse effects

• Activation of β2-receptors in other tissues accounts for the common ‘fight or flight’ adverse effects of tachycardia, palpitations, anxiety and tremor. 
• They promote glycogenolysis, so may increase the serum glucose concentration. 
• At high doses, serum lactate levels may also rise. 
• Long-acting β2-agonists can cause muscle cramps.

 

Warnings

• Long-acting β2-agonists should be used in asthma only if an inhaled corticosteroid is also part of therapy. This is because, without a steroid, long-acting β2-agonists are associated with increased asthma deaths. 
• Care should be taken when prescribing β2-agonists for patients with cardiovascular disease, in whom tachycardia may provoke angina or arrhythmias. This is especially pertinent in the treatment of hyperkalaemia, when high doses may be necessary.

 

Important interactions

• Beta-blockers may reduce the effectiveness of β2-agonists. Concomitant use of high-dose nebulised β2-agonists with theophylline and corticosteroids can lead to hypokalaemia, so serum potassium concentrations should be monitored.

β-blockers

Also known as

• Beta blockers

Key examples

• Bisoprolol
• Atenolol
• Propranolol
• Metoprolol

 

Common indications

• Ischaemic heart disease: as a first-line option to improve symptoms and prognosis associated with angina and acute coronary syndrome.
• Chronic heart failure: as a first-line option to improve prognosis.
• Atrial fibrillation: as a first-line option to reduce the ventricular rate and, in paroxysmal atrial fibrillation, to maintain sinus rhythm.
• Supraventricular tachycardia (SVT): as a first-line option in patients without circulatory compromise to restore sinus rhythm.
• Hypertension: although not generally indicated for initial therapy, they may be used when other medicines (e.g. calcium channel blockers, ACE inhibitors, thiazide diuretics) are insufficient or inappropriate.

 

Mechanisms of action

• Beta1-adrenoreceptors are located mainly in the heart, whereas β2-adrenoreceptors are found mostly in smooth muscle of blood vessels and the airways. Via the β1-receptor, β-blockers reduce force of contraction and speed of conduction in the heart. This relieves myocardial ischaemia by reducing cardiac work and oxygen demand, and increasing myocardial perfusion. They improve prognosis in heart failure by ‘protecting’ the heart from the effects of chronic sympathetic stimulation. They slow the ventricular rate in atrial fibrillation mainly by prolonging the refractory period of the atrioventricular (AV) node. SVT often involves a self-perpetuating (‘re-entry’) circuit that takes in the AV node; β-blockers may break this and restore sinus rhythm. In hypertension, β-blockers lower blood pressure through a variety of means, one of which is by reducing renin secretion from the kidney, since this is mediated by β1-receptors.

 

Important adverse effects

• Beta-blockers commonly cause fatigue, cold extremities, headache and gastrointestinal disturbance (e.g. nausea). 
• They can cause sleep disturbance and nightmares. 
• They may cause impotence in men.

 

Warnings

• In patients with asthma, β-blockers can cause life-threatening bronchospasm and should be avoided. This effect is mediated by blockade of β2-adrenoreceptors in the airways. Beta-blockers are usually safe in chronic obstructive pulmonary disease, although it is prudent to choose a β-blocker that is relatively β1-selective (e.g. atenolol, bisoprolol, metoprolol), rather than non-selective (e.g. propranolol). 
• When used in heart failure, β-blockers should be started at a low dose and increased slowly, as they may initially impair cardiac function. They should be avoided in patients with haemodynamic instability and are contraindicated in heart block. Beta-blockers generally require dosage reduction in significant hepatic failure.

 

Important interactions

• Beta-blockers must not be used with non-dihydropyridine calcium channel blockers (e.g. verapamil, diltiazem). 
• This combination can cause heart failure, bradycardia, and even asystole.

Corticosteroids (glucocorticoids), systemic

Key examples

• Prednisolone
• Hydrocortisone
• Dexamethasone

 

Common indications

1. To treat allergic or inflammatory disorders, e.g. anaphylaxis, asthma.
2. Suppression of autoimmune disease, e.g. inflammatory bowel disease, inflammatory arthritis.
3. In the treatment of some cancers as part of chemotherapy or to reduce tumour-associated swelling.
4. Hormone replacement in adrenal insufficiency or hypopituitarism.

 

Mechanisms of action

• These corticosteroids exert mainly glucocorticoid effects. 
• They bind to cytosolic glucocorticoid receptors, which then translocate to the nucleus and bind to glucocorticoid-response elements, which regulate gene expression. 
• Corticosteroids are most commonly prescribed to modify the immune response. 
• They upregulate anti-inflammatory genes and downregulate pro-inflammatory genes (e.g. cytokines, tumour necrosis factor alpha). 
• Direct actions on inflammatory cells include suppression of circulating monocytes and eosinophils. 
• Their metabolic effects include increased gluconeogenesis from increased circulating amino and fatty acids, released by catabolism (breakdown) of muscle and fat. 
• These drugs also have mineralocorticoid effects, stimulating Na+ and water retention and K+ excretion in the renal tubule.

 

Important adverse effects

• Immunosuppression increases the risk and severity of infection and alters the host response. 
• Metabolic effects include diabetes mellitus and osteoporosis. Increased catabolism causes proximal muscle weakness, skin thinning with easy bruising and gastritis. 
• Mood and behavioural changes include insomnia, confusion, psychosis and suicidal ideas. 
• Hypertension, hypokalaemia and oedema can result from mineralocorticoid actions.
• Corticosteroid treatment suppresses pituitary adrenocorticotropic hormone (ACTH) secretion, switching off the stimulus for normal adrenal cortisol production. In prolonged treatment, this causes adrenal atrophy, preventing endogenous cortisol secretion. If corticosteroids are withdrawn suddenly, an acute Addisonian crisis with cardiovascular collapse may occur. Slow withdrawal is required to allow recovery of adrenal function. 
• Symptoms of chronic glucocorticoid deficiency that occur during treatment withdrawal include fatigue, weight loss and arthralgia.

 

Warnings

• Corticosteroids should be prescribed with caution in people with infection and in children (in whom they can suppress growth).

 

Important interactions

• Corticosteroids increase the risk of peptic ulceration and gastrointestinal bleeding when used with NSAIDs and enhance hypokalaemia in patients taking β2-agonists, theophylline, loop or thiazide diuretics. 
• Their efficacy may be reduced by cytochrome P450 inducers (e.g. phenytoin, carbamazepine, rifampicin). 
• Corticosteroids reduce the immune response to vaccines.

Opioids, weak/moderate

Key examples

• Tramadol
• Codeine
• Dihydrocodeine

 

Common indications

• For mild-to-moderate pain, including post-operative pain, as second-line agents when simple analgesics, such as paracetamol, are insufficient. 
• Weak opioids are on the second rung of the World Health Organization pain ladder.

 

Mechanisms of action

• In unmodified form, codeine and dihydrocodeine are very weak opioids. 
• They are metabolised in the liver to produce relatively small amounts of morphine (from codeine) or dihydromorphine (from dihydrocodeine). 
• These metabolites, which are stronger agonists of opioid µ (mu) receptors (see Opioids, strong), probably account for most of the analgesic effect. 
• About 10 of Caucasians have a less active form of the key metabolising enzyme (called cytochrome P450 2D6), and these people may find codeine and dihydrocodine largely ineffective. 
• Tramadol is a synthetic analogue of codeine; it is perhaps best classified as a ‘moderate’ strength opioid. Like codeine, tramadol and its active metabolite are µ-receptor agonists. 
• Unlike other opioids, tramadol also affects serotonergic and adrenergic pathways, where it is thought to act as a serotonin and noradrenaline reuptake inhibitor.  This probably contributes to its analgesic effect.

 

Important adverse effects

• Common side effects of weak opioids include nausea, constipation, dizziness and drowsiness. All opioids can cause neurological and respiratory depression when taken in overdose. Tramadol may cause less constipation and respiratory depression than other opioids. Codeine and dihydrocodeine must never be given intravenously, as this can cause a severe reaction similar to anaphylaxis. This is mediated by histamine release, but does not have an ‘allergic’ basis.

 

Warnings

• Caution must be exercised when prescribing an opioid in the context of significant respiratory disease. Tramadol, codeine and dihydrocodeine rely on both the liver and the kidneys for their elimination. Doses should therefore be reduced in renal impairment and hepatic impairment, and also in the elderly. Tramadol lowers the seizure threshold so is best avoided in patients with epilepsy, and certainly should not be used in those with uncontrolled epilepsy.

 

Important interactions

• Opioids should ideally not be used with other sedating drugs (e.g. antipsychotics, benzodiazepines and tricyclic antidepressants). Where their combination is unavoidable, closer monitoring is necessary. Tramadol should not be used with other drugs that lower the seizure threshold, such as serotonin-selective reuptake inhibitors and tricyclic antidepressants.

Opioids, strong

Key examples

• Morphine
• Oxycodone

 

Common indications

1. For rapid relief of acute severe pain, including post-operative pain and pain associated with acute myocardial infarction.
2. For relief of chronic pain, when paracetamol, NSAIDs and weak opioids are insufficient (‘rung 3’ of the WHO pain ladder).
3. For relief of breathlessness in the context of end-of-life care.
4. To relieve breathlessness and anxiety in acute pulmonary oedema, alongside oxygen, furosemide and nitrates.

 

Mechanisms of action

• The term opioids encompasses naturally-occurring opiates (e.g. morphine) plus synthetic analogues (e.g. oxycodone). Morphine and oxycodone are strong opioids. 
• The therapeutic action of opioids arises from activation of opioid µ (mu) receptors in the central nervous system. 
• Activation of these G protein-coupled receptors has several effects that, overall, reduce neuronal excitability and pain transmission. 
• In the medulla, they blunt the response to hypoxia and hypercapnoea, reducing respiratory drive and breathlessness. 
• By relieving pain, breathlessness and associated anxiety, opioids reduce sympathetic nervous system (fight or flight) activity. 
• Thus, in myocardial infarction and acute pulmonary oedema they may reduce cardiac work and oxygen demand, as well as relieving symptoms. 
• That said, although commonly used, the efficacy and safety of morphine in acute pulmonary oedema is not firmly established.

 

Important adverse effects

• Opioids cause respiratory depression by reducing respiratory drive. They may cause euphoria and detachment, and in higher doses, neurological depression. They can activate the chemoreceptor trigger zone, causing nausea and vomiting, although this tends to settle with continued use. 
• Pupillary constriction occurs due to stimulation of the Edinger–Westphal nucleus. In the large intestine, activation of µ receptors increases smooth muscle tone and reduces motility leading to constipation. In the skin, opioids may cause histamine release, leading to itching, urticaria, vasodilatation and sweating. 
• Continued use can lead to tolerance (a state in which the dose required to produce the same effect increases over time) and dependence. Dependence becomes apparent on cessation of the opioid, when a withdrawal reaction occurs (see Clinical tip).

 

Warnings

• Most opioids rely on the liver and the kidneys for elimination, so doses should be reduced in hepatic failure and renal impairment and in the elderly. 
• Do not give opioids in respiratory failure except under senior guidance (e.g. in palliative care). 
• Avoid opioids in biliary colic, as they may cause spasm of the sphincter of Oddi, which may worsen pain.

 

Important interactions

• Opioids should ideally not be used with other sedating drugs (e.g. antipsychotics, benzodiazepines and tricyclic antidepressants). Where their combination is unavoidable, close monitoring is necessary.

Antiemetics, phenothiazines

Key examples

• Prochlorperazine
• Chlorpromazine

 

Common indications

1. Prophylaxis and treatment of nausea and vomiting in a wide range of conditions, particularly when due to vertigo. However, due to their side effect profile, other antiemetic classes are usually preferable.
2. Psychotic disorders, such as schizophrenia, where they are used as first-generation (typical) antipsychotics.

 

Mechanisms of action

• Nausea and vomiting are triggered by a variety of factors, including gut irritation, drugs, motion and vestibular disorders, as well as higher stimuli (sights, smells, emotions). 
• The various pathways converge on a ‘vomiting centre’ in the medulla, which receives inputs from the chemoreceptor trigger zone (CTZ), the solitary tract nucleus (which is innervated by the vagus nerve), the vestibular system and higher neurological centres. 
• The antiemetic properties of phenothiazines arise from blockade of various receptors, including dopamine (D2) receptors in the CTZ and gut (see Antiemetics, dopamine D2-receptor antagonists) and, to a lesser extent, histamine (H1) and acetylcholine (muscarinic) receptors in the vomiting centre and vestibular system (see Antiemetics, histamine H1-receptor antagonists). 
• This makes them effective for nausea and vomiting in a wide range of situations, including chemotherapy, radiotherapy and vertigo.

 

Important adverse effects

• Drowsiness and postural hypotension are relatively common with phenothiazines. 
• Movement abnormalities, termed extrapyramidal syndromes, are a major drawback of their use. They arise from D2 receptor blockade via the same mechanism as for other first-generation (typical) antipsychotics. 
• In the context of short-term treatment for nausea and vomiting, this is most likely to take the form of an acute dystonic reaction such as oculogyric crisis. 
• In longer-term treatment (which is more likely when they are used as an antipsychotic), other extrapyramidal syndromes such as tardive dyskinesia may occur (see Antipsychotics, first-generation [typical]). 
• Like all antipsychotics, phenothiazines can cause QT-interval prolongation.

 

Warnings

• Due to their sedative effect and potential for hepatotoxicity, these drugs should be avoided in patients with severe liver disease.
• They should also be avoided in patients susceptible to anticholinergic side effects, such as those with prostatic hypertrophy (who may develop urinary retention). 
• Doses should be reduced in the elderly.

 

Important interactions

• You should consult the BNF when prescribing for a patient taking these drugs as there is an extensive list of interactions. 
• Prominent among these are drugs that prolong the QT interval, such as antipsychotics, amiodarone, ciprofloxacin, macrolides, quinine and SSRIs.

Vaccines

Key examples

• Childhood vaccines
• Influenza vaccine
• Pneumococcal vaccine

 

Common indications

1. Childhood vaccines are routinely offered to all children as part of the childhood immunisation schedule.
2. Influenza vaccine is offered annually in at-risk groups including people aged over 6 months with chronic respiratory, heart, liver, renal or neurological disease; diabetes mellitus; immunosuppression; or HIV.
3. Pneumococcal vaccine forms part of the childhood immunisation schedule. It is also offered for once-only administration in at-risk groups. These are similar to the at-risk groups for influenza vaccine, but with the addition of patients aged over 65 years and those with other risk factors for pneumococcal disease (cochlear implant, risk factors for cerebrospinal fluid leakage, history of invasive pneumococcal disease, occupational exposure to metal fumes and absence of a functional spleen).

 

Mechanisms of action

• Vaccination involves administration of an antigen to incite an adaptive immune response and generate an immune ‘memory,’ usually in the form of memory B cells. 
• This facilitates a more rapid and specific immune response on re-exposure to the antigen, attenuating the severity of infection and often rendering it subclinical. 
• The antigen in vaccines may be provided as an inactivated form of the infectious agent (e.g. as in the influenza vaccine); a live but attenuated form of the infectious agent (e.g. measles, mumps and rubella [MMR] vaccine); specific protein or peptide components of the infectious agent (e.g. pneumococcal vaccine); or as a detoxified form of the exotoxin that would usually be produced by the infectious agent (e.g. tetanus toxoid vaccine).

 

Important adverse effects

• Vaccines are very safe. 
• The most common side effects are local reactions comprising pain, swelling and redness; and mild systemic effects such as fever, headache and myalgia. 
• The MMR vaccine may cause a mild measles-like illness (including a rash) about 1 week after vaccination, and occasionally a mumps-like illness (with parotid swelling) in the third week. 
• Very rarely, vaccines may cause severe hypersensitivity reactions including anaphylaxis.

 

Warnings

• Mild intercurrent illness usually does not present a barrier to vaccination. 
• Vaccines are contraindicated in patients who have had an anaphylactic reaction to a past dose or to one of its constituents. 
• Live vaccines are contraindicated in patients with significant immunosuppression, and are usually avoided in pregnancy.

 

Important interactions

• Immunosuppressive drugs (including systemic corticosteroids) reduce the immune response to (and therefore effectiveness of) vaccines, and may permit generalised infection with live vaccines.

Thiazolidinediones

Key examples

• Pioglitazone

 

Common indications

Type 2 diabetes mellitus:

• As a single agent in overweight patients where metformin is contraindicated or not tolerated.
• Added as a second agent to metformin or a sulphonylurea where blood glucose control is inadequate on one drug and the metformin/sulphonylurea combination is contraindicated or not tolerated.
• Added as a third agent with metformin and a sulphonylurea where blood glucose control is inadequate as an alternative to starting insulin.

 

Mechanisms of action

• Thiazolidinediones are insulin sensitisers. 
• They lower blood glucose by activating the gamma subclass of nuclear peroxisome proliferator-activated receptors (PPARγ). 
• This induces genes which enhance insulin action in skeletal muscle, adipose tissue and the liver, with increased peripheral glucose uptake and utilisation and reduced hepatic gluconeogenesis. 
• Thiazolidinediones do not stimulate pancreatic insulin secretion, hence do not cause hypoglycaemia. 
• They cause weight gain, which can increase insulin resistance.

 

Important adverse effects

• Adverse effects of pioglitazone include gastrointestinal upset, anaemia and minor neurological effects such as dizziness, headache and disturbed vision. 
• More serious side effects include oedema and cardiac failure, particularly where pioglitazone is prescribed with insulin. 
• Pioglitazone is associated with a small increase in the risk of bladder cancer and an increase in bone fractures in women. 
• Idiosyncratic reactions include severe liver toxicity. 
• Pioglitazone is the only thiazolidinedione currently available for prescription in the UK. 
• The marketing authorisation (license) for rosiglitazone has been suspended as cardiovascular risk associated with this drug appears greater than its potential benefits. 
• Troglitazone was withdrawn from the market due to liver toxicity.

 

Warnings

• Pioglitazone should be avoided or prescribed with caution in people at increased risk of serious adverse effects. 
• It is contraindicated in people with heart failure and should be used with caution in cardiovascular disease. 
• It is contraindicated if there is known bladder cancer or macroscopic haematuria and should be used with caution in people with risk factors for bladder cancer (e.g. smoking, occupational exposure, prior pelvic irradiation). 
• Careful consideration should be given when prescribing pioglitazone for elderly patients, who tend to have increased risk of cardiac disease, bladder cancer and bone fractures. 
• Pioglitazone is extensively metabolised in the liver and can cause liver toxicity, so should be used with caution in hepatic impairment.

 

Important interactions

• Pioglitazone is usually prescribed in combination with other antidiabetic drugs, which increases the risk of adverse effects, e.g. hypoglycaemia and cardiac failure. 
• There are no other significant drug interactions.

Nicorandil

Common indications

• For prevention and treatment of chest pain in people with stable angina. 
• First choice treatments for stable angina are β-blockers and calcium channel blockers, individually or in combination. 
• Nicorandil (or a long-acting nitrate) may be used if these drugs are insufficient or not tolerated.

 

Mechanisms of action

• Nicorandil causes both arterial and venous vasodilatation through its actions as a nitrate (see Nitrates) and by activating K+-ATP channels. 
• Efflux of K+ through activated K+-ATP channels leads to hyperpolarisation of the cell membrane and subsequent inactivation of voltage-gated Ca2+ channels. The net effect is a decrease in free intracellular calcium. As calcium is required for smooth muscle contraction, relaxation and vasodilatation occur. 
• The effect of this is to reduce cardiac preload and systemic and coronary vascular resistance. 
• This improves myocardial perfusion, and decreases myocardial work and oxygen demand. 
• Clinically, this reduces the frequency and severity of angina attacks.

 

Important adverse effects

• Unwanted effects of vasodilatation include flushing, dizziness and headache. 
• Nicorandil can also cause nausea, vomiting and hypotension. 
• Less frequently, it can cause gastrointestinal, skin or mucosal ulceration, which only responds to withdrawal of treatment.

 

Warnings

• You should not routinely prescribe nicorandil for patients with poor left ventricular function, hypotension or pulmonary oedema, as it can worsen these conditions.

 

Important interactions

• As with nitrates, the hypotensive side effects of nicorandil are significantly enhanced by phosphodiesterase inhibitors (e.g. sildenafil). 
• They should not be prescribed together.

Laxatives, bulk-forming

Key examples

• Ispaghula husk
• Methylcellulose
• Sterculia

 

Common indications

1. Constipation and faecal impaction, particularly in patients who cannot increase their dietary fibre intake.
2. Mild chronic diarrhoea associated with diverticular disease or irritable bowel syndrome.

 

Mechanisms of action

• Bulk-forming laxatives contain a hydrophilic substance, such as a polysaccharide or cellulose, which is not absorbed or broken down in the gut. 
• Like dietary fibre, this attracts water into the stool and increases its mass. 
• Adequate fluid intake is therefore important to the action of bulk-forming laxatives. 
• Increased stool bulk stimulates peristalsis and helps to relieve constipation. It can also help in chronic diarrhoea. This can be useful for some patients with diverticular disease, irritable bowel syndrome, or when managing stoma output.

 

Important adverse effects

• These drugs are generally well tolerated, with mild abdominal distension and flatulence being the most common side effects. Rarely, but more seriously, they may cause faecal impaction and gastrointestinal obstruction.

 

Warnings

• They should not be used in patients with subacute or established intestinal obstruction or faecal impaction, and in general should not be used in patients with ileus.

 

Important interactions

• There are no clinically significant adverse drug interactions with bulk-forming laxatives.

Dipyridamole

Common indications

• Cerebrovascular disease for secondary prevention of stroke. Dipyridamole is currently first-line therapy following a transient ischaemic attack, and second-line therapy following an ischaemic stroke where clopidogrel is contraindicated or not tolerated. It should usually be given in combination with aspirin but can be used as monotherapy if aspirin is contraindicated or not tolerated.
• To induce tachycardia during a myocardial perfusion scan in the diagnosis of ischaemic heart disease.

 

Mechanisms of action

• Dipyridamole has both antiplatelet and vasodilatory effects. 
• Although the exact mechanism of its antiplatelet action is controversial, the end effect is an increase in intra-platelet cyclic adenosine monophosphate (cAMP) that inhibits platelet aggregation, reducing the risk of arterial occlusion. 
• Dipyridamole also blocks cellular uptake of adenosine, prolonging its effect on blood vessels to produce vasodilation.

 

Important adverse effects

• The side effects of dipyridamole relate to its vasodilatory effects and include headache, flushing, dizziness and gastrointestinal symptoms that normally improve with time. 
• As with other antiplatelet agents there is an increased risk of bleeding. 
• Rarely dipyridamole can affect platelet numbers as well as function, causing thrombocytopaenia.

 

Warnings

• Dipyridamole should be used with caution in patients with ischaemic heart disease, aortic stenosis and heart failure as it causes vasodilatation and tachycardia that can exacerbate these conditions. 
• This effect is exploited diagnostically in myocardial perfusion scans, where radionucleotide distribution is compared in heart muscle at baseline and during tachycardia induced by intravenous dipyridamole. 
• Reduced perfusion after dipyridamole indicates cardiac ischaemia. 

 

Important interactions

• Dipyridamole inhibits cellular uptake of adenosine. 
• This prolongs its effects on the heart, increasing the risk of cardiac arrest. The dose of adenosine should therefore be reduced in patients treated with dipyridamole. 
• There is an increased risk of bleeding where dipyridamole is combined with other antiplatelet agents (aspirin, clopidogrel) and anticoagulants (heparin, warfarin).

Antiemetics, dopamine D2-receptor antagonists

Key examples

• Metoclopramide
• Domperidone

 

Common indications

• Prophylaxis and treatment of nausea and vomiting in a wide range of conditions, but particularly in the context of reduced gut motility.

 

Mechanisms of action

• Nausea and vomiting are triggered by a variety of factors, including gut irritation, drugs, motion and vestibular disorders, as well as higher stimuli (sights, smells, emotions). The various pathways converge on a ‘vomiting centre’ in the medulla, which receives inputs from the chemoreceptor trigger zone, the solitary tract nucleus (which is innervated by the vagus nerve), the vestibular system and higher neurological centres. Dopamine, acting via D2 receptors, is relevant in two respects. 
• First, the D2 receptor is the main receptor in the chemoreceptor trigger zone (CTZ), which is the area responsible for sensing emetogenic substances in the blood (e.g. drugs). Second, dopamine is an important neurotransmitter in the gut, where it promotes relaxation of the stomach and lower oesophageal sphincter and inhibits gastroduodenal coordination. 
• Drugs that block D2 receptors therefore have a prokinetic effect – promoting gastric emptying – which contributes to their antiemetic action. 
• They are effective in nausea and vomiting due to CTZ stimulation (e.g. due to drugs) and reduced gut motility (e.g. due to opioids or diabetic gastroparesis).

 

Important adverse effects

• Diarrhoea is probably the most common side effect of D2-blocking antiemetics. 
• Metoclopramide can induce extrapyramidal syndromes (movement abnormalities) via the same mechanism as for antipsychotics. 
• In the context of short-term treatment for nausea and vomiting, this is most likely to take the form of an acute dystonic reaction such as an oculogyric crisis. 
• Domperidone tends not to cause extrapyramidal symptoms because it does not cross the blood–brain barrier (note that the chemoreceptor trigger zone is largely outside the blood–brain barrier, so this characteristic does not affect its antiemetic action).

 

Warnings

• Extrapyramidal side effects are more common in children and young adults so its use should be avoided in these groups. 
• As both drugs have prokinetic effects, they are contraindicated in patients with gastrointestinal obstruction and perforation.

 

Important interactions

• The risk of extrapyramidal side effects is increased when metoclopramide is prescribed with antipsychotics. 
• It should not be combined with dopaminergic agents for Parkinson’s disease, as it will antagonise their effects. 
• Domperidone is not subject to these interactions.

Antiemetics, histamine H1-receptor antagonists

Key examples

• Cyclizine 
• Cinnarizine
• Promethazine

 

Common indications

• Prophylaxis and treatment of nausea and vomiting, particularly in the context of motion sickness or vertigo.

 

Mechanisms of action

• Nausea and vomiting are triggered by a variety of factors, including gut irritation, drugs, motion and vestibular disorders, as well as higher stimuli (sights, smells, emotions). 
• The various pathways converge on a ‘vomiting centre’ in the medulla, which receives inputs from the chemoreceptor trigger zone (CTZ), the solitary tract nucleus (which is innervated by the vagus nerve), the vestibular system and higher neurological centres. Histamine (H1) and acetylcholine (muscarinic) receptors predominate in the vomiting centre and in its communication with the vestibular system. 
• Drugs such as cyclizine block both of these receptors. 
• This makes them useful treatments for nausea and vomiting in a wide range of conditions (e.g. drug-induced, post-operative, radiotherapy), but most particularly when associated with motion or vertigo.

 

Important adverse effects

• The most common adverse effect is drowsiness. Cyclizine is the least sedating drug in this class and is therefore usually preferred. 
• Due to their anticholinergic effects they may cause dry throat and mouth. This is usually undesirable, but in patients with copious mucosal secretions it may be beneficial. 
• After IV injection they may cause transient tachycardia, which the patient may notice as palpitations. Along with their central anticholinergic effects (excitation or depression) this may make for a rather unpleasant experience.

 

Warnings

• Due to their sedating effect, these drugs should be avoided in patients at risk of hepatic encephalopathy. 
• They should also be avoided in patients susceptible to anticholinergic side effects, such as those with prostatic hypertrophy (who may develop urinary retention). 
• Use with caution in severe heart failure—may cause fall in cardiac output and associated increase in heart rate.

 

Important interactions

• Sedation may be greater when combined with other sedative drugs (e.g. benzodiazepines, opioids). 
• Anticholinergic effects may be more pronounced in patients taking ipratropium or tiotropium.