Adverse Drug Reactions (ADRs) refer to the harmful effects associated with the use of a medication at a normal dose. These reactions are classified into two types: Type A and Type B. Type A reactions can be predicted from the pharmacology of the drug and are dose-dependent, meaning they can be reversed by withdrawing the drug. On the other hand, Type B reactions cannot be predicted from the known pharmacology of the drug and include allergic reactions.

Type A reactions account for up to 80% of all ADRs, while Type B reactions are less common. Allergic reactions are a type of Type B reaction and are further subdivided by Gell and Coombs into four types: Type I (IgE-mediated) reactions, Type II (cytotoxic) reactions, Type III (immune complex) reactions, and Type IV (cell-mediated) reactions. Proper identification and management of ADRs are crucial in ensuring patient safety and optimizing treatment outcomes.

Nalmefene is a medication that affects the opioid system by partially activating the κ receptor and blocking the μ and σ receptors. It is believed to reduce the pleasurable effects of alcohol by targeting the mesolimbic system and opioid receptors, helping individuals decrease their alcohol consumption.

Acamprosate works by targeting NMDA and GABA receptors, which can reduce the urge to drink alcohol.

Disulfiram inhibits the enzyme acetaldehyde dehydrogenase, which is involved in breaking down alcohol. If someone drinks alcohol while taking disulfiram, they may experience a severe and potentially deadly reaction due to the buildup of acetaldehyde. Disulfiram is typically used by individuals who have stopped drinking and want to maintain their sobriety.

Naltrexone is a medication that blocks opioid receptors and can be used to treat both opioid and alcohol addiction.

Naloxone is a short-acting medication that blocks opioid receptors and is used in emergency situations to treat opioid overdose.

EPSE’s have been linked to the use of fluoxetine, and all of the treatment options are utilized to address them.

Extrapyramidal side-effects (EPSE’s) are a group of side effects that affect voluntary motor control, commonly seen in patients taking antipsychotic drugs. EPSE’s include dystonias, parkinsonism, akathisia, and tardive dyskinesia. They can be frightening and uncomfortable, leading to problems with non-compliance and can even be life-threatening in the case of laryngeal dystonia. EPSE’s are thought to be due to antagonism of dopaminergic D2 receptors in the basal ganglia. Symptoms generally occur within the first few days of treatment, with dystonias appearing quickly, within a few hours of administration of the first dose. Newer antipsychotics tend to produce less EPSE’s, with clozapine carrying the lowest risk and haloperidol carrying the highest risk. Akathisia is the most resistant EPSE to treat. EPSE’s can also occur when antipsychotics are discontinued (withdrawal dystonia).

To ensure adherence, it is crucial to prescribe medication based on the individual’s needs to prevent sexual issues. Among the options provided, mirtazapine has the least occurrence of sexual dysfunction.

Antidepressants can cause sexual dysfunction as a side-effect, although the rates vary. The impact on sexual desire, arousal, and orgasm can differ depending on the type of antidepressant. It is important to rule out other causes and consider non-pharmacological strategies such as reducing the dosage of taking drug holidays. If necessary, switching to a lower risk antidepressant of using pharmacological options such as phosphodiesterase inhibitors of mirtazapine augmentation can be considered. The Maudsley Guidelines 14th Edition provides a helpful table outlining the risk of sexual dysfunction for different antidepressants.

Out of these options, only the cytotoxic reaction is immunologic and specifically mediated by antibodies.

Adverse Drug Reactions (ADRs) refer to the harmful effects associated with the use of a medication at a normal dose. These reactions are classified into two types: Type A and Type B. Type A reactions can be predicted from the pharmacology of the drug and are dose-dependent, meaning they can be reversed by withdrawing the drug. On the other hand, Type B reactions cannot be predicted from the known pharmacology of the drug and include allergic reactions.

Type A reactions account for up to 80% of all ADRs, while Type B reactions are less common. Allergic reactions are a type of Type B reaction and are further subdivided by Gell and Coombs into four types: Type I (IgE-mediated) reactions, Type II (cytotoxic) reactions, Type III (immune complex) reactions, and Type IV (cell-mediated) reactions. Proper identification and management of ADRs are crucial in ensuring patient safety and optimizing treatment outcomes.

Extrapyramidal side-effects (EPSE’s) are a group of side effects that affect voluntary motor control, commonly seen in patients taking antipsychotic drugs. EPSE’s include dystonias, parkinsonism, akathisia, and tardive dyskinesia. They can be frightening and uncomfortable, leading to problems with non-compliance and can even be life-threatening in the case of laryngeal dystonia. EPSE’s are thought to be due to antagonism of dopaminergic D2 receptors in the basal ganglia. Symptoms generally occur within the first few days of treatment, with dystonias appearing quickly, within a few hours of administration of the first dose. Newer antipsychotics tend to produce less EPSE’s, with clozapine carrying the lowest risk and haloperidol carrying the highest risk. Akathisia is the most resistant EPSE to treat. EPSE’s can also occur when antipsychotics are discontinued (withdrawal dystonia).

Opioid Pharmacology and Treatment Medications

Opioids work by binding to opioid receptors in the brain, specifically the µ, k, and δ receptors. The µ receptor is the main target for opioids and mediates euphoria, respiratory depression, and dependence. Dopaminergic cells in the ventral tegmental area produce dopamine, which is released into the nucleus accumbens upon stimulation of µ receptors, leading to the reward and euphoria that drives repeated use. However, with repeated exposure, µ receptors become less responsive, leading to dysphoria and drug craving.

There are several medications used in opioid treatment. Methadone is a full agonist targeting µ receptors, with some action against k and δ receptors, and has a half-life of 15-22 hours. However, it carries a risk of respiratory depression, especially when used with hypnotics and alcohol. Buprenorphine is a partial agonist targeting µ receptors, as well as a partial k agonist of functional antagonist and a weak δ antagonist. It has a high affinity for µ receptors and a longer half-life of 24-42 hours, making it safer than methadone. Naloxone is an antagonist targeting all opioid receptors and is used to reverse opioid overdose, with a half-life of 30-120 minutes. However, it can cause noncardiogenic pulmonary edema in some cases. Naltrexone is a reversible competitive antagonist at µ and ĸ receptors, with a half-life of 4-6 hours, and is used as an adjunctive prophylactic treatment for detoxified formerly opioid-dependent people.

Alpha2 adrenergic agonists, such as clonidine and lofexidine, can ameliorate opioid withdrawal symptoms associated with the noradrenaline system, including sweating, shivering, and runny nose and eyes. The locus coeruleus, a nucleus in the pons with a high density of noradrenergic neurons possessing µ-opioid receptors, is involved in wakefulness, blood pressure, breathing, and overall alertness. Exposure to opioids results in heightened neuronal activity of the nucleus cells, and if opioids are not present to suppress this activity, increased amounts of norepinephrine are released, leading to withdrawal symptoms. Clonidine was originally developed as an antihypertensive, but its antihypertensive effects are problematic in detox, so lofexidine was developed as an alternative with less hypotensive effects.

Antipsychotics can be classified in different ways, with the most common being typical (first generation) and atypical (second generation) types. Typical antipsychotics block dopamine (D2) receptors and have varying degrees of M1, Alpha-1, and H1 receptor blockade. Atypical antipsychotics have a lower propensity for extrapyramidal side-effects and are attributed to the combination of relatively lower D2 antagonism with 5HT2A antagonism. They are also classified by structure, with examples including phenothiazines, butyrophenones, thioxanthenes, diphenylbutylpiperidine, dibenzodiazepines, benzoxazoles, thienobenzodiazepine, substituted benzamides, and arylpiperidylindole (quinolone). Studies have found little evidence to support the superiority of atypicals over typicals in terms of efficacy, discontinuation rates, of adherence, with the main difference being the side-effect profile. The Royal College also favors classification by structure.

Tricyclic Antidepressants: Uses, Types, and Side-Effects

Tricyclic antidepressants (TCAs) are a type of medication used for depression and neuropathic pain. However, due to their side-effects and toxicity in overdose, they are not commonly used for depression anymore. TCAs can be divided into two types: first generation (tertiary amines) and second generation (secondary amines). The secondary amines have a lower side effect profile and act primarily on noradrenaline, while the tertiary amines boost serotonin and noradrenaline.

Some examples of secondary amines include desipramine, nortriptyline, protriptyline, and amoxapine. Examples of tertiary amines include amitriptyline, lofepramine, imipramine, clomipramine, dosulepin (dothiepin), doxepin, trimipramine, and butriptyline. Common side-effects of TCAs include drowsiness, dry mouth, blurred vision, constipation, and urinary retention.

Low-dose amitriptyline is commonly used for neuropathic pain and prophylaxis of headache. Lofepramine has a lower incidence of toxicity in overdose. However, amitriptyline and dosulepin (dothiepin) are considered the most dangerous in overdose. It is important to consult with a healthcare provider before taking any medication and to follow their instructions carefully.

Serotonin Syndrome and Neuroleptic Malignant Syndrome are two conditions that can be difficult to differentiate. Serotonin Syndrome is caused by excess serotonergic activity in the CNS and is characterized by neuromuscular abnormalities, altered mental state, and autonomic dysfunction. On the other hand, Neuroleptic Malignant Syndrome is a rare acute disorder of thermoregulation and neuromotor control that is almost exclusively caused by antipsychotics. The symptoms of both syndromes can overlap, but there are some distinguishing clinical features. Hyper-reflexia, ocular clonus, and tremors are more prominent in Serotonin Syndrome, while Neuroleptic Malignant Syndrome is characterized by uniform ‘lead-pipe’ rigidity and hyporeflexia. Symptoms of Serotonin Syndrome usually resolve within a few days of stopping the medication, while Neuroleptic Malignant Syndrome can take up to 14 days to remit with appropriate treatment. The following table provides a useful guide to the main differentials of Serotonin Syndrome and Neuroleptic Malignant Syndrome.

Antipsychotics are commonly used to treat various mental health conditions. Most atypical antipsychotics require twice daily administration due to their short half-lives, except for olanzapine, aripiprazole, and risperidone. These medications have longer half-lives and can be administered once daily. A recent randomized controlled trial compared once versus twice daily dosing of risperidone and olanzapine and found no significant difference in effectiveness and efficacy outcomes. However, the study suggests that once-daily dosing may be preferable due to lower mean dose and better side effect profile, especially for olanzapine.

Direct contact with chlorpromazine should be avoided by pharmacists and nurses due to its association with contact dermatitis.

Antipsychotic Half-life and Time to Steady State

Antipsychotic medications are commonly used to treat various mental health conditions, including schizophrenia and bipolar disorder. Understanding the half-life and time to steady state of these medications is important for determining dosing and monitoring their effectiveness.

Aripiprazole has a half-life of 75 hours and takes approximately 2 weeks to reach steady state. Olanzapine has a half-life of 30 hours and takes about 1 week to reach steady state. Risperidone has a half-life of 20 hours when taken orally and takes 2-3 days to reach steady state. Clozapine and Amisulpride both have a half-life of 12 hours and take 2-3 days to reach steady state. Ziprasidone has a shorter half-life of 7 hours and takes 2-3 days to reach steady state. Quetiapine has the shortest half-life of 6 hours and also takes 2-3 days to reach steady state.

Knowing the half-life and time to steady state of antipsychotic medications can help healthcare providers determine the appropriate dosing and frequency of administration. It can also aid in monitoring the effectiveness of the medication and adjusting the treatment plan as needed.

The ‘cheese reaction’ is a potential adverse effect of phenelzine, a type of medication known as a monoamine oxidase inhibitor (MAOI). When a person takes phenelzine, foods that contain high levels of tyramine are not broken down properly due to the inhibition of MAO. This causes tyramine to enter the bloodstream and trigger the release of noradrenaline, which can lead to dangerous spikes in blood pressure.

The term ‘cheese reaction’ comes from the fact that many types of cheese are particularly high in tyramine. While early MAOIs irreversibly inhibit monoamine oxidase, newer medications like moclobemide are reversible and considered to be safer.

Prescribing in the Elderly: Iatrogenic Consequences

Many medications, both prescribed and over-the-counter, can have significant adverse effects in the elderly population. It is important to note that the lists provided below are not exhaustive, and only the most common and important examples are given.

