Angiotensin-Converting Enzyme (ACE)-inhibitors

Indications

Angiotensin-converting enzyme (ACE) inhibitors are used in the treatment of hypertension, heart failure, diabetic nephropathy, and coronary artery disease. 

Mechanism of action

ACE-inhibitors block angiotensin-converting enzyme, which acts to convert angiotensin I to angiotensin II. Angiotensin II is responsible for:

• producing vasoconstriction of precapillary arterioles and postcapillary venules
• the production and release of aldosterone
• inhibiting norepinephrine reuptake
• stimulating the adrenal medulla to release catecholamines
• the hypertrophy of smooth muscle cells within blood vessels and cardiac myocytes
• reducing excretion of water and sodium within urine.

The majority of side effects produced by ACE-inhibitors are therefore a result of reduced angiotensin II production, which results in increased urinary excretion of water and sodium, reduced arterial and venous pressure, and reduced hypertrophy of vascular and cardiac musculature.

Examples

Ramipril, lisinopril, enalapril, captopril, fosinopril.

Adverse effects

Adverse drug effect	Mechanism	Comments
Dry cough	Precise mechanism unknown; postulated to be due to increased local concentrations of kinins and substance P. These substances are metabolised by ACE; concentrations are therefore increased with ACE inhibitor use. This may lead to stimulation of sensory (C-) fibres present in the upper airway. ACE inhibition may also lead to increased levels of thromboxane via activation of the arachidonic pathway, which may cause bronchoconstriction.	Usually begins 1-2 weeks of starting therapy and resolves within 1-4 days of discontinuation. Females more commonly affected than males. Patients should be switched to angiotensin II receptor blocker.
Hypotension	Reduced angiotensin II production, which results in increased urinary excretion of water and sodium and reduced arterial and venous pressure.	May manifest as dizziness, weakness or syncope. May be seen in volume-depleted patients or those with heart failure. Commencement at low dose e.g. 2.5mg enalapril BD can reduce effect.
Impaired renal function	Reduced glomerular filtration rate (GFR); more commonly seen in patients with pre-existing chronic kidney disease (CKD), bilateral renal artery stenosis, heart failure, polycystic kidney disease. Believed a result of pre-existing reduction in intrarenal perfusion pressure, with a resulting angiotensin II-induced increase in postglomerular arteriole resistance. Reduced angiotensin II will therefore lower intraglomerular pressure and reduce GFR.	Rise in serum creatinine seen 3-5 days after institution of ACE-inhibitor. Most often GFR reduces by 5-25% but can be >30%. If serum creatinine rises >30% above baseline within 6-8 weeks, ACE-inhibitor should be discontinued.
Hyperkalaemia	Aldosterone is the main hormone that stimulates urinary potassium excretion. Angiotensin II increases aldosterone production, so reduction of angiotensin II with ACE-inhibitor use increases serum potassium concentration.	Usually only mild increase in serum potassium seen in patients with normal renal function; more severe in CKD, diabetes, older patients, and simultaneous use of potassium-sparing diuretics or NSAIDs.
Anaemia	Suppression of erythropoietin production; increased risk in presence of CKD. In this setting, the accumulation of N-acetyl-seryl-aspartyl-lysyl-proline suppresses stem cell division.
Angioedema / anaphylactoid reactions	ACE is involved in the metabolism of bradykinin, its metabolite, des-Arg9-BK, and substance P. The accumulation of these three peptides during ACE-inhibition leads to an increase in secondary metabolic enzymes which predispose patients to developing angioedema.	Risk factors include history of previous angioedema, female gender, age over 65 years, concurrent aspirin/NSAID use, smoking and genetic factors.
Pancreatitis	Precise mechanism unknown; may be a result of angioedema of pancreatic duct resulting in obstruction
Complications in pregnancy	ACE-inhibitors are contraindicated during pregnancy; they cross the placenta and reduce fetal angiotensin II levels, which are normally required to maintain fetal GFR. Exposure in second and third trimesters leads to impaired renal function and can lead to oligohydramnios and renal failure after delivery. Little is known about first-trimester exposure but there is a higher risk of major congenital malformations compared with nonexposed foetuses.