Medications Linked to Delirium and Other Cognitive Disorders

Medications are the most common reversible cause of delirium and dementia in the elderly. Many medications can cause cognitive impairment, but the classes of drugs most strongly associated with the development of drug-induced dementia are opioids, benzodiazepines, and anticholinergics.

According to a systematic review done in 2011 (Clegg, 2011), long-acting benzodiazepines (e.g., diazepam) are more troublesome than those that are shorter-acting. Opioids are associated with an approximately 2-fold increased risk of delirium in medical and surgical patients (Clegg, 2011). Pethidine appears to have a higher risk of delirium compared with other members of the opioid class. This may be because pethidine can accumulate when renal function is impaired and is converted to a metabolite with anticholinergic properties.

Some antipsychotic drugs have considerable antimuscarinic (anticholinergic) activity (e.g., chlorpromazine and clozapine), which may cause of worsen delirium. Delirium is uncommon in newer antipsychotics (but has been reported).

Medications Linked to Mood Changes

The following medications are well known to precipitate mood changes:

– Centrally-acting antihypertensives (e.g., methyldopa, reserpine, and clonidine) can cause depressive symptoms.
– Interferon-a is capable of inducing depressive symptoms.
– Digoxin is capable of inducing depressive symptoms.
– Corticosteroids can cause depressive, manic, and mixed symptoms with of without psychosis.
– Antidepressants can precipitate mania.

Medications Linked to Psychosis

The following medications are well known to precipitate psychosis:

– Anti-Parkinson’s Medications (e.g., bromocriptine, amantadine, selegiline, anticholinergics (e.g., trihexyphenidyl, benztropine, benzhexol), and levodopa).
– Corticosteroids

Medications Linked to Anxiety

The following medications are well known to precipitate anxiety:

– Stimulants
– β adrenergic inhalers

Phenytoin, carbamazepine, and lamotrigine stabilize Na channels, while valproate, benzodiazepines, and z-drugs act on GABA receptors. Topiramate has a dual action by combining both mechanisms. The exact way in which GABA receptors are affected is not fully understood, as gabapentin does not bind to them of affect GABA synthesis of uptake. Instead, gabapentin binds to various sites in the brain associated with voltage-gated calcium channels, particularly alpha-2-delta-1, which appears to inhibit the release of excitatory neurotransmitters in the presynaptic area.

Mechanisms of Action of Different Drugs

Understanding the mechanisms of action of different drugs is crucial for medical professionals. It is a common topic in exams and can earn easy marks if studied well. This article provides a list of drugs and their mechanisms of action in different categories such as antidepressants, anti dementia drugs, mood stabilizers, anxiolytic/hypnotic drugs, antipsychotics, drugs of abuse, and other drugs. For example, mirtazapine is a noradrenaline and serotonin specific antidepressant that works as a 5HT2 antagonist, 5HT3 antagonist, H1 antagonist, alpha 1 and alpha 2 antagonist, and moderate muscarinic antagonist. Similarly, donepezil is a reversible acetylcholinesterase inhibitor used as an anti dementia drug, while valproate is a GABA agonist and NMDA antagonist used as a mood stabilizer. The article also explains the mechanisms of action of drugs such as ketamine, phencyclidine, buprenorphine, naloxone, atomoxetine, varenicline, disulfiram, acamprosate, and sildenafil.

Side effects of sildenafil (viagra) that occur frequently (affecting more than 1 in 10 people) include:

Antidepressants can cause sexual dysfunction as a side-effect, although the rates vary. The impact on sexual desire, arousal, and orgasm can differ depending on the type of antidepressant. It is important to rule out other causes and consider non-pharmacological strategies such as reducing the dosage of taking drug holidays. If necessary, switching to a lower risk antidepressant of using pharmacological options such as phosphodiesterase inhibitors of mirtazapine augmentation can be considered. The Maudsley Guidelines 14th Edition provides a helpful table outlining the risk of sexual dysfunction for different antidepressants.

It is advisable to avoid agents with longer half lives as they have a tendency to induce drowsiness in patients.

Benzodiazepines are a class of drugs commonly used to treat anxiety and sleep disorders. It is important to have a working knowledge of the more common benzodiazepines and their half-life. Half-life refers to the amount of time it takes for half of the drug to be eliminated from the body.

Some of the more common benzodiazepines and their half-life include diazepam with a half-life of 20-100 hours, clonazepam with a half-life of 18-50 hours, chlordiazepoxide with a half-life of 5-30 hours, nitrazepam with a half-life of 15-38 hours, temazepam with a half-life of 8-22 hours, lorazepam with a half-life of 10-20 hours, alprazolam with a half-life of 10-15 hours, oxazepam with a half-life of 6-10 hours, zopiclone with a half-life of 5-6 hours, zolpidem with a half-life of 2 hours, and zaleplon with a half-life of 2 hours. Understanding the half-life of these drugs is important for determining dosages and timing of administration.

Certain substances can either induce or inhibit the activity of enzymes responsible for metabolizing drugs in the body. Inducers include smoking, alcohol, barbiturates, carbamazepine, Phenytoin, and St John’s Wort, while inhibitors include chlorpromazine, SSRIs, and grapefruit juice.

The Cytochrome P450 system is a group of enzymes that metabolize drugs by altering their functional groups. The system is located in the liver and small intestine and is involved in drug interactions through enzyme induction of inhibition. Notable inducers include smoking, alcohol, and St John’s Wort, while notable inhibitors include grapefruit juice and some SSRIs. CYP2D6 is important due to genetic polymorphism, and CYP3A4 is the most abundant subfamily and is commonly involved in interactions. Grapefruit juice inhibits both CYP1A2 and CYP3A4, while tobacco smoking induces CYP1A2. The table summarizes the main substrates, inhibitors, and inducers for each CYP enzyme.

Teratogens and Their Associated Defects

Valproic acid is a teratogen that has been linked to various birth defects, including neural tube defects, hypospadias, cleft lip/palate, cardiovascular abnormalities, developmental delay, endocrinological disorders, limb defects, and autism (Alsdorf, 2005). Lithium has been associated with cardiac anomalies, specifically Ebstein’s anomaly. Alcohol consumption during pregnancy can lead to cleft lip/palate and fetal alcohol syndrome. Phenytoin has been linked to fingernail hypoplasia, craniofacial defects, limb defects, cerebrovascular defects, and mental retardation. Similarly, carbamazepine has been associated with fingernail hypoplasia and craniofacial defects. Diazepam has been linked to craniofacial defects, specifically cleft lip/palate (Palmieri, 2008). The evidence for steroids causing craniofacial defects is not convincing, according to the British National Formulary (BNF). Selective serotonin reuptake inhibitors (SSRIs) have been associated with congenital heart defects and persistent pulmonary hypertension (BNF). It is important for pregnant women to avoid exposure to these teratogens to reduce the risk of birth defects in their babies.

Individuals with hepatic impairment should avoid taking agomelatine and duloxetine due to contraindications. It is recommended to avoid sedative TCAs, such as trimipramine, imipramine, dothiepin, and amitriptyline.

Hepatic Impairment: Recommended Drugs

Patients with hepatic impairment may experience reduced ability to metabolize drugs, toxicity, enhanced dose-related side effects, reduced ability to synthesize plasma proteins, and elevated levels of drugs subject to first-pass metabolism due to reduced hepatic blood flow. The Maudsley Guidelines 14th Ed recommends the following drugs for patients with hepatic impairment:

Antipsychotics: Paliperidone (if depot required), Amisulpride, Sulpiride

Antidepressants: Sertraline, Citalopram, Paroxetine, Vortioxetine (avoid TCA and MAOI)

Mood stabilizers: Lithium

Sedatives: Lorazepam, Oxazepam, Temazepam, Zopiclone 3.75mg (with care)

Pharmacological management of dementia involves the use of acetylcholinesterase inhibitors (AChE inhibitors) and memantine. AChE inhibitors prevent the breakdown of acetylcholine, which is deficient in Alzheimer’s due to the loss of cholinergic neurons. Donepezil, galantamine, and rivastigmine are commonly used AChE inhibitors in the management of Alzheimer’s. However, gastrointestinal side effects such as nausea and vomiting are common with these drugs.

Memantine, on the other hand, is an NMDA receptor antagonist that blocks the effects of pathologically elevated levels of glutamate that may lead to neuronal dysfunction. It has a half-life of 60-100 hours and is primarily renally eliminated. Common adverse effects of memantine include somnolence, dizziness, hypertension, dyspnea, constipation, headache, and elevated liver function tests.

Overall, pharmacological management of dementia aims to improve cognitive function and slow down the progression of the disease. However, it is important to note that these drugs do not cure dementia and may only provide temporary relief of symptoms.

Although many drugs are metabolized by CYP1A2, grapefruit juice does not have a significant effect on the metabolism of lithium, as the majority of lithium is excreted without undergoing significant metabolic changes.

The Cytochrome P450 system is a group of enzymes that metabolize drugs by altering their functional groups. The system is located in the liver and small intestine and is involved in drug interactions through enzyme induction of inhibition. Notable inducers include smoking, alcohol, and St John’s Wort, while notable inhibitors include grapefruit juice and some SSRIs. CYP2D6 is important due to genetic polymorphism, and CYP3A4 is the most abundant subfamily and is commonly involved in interactions. Grapefruit juice inhibits both CYP1A2 and CYP3A4, while tobacco smoking induces CYP1A2. The table summarizes the main substrates, inhibitors, and inducers for each CYP enzyme.

Alcohol withdrawal is a common issue in the UK, and Chlordiazepoxide (Librium) is a benzodiazepine that is frequently used to treat it. This medication is safe, effective, and allows for flexible dosing. Acamprosate is another medication that is licensed for the treatment of alcohol cravings, while Carbamazepine may be used in cases where there is a risk of withdrawal seizures. Chlormethiazole, also known as Heminevrin, was once widely used for alcohol withdrawal but is now less commonly used due to its relative toxicity. Chlorpromazine, a typical antipsychotic, is not typically used in uncomplicated cases of alcohol withdrawal.

If an individual is taking lithium regularly, a steady state level should be achieved within a week. If there are unexpected changes in the serum lithium level in an otherwise healthy person, it may indicate non-compliance with medication. The concomitant use of NSAIDs is unlikely to cause a significant increase in serum lithium levels, and mild renal impairment of normal plasma urea levels would not typically result in such an increase. Additionally, a normal pharmacokinetic profile would be expected to reach a steady state level after a week of regular dosing. Normal plasma urea levels suggest that dehydration is not a likely cause of the changes in serum lithium levels.

Disinhibitory Drug Reactions: Understanding Paradoxical Reactions to Benzodiazepines

Benzodiazepines are commonly prescribed for anxiety and sleep disorders, but they are also associated with paradoxical reactions, also known as disinhibitory reactions. These reactions are unexpected increases in aggressive behavior, sexual disinhibition, hyperactivity, vivid dreams, and hostility. However, the prevalence of these reactions is difficult to determine, as study findings vary widely from 1% to 58%.

Certain factors increase the risk of paradoxical reactions, including a history of aggression of poor impulse control, extremes of age (elderly of young), benzodiazepines with short half-lives, high doses of benzodiazepines, and intravenous administration of benzodiazepines. It is important to record these reactions, and if they are severe, it is advisable to avoid future use of benzodiazepines.

Priapism: A Painful and Persistent Erection

Priapism is a condition characterized by a prolonged and painful erection, which can occur in males and even in the clitoris. Although rare, certain medications such as antipsychotics and antidepressants have been known to cause priapism. The primary mechanism behind this condition is alpha blockade, although other mechanisms such as serotonin-mediated pathways have also been suggested. Some of the drugs most commonly associated with priapism include Trazodone, Chlorpromazine, and Thioridazine. Treatment involves the use of alpha-adrenergic agonists, which can be administered orally of injected directly into the penis. Priapism is a serious condition that can lead to complications such as penile amputation, although such cases are extremely rare.

Antidepressants: Mechanism of Action

Antidepressants are a class of drugs used to treat depression and other mood disorders. The mechanism of action of antidepressants varies depending on the specific drug. Here are some examples:

Mirtazapine is a noradrenaline and serotonin specific antidepressant (NaSSa). It works by blocking certain receptors in the brain, including 5HT-1, 5HT-2, 5HT-3, and H1 receptors. It also acts as a presynaptic alpha 2 antagonist, which stimulates the release of noradrenaline and serotonin.

Venlafaxine and duloxetine are both serotonin and noradrenaline reuptake inhibitors (SNRIs). They work by blocking the reuptake of these neurotransmitters, which increases their availability in the brain.

Reboxetine is a noradrenaline reuptake inhibitor (NRI). It works by blocking the reuptake of noradrenaline, which increases its availability in the brain.

Bupropion is a noradrenaline and dopamine reuptake inhibitor (NDRI). It works by blocking the reuptake of these neurotransmitters, which increases their availability in the brain.

Trazodone is a weak serotonin reuptake inhibitor (SRI) and 5HT agonist. It works by increasing the availability of serotonin in the brain.

St John’s Wort is a natural supplement that has been used to treat depression. It has a weak monoamine oxidase inhibitor (MAOI) effect and a weak SNRI effect.

In summary, antidepressants work by increasing the availability of certain neurotransmitters in the brain, such as serotonin, noradrenaline, and dopamine. The specific mechanism of action varies depending on the drug.

The sole anticholinergic side effect is memory impairment, while the remaining choices are instances of cholinergic side effects.

Receptors and Side-Effects

Histamine H1 Blockade:
– Weight gain
– Sedation

Alpha 1 Blockade:
– Orthostatic hypotension
– Sedation
– Sexual dysfunction
– Priapism

Muscarinic Central M1 Blockade:
– Agitation
– Delirium
– Memory impairment
– Confusion
– Seizures

Muscarinic Peripheral M1 Blockade:
– Dry mouth
– Ataxia
– Blurred vision
– Narrow angle glaucoma
– Constipation
– Urinary retention
– Tachycardia

Each receptor has specific effects on the body, but they can also have side-effects. Histamine H1 blockade can cause weight gain and sedation. Alpha 1 blockade can lead to orthostatic hypotension, sedation, sexual dysfunction, and priapism. Muscarinic central M1 blockade can cause agitation, delirium, memory impairment, confusion, and seizures. Muscarinic peripheral M1 blockade can result in dry mouth, ataxia, blurred vision, narrow angle glaucoma, constipation, urinary retention, and tachycardia. It is important to be aware of these potential side-effects when using medications that affect these receptors.

Clomipramine as a Second-Line Treatment for OCD

Paragraph: Clomipramine is a tricyclic antidepressant (TCA) that has a high affinity for serotonin receptors, making it the most serotonergic TCA. The National Institute for Health and Care Excellence (NICE) guidelines recommend clomipramine as a second-line treatment for obsessive-compulsive disorder (OCD). However, patients may find antimuscarinic side effects, such as dry mouth and constipation, difficult to tolerate. It is worth noting that using TCAs for nerve and chronic pain is not an approved indication.

EPSE’s occur as a result of the inhibition of dopaminergic D2 receptors in the basal ganglia. The administration of a dopamine antagonist would exacerbate EPSE’s. Antipsychotics function as dopamine antagonists.

Extrapyramidal side-effects (EPSE’s) are a group of side effects that affect voluntary motor control, commonly seen in patients taking antipsychotic drugs. EPSE’s include dystonias, parkinsonism, akathisia, and tardive dyskinesia. They can be frightening and uncomfortable, leading to problems with non-compliance and can even be life-threatening in the case of laryngeal dystonia. EPSE’s are thought to be due to antagonism of dopaminergic D2 receptors in the basal ganglia. Symptoms generally occur within the first few days of treatment, with dystonias appearing quickly, within a few hours of administration of the first dose. Newer antipsychotics tend to produce less EPSE’s, with clozapine carrying the lowest risk and haloperidol carrying the highest risk. Akathisia is the most resistant EPSE to treat. EPSE’s can also occur when antipsychotics are discontinued (withdrawal dystonia).

Clozapine is an atypical antipsychotic drug that acts as an antagonist at various receptors, including dopamine, histamine, serotonin, adrenergic, and cholinergic receptors. It is mainly metabolized by CYP1A2, and its plasma levels can be affected by inducers and inhibitors of this enzyme. Clozapine is associated with several side effects, including drowsiness, constipation, weight gain, and hypersalivation. Hypersalivation is a paradoxical side effect, and its mechanism is not fully understood, but it may involve clozapine agonist activity at the muscarinic M4 receptor and antagonist activity at the alpha-2 adrenoceptor. Clozapine is also associated with several potentially dangerous adverse events, including agranulocytosis, myocarditis, seizures, severe orthostatic hypotension, increased mortality in elderly patients with dementia-related psychosis, colitis, pancreatitis, thrombocytopenia, thromboembolism, and insulin resistance and diabetes mellitus. The BNF advises caution in using clozapine in patients with prostatic hypertrophy, susceptibility to angle-closure glaucoma, and adults over 60 years. Valproate should be considered when using high doses of clozapine, plasma levels > 0.5 mg/l, of when the patient experiences seizures. Myocarditis is a rare but potentially fatal adverse event associated with clozapine use, and its diagnosis is based on biomarkers and clinical features. The mortality rate of clozapine-induced myocarditis is high, and subsequent use of clozapine in such cases leads to recurrence of myocarditis in most cases.

The alpha adrenergic antagonism caused by Trazodone can lead to priapism. Trazodone is an antidepressant that is similar to tricyclics and is commonly prescribed for depression with anxiety and the need for sedation.

Mechanisms of Action of Different Drugs

Understanding the mechanisms of action of different drugs is crucial for medical professionals. It is a common topic in exams and can earn easy marks if studied well. This article provides a list of drugs and their mechanisms of action in different categories such as antidepressants, anti dementia drugs, mood stabilizers, anxiolytic/hypnotic drugs, antipsychotics, drugs of abuse, and other drugs. For example, mirtazapine is a noradrenaline and serotonin specific antidepressant that works as a 5HT2 antagonist, 5HT3 antagonist, H1 antagonist, alpha 1 and alpha 2 antagonist, and moderate muscarinic antagonist. Similarly, donepezil is a reversible acetylcholinesterase inhibitor used as an anti dementia drug, while valproate is a GABA agonist and NMDA antagonist used as a mood stabilizer. The article also explains the mechanisms of action of drugs such as ketamine, phencyclidine, buprenorphine, naloxone, atomoxetine, varenicline, disulfiram, acamprosate, and sildenafil.

Dextromethorphan is a medication used to suppress coughing and is commonly found in various cold and cough remedies available without a prescription. It is important to note that it can interact with MAOIs, which are a type of medication used to treat depression and other mental health conditions.

MAOIs: A Guide to Mechanism of Action, Adverse Effects, and Dietary Restrictions

First introduced in the 1950s, MAOIs were the first antidepressants introduced. However, they are not the first choice in treating mental health disorders due to several dietary restrictions and safety concerns. They are only a treatment option when all other medications are unsuccessful. MAOIs may be particularly useful in atypical depression (over eating / over sleeping, mood reactivity).

MAOIs block the monoamine oxidase enzyme, which breaks down different types of neurotransmitters from the brain: norepinephrine, serotonin, dopamine, as well as tyramine. There are two types of monoamine oxidase, A and B. The MOA A are mostly distributed in the placenta, gut, and liver, but MOA B is present in the brain, liver, and platelets. Selegiline and rasagiline are irreversible and selective inhibitors of MAO type B, but safinamide is a reversible and selective MAO B inhibitor.

The most common adverse effects of MAOIs occurring early in treatment are orthostatic hypotension, daytime sleepiness, insomnia, and nausea; later common effects include weight gain, muscle pain, myoclonus, paraesthesia, and sexual dysfunction.

Pharmacodynamic interactions with MAOIs can cause two types of problem: serotonin syndrome (mainly due to SSRIs) and elevated blood pressure (caused by indirectly acting sympathomimetic amines releasers, like pseudoephedrine and phenylephrine). The combination of MAOIs and some TCAs appears safe. Only those TCAs with significant serotonin reuptake inhibition (clomipramine and imipramine) are likely to increase the risk of serotonin syndrome.

Tyramine is a monoamine found in various foods, and is an indirect sympathomimetic that can cause a hypertensive reaction in patients receiving MAOI therapy. For this reason, dietary restrictions are required for patients receiving MAOIs. These restrictions include avoiding matured/aged cheese, fermented sausage, improperly stored meat, fava of broad bean pods, and certain drinks such as on-tap beer. Allowed foods include fresh cottage cheese, processed cheese slices, fresh packaged of processed meat, and other alcohol (no more than two bottled or canned beers of two standard glasses of wine, per day).

Antidepressants and Weight Gain

Studies suggest that certain types of antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), may be more likely to cause weight gain than newer antidepressants like selective serotonin reuptake inhibitors (SSRIs). However, mirtazapine, a newer antidepressant, may have a similar risk for weight gain as TCAs. Among SSRIs, paroxetine may have a higher risk for weight gain during long-term treatment compared to other SSRIs. On the other hand, bupropion and nefazodone may have a lower risk for weight gain than SSRIs in the long term.

The ‘Z drugs’ (zopiclone, zolpidem, zaleplon) are beneficial for nighttime sedation due to their relatively brief half-lives.

Benzodiazepines are a class of drugs commonly used to treat anxiety and sleep disorders. It is important to have a working knowledge of the more common benzodiazepines and their half-life. Half-life refers to the amount of time it takes for half of the drug to be eliminated from the body.

Some of the more common benzodiazepines and their half-life include diazepam with a half-life of 20-100 hours, clonazepam with a half-life of 18-50 hours, chlordiazepoxide with a half-life of 5-30 hours, nitrazepam with a half-life of 15-38 hours, temazepam with a half-life of 8-22 hours, lorazepam with a half-life of 10-20 hours, alprazolam with a half-life of 10-15 hours, oxazepam with a half-life of 6-10 hours, zopiclone with a half-life of 5-6 hours, zolpidem with a half-life of 2 hours, and zaleplon with a half-life of 2 hours. Understanding the half-life of these drugs is important for determining dosages and timing of administration.

Biogenic Amines: Understanding the Neurotransmitters

Biogenic amines are a class of compounds that are derived from amino acids. These compounds play a crucial role in the functioning of the nervous system. Biogenic amine neurotransmitters include catecholamines (adrenaline, noradrenaline, and dopamine), serotonin, and histamine. A useful mnemonic to remember these neurotransmitters is HANDS (Histamine, Adrenaline, Noradrenaline, Dopamine, Serotonin).

Catecholamines are involved in the body’s response to stress and are responsible for the fight or flight response. Adrenaline and noradrenaline are catecholamines that are released by the adrenal glands in response to stress. Dopamine is involved in the reward system of the brain and is associated with pleasure and motivation.

Serotonin is a neurotransmitter that is involved in mood regulation, appetite, and sleep. It is also involved in the regulation of pain and the perception of pain.

Histamine is involved in the immune response and is responsible for the symptoms of allergies. It is also involved in the regulation of sleep and wakefulness.

Understanding the role of biogenic amines in the nervous system is crucial for the development of treatments for neurological and psychiatric disorders.

Haloperidol causes a significant prolongation of the QTc interval, resulting in a ‘high effect’. This effect is observed even at normal doses, with a prolongation of more than 20 msec. In contrast, aripiprazole, Mirtazapine, and paliperidone do not affect the QTc interval. Additionally, most SSRIs do not have an impact on the QTc interval, except for citalopram.

Stevens-Johnson syndrome (SJS) is a rare but life-threatening skin reaction disease, often caused by carbamazepine. Symptoms include widespread blisters, flat atypical targets-shaped lesions, erythema, necrosis, and extensive sloughing of the epidermis. Patients may experience fever, myalgia, and general weakness for 1 to 3 days before the development of cutaneous lesions. Hospitalization may be necessary for serious dermatological reactions, which can be fatal. SJS/TEN cases typically occur within the first few months of treatment, with a median latency period of 15 days for the development of SJS with carbamazepine. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. It is important to note that skin lesions are usually preceded by fever and malaise by 1-3 days in patients newly prescribed carbamazepine. Immediate discontinuation of the causative agent is essential once identified.

Carbamazepine: Uses, Mechanism of Action, Contraindications, Warnings, and Side-Effects

Carbamazepine, also known as Tegretol, is a medication commonly used in the treatment of epilepsy, particularly partial seizures. It is also used for neuropathic pain, bipolar disorder, and other conditions. The drug works by binding to sodium channels and increasing their refractory period.

However, carbamazepine has notable contraindications, including a history of bone marrow depression and combination with monoamine oxidase inhibitors (MAOIs). It also carries warnings for serious dermatological reactions such as toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome.

Common side-effects of carbamazepine include leucopenia, ataxia, dizziness, somnolence, vomiting, nausea, urticaria, and fatigue. Other side-effects include thrombocytopenia, eosinophilia, oedema, fluid retention, weight increase, hyponatraemia, and blood osmolarity decreased due to an antidiuretic hormone (ADH)-like effect, leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, confusional state, neurological disorders, diplopia, accommodation disorders (e.g. blurred vision), and dry mouth.

In summary, carbamazepine is a medication with multiple uses, but it also carries significant contraindications, warnings, and side-effects that should be carefully considered before use.

Antidepressants have varying half lives, with fluoxetine having one of the longest at four to six days. Agomelatine, on the other hand, has a much shorter half life of approximately one to two hours. Citalopram has a half life of approximately 36 hours, while duloxetine has a half life of approximately 12 hours. Paroxetine falls in the middle with a half life of approximately 24 hours. For more information on antidepressant discontinuation syndrome, refer to the article by Warner et al. (2006).

Lithium has a tendency to remain unattached to proteins and instead remains unbound within the body, resulting in its efficient elimination from the bloodstream through haemodialysis.

Lithium – Pharmacology

Pharmacokinetics:
Lithium salts are rapidly absorbed following oral administration and are almost exclusively excreted by the kidneys unchanged. Blood samples for lithium should be taken 12 hours post-dose.

Ebstein’s:
Ebstein’s anomaly is a congenital malformation consisting of a prolapse of the tricuspid valve into the right ventricle. It occurs in 1:20,000 of the general population. Initial data suggested it was more common in those using lithium but this had not held to be true.

Contraindications:
Addison’s disease, Brugada syndrome, cardiac disease associated with rhythm disorders, clinically significant renal impairment, untreated of untreatable hypothyroidism, low sodium levels.

Side-effects:
Common side effects include nausea, tremor, polyuria/polydipsia, rash/dermatitis, blurred vision, dizziness, decreased appetite, drowsiness, metallic taste, and diarrhea. Side-effects are often dose-related.

Long-term use is associated with hypothyroidism, hyperthyroidism, hypercalcemia/hyperparathyroidism, irreversible nephrogenic diabetes insipidus, and reduced GFR.

Lithium-induced diabetes insipidus:
Treatment options include stopping lithium (if feasible), keeping levels within 0.4-0.8 mmol/L, once-daily dose of the drug taken at bedtime, amiloride, thiazide diuretics, indomethacin, and desmopressin.

Toxicity:
Lithium salts have a narrow therapeutic/toxic ratio. Risk factors for lithium toxicity include drugs altering renal function, decreased circulating volume, infections, fever, decreased oral intake of water, renal insufficiency, and nephrogenic diabetes insipidus. Features of lithium toxicity include GI symptoms and neuro symptoms.

Pre-prescribing:
Before prescribing lithium, renal function, cardiac function, thyroid function, FBC, and BMI should be checked. Women of childbearing age should be advised regarding contraception, and information about toxicity should be provided.

Monitoring:
Lithium blood levels should be checked weekly until stable, and then every 3-6 months once stable. Thyroid and renal function should be checked every 6 months. Patients should be issued with an information booklet, alert card, and record book.

Out of the given options, amisulpride is the most suitable medication as it is not extensively metabolized by the liver. However, it should be avoided in individuals with established renal failure as a normal glomerular filtration rate is considered to be >90 ml/min/1.73m2.

Hepatic Impairment: Recommended Drugs

Patients with hepatic impairment may experience reduced ability to metabolize drugs, toxicity, enhanced dose-related side effects, reduced ability to synthesize plasma proteins, and elevated levels of drugs subject to first-pass metabolism due to reduced hepatic blood flow. The Maudsley Guidelines 14th Ed recommends the following drugs for patients with hepatic impairment:

Antipsychotics: Paliperidone (if depot required), Amisulpride, Sulpiride

Antidepressants: Sertraline, Citalopram, Paroxetine, Vortioxetine (avoid TCA and MAOI)

Mood stabilizers: Lithium

Sedatives: Lorazepam, Oxazepam, Temazepam, Zopiclone 3.75mg (with care)

Memantine is a type of medication that works by blocking the NMDA receptors in the brain. These receptors are activated by glutamate, a neurotransmitter that is involved in many important brain functions. However, in some individuals, these receptors can become hypersensitive to glutamate, leading to excessive activation and the death of nerve cells. This is known as excitotoxicity.

Memantine works by decreasing the sensitivity of the NMDA receptors to glutamate. It does this by binding to a different site on the receptor than glutamate does, which changes the shape of the receptor and makes it more difficult for glutamate to bind. This prevents excessive activation of the NMDA receptors and helps to protect nerve cells from damage. Memantine is known as a non-competitive antagonist because it binds to a different site on the receptor than the neurotransmitter it is blocking.

Mechanisms of Action of Different Drugs

Understanding the mechanisms of action of different drugs is crucial for medical professionals. It is a common topic in exams and can earn easy marks if studied well. This article provides a list of drugs and their mechanisms of action in different categories such as antidepressants, anti dementia drugs, mood stabilizers, anxiolytic/hypnotic drugs, antipsychotics, drugs of abuse, and other drugs. For example, mirtazapine is a noradrenaline and serotonin specific antidepressant that works as a 5HT2 antagonist, 5HT3 antagonist, H1 antagonist, alpha 1 and alpha 2 antagonist, and moderate muscarinic antagonist. Similarly, donepezil is a reversible acetylcholinesterase inhibitor used as an anti dementia drug, while valproate is a GABA agonist and NMDA antagonist used as a mood stabilizer. The article also explains the mechanisms of action of drugs such as ketamine, phencyclidine, buprenorphine, naloxone, atomoxetine, varenicline, disulfiram, acamprosate, and sildenafil.

The Bazett formula adjusts the QT interval for heart rate by taking the square root of the R-R interval and dividing the QT interval by it.

QTc Prolongation: Risks and Identification

The QT interval is a measure of the time it takes for the ventricles to repolarize and is calculated from the beginning of the QRS complex to the end of the T wave. However, the QT interval varies with the heart rate, making it difficult to use a single number as a cut-off for a prolonged QT. Instead, a corrected QT interval (QTc) is calculated for each heart rate using various formulas. A QTc over the 99th percentile is considered abnormally prolonged, with approximate values of 470 ms for males and 480 ms for females.

Prolonged QT intervals can lead to torsade de pointes (TdP), a polymorphic ventricular tachycardia that can be fatal if it degenerates into ventricular fibrillation. TdP is characterized by a twisting of the QRS complexes around an isoelectric line and is often asymptomatic but can also be associated with syncope and death. An accurate diagnosis requires an ECG to be recorded during the event. It is important to note that an increase in the QT interval due to a new conduction block should not be considered indicative of acquired LQTS and risk for TdP.

Pharmacokinetics is the study of how drugs are affected by the body. This includes how drugs are absorbed into the bloodstream, distributed throughout the body, metabolized into different forms, and eliminated from the body. The acronym ADME is often used to remember these processes. Absorption refers to the transportation of the drug from the site of administration to the bloodstream. Hydrophobic drugs are absorbed better than hydrophilic ones. Distribution refers to the movement of the drug from the bloodstream to other areas of the body. Metabolism involves the conversion of the drug into different forms, often to make it more easily excreted by the kidneys. This process occurs in two phases, involving reduction of hydrolysis in phase 1 and conjugation in phase 2. Excretion refers to the elimination of the drug from the body, which mainly occurs through the kidneys and biliary system.

Pramipexole, a dopamine agonist used to treat Parkinson’s disease, has been linked to the development of pathological gambling, which is disproportionately common in patients with Parkinson’s disease. While levodopa treatment alone is not associated with pathological gambling, all dopamine agonists have been implicated, with pramipexole being the most common due to its high selectivity for D3 receptors in the limbic system. Quetiapine is unlikely to cause pathological gambling, and amantadine, a weaker dopamine agonist than pramipexole, is also less likely to be implicated. Memantine, an NMDA antagonist that reduces glutamate excitability, may have some potential in treating pathological gambling.

Mechanisms of Action of Different Drugs

Understanding the mechanisms of action of different drugs is crucial for medical professionals. It is a common topic in exams and can earn easy marks if studied well. This article provides a list of drugs and their mechanisms of action in different categories such as antidepressants, anti dementia drugs, mood stabilizers, anxiolytic/hypnotic drugs, antipsychotics, drugs of abuse, and other drugs. For example, mirtazapine is a noradrenaline and serotonin specific antidepressant that works as a 5HT2 antagonist, 5HT3 antagonist, H1 antagonist, alpha 1 and alpha 2 antagonist, and moderate muscarinic antagonist. Similarly, donepezil is a reversible acetylcholinesterase inhibitor used as an anti dementia drug, while valproate is a GABA agonist and NMDA antagonist used as a mood stabilizer. The article also explains the mechanisms of action of drugs such as ketamine, phencyclidine, buprenorphine, naloxone, atomoxetine, varenicline, disulfiram, acamprosate, and sildenafil.

Lithium – Pharmacology

Pharmacokinetics:
Lithium salts are rapidly absorbed following oral administration and are almost exclusively excreted by the kidneys unchanged. Blood samples for lithium should be taken 12 hours post-dose.

Ebstein’s:
Ebstein’s anomaly is a congenital malformation consisting of a prolapse of the tricuspid valve into the right ventricle. It occurs in 1:20,000 of the general population. Initial data suggested it was more common in those using lithium but this had not held to be true.

Contraindications:
Addison’s disease, Brugada syndrome, cardiac disease associated with rhythm disorders, clinically significant renal impairment, untreated of untreatable hypothyroidism, low sodium levels.

Side-effects:
Common side effects include nausea, tremor, polyuria/polydipsia, rash/dermatitis, blurred vision, dizziness, decreased appetite, drowsiness, metallic taste, and diarrhea. Side-effects are often dose-related.

Long-term use is associated with hypothyroidism, hyperthyroidism, hypercalcemia/hyperparathyroidism, irreversible nephrogenic diabetes insipidus, and reduced GFR.

Lithium-induced diabetes insipidus:
Treatment options include stopping lithium (if feasible), keeping levels within 0.4-0.8 mmol/L, once-daily dose of the drug taken at bedtime, amiloride, thiazide diuretics, indomethacin, and desmopressin.

Toxicity:
Lithium salts have a narrow therapeutic/toxic ratio. Risk factors for lithium toxicity include drugs altering renal function, decreased circulating volume, infections, fever, decreased oral intake of water, renal insufficiency, and nephrogenic diabetes insipidus. Features of lithium toxicity include GI symptoms and neuro symptoms.

Pre-prescribing:
Before prescribing lithium, renal function, cardiac function, thyroid function, FBC, and BMI should be checked. Women of childbearing age should be advised regarding contraception, and information about toxicity should be provided.

Monitoring:
Lithium blood levels should be checked weekly until stable, and then every 3-6 months once stable. Thyroid and renal function should be checked every 6 months. Patients should be issued with an information booklet, alert card, and record book.

Monoamine oxidase inhibitors (MAOIs) increase levels of noradrenaline, serotonin, and dopamine by inhibiting one of both of the monoamine oxidase enzymes, MAO-A and MAO-B. This is different from selective serotonin reuptake inhibitors (SSRIs) and tricyclics, which primarily affect serotonin levels. Tricyclics have anticholinergic and noradrenergic side effects, while SSRIs cause fewer anticholinergic effects but may lead to gastrointestinal problems, agitation, insomnia, and headaches. MAOIs have their own set of potential side effects, including interactions with certain foods and medications, as well as possible hypertensive crises.

The First Pass Effect in Psychiatric Drugs

The first-pass effect is a process in drug metabolism that significantly reduces the concentration of a drug before it reaches the systemic circulation. This phenomenon is related to the liver and gut wall, which absorb and metabolize the drug before it can enter the bloodstream. Psychiatric drugs are not exempt from this effect, and some undergo a significant reduction in concentration before reaching their target site. Examples of psychiatric drugs that undergo a significant first-pass effect include imipramine, fluphenazine, morphine, diazepam, and buprenorphine. On the other hand, some drugs undergo little to no first-pass effect, such as lithium and pregabalin.

Orally administered drugs are the most affected by the first-pass effect. However, there are other routes of administration that can avoid of partly avoid this effect. These include sublingual, rectal (partly avoids first pass), intravenous, intramuscular, transdermal, and inhalation. Understanding the first-pass effect is crucial in drug development and administration, especially in psychiatric drugs, where the concentration of the drug can significantly affect its efficacy and safety.

Serotonin Syndrome and Neuroleptic Malignant Syndrome are two conditions that can be difficult to differentiate. Serotonin Syndrome is caused by excess serotonergic activity in the CNS and is characterized by neuromuscular abnormalities, altered mental state, and autonomic dysfunction. On the other hand, Neuroleptic Malignant Syndrome is a rare acute disorder of thermoregulation and neuromotor control that is almost exclusively caused by antipsychotics. The symptoms of both syndromes can overlap, but there are some distinguishing clinical features. Hyper-reflexia, ocular clonus, and tremors are more prominent in Serotonin Syndrome, while Neuroleptic Malignant Syndrome is characterized by uniform ‘lead-pipe’ rigidity and hyporeflexia. Symptoms of Serotonin Syndrome usually resolve within a few days of stopping the medication, while Neuroleptic Malignant Syndrome can take up to 14 days to remit with appropriate treatment. The following table provides a useful guide to the main differentials of Serotonin Syndrome and Neuroleptic Malignant Syndrome.

While the majority of SSRIs are believed to have minimal impact on the QTc interval, studies have demonstrated that citalopram and escitalopram can lead to QTc prolongation.

Antidepressants and Their Cardiac Effects

SSRIs are generally recommended for patients with cardiac disease as they may protect against myocardial infarction (MI). Untreated depression worsens prognosis in cardiovascular disease. Post MI, SSRIs and mirtazapine have either a neutral of beneficial effect on mortality. Sertraline is recommended post MI, but other SSRIs and mirtazapine are also likely to be safe. However, citalopram is associated with Torsades de pointes (mainly in overdose). Bupropion, citalopram, escitalopram, moclobemide, lofepramine, and venlafaxine should be used with caution of avoided in those at risk of serious arrhythmia (those with heart failure, left ventricular hypertrophy, previous arrhythmia, of MI).

Tricyclic antidepressants (TCAs) have established arrhythmogenic activity which arises as a result of potent blockade of cardiac sodium channels and variable activity at potassium channels. ECG changes produced include PR, QRS, and QT prolongation and the Brugada syndrome. Lofepramine is less cardiotoxic than other TCAs and seems to lack the overdose arrhythmogenicity of other TCAs. QT changes are not usually seen at normal clinical doses of antidepressants (but can occur, particularly with citalopram/escitalopram). The arrhythmogenic potential of TCAs and other antidepressants is dose-related.

Overall, SSRIs are recommended for patients with cardiac disease, while caution should be exercised when prescribing TCAs and other antidepressants, especially in those at risk of serious arrhythmia. It is important to monitor patients closely for any cardiac effects when prescribing antidepressants.

The observation that haloperidol, which has a high D2 occupancy, has a greater likelihood of causing EPSE, while clozapine, which has a lower D2 occupancy, has a lower risk, is in line with the research.

Extrapyramidal side-effects (EPSE’s) are a group of side effects that affect voluntary motor control, commonly seen in patients taking antipsychotic drugs. EPSE’s include dystonias, parkinsonism, akathisia, and tardive dyskinesia. They can be frightening and uncomfortable, leading to problems with non-compliance and can even be life-threatening in the case of laryngeal dystonia. EPSE’s are thought to be due to antagonism of dopaminergic D2 receptors in the basal ganglia. Symptoms generally occur within the first few days of treatment, with dystonias appearing quickly, within a few hours of administration of the first dose. Newer antipsychotics tend to produce less EPSE’s, with clozapine carrying the lowest risk and haloperidol carrying the highest risk. Akathisia is the most resistant EPSE to treat. EPSE’s can also occur when antipsychotics are discontinued (withdrawal dystonia).

Antipsychotic drugs are known to cause weight gain, but some more than others. The reason for this is not due to a direct metabolic effect, but rather an increase in appetite and a decrease in activity levels. The risk of weight gain appears to be linked to clinical response. There are several suggested mechanisms for this, including antagonism of certain receptors and hormones that stimulate appetite. The risk of weight gain varies among different antipsychotics, with clozapine and olanzapine having the highest risk. Management strategies for antipsychotic-induced weight gain include calorie restriction, low glycemic index diet, exercise, and switching to an alternative antipsychotic. Aripiprazole, ziprasidone, and lurasidone are recommended as alternative options. Other options include aripiprazole augmentation, metformin, orlistat, liraglutide, and topiramate.

Hyponatremia in Psychiatric Patients

Hyponatremia, of low serum sodium, can occur in psychiatric patients due to the disorder itself, its treatment, of other medical conditions. Symptoms include nausea, confusion, seizures, and muscular cramps. Drug-induced hyponatremia is known as the syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), which results from excessive secretion of ADH and fluid overload. Diagnosis is based on clinically euvolaemic state with low serum sodium and osmolality, raised urine sodium and osmolality. SSRIs, SNRIs, and tricyclics are the most common drugs that can cause SIADH. Risk factors for SIADH include starting a new drug, and treatment usually involves fluid restriction and sometimes demeclocycline.

ADHD medications can be classified into stimulant and non-stimulant drugs. The therapeutic effects of these drugs are believed to be mediated through the action of noradrenaline in the prefrontal cortex. Common side effects of these drugs include decreased appetite, insomnia, nervousness, headache, and nausea. Stimulant drugs like dexamphetamine, methylphenidate, and lisdexamfetamine inhibit the reuptake of dopamine and noradrenaline. Non-stimulant drugs like atomoxetine, guanfacine, and clonidine work by increasing noradrenaline levels in the synaptic cleft through different mechanisms. The most common side effects of these drugs are decreased appetite, somnolence, headache, and abdominal pain.

Mirtazapine and Mianserin are significant NaSSA’s (Noradrenergic and specific serotonergic antidepressants) that function by blocking adrenergic and serotonergic receptors. In contrast to the majority of antidepressants, they do not impact the reuptake of serotonin.

Mechanisms of Action of Different Drugs

Understanding the mechanisms of action of different drugs is crucial for medical professionals. It is a common topic in exams and can earn easy marks if studied well. This article provides a list of drugs and their mechanisms of action in different categories such as antidepressants, anti dementia drugs, mood stabilizers, anxiolytic/hypnotic drugs, antipsychotics, drugs of abuse, and other drugs. For example, mirtazapine is a noradrenaline and serotonin specific antidepressant that works as a 5HT2 antagonist, 5HT3 antagonist, H1 antagonist, alpha 1 and alpha 2 antagonist, and moderate muscarinic antagonist. Similarly, donepezil is a reversible acetylcholinesterase inhibitor used as an anti dementia drug, while valproate is a GABA agonist and NMDA antagonist used as a mood stabilizer. The article also explains the mechanisms of action of drugs such as ketamine, phencyclidine, buprenorphine, naloxone, atomoxetine, varenicline, disulfiram, acamprosate, and sildenafil.

While myoclonus can be scary for patients, it is typically not a danger to their lives. On the other hand, the muscle stiffness that occurs in serotonin syndrome is extremely severe and can result in the failure of multiple organs (Ahuja 2009).

Serotonin Syndrome and Neuroleptic Malignant Syndrome are two conditions that can be difficult to differentiate. Serotonin Syndrome is caused by excess serotonergic activity in the CNS and is characterized by neuromuscular abnormalities, altered mental state, and autonomic dysfunction. On the other hand, Neuroleptic Malignant Syndrome is a rare acute disorder of thermoregulation and neuromotor control that is almost exclusively caused by antipsychotics. The symptoms of both syndromes can overlap, but there are some distinguishing clinical features. Hyperreflexia, ocular clonus, and tremors are more prominent in Serotonin Syndrome, while Neuroleptic Malignant Syndrome is characterized by uniform ‘lead-pipe’ rigidity and hyporeflexia. Symptoms of Serotonin Syndrome usually resolve within a few days of stopping the medication, while Neuroleptic Malignant Syndrome can take up to 14 days to remit with appropriate treatment. The following table provides a useful guide to the main differentials of Serotonin Syndrome and Neuroleptic Malignant Syndrome.

Tamoxifen metabolism to its active metabolite may be inhibited by the use of fluoxetine and paroxetine, therefore, these medications should be avoided in patients receiving tamoxifen. Venlafaxine is considered the safest choice of antidepressant as it has little to no effect on tamoxifen metabolism. Mirtazapine has been found to have minimal effect on CYP2D6, while the other commonly prescribed antidepressants have mild to moderate degrees of CYP2D6 inhibition.

Antidepressants: Mechanism of Action

Antidepressants are a class of drugs used to treat depression and other mood disorders. The mechanism of action of antidepressants varies depending on the specific drug. Here are some examples:

Mirtazapine is a noradrenaline and serotonin specific antidepressant (NaSSa). It works by blocking certain receptors in the brain, including 5HT-1, 5HT-2, 5HT-3, and H1 receptors. It also acts as a presynaptic alpha 2 antagonist, which stimulates the release of noradrenaline and serotonin.

Venlafaxine and duloxetine are both serotonin and noradrenaline reuptake inhibitors (SNRIs). They work by blocking the reuptake of these neurotransmitters, which increases their availability in the brain.

Reboxetine is a noradrenaline reuptake inhibitor (NRI). It works by blocking the reuptake of noradrenaline, which increases its availability in the brain.

Bupropion is a noradrenaline and dopamine reuptake inhibitor (NDRI). It works by blocking the reuptake of these neurotransmitters, which increases their availability in the brain.

Trazodone is a weak serotonin reuptake inhibitor (SRI) and 5HT agonist. It works by increasing the availability of serotonin in the brain.

St John’s Wort is a natural supplement that has been used to treat depression. It has a weak monoamine oxidase inhibitor (MAOI) effect and a weak SNRI effect.

In summary, antidepressants work by increasing the availability of certain neurotransmitters in the brain, such as serotonin, noradrenaline, and dopamine. The specific mechanism of action varies depending on the drug.

Antidepressants (Licensed Indications)

The following table outlines the specific licensed indications for antidepressants in adults, as per the Maudsley Guidelines and the British National Formulary. It is important to note that all antidepressants are indicated for depression.

– Nocturnal enuresis in children: Amitriptyline, Imipramine, Nortriptyline
– Phobic and obsessional states: Clomipramine
– Adjunctive treatment of cataplexy associated with narcolepsy: Clomipramine
– Panic disorder and agoraphobia: Citalopram, Escitalopram, Sertraline, Paroxetine, Venlafaxine
– Social anxiety/phobia: Escitalopram, Paroxetine, Sertraline, Moclobemide, Venlafaxine
– Generalised anxiety disorder: Escitalopram, Paroxetine, Duloxetine, Venlafaxine
– OCD: Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Clomipramine
– Bulimia nervosa: Fluoxetine
– PTSD: Paroxetine, Sertraline

Gabapentin, lithium, and topiramate require minimal of no hepatic metabolism, allowing them to be excreted without undergoing significant liver alteration.

Drug Clearance: Understanding the Rate of Drug Removal from the Body

Drug clearance refers to the efficiency of drug removal from the plasma, and is measured as the volume of plasma cleared of a drug over a specific time period. The unit of measurement for drug clearance is volume per time. Clearance of a drug involves both metabolism and excretion. When drug intake equals clearance, it is referred to as a steady state, which is usually achieved by 4.5 half-lives. The time taken to reach steady state depends on the half-life of the drug.

There are two main types of clearance: hepatic and renal. Hepatic clearance involves the conversion of the parent drug into a different chemical entity by the liver enzymes, while renal clearance involves the removal of the drug from the plasma into the urine. The clearance of a drug can take one of two forms: zero and first-order kinetics. In zero-order reactions, the clearance of a drug is constant and not related to the concentration of the drug in the plasma. This type of reaction is typically found when the material needed for the reaction to proceed (e.g. enzyme) is saturated. Ethanol and Phenytoin are good examples of this.

Most drugs tend to follow first-order reactions, where the clearance is related to the concentration of the drug in the plasma. The half-life of a drug is the time taken for its concentration to fall by half. In first-order reactions, this is constant. In zero-order reactions, it gets progressively shorter.

It is important to note that elimination and clearance are not the same. Elimination is the irreversible removal of the drug from the body, while clearance is a theoretical volume of blood that is cleared of the drug per unit of time, which is independent of the drug dose of concentration. Understanding drug clearance is crucial in determining the appropriate dosing regimen for a drug.

Antidepressants can cause discontinuation symptoms when patients stop taking them, regardless of the type of antidepressant. These symptoms usually occur within 5 days of stopping the medication and can last up to 3 weeks. Symptoms include flu-like symptoms, dizziness, insomnia, vivid dreams, irritability, crying spells, and sensory symptoms. SSRIs and related drugs with short half-lives, such as paroxetine and venlafaxine, are particularly associated with discontinuation symptoms. Tapering antidepressants at the end of treatment is recommended to prevent these symptoms. TCAs and MAOIs are also associated with discontinuation symptoms, with amitriptyline and imipramine being the most common TCAs and all MAOIs being associated with prominent discontinuation symptoms. Patients at highest risk for discontinuation symptoms include those on antidepressants with shorter half-lives, those who have been taking antidepressants for 8 weeks of longer, those using higher doses, younger people, and those who have experienced discontinuation symptoms before. Agomelatine is not associated with any discontinuation syndrome. If a discontinuation reaction occurs, restarting the antidepressant of switching to an alternative with a longer half-life and tapering more slowly may be necessary. Explanation and reassurance are often sufficient for mild symptoms. These guidelines are based on the Maudsley Guidelines 14th Edition and a study by Tint (2008).

In certain cases, the addition of 5-10 mg of aripiprazole has demonstrated the ability to restore hyperprolactinaemia to normal levels.

Antipsychotics and Sexual Dysfunction: Causes, Risks, and Management

Sexual dysfunction is a common side effect of antipsychotic medication, with the highest risk associated with risperidone and haloperidol due to their effect on prolactin levels. Clozapine, olanzapine, quetiapine, aripiprazole, asenapine, and lurasidone are associated with lower rates of sexual dysfunction. The Arizona Sexual Experiences Scale (ASEX) can be used to measure sexual dysfunction before and during treatment. Management options include excluding other causes, watchful waiting, dose reduction, switching to a lower risk agent, adding aripiprazole, considering an antidote medication, of using sildenafil for erectile dysfunction. It is important to address sexual dysfunction to improve quality of life and medication adherence.

Mechanisms of Action of Different Drugs

Understanding the mechanisms of action of different drugs is crucial for medical professionals. It is a common topic in exams and can earn easy marks if studied well. This article provides a list of drugs and their mechanisms of action in different categories such as antidepressants, anti dementia drugs, mood stabilizers, anxiolytic/hypnotic drugs, antipsychotics, drugs of abuse, and other drugs. For example, mirtazapine is a noradrenaline and serotonin specific antidepressant that works as a 5HT2 antagonist, 5HT3 antagonist, H1 antagonist, alpha 1 and alpha 2 antagonist, and moderate muscarinic antagonist. Similarly, donepezil is a reversible acetylcholinesterase inhibitor used as an anti dementia drug, while valproate is a GABA agonist and NMDA antagonist used as a mood stabilizer. The article also explains the mechanisms of action of drugs such as ketamine, phencyclidine, buprenorphine, naloxone, atomoxetine, varenicline, disulfiram, acamprosate, and sildenafil.

Rivastigmine inhibits cholinesterase in a reversible manner.

Mechanisms of Action of Different Drugs

Understanding the mechanisms of action of different drugs is crucial for medical professionals. It is a common topic in exams and can earn easy marks if studied well. This article provides a list of drugs and their mechanisms of action in different categories such as antidepressants, anti dementia drugs, mood stabilizers, anxiolytic/hypnotic drugs, antipsychotics, drugs of abuse, and other drugs. For example, mirtazapine is a noradrenaline and serotonin specific antidepressant that works as a 5HT2 antagonist, 5HT3 antagonist, H1 antagonist, alpha 1 and alpha 2 antagonist, and moderate muscarinic antagonist. Similarly, donepezil is a reversible acetylcholinesterase inhibitor used as an anti dementia drug, while valproate is a GABA agonist and NMDA antagonist used as a mood stabilizer. The article also explains the mechanisms of action of drugs such as ketamine, phencyclidine, buprenorphine, naloxone, atomoxetine, varenicline, disulfiram, acamprosate, and sildenafil.

Biogenic Amines: Understanding the Neurotransmitters

Biogenic amines are a class of compounds that are derived from amino acids. These compounds play a crucial role in the functioning of the nervous system. Biogenic amine neurotransmitters include catecholamines (adrenaline, noradrenaline, and dopamine), serotonin, and histamine. A useful mnemonic to remember these neurotransmitters is HANDS (Histamine, Adrenaline, Noradrenaline, Dopamine, Serotonin).

Catecholamines are involved in the body’s response to stress and are responsible for the fight or flight response. Adrenaline and noradrenaline are catecholamines that are released by the adrenal glands in response to stress. Dopamine is involved in the reward system of the brain and is associated with pleasure and motivation.

Serotonin is a neurotransmitter that is involved in mood regulation, appetite, and sleep. It is also involved in the regulation of pain and the perception of pain.

Histamine is involved in the immune response and is responsible for the symptoms of allergies. It is also involved in the regulation of sleep and wakefulness.

Understanding the role of biogenic amines in the nervous system is crucial for the development of treatments for neurological and psychiatric disorders.

While the upper limit technically reaches 439, it is evident that 440 is the optimal choice among the options provided.

Amantadine and QTc Prolongation

Amantadine is a medication used to treat Parkinson’s disease and influenza. It has been associated with QTc prolongation, which can increase the risk of Torsades de points. Therefore, caution should be exercised when prescribing amantadine to patients with risk factors for QT prolongation. If a patient is already taking amantadine and develops a prolonged QTc interval, the medication should be discontinued and an alternative treatment considered. It is important to monitor the QTc interval in patients taking amantadine, especially those with risk factors for QT prolongation.

Modafinil: A Psychostimulant for Wakefulness and Attention Enhancement

Modafinil is a type of psychostimulant that is known to improve wakefulness, attention, and vigilance. Although it is similar to amphetamines, it does not produce the same euphoric effects and is not associated with dependence of tolerance. Additionally, it does not seem to cause psychosis. Modafinil is approved for the treatment of narcolepsy, obstructive sleep apnea, and chronic shift work. It is also suggested as an adjunctive treatment for depression by the Maudsley. Recently, it has gained popularity as a smart drug due to its potential to enhance cognitive functioning in healthy individuals.

Amphetamine engages in competition with the DAT instead of obstructing it.

Mechanisms of action for illicit drugs can be classified based on their effects on ionotropic receptors of ion channels, G coupled receptors, of monoamine transporters. Cocaine and amphetamine both increase dopamine levels in the synaptic cleft, but through different mechanisms. Cocaine directly blocks the dopamine transporter, while amphetamine binds to the transporter and increases dopamine efflux through various mechanisms, including inhibition of vesicular monoamine transporter 2 and monoamine oxidase, and stimulation of the intracellular receptor TAAR1. These mechanisms result in increased dopamine levels in the synaptic cleft and reuptake inhibition.

Drug Stability

The stability of drugs can vary greatly, with some medications being unable to be included in compliance aids due to their susceptibility to environmental factors. Certain drugs have a tendency to absorb moisture from the air, rendering them ineffective, with light known to accelerate this process. Examples of drugs that are unsuitable for compliance aids due to their susceptibility to environmental factors include Sodium valproate, Zopiclone, Venlafaxine, Topiramate, Methylphenidate, Mirtazapine, Olanzapine, Amisulpride, and Aripiprazole.

Plasma concentrations of lithium may be decreased by both sodium bicarbonate and aminophylline.

Lithium – Pharmacology

Pharmacokinetics:
Lithium salts are rapidly absorbed following oral administration and are almost exclusively excreted by the kidneys unchanged. Blood samples for lithium should be taken 12 hours post-dose.

Ebstein’s:
Ebstein’s anomaly is a congenital malformation consisting of a prolapse of the tricuspid valve into the right ventricle. It occurs in 1:20,000 of the general population. Initial data suggested it was more common in those using lithium but this had not held to be true.

Contraindications:
Addison’s disease, Brugada syndrome, cardiac disease associated with rhythm disorders, clinically significant renal impairment, untreated of untreatable hypothyroidism, low sodium levels.

Side-effects:
Common side effects include nausea, tremor, polyuria/polydipsia, rash/dermatitis, blurred vision, dizziness, decreased appetite, drowsiness, metallic taste, and diarrhea. Side-effects are often dose-related.

Long-term use is associated with hypothyroidism, hyperthyroidism, hypercalcemia/hyperparathyroidism, irreversible nephrogenic diabetes insipidus, and reduced GFR.

Lithium-induced diabetes insipidus:
Treatment options include stopping lithium (if feasible), keeping levels within 0.4-0.8 mmol/L, once-daily dose of the drug taken at bedtime, amiloride, thiazide diuretics, indomethacin, and desmopressin.

Toxicity:
Lithium salts have a narrow therapeutic/toxic ratio. Risk factors for lithium toxicity include drugs altering renal function, decreased circulating volume, infections, fever, decreased oral intake of water, renal insufficiency, and nephrogenic diabetes insipidus. Features of lithium toxicity include GI symptoms and neuro symptoms.

Pre-prescribing:
Before prescribing lithium, renal function, cardiac function, thyroid function, FBC, and BMI should be checked. Women of childbearing age should be advised regarding contraception, and information about toxicity should be provided.

Monitoring:
Lithium blood levels should be checked weekly until stable, and then every 3-6 months once stable. Thyroid and renal function should be checked every 6 months. Patients should be issued with an information booklet, alert card, and record book.

The cytochrome P450 enzyme system, responsible for metabolizing SSRIs and certain cholesterol-lowering medications, can be inhibited by consuming grapefruit juice and other juices like lime juice. Therefore, patients taking SSRI antidepressants should avoid these juices.

The First Pass Effect in Psychiatric Drugs

The first-pass effect is a process in drug metabolism that significantly reduces the concentration of a drug before it reaches the systemic circulation. This phenomenon is related to the liver and gut wall, which absorb and metabolize the drug before it can enter the bloodstream. Psychiatric drugs are not exempt from this effect, and some undergo a significant reduction in concentration before reaching their target site. Examples of psychiatric drugs that undergo a significant first-pass effect include imipramine, fluphenazine, morphine, diazepam, and buprenorphine. On the other hand, some drugs undergo little to no first-pass effect, such as lithium and pregabalin.

Orally administered drugs are the most affected by the first-pass effect. However, there are other routes of administration that can avoid of partly avoid this effect. These include sublingual, rectal (partly avoids first pass), intravenous, intramuscular, transdermal, and inhalation. Understanding the first-pass effect is crucial in drug development and administration, especially in psychiatric drugs, where the concentration of the drug can significantly affect its efficacy and safety.

Due to their increased vulnerability to anticholinergic side effects, elderly individuals are at a higher risk of experiencing delirium. The first generation of H1 antihistamines, which have a greater tendency for anticholinergic side effects, are more likely to trigger delirium in the elderly. Benadryl, an over-the-counter medication in the UK used to treat hay fever, contains diphenhydramine as its active ingredient.

Antihistamines: Types and Uses

Antihistamines are drugs that block the effects of histamine, a neurotransmitter that regulates physiological function in the gut and potentiates the inflammatory and immune responses of the body. There are two types of antihistamines: H1 receptor blockers and H2 receptor blockers. H1 blockers are mainly used for allergic conditions and sedation, while H2 blockers are used for excess stomach acid.

There are also first and second generation antihistamines. First generation antihistamines, such as diphenhydramine and promethazine, have uses in psychiatry due to their ability to cross the blood brain barrier and their anticholinergic properties. They tend to be sedating and are useful for managing extrapyramidal side effects. Second generation antihistamines, such as loratadine and cetirizine, show limited penetration of the blood brain barrier and are less sedating.

It is important to note that there are contraindications to first-generation antihistamines, including benign prostatic hyperplasia, angle-closure glaucoma, and pyloric stenosis in infants. These do not apply to second-generation antihistamines.

Disinhibitory Drug Reactions: Understanding Paradoxical Reactions to Benzodiazepines

Benzodiazepines are commonly prescribed for anxiety and sleep disorders, but they are also associated with paradoxical reactions, also known as disinhibitory reactions. These reactions are unexpected increases in aggressive behavior, sexual disinhibition, hyperactivity, vivid dreams, and hostility. However, the prevalence of these reactions is difficult to determine, as study findings vary widely from 1% to 58%.

Certain factors increase the risk of paradoxical reactions, including a history of aggression of poor impulse control, extremes of age (elderly of young), benzodiazepines with short half-lives, high doses of benzodiazepines, and intravenous administration of benzodiazepines. It is important to record these reactions, and if they are severe, it is advisable to avoid future use of benzodiazepines.

There exist two primary opioid antagonists.

Mechanisms of Action of Different Drugs

Understanding the mechanisms of action of different drugs is crucial for medical professionals. It is a common topic in exams and can earn easy marks if studied well. This article provides a list of drugs and their mechanisms of action in different categories such as antidepressants, anti dementia drugs, mood stabilizers, anxiolytic/hypnotic drugs, antipsychotics, drugs of abuse, and other drugs. For example, mirtazapine is a noradrenaline and serotonin specific antidepressant that works as a 5HT2 antagonist, 5HT3 antagonist, H1 antagonist, alpha 1 and alpha 2 antagonist, and moderate muscarinic antagonist. Similarly, donepezil is a reversible acetylcholinesterase inhibitor used as an anti dementia drug, while valproate is a GABA agonist and NMDA antagonist used as a mood stabilizer. The article also explains the mechanisms of action of drugs such as ketamine, phencyclidine, buprenorphine, naloxone, atomoxetine, varenicline, disulfiram, acamprosate, and sildenafil.

Serotonin Syndrome and Neuroleptic Malignant Syndrome are two conditions that can be difficult to differentiate. Serotonin Syndrome is caused by excess serotonergic activity in the CNS and is characterized by neuromuscular abnormalities, altered mental state, and autonomic dysfunction. On the other hand, Neuroleptic Malignant Syndrome is a rare acute disorder of thermoregulation and neuromotor control that is almost exclusively caused by antipsychotics. The symptoms of both syndromes can overlap, but there are some distinguishing clinical features. Hyper-reflexia, ocular clonus, and tremors are more prominent in Serotonin Syndrome, while Neuroleptic Malignant Syndrome is characterized by uniform ‘lead-pipe’ rigidity and hyporeflexia. Symptoms of Serotonin Syndrome usually resolve within a few days of stopping the medication, while Neuroleptic Malignant Syndrome can take up to 14 days to remit with appropriate treatment. The following table provides a useful guide to the main differentials of Serotonin Syndrome and Neuroleptic Malignant Syndrome.

The Cytochrome P450 system is a group of enzymes that metabolize drugs by altering their functional groups. The system is located in the liver and small intestine and is involved in drug interactions through enzyme induction of inhibition. Notable inducers include smoking, alcohol, and St John’s Wort, while notable inhibitors include grapefruit juice and some SSRIs. CYP2D6 is important due to genetic polymorphism, and CYP3A4 is the most abundant subfamily and is commonly involved in interactions. Grapefruit juice inhibits both CYP1A2 and CYP3A4, while tobacco smoking induces CYP1A2. The table summarizes the main substrates, inhibitors, and inducers for each CYP enzyme.

Unlike other antidepressants, agomelatine (Valdoxan) does not affect serotonin transmission and is a melatonin agonist. It has a good safety profile and there have been no reported cases of hyponatraemia associated with its use. On the other hand, the other listed antidepressants have been linked to hyponatraemia.

Amantadine and QTc Prolongation

Amantadine is a medication used to treat Parkinson’s disease and influenza. It has been associated with QTc prolongation, which can increase the risk of Torsades de points. Therefore, caution should be exercised when prescribing amantadine to patients with risk factors for QT prolongation. If a patient is already taking amantadine and develops a prolonged QTc interval, the medication should be discontinued and an alternative treatment considered. It is important to monitor the QTc interval in patients taking amantadine, especially those with risk factors for QT prolongation.

In the treatment of Alzheimer’s disease, acetylcholinesterase inhibitors such as galantamine are utilized to enhance central acetylcholine levels. Although they share this common mechanism of action, there are variations in how they function. Unlike galantamine, rivastigmine has the ability to inhibit butyrylcholinesterase.

The half-life of a drug is the time taken for its concentration to fall to one half of its value. Drugs with long half-lives may require a loading dose to achieve therapeutic plasma concentrations rapidly. It takes about 4.5 half-lives to reach steady state plasma levels. Most drugs follow first order kinetics, where a constant fraction of the drug in the body is eliminated per unit time. However, some drugs may follow zero order kinetics, where the plasma concentration of the drug decreases at a constant rate, despite the concentration of the drug. For drugs with nonlinear kinetics of dose-dependent kinetics, the relationship between the AUC of CSS and dose is not linear, and the kinetic parameters may vary depending on the administered dose.

A lack of vitamin C is commonly linked to gum inflammation and bleeding.

Thiamine Deficiency and Alcohol-Related Brain Disease

Thiamine deficiency is a well-known cause of a neurological disorder called Wernicke-Korsakoff syndrome (WKS) in individuals with alcohol use disorder. Thiamine, also known as vitamin B1, is an essential nutrient that cannot be produced by the body and must be obtained through the diet. Thiamine is required for the proper functioning of enzymes involved in the metabolism of carbohydrates, the synthesis of neurotransmitters, nucleic acids, fatty acids, and complex sugar molecules, and the body’s defense against oxidative stress.

Three enzymes that require thiamine as a cofactor are transketolase, pyruvate dehydrogenase (PDH), and alpha ketoglutarate dehydrogenase (KGDH), all of which participate in the breakdown of carbohydrates. Thiamine deficiency leads to suboptimal levels of functional enzymes in the cell, which can cause cell damage in the central nervous system through cell necrosis, cellular apoptosis, and oxidative stress.

Alcoholism can contribute to thiamine deficiency through inadequate nutritional intake, decreased absorption of thiamine from the gastrointestinal tract, and impaired utilization of thiamine in the cells. Giving thiamine to patients with WKS can reverse many of the acute symptoms of the disease, highlighting the importance of this nutrient in the prevention and treatment of alcohol-related brain disease.

This is a case of neuroleptic malignant syndrome, which is primarily associated with the use of antipsychotic medications. The key features of NMS include mental status changes, muscular rigidity, hyperthermia, and autonomic instability, typically presenting as tachycardia. Mental state changes are often the first symptom to appear.

Serotonin Syndrome and Neuroleptic Malignant Syndrome are two conditions that can be difficult to differentiate. Serotonin Syndrome is caused by excess serotonergic activity in the CNS and is characterized by neuromuscular abnormalities, altered mental state, and autonomic dysfunction. On the other hand, Neuroleptic Malignant Syndrome is a rare acute disorder of thermoregulation and neuromotor control that is almost exclusively caused by antipsychotics. The symptoms of both syndromes can overlap, but there are some distinguishing clinical features. Hyper-reflexia, ocular clonus, and tremors are more prominent in Serotonin Syndrome, while Neuroleptic Malignant Syndrome is characterized by uniform ‘lead-pipe’ rigidity and hyporeflexia. Symptoms of Serotonin Syndrome usually resolve within a few days of stopping the medication, while Neuroleptic Malignant Syndrome can take up to 14 days to remit with appropriate treatment. The following table provides a useful guide to the main differentials of Serotonin Syndrome and Neuroleptic Malignant Syndrome.

Antipsychotic drugs are known to cause weight gain, but some more than others. The reason for this is not due to a direct metabolic effect, but rather an increase in appetite and a decrease in activity levels. The risk of weight gain appears to be linked to clinical response. There are several suggested mechanisms for this, including antagonism of certain receptors and hormones that stimulate appetite. The risk of weight gain varies among different antipsychotics, with clozapine and olanzapine having the highest risk. Management strategies for antipsychotic-induced weight gain include calorie restriction, low glycemic index diet, exercise, and switching to an alternative antipsychotic. Aripiprazole, ziprasidone, and lurasidone are recommended as alternative options. Other options include aripiprazole augmentation, metformin, orlistat, liraglutide, and topiramate.

The most likely diagnosis for the women’s medical history is SIADH, which is believed to be caused by the antidepressant she recently began taking. This condition would be reflected in her U & E results, which would indicate a low level of sodium.

Hyponatremia in Psychiatric Patients

Hyponatremia, of low serum sodium, can occur in psychiatric patients due to the disorder itself, its treatment, of other medical conditions. Symptoms include nausea, confusion, seizures, and muscular cramps. Drug-induced hyponatremia is known as the syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), which results from excessive secretion of ADH and fluid overload. Diagnosis is based on clinically euvolaemic state with low serum sodium and osmolality, raised urine sodium and osmolality. SSRIs, SNRIs, and tricyclics are the most common drugs that can cause SIADH. Risk factors for SIADH include starting a new drug, and treatment usually involves fluid restriction and sometimes demeclocycline.

While NICE recommends mirtazapine for the treatment of PTSD, its license only permits its use for major depression.

Antidepressants (Licensed Indications)

The following table outlines the specific licensed indications for antidepressants in adults, as per the Maudsley Guidelines and the British National Formulary. It is important to note that all antidepressants are indicated for depression.

– Nocturnal enuresis in children: Amitriptyline, Imipramine, Nortriptyline
– Phobic and obsessional states: Clomipramine
– Adjunctive treatment of cataplexy associated with narcolepsy: Clomipramine
– Panic disorder and agoraphobia: Citalopram, Escitalopram, Sertraline, Paroxetine, Venlafaxine
– Social anxiety/phobia: Escitalopram, Paroxetine, Sertraline, Moclobemide, Venlafaxine
– Generalised anxiety disorder: Escitalopram, Paroxetine, Duloxetine, Venlafaxine
– OCD: Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Clomipramine
– Bulimia nervosa: Fluoxetine
– PTSD: Paroxetine, Sertraline

Drug Interactions: Understanding the Different Types

Drug interactions can occur in different ways, and it is important to understand the different types to avoid potential harm. Pharmacokinetic drug interactions happen when one drug affects the metabolism, absorption, of excretion of another drug. This can be due to enzyme induction of inhibition, changes in gastrointestinal tract motility and pH, chelation, competition for renal tubular transport, of changes in protein binding. On the other hand, pharmacodynamic drug interactions occur when one drug directly alters the effect of another drug. This can happen through synergism, antagonism, of interaction at receptors, such as allosteric modulation. It is important to note that pharmacodynamic drug interactions do not involve any absorption, distribution, metabolism, of excretion processes directly. By understanding the different types of drug interactions, healthcare professionals can better manage patients’ medications and prevent potential adverse effects.

Torsades de pointes may not be present on an ECG even if the patient experiences recurring episodes, as it has a tendency to appear and disappear.

QTc Prolongation: Risks and Identification

The QT interval is a measure of the time it takes for the ventricles to repolarize and is calculated from the beginning of the QRS complex to the end of the T wave. However, the QT interval varies with the heart rate, making it difficult to use a single number as a cut-off for a prolonged QT. Instead, a corrected QT interval (QTc) is calculated for each heart rate using various formulas. A QTc over the 99th percentile is considered abnormally prolonged, with approximate values of 470 ms for males and 480 ms for females.

Prolonged QT intervals can lead to torsade de pointes (TdP), a polymorphic ventricular tachycardia that can be fatal if it degenerates into ventricular fibrillation. TdP is characterized by a twisting of the QRS complexes around an isoelectric line and is often asymptomatic but can also be associated with syncope and death. An accurate diagnosis requires an ECG to be recorded during the event. It is important to note that an increase in the QT interval due to a new conduction block should not be considered indicative of acquired LQTS and risk for TdP.

Reboxetine, Atomoxetine, and Maprotiline are all important Norepinephrine Reuptake Inhibitors (NRIs) that specifically target noradrenaline.

Antidepressants: Mechanism of Action

Antidepressants are a class of drugs used to treat depression and other mood disorders. The mechanism of action of antidepressants varies depending on the specific drug. Here are some examples:

Mirtazapine is a noradrenaline and serotonin specific antidepressant (NaSSa). It works by blocking certain receptors in the brain, including 5HT-1, 5HT-2, 5HT-3, and H1 receptors. It also acts as a presynaptic alpha 2 antagonist, which stimulates the release of noradrenaline and serotonin.

Venlafaxine and duloxetine are both serotonin and noradrenaline reuptake inhibitors (SNRIs). They work by blocking the reuptake of these neurotransmitters, which increases their availability in the brain.

Reboxetine is a noradrenaline reuptake inhibitor (NRI). It works by blocking the reuptake of noradrenaline, which increases its availability in the brain.

Bupropion is a noradrenaline and dopamine reuptake inhibitor (NDRI). It works by blocking the reuptake of these neurotransmitters, which increases their availability in the brain.

Trazodone is a weak serotonin reuptake inhibitor (SRI) and 5HT agonist. It works by increasing the availability of serotonin in the brain.

St John’s Wort is a natural supplement that has been used to treat depression. It has a weak monoamine oxidase inhibitor (MAOI) effect and a weak SNRI effect.

In summary, antidepressants work by increasing the availability of certain neurotransmitters in the brain, such as serotonin, noradrenaline, and dopamine. The specific mechanism of action varies depending on the drug.

Antipsychotics and Sexual Dysfunction: Causes, Risks, and Management

Sexual dysfunction is a common side effect of antipsychotic medication, with the highest risk associated with risperidone and haloperidol due to their effect on prolactin levels. Clozapine, olanzapine, quetiapine, aripiprazole, asenapine, and lurasidone are associated with lower rates of sexual dysfunction. The Arizona Sexual Experiences Scale (ASEX) can be used to measure sexual dysfunction before and during treatment. Management options include excluding other causes, watchful waiting, dose reduction, switching to a lower risk agent, adding aripiprazole, considering an antidote medication, of using sildenafil for erectile dysfunction. It is important to address sexual dysfunction to improve quality of life and medication adherence.

Tricyclic Antidepressants: First and Second Generation

Tricyclic antidepressants are classified into two generations: first generation of tertiary amines, and second generation of secondary amines. The secondary amines are known to have fewer side effects and primarily affect noradrenaline, while the tertiary amines are believed to enhance both serotonin and noradrenaline.

Secondary amines include Desipramine, Nortriptyline, Protriptyline, and Amoxapine. On the other hand, tertiary amines include Amitriptyline, Lofepramine, Imipramine, Clomipramine, Dosulepin (Dothiepin), Doxepin, Trimipramine, and Butriptyline.

By understanding the differences between the two generations of tricyclic antidepressants, healthcare professionals can better tailor their treatment plans to their patients’ needs.

MAOIs: A Guide to Mechanism of Action, Adverse Effects, and Dietary Restrictions

First introduced in the 1950s, MAOIs were the first antidepressants introduced. However, they are not the first choice in treating mental health disorders due to several dietary restrictions and safety concerns. They are only a treatment option when all other medications are unsuccessful. MAOIs may be particularly useful in atypical depression (over eating / over sleeping, mood reactivity).

MAOIs block the monoamine oxidase enzyme, which breaks down different types of neurotransmitters from the brain: norepinephrine, serotonin, dopamine, as well as tyramine. There are two types of monoamine oxidase, A and B. The MOA A are mostly distributed in the placenta, gut, and liver, but MOA B is present in the brain, liver, and platelets. Selegiline and rasagiline are irreversible and selective inhibitors of MAO type B, but safinamide is a reversible and selective MAO B inhibitor.

The most common adverse effects of MAOIs occurring early in treatment are orthostatic hypotension, daytime sleepiness, insomnia, and nausea; later common effects include weight gain, muscle pain, myoclonus, paraesthesia, and sexual dysfunction.

Pharmacodynamic interactions with MAOIs can cause two types of problem: serotonin syndrome (mainly due to SSRIs) and elevated blood pressure (caused by indirectly acting sympathomimetic amines releasers, like pseudoephedrine and phenylephrine). The combination of MAOIs and some TCAs appears safe. Only those TCAs with significant serotonin reuptake inhibition (clomipramine and imipramine) are likely to increase the risk of serotonin syndrome.

Tyramine is a monoamine found in various foods, and is an indirect sympathomimetic that can cause a hypertensive reaction in patients receiving MAOI therapy. For this reason, dietary restrictions are required for patients receiving MAOIs. These restrictions include avoiding matured/aged cheese, fermented sausage, improperly stored meat, fava of broad bean pods, and certain drinks such as on-tap beer. Allowed foods include fresh cottage cheese, processed cheese slices, fresh packaged of processed meat, and other alcohol (no more than two bottled or canned beers of two standard glasses of wine, per day).

The preferred initial treatment for alcohol withdrawal syndrome is benzodiazepines.

Blurred vision occurs as a result of muscarinic blockade, which causes the pupils to dilate (mydriasis).

Receptors and Side-Effects

Histamine H1 Blockade:
– Weight gain
– Sedation

Alpha 1 Blockade:
– Orthostatic hypotension
– Sedation
– Sexual dysfunction
– Priapism

Muscarinic Central M1 Blockade:
– Agitation
– Delirium
– Memory impairment
– Confusion
– Seizures

Muscarinic Peripheral M1 Blockade:
– Dry mouth
– Ataxia
– Blurred vision
– Narrow angle glaucoma
– Constipation
– Urinary retention
– Tachycardia

Each receptor has specific effects on the body, but they can also have side-effects. Histamine H1 blockade can cause weight gain and sedation. Alpha 1 blockade can lead to orthostatic hypotension, sedation, sexual dysfunction, and priapism. Muscarinic central M1 blockade can cause agitation, delirium, memory impairment, confusion, and seizures. Muscarinic peripheral M1 blockade can result in dry mouth, ataxia, blurred vision, narrow angle glaucoma, constipation, urinary retention, and tachycardia. It is important to be aware of these potential side-effects when using medications that affect these receptors.

The combination of the patient’s symptoms and medical history strongly suggests the presence of neuromuscular malignant syndrome. To confirm the diagnosis, a serum creatine kinase test would be the most beneficial investigation to conduct. Although creatine kinase is a highly sensitive marker for muscle tissue damage, it is not specific to this condition and may also be elevated in other conditions such as acute alcohol intoxication of acute psychosis.

Serotonin Syndrome and Neuroleptic Malignant Syndrome are two conditions that can be difficult to differentiate. Serotonin Syndrome is caused by excess serotonergic activity in the CNS and is characterized by neuromuscular abnormalities, altered mental state, and autonomic dysfunction. On the other hand, Neuroleptic Malignant Syndrome is a rare acute disorder of thermoregulation and neuromotor control that is almost exclusively caused by antipsychotics. The symptoms of both syndromes can overlap, but there are some distinguishing clinical features. Hyper-reflexia, ocular clonus, and tremors are more prominent in Serotonin Syndrome, while Neuroleptic Malignant Syndrome is characterized by uniform ‘lead-pipe’ rigidity and hyporeflexia. Symptoms of Serotonin Syndrome usually resolve within a few days of stopping the medication, while Neuroleptic Malignant Syndrome can take up to 14 days to remit with appropriate treatment. The following table provides a useful guide to the main differentials of Serotonin Syndrome and Neuroleptic Malignant Syndrome.

The study on prazosin, an alpha-1 adrenoceptor antagonist, and its potential effectiveness in reducing PTSD symptoms in male and female soldiers is noteworthy. It is a logical progression in the search for a suitable therapeutic agent based on the observed physiological and phenomenological responses to traumatic experiences and PTSD symptoms. The clinical efficacy of prazosin was evaluated, taking into account the potential risk of significant hypotension due to its alpha-1 blocking properties, which was not observed. While all the other agents have been used to treat PTSD, only paroxetine is approved for this purpose.

A Historical Note on the Development of Zimelidine, the First Selective Serotonin Reuptake Inhibitor

In 1960s, evidence began to emerge suggesting a significant role of serotonin in depression. This led to the development of zimelidine, the first selective serotonin reuptake inhibitor (SSRI). Zimelidine was derived from pheniramine and was marketed in Europe in 1982. However, it was removed from the market in 1983 due to severe side effects such as hypersensitivity reactions and Guillain-Barre syndrome.

Despite its short-lived availability, zimelidine paved the way for the development of other SSRIs such as fluoxetine, which was approved by the FDA in 1987 and launched in the US market in 1988 under the trade name Prozac. The development of SSRIs revolutionized the treatment of depression and other mood disorders, providing a safer and more effective alternative to earlier antidepressants such as the tricyclics and MAO inhibitors.

Daily administration results in increased maximum concentration but more importantly decreased minimum concentration, which is believed to facilitate renal restoration.

Lithium – Pharmacology

Pharmacokinetics:
Lithium salts are rapidly absorbed following oral administration and are almost exclusively excreted by the kidneys unchanged. Blood samples for lithium should be taken 12 hours post-dose.

Ebstein’s:
Ebstein’s anomaly is a congenital malformation consisting of a prolapse of the tricuspid valve into the right ventricle. It occurs in 1:20,000 of the general population. Initial data suggested it was more common in those using lithium but this had not held to be true.

Contraindications:
Addison’s disease, Brugada syndrome, cardiac disease associated with rhythm disorders, clinically significant renal impairment, untreated of untreatable hypothyroidism, low sodium levels.

Side-effects:
Common side effects include nausea, tremor, polyuria/polydipsia, rash/dermatitis, blurred vision, dizziness, decreased appetite, drowsiness, metallic taste, and diarrhea. Side-effects are often dose-related.

Long-term use is associated with hypothyroidism, hyperthyroidism, hypercalcemia/hyperparathyroidism, irreversible nephrogenic diabetes insipidus, and reduced GFR.

Lithium-induced diabetes insipidus:
Treatment options include stopping lithium (if feasible), keeping levels within 0.4-0.8 mmol/L, once-daily dose of the drug taken at bedtime, amiloride, thiazide diuretics, indomethacin, and desmopressin.

Toxicity:
Lithium salts have a narrow therapeutic/toxic ratio. Risk factors for lithium toxicity include drugs altering renal function, decreased circulating volume, infections, fever, decreased oral intake of water, renal insufficiency, and nephrogenic diabetes insipidus. Features of lithium toxicity include GI symptoms and neuro symptoms.

Pre-prescribing:
Before prescribing lithium, renal function, cardiac function, thyroid function, FBC, and BMI should be checked. Women of childbearing age should be advised regarding contraception, and information about toxicity should be provided.

Monitoring:
Lithium blood levels should be checked weekly until stable, and then every 3-6 months once stable. Thyroid and renal function should be checked every 6 months. Patients should be issued with an information booklet, alert card, and record book.

– Lithium toxicity occurs at levels above 1.4 mmol/L
– Symptoms include anorexia, diarrhea, vomiting, ataxia, nystagmus, dysarthria, confusion, and seizures
– Fine tremor can occur in therapeutic range, but becomes coarser in toxicity
– If allowed to progress, toxicity can result in coma with hyperreflexia and increased tone, and irreversible neurological damage
– Treatment is supportive, with attention to electrolytes, fluid balance, renal function, and seizure control
– Bowel irrigation can be used in significant recent overdose, diuretics should be avoided, and haemodialysis may be required
– Benzodiazepines can control agitation.

The First Pass Effect in Psychiatric Drugs

The first-pass effect is a process in drug metabolism that significantly reduces the concentration of a drug before it reaches the systemic circulation. This phenomenon is related to the liver and gut wall, which absorb and metabolize the drug before it can enter the bloodstream. Psychiatric drugs are not exempt from this effect, and some undergo a significant reduction in concentration before reaching their target site. Examples of psychiatric drugs that undergo a significant first-pass effect include imipramine, fluphenazine, morphine, diazepam, and buprenorphine. On the other hand, some drugs undergo little to no first-pass effect, such as lithium and pregabalin.

Orally administered drugs are the most affected by the first-pass effect. However, there are other routes of administration that can avoid of partly avoid this effect. These include sublingual, rectal (partly avoids first pass), intravenous, intramuscular, transdermal, and inhalation. Understanding the first-pass effect is crucial in drug development and administration, especially in psychiatric drugs, where the concentration of the drug can significantly affect its efficacy and safety.

The effectiveness of minocycline, a tetracycline antibiotic, in providing neuroprotection has been observed in vitro. This study aimed to evaluate the impact of minocycline on