Table 8: Adverse Effects

Amiodarone

Indications

The main indications for amiodarone are: 

• atrial arrhythmias (restoration and maintenance of sinus rhythm in patients with atrial fibrillation, ventricular rate control in atrial fibrillation with rapid ventricular response, atrial flutter, atrial tachycardias)
• ventricular arrhythmias (ventricular premature beats, non-sustained ventricular tachycardia, sustained ventricular tachycardia and ventricular fibrillation)
• secondary prevention of ventricular arrhythmias in patients with implantable cardioverter-defibrillators (ICD) 
• for resuscitation during cardiac arrest in patients with a shockable rhythm, after 3 shocks have been delivered.

Drug class and mechanism of action

Amiodarone is a class III antiarrhythmic agent. It blocks potassium channels within cardiac tissues, thus blocking outward flowing potassium currents. This influences the cardiac excitation process by prolonging the repolarisation time, action potential duration and refractory period. It also exerts effects on calcium channels, adrenergic receptors, and blocks sodium channels in the depolarised state, particularly the late sodium current. 

Adverse effects

Adverse effects of amiodarone will be subdivided into pulmonary toxicity, thyroid toxicity, cardiac toxicity, hepatoxicity, adverse ocular effects, and adverse dermatological effects. 

Pulmonary toxicity

Pulmonary toxicity is one of the commonest adverse effects of amiodarone. Pulmonary toxicity may take several weeks to several years to develop. The most common form of pulmonary toxicity secondary to long-term exposure to amiodarone is chronic interstitial pneumonitis, the typical presentation of which is dyspnoea, dry cough, pleuritic pain, fever and weight loss. Other forms of pulmonary toxicity that have been demonstrated secondary to amiodarone therapy include:

• eosinophilic pneumonia
• organising pneumonia
• alveolar haemorrhage
• pulmonary nodules
• acute respiratory distress syndrome. 

The pathogenesis of pulmonary toxicity is thought to occur either through direct cytotoxicity, or via an indirect immune-mediated reaction (for further details see ‘Drug-induced interstitial lung disease’ section of this chapter). Risk factors include higher cumulative doses, higher daily doses, increased age and pre-existing lung disease. Treatment includes drug discontinuation and systemic corticosteroid therapy.

Thyroid toxicity

Thyroid toxicity may be the commonest adverse reaction to amiodarone. Again, higher individual doses and higher cumulative doses are risk factors. Pre-existing thyroid pathology and iodine intake influence the nature of thyroid dysfunction that occurs; both hypothyroidism and hyperthyroidism are seen as a result of amiodarone use. Their presentation is similar to non-iatrogenic hypo- and hyperthyroidism respectively, but the beta-blocking effect of amiodarone may make symptoms of hyperthyroidism harder to detect. The effects of amiodarone on thyroid function are due to both its iodine content and its intrinsic drug properties.

Intrinsic drug effects of amiodarone on thyroid function are as follows:

• inhibition of 5’-monodeiodination of thyroxine (T4) outer ring and resulting reduction in triiodothyronine (T3) production
• reduced T3-nuclear receptor binding due to direct blocking by amiodarone molecules and its metabolites, leading to diminished expression of certain genes involved in thyroid hormone production
• direct toxic effect on thyroid follicular cells causing a destructive thyroiditis.

The iodine-related effects of amiodarone are:

• development of goitre and hypothyroidism in patients with underlying Hashimoto’s disease, due increased iodine load and disruption of the normal mechanisms that inhibit iodine transport and thyroid hormone synthesis when iodine levels are raised
• increased thyroid hormone synthesis and thyrotoxicosis in patients with a nodular goitre containing regions of thyroid tissue that function autonomously. 

Individuals with underlying Hashimoto’s thyroiditis or positive antithyroid antibodies are more likely to develop hypothyroidism secondary to amiodarone therapy. Those with underlying multinodular goitre or latent Graves’ disease are at risk of developing hyperthyroidism, as the excess iodine from amiodarone leads to increased thyroid hormone production. 

In parts of the world where individuals tend to be iodine-replete, amiodarone induced hypothyroidism is more common than hyperthyroidism; however, in regions that are iodine-deficient, the opposite is true. Patients with hypothyroidism can be treated with thyroid hormone replacement and may be able to continue on amiodarone therapy, while those with hyperthyroidism may require cessation of amiodarone and treatment with an alternative antiarrhythmic medication; endocrinologist input is also required in the management of amiodarone-induced hyperthyroidism.

Cardiac toxicity

Cardiotoxic effect	Mechanism
Excessive bradycardia and atrioventricular (AV) block	Predominantly due to calcium channel blocking effect of amiodarone
QT prolongation	Prolongation of the QT interval is an expected effect of amiodarone; in very rare instances, this can lead to pro-arrhythmia. Exact mechanisms are not known; more likely to occur in concurrence with other factors contributing to prolonged QT interval (hypokalaemia, hypomagnesaemia, use of other QT-prolonging drugs).
Interaction with implantable cardioverter-defibrillators (ICDs)	Causes slowing of ventricular rate which may prevent ventricular tachycardia recognition by device; amiodarone metabolite (desethylamiodarone) increases defibrillation threshold at higher doses.

Table 9: Cardiac Toxicity

Hepatotoxicity

Around one quarter of patients demonstrate a transient rise in serum aminotransferase levels after amiodarone is initiated. A much smaller proportion of patients (around 3%) develop symptomatic hepatitis, which may progress in some circumstances to cirrhosis, and liver failure. A rise in bilirubin and clinical jaundice can also be seen with amiodarone use. The hepatic effects of amiodarone are believed due to both direct hepatotoxicity of the drug, and idiosyncratic effects of its metabolites. 

Adverse ocular effects

The two main ocular effects of amiodarone to be aware of are corneal micro-deposition and optic neuropathy. 

Corneal microdeposits are present in most patients on long-term amiodarone treatment and rarely affect vision, or produce only mild effects. They occur due to secretion within tears produced by the lacrimal gland, and accumulate on the corneal surface at the junction of the lower third and upper two thirds of the cornea, in a pattern resembling cat’s whiskers. Visual acuity is not affected, but a minority of patients may complain of halos around lights, visual blurring or photophobia. 

Optic neuropathy can occur secondary to amiodarone therapy and cause unilateral or bilateral visual loss. It has the potential to progress to permanent blindness, and therefore cessation of amiodarone therapy and treatment with an alternative antiarrhythmic drug is advised where possible in the event of this adverse drug effect. More evidence is required to determine whether this effect is related to the duration of amiodarone therapy.

Warfarin

Indications

Warfarin is used for its anticoagulation properties for the prevention or treatment of thromboembolic disease. Those conditions in which it may be used include: 

• prosthetic heart valves 
• antiphospholipid syndrome
• atrial fibrillation (AF)
• venous thromboembolism including deep vein thrombosis and pulmonary embolism. 

Note that in the settings of AF and venous thromboembolic disease, direct oral anticoagulants (DOAC) are the preferred drug to achieve anticoagulation due to reduced bleeding risk (particularly relevant in older adults) and reduced need for international normalised ratio (INR) monitoring. There are some situations, however, when warfarin may be chosen, for example due to lower cost, liver or renal impairment, extremes of body weight, patient preference, and availability of and familiarity with reversal agents.

Drug class and mechanism of action

Warfarin is a vitamin-K antagonist. It is a coumarin derivative which produces its anticoagulant effects by inhibiting the hepatic vitamin K epoxide reductase complex. Inhibition of this complex results in decreased levels of vitamin K in its reduced form, which normally acts as a cofactor for gamma-carboxylation of vitamin K-dependent clotting factors (II [prothrombin], VII, IX and X), and proteins C and S. These vitamin-K dependent clotting factors therefore cannot function to promote haemostasis, as they cannot bind calcium and phospholipid membranes.

Adverse effects

Bleeding

In reducing the risk of thrombosis, warfarin simultaneously increases the risk of bleeding. Whilst warfarin technically doesn’t itself cause bleeding, in the incidence of a damage to a blood vessel wall, haemostasis is impaired as a result of warfarin therapy, leading to increased likelihood of significant haemorrhage.  Factors which increase the risk of bleeding in patients treated with warfarin include supratherapeutic INR, older age, prior bleeding, and comorbidities such as pre-existing bleeding disorders, diabetes, hepatic pathology, renal pathology and malignancy. Bleeding risk can be mediated by careful selection of the most suitable anticoagulation therapy taking into account individual patient factors; close INR monitoring and careful dose adjustment as required; thorough counselling regarding adherence; and addressing modifiable risk factors such as hypertension, renal and hepatic disease, falls prevention, and limiting use of drugs increasing bleeding risk (such as antiplatelets and interacting medications). The treatment of supratherapeutic INR and/or bleeding in patients taking warfarin may be managed by the administration of vitamin K, prothrombin complex concentrate, and in some situations, tranexamic acid, dependent on the severity of bleeding and the INR value.

Skin necrosis

Skin necrosis may be seen and is most likely within the first few days following initiation of warfarin anticoagulation, particularly when larger doses are used. It occurs most commonly on the trunk, digits, penis, and breast tissue. The mechanism is believed to be due to a reduction in protein C levels. 

Cholesterol embolization

Cholesterol embolization is a rare complication of warfarin use. It occurs due to embolization of cholesterol crystals and presents as dark purple mottling of the soles of the feet and the lateral aspects of the toes. It has been referred to as ‘blue toe syndrome’. 

Vascular calcification

Studies have demonstrated that coronary, femoral and aortic artery calcification increases in a significant proportion of patients taking warfarin therapy, and that this increases duration of therapy increases. However, there is no evidence to suggest that there is an associated increased risk of related clinical events (myocardial infarction, stroke, or peripheral vascular disease). 

Teratogenicity

Warfarin has a dose-related teratogenic effect. It carries the highest risk during the 6th and 12th weeks of gestation. Most commonly, teratogenic effects manifest as abnormalities of cartilage and bone development, for example chondrodysplasia punctata (causing calcific stippling of cartilage and other soft tissues surrounding bony articulations) and hypoplasia of the limbs. The mechanism for these effects is unclear.

Glucocorticoid therapy

Indications

Glucocorticoid therapy may take the form of systemic (intravenous or oral), topical, inhaled, or intraarticular therapy. This section will focus specifically on the adverse effects of systemic therapy. The indications for glucocorticoid therapy are numerous, but in general it is used for autoimmune, allergic, and inflammatory diseases; it may also be used to establish a diagnosis of Cushing’s syndrome, and to treat adrenal insufficiency. Examples of glucocorticoids include prednisolone, prednisone, methylprednisolone, dexamethasone, triamcinolone, and betamethasone. 

Mechanism of action

Glucocorticoids are hormones released as a physiological response to stress (primary stress hormones). Adrenal glucocorticoid release is under the control of the hypothalamic-pituitary-axis (HPA). Synthetic derivatives of glucocorticoid hormones are used to treat a wide range of inflammatory and immune disorders. Glucocorticoid molecules act via the intracellular glucocorticoid receptor (GR) found within a variety of tissues, with different tissues showing variability in responses to GR binding due to differences in GR variants. GRs are activated as a result of glucocorticoid molecule binding, and subsequently up- or downregulate the expression of many genes via direct DNA binding. GRs also function via non-genomic pathways, which are poorly understood. The effects of exogenous glucocorticoid administration result largely from either suppression of the HPA, or the development of iatrogenic Cushing’s syndrome.

Adverse effects

Cardiovascular 

At higher doses, glucocorticoids promote fluid retention. Patients with pre-existing cardiac and renal disease are at particular risk of this effect. Hypertension is also seen, again particularly in those on higher-dose therapy, and is present in 20% of patients diagnosed with iatrogenic Cushing’s syndrome. Patients receiving glucocorticoid therapy are at higher risk of myocardial infarction, angina, stroke, transient ischaemic attack, and heart failure. The risk of developing atrial fibrillation, atrial flutter, and sudden cardiac death is also reportedly higher in patients receiving glucocorticoids. 

Endocrine /metabolic 

Hyperglycaemia is a notable metabolic effect of patients receiving glucocorticoid therapy. The effect is dose-related. In patients without pre-existing diabetes, the largest increase is seen in postprandial blood glucose levels; a less marked increase is also demonstrated in fasting glucose levels. The development of diabetes mellitus as a result of glucocorticoid therapy in patients with previously normal glucose tolerance is rare. In patients with pre-existing diabetes, an increase in blood glucose levels, and thus challenging diabetic control, may be seen. Patients with early previously undiagnosed diabetes or impaired glucose tolerance may develop diabetic ketoacidosis or hyperglycaemic hyperosmolar state. The mechanism by which glucocorticoids result in hyperglycaemia is believed to be attributable to a combination of factors, including receptor functions, increased hepatic gluconeogenesis, and reduced uptake of glucose in adipose tissue. 

A second endocrine effect of glucocorticoids is inhibition of the HPA, with abrupt withdrawal of exogenous glucocorticoid leading to acute adrenal insufficiency and associated hypotension and/or shock. Additional features such as weakness, nausea, vomiting, anorexia, fever and confusion are commonly seen in the event of adrenal crisis.  Thus, a tapering regimen is recommended in patients receiving glucocorticoids for greater than 2 weeks.

Bone

Glucocorticoid use is associated with reduction in bone mineral density leading to osteoporosis. The risk of osteoporotic fracture is also increased. This effect is a result of both increased bone resorption through stimulation of osteoclast proliferation and differentiation, and reduced bone formation as a result of inhibition of osteoblast development. Vertebral fractures are the most common. These phenomena of osteoporosis and fractures are most often seen in the first few months of treatment with glucocorticoids. Osteonecrosis is also seen with high-dose steroid use. The mechanism for this is unclear but one proposed theory is that glucocorticoids stimulate an increase in circulating lipids which result in microembolism within arterial supply to bones. 

Muscle

Occasionally, myopathy is seen as a result of glucocorticoid therapy. This manifests as painless proximal weakness in the upper and lower limbs. The pathogenesis of this relates to both catabolic and anti-anabolic effects of glucocorticoids, likely mediated through muscle glucocorticoid receptors. 

Gastrointestinal 

The main gastrointestinal (GI) side effects of glucocorticoids are gastritis, ulcer formation, and gastrointestinal bleeding. This risk is significantly increased when glucocorticoids are used concurrently with non-steroidal anti-inflammatory drugs (NSAIDs). Further possible GI effects include gastrointestinal tract perforation, hepatic steatosis and even cirrhosis. There is mixed evidence as to whether they may cause acute pancreatitis; some studies suggest that the underlying disease for which glucocorticoids are indicated, for example systemic lupus erythematosus (SLE), is in fact the causative factor making this more likely in patients taking glucocorticoids.

Neuropsychiatric 

Psychiatric and cognitive effects seen include emotional lability, mania, hypomania, depression, psychosis confusion, delirium, and memory impairment. These tend to be dependent on glucocorticoid dose and duration of therapy. Older patients are particularly at increased risk of particular mood and memory disturbances, including depression, mania and hypomania, confusion, delirium and memory impairment. ‘Steroid dementia’ is a term given to a phenomenon whereby severe memory impairment develops in smaller group of patients (approximately 1%), which may persist for up to 11 months following cessation of treatment. Often reported are also disturbances in sleep, which results particularly from evening doses which disrupts the normal diurnal pattern of endogenous cortisol release. 

Mood disorders in glucocorticoid use typically take the form of a sense of euphoria, hypomania, mania, or anxiety within the first few days. Symptoms are more severe in higher-dose therapy. In longer-term therapy, depression is more commonly seen. Psychosis may be seen, but this is almost exclusively seen in patients on long term therapy and high doses (at least 20mg prednisolone per day). These patients tend to respond well to antipsychotic medication. An increased risk of suicide is reported in patients taking glucocorticoids, in particular in younger patient groups (however absolute risk is low). 

Rarer reported neuropsychiatric effects include pseudotumour cerebri, panic disorder and akathisia.

Ophthalmic

The main ophthalmic effects of glucocorticoids are cataract and glaucoma. Cataracts occur in patients on long-term therapy and this is a dose-related effect. Most commonly they are posterior subcapsular cataracts and are usually seen bilaterally. 

Raised intraocular pressure occurs more commonly in patients using topical steroid therapy (i.e. eye drops, and dermatological use on the eyelids and in the periorbital region) but it can also be seen with systemic therapy, particularly in long term use. While the pathogenesis is not certain, it is believed to be a result of reduced drainage through the trabecular meshwork. 

More rarely, lid swelling and exophthalmos can be seen in association with glucocorticoid use. 

Dermatologic 

Skin thinning and bruising are commonly seen and can occur even with low daily doses of glucocorticoid use. The prevalence of these features has been shown to increase with higher doses. 

Cushingoid features of central obesity, moon facies and buffalo hump can be seen within the first two months of glucocorticoid use, but the prevalence again increases with increasing dose and duration of therapy. While the prevalence of Cushingoid features shows a linear effect with relation to dose, weight gain shows a threshold effect, with no significant change in weight seen below 5mg per day or above 7.5mg per day of prednisolone. 

Acne, facial erythema, striae, and hirsutism are additional dermatologic effects seen in association with glucocorticoid use.

Immune 

There is a dose-related increase in the risk of infection with glucocorticoid use. Infectious pathogens are typically common bacteria, viruses and fungi. This is mediated via effects on both innate and acquired immunity. The main mechanisms of glucocorticoid effects on the immune system are via its direct effects on DNA, which result in:

• increased production of anti-inflammatory gene products (e.g. I-kappa-B-alpha, interleukin-1 receptor II)
• blocking the effects of pro-inflammatory genes (e.g. interleukin-1 alpha and beta) 
• inhibition of cytokine synthesis. 

Clinical features of infection may be masked by glucocorticoid use, making it more difficult to detect, as a result of inhibition of cytokine release and dampened inflammatory response.  

Haematologic 

Glucocorticoid therapy induces a leukocytosis, which is largely a neutrophilia. This results from a reduction in the adherence of neutrophils to the vascular endothelium, and increased mobilisation of granulocytes from the bone marrow.

Anti-epileptic drugs

Antiepileptic drugs (AEDs) form a group of drugs that encompasses a wide range of medications which fall into several discrete classes of drugs. The drug classes have differing pharmacological properties and mechanisms of action, and hence differing side effect profiles. Here, some of the commonest mechanisms of action of AEDs will be reviewed, then some of the more commonly used AEDs and their side effect profiles will be discussed individually. 

Mechanisms of action

AEDs may be classified on the basis of their mechanism, although it should be noted that several drugs exert their effects via multiple mechanisms; furthermore, for some specific drugs the mechanism is unknown.

Drugs which block sodium currents

The most common mechanism via which AEDs act is via voltage-gated sodium-channel inhibition. Voltage-gated sodium channels contribute to the generation and propagation of action potentials in neurons. Sodium channels in the brain have roles within both inhibitory interneurons and excitatory neurons. When neurons are hyperpolarised, voltage-gated sodium channels are closed (resting); during depolarisation they open; and they close again and become inactivated in the period after depolarisation. The action of most AEDs which influence voltage-gated sodium channels results from binding when the channel is in the inactivated state, thus prolonging the period of inactivity and delaying the transition from the inactivated state to the resting state. Prolongation of this inactivated state inhibits high-frequency repetitive firing of action potentials. This inhibition of repetitive firing acts to inhibit seizure-related neuron firing.

Examples: 

• Phenytoin
• Carbamazepine
• Lamotrigine
• Oxcarbazepine
• Lacosamide
• Topiramate

Drugs which block calcium currents

AEDs may also act to inhibit voltage-gated calcium channels. There are two ways in which this effect may inhibit seizure activity; first, through inhibition of T-type calcium channels, which are normally involved in the generation of oscillatory neuronal activity in thalamo-cortical pathways, and are of particular benefit in the treatment of absence seizures; second, via inhibition of neuronal N- and P/Q type calcium channels, thus reducing the release of glutamate into the synapse.

Examples:

• Ethosuximide
• Valproate
• Gabapentin
• Pregabalin

Drugs which enhance GABA-ergic chloride currents

GABA is an inhibitory neurotransmitter acting on GABAA and GABAB receptors. GABAA receptors mediate neuronal excitability through tonic and phasic inhibition. Phasic inhibition refers to the modulation of transient, rapidly degrading currents, while modulation of longer-lasting, slowly degrading currents is known as tonic inhibition. GABAergic AEDs act by enhancing inhibitory activity; this is through a variety of effects, including allosteric binding to GABAA which increasing the affinity of GABA binding, increasing the concentration of synaptic GABA, and prolonging the duration and/or increasing the frequency of chloride channel activation that occurs as a result of GABAA activation.

Examples:

• Valproate
• Benzodiazepines
• Vigabatrin
• Topiramate

Drugs which block glutamatergic currents

Glutamate is an excitatory neurotransmitter. Glutamate binds to postsynaptic receptors and hence increase cationic conductance and promote neuronal depolarisation. Although few AEDs act exclusively at glutamate receptors, several exert some of their action via this pathway by blocking receptor binding and blocking excitatory glutamatergic activity. Several AEDs also exert an inhibitory effect on neuronal firing through inhibition of presynaptic glutamate release. This effect is a result of blockade of sodium and calcium channels.

Examples: 

• Topiramate
• Levetiracetam
• Phenobarbital 

Specific AEDs and their associated adverse effects

Benzodiazepines

• Sedation
• Withdrawal seizures with abrupt cessation
• Ataxia
• Dysarthria
• Depressed mood
• Behavioural changes / aggression

Carbamazepine

• Bone marrow suppression
• Toxic epidermal necrolysis (TEN) or Stevens-Johson Syndrome (SJS)
• Hyponatraemia
• Rash
• Fluid retention
• Nausea and vomiting
• Diarrhoea 

Phenytoin / fosphenytoin 

• Gingival hyperplasia 
• Rash – rarely SJS / TEN
• Increase in body hair
• Reduced bone mineral density
• Folate deficiency 
• Confusion 
• Diplopia
• Ataxia 
• Peripheral neuropathy
• Sexual dysfunction 

Valproate

• Nausea and vomiting
• Ecchymosis
• Weight gain
• Metabolic syndrome 
• Thrombocytopenia
• Subclinical hypothyroidism
• Polycystic ovarian syndrome 
• Teratogenic effects 
• Acute liver injury
• Acute pancreatitis
• Hyperammonaemic encephalopathy 

Ethosuximide

• Sleep disturbance
• Sedation
• Nausea and vomiting 

Gabapentin

• Sedation
• Ataxia
• Weight gain
• Risk of respiratory depression in overdose and concurrent opioid administration

Pregabalin

• Sedation
• Ataxia
• Dizziness 
• Increased body habitus
• Fluid retention
• Diplopia 
• Weakness 
• Tremor
• Mood disturbance 

Lacosamide

• PR interval prolongation on electrocardiogram (ECG) – therefore caution advised in patients with pre-existing conduction disease and other medications which may enhance this effect
• Nausea and vomiting
• Ataxia
• Vertigo 

Topiramate

• Cognitive impairment
• Sedation
• Fatigue
• Weight loss 
• Mood disturbance
• Metabolic acidosis
• Renal calculi 
• Reduced bone mineral density
• Ophthalmological effects including acute angle closure glaucoma and acute myopia 

Lamotrigine

• Nausea 
• Dizziness 
• Sedation 
• Rash, including risk of TEN/SJS
• Cardiac arrhythmias 
• Drug reaction with eosinophilia and systemic symptoms (DRESS) (rare) 
• Haemophagocytic lymphohistiocytosis (rare) 
• Disseminated intravascular coagulation (rare) 

Levetiracetam

• Acute behaviour disturbance or psychosis
• Sedation 
• Dizziness 
• Predisposition to upper respiratory tract infections 

Phenobarbital

• Sedation
• Mood disturbance 
• Behavioural change
• Reduced bone mineral density
• Palmar fascia thickening 
• Frozen shoulder 
• Teratogenic effects

Oxcarbazepine

• Sedation 
• Vertigo
• Hyponatraemia
• Headache
• Rash – rarely SJS, TEN
• Anaphylaxis / angioedema (rare) 
• Pancytopenia / agranulocytosis 

Vigabatrin

• Sedation
• Headache
• Dizziness
• Depressed mood
• Increased body habitus 
• Hypersensitivity reactions
• Irreversible visual field defects

First generation anti-psychotic drugs

Antipsychotic medications, used in the treatment of acute psychosis, chronic schizophrenia, bipolar disorder and treatment-resistant depression, are divided into two classes: first-generation (or “typical”) antipsychotics, and second-generation (or “atypical) antipsychotics. 

First- and second-generation antipsychotics differ both in their mechanism of action, and in their side effect profile; however, it should be noted that there exist significant areas of overlap with regards to adverse drug effects between the two classes. Furthermore, individual drug types exhibit differences in their side effect profiles when compared with other members of the same antipsychotic class. Generally speaking, first-generation antipsychotics (FGAs) are more likely to cause extra-pyramidal side effects (EPSEs) and tardive dyskinesias than second-generation antipsychotics (SGAs). While metabolic disturbance is more typically associated with SGAs than FGAs, emerging evidence suggests this in fact occurs in both classes with similar frequency.

Mechanism of action

The primary mechanism of action of FGAs is thought to be via neuronal dopamine-2 (D2) receptor antagonism; activity at muscarinic, histaminergic, 5-HT2a and alpha-1 receptors is also seen. 

Examples

• Haloperidol
• Fluphenazine
• Perphenazine 
• Pimozide
• Thiothixene
• Chlorpromazine
• Thioridazine

Adverse effects

• Extrapyramidal side effects (EPSEs) 
  • Akathisia – motor disturbance resulting in restlessness, an urge for constant movement, often accompanied by visibly excessive movements
  • Parkinsonism – rigidity, tremor, bradykinesia, cogwheeling, hypomimia 
  • Acute dystonias – this refers to involuntary contraction of a muscle group or groups, which is frequently distressing to the patient. Examples include oculogyric crisis, torticollis, opisthotonos and laryngospasm (which may be fatal without appropriate and swift management). 
• Tardive dyskinesias
  • This refers to involuntary, repetitive movements, which may involve the tongue, lips (e.g. lip-smacking), jaw, trunk, and limbs. ‘Writhing’ movements of the torso, limbs or tongue may be seen
  • Often of little concern to the patient
  • Long-term disability or cosmetic deformity may occur if not addressed.
• Metabolic complications – includes weight gain, hyperlipidaemia, diabetes mellitus and cardiovascular sequelae.
• Neuroleptic malignant syndrome – the characteristic features are muscle rigidity, altered mental status, fever and dysautonomia. Rhabdomyolysis may occur. The aetiology is unclear but a previous episode of neuroleptic malignant syndrome appears to be the biggest risk factor. 
• QT prolongation / sudden cardiac death – haloperidol, chlorpromazine and thioridazine are associated with particularly increased risk of QT prolongation. The increased incidence of sudden cardiac death seen with FGAs is attributed to prolonged QT interval. Baseline ECG and annual monitoring of the QT interval is recommended. 
• Anticholinergic side effects – such as dry mouth, urinary retention, constipation, and blurred vision; particularly seen in association with chlorpromazine and thioridazine. 
• Postural hypotension – seen most with chlorpromazine and thioridazine. The mechanism is believed to be secondary to alpha-adrenergic receptor antagonism.
• Agranulocytosis – FGAs carry a very small risk of agranulocytosis, the development of which may be fatal. It has been reported with the use of chlorpromazine, fluphenazine and thioridazine.  
• Hyperprolactinaemia – this may present with menstrual cycle abnormalities, galactorrhoea, and sexual dysfunction. It occurs secondary to dopamine inhibition, hence reducing the dopaminergic inhibition of prolactin release from the anterior pituitary gland. 

Other side effects of FGAs include falls, seizures, increased mortality, sexual dysfunction, retinitis pigmentosa, and cholestatic jaundice.

Second generation anti-psychotic drugs

Mechanism of action

The main mechanism of action of SGAs is via serotonin 5HT2A receptor binding and dopaminergic D2/D3 binding. 

Examples 

• Aripiprazole
• Clozapine 
• Olanzapine
• Paliperidone 
• Quetiapine
• Risperidone

Adverse effects 

• Metabolic syndrome – risk appears highest with clozapine and olanzapine. 
• EPSEs – although the risk is reduced with SGAs as compared with FGAs generally, among SGAs risperidone carries the highest risk of EPSEs. This is more commonly seen at higher doses. 
• Tardive dyskinesias – this is substantially less likely to occur with SGAs than with FGAs. Of the SGAs, risperidone and aripiprazole carry relatively higher risk, while quetiapine carries a lower risk, and clozapine use is not associated with tardive dyskinesias. 
• QT prolongation / sudden cardiac death – may be seen with quetiapine, risperidone and olanzapine 
• Myocarditis / cardiomyopathy – such cardiac complications have been reported with clozapine use and are thought to result from a hypersensitivity reaction. 
• Postural hypotension – this is believed to occur secondary to alpha-adrenergic receptor antagonism and is seen across the SGAs with varying frequencies. 
• Hyperprolactinaemia – risperidone is one of the SGAs most strongly linked to hyperprolactinaemia; in contrast, this is rarely seen with clozapine, aripiprazole or quetiapine.  
• Neuroleptic malignant syndrome – while most strongly linked to FGAs, neuroleptic malignant syndrome has also been demonstrated with SGA use.
• Agranulocytosis – this is a well-recognised side effect of clozapine. Following initiation of clozapine, weekly monitoring of the differentiated white cell count should be performed for 18 weeks; two-weekly for up to 12 months after initiation; then monthly thereafter. 
• Hypersensitivity syndrome – drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with SGA use.
• Anticholinergic side effects – most commonly seen with clozapine, although note that clozapine may more commonly cause sialorrhoea than dry mouth.

Other side effects include cataract, seizures, sedation, sexual dysfunction, falls, increased mortality, and hypothyroidism.

The National Institute for Health and Care Excellence (NICE) recommends monitoring of multiple parameters during antipsychotic therapy, including:  

• Weight
• Waist circumference
• Pulse
• Blood pressure
• Serum lipid levels
• Fasting glucose levels or HbA1c
• Adherence
• Development of movement disorders
• Symptomatic or behavioural changes
• Other reported side effects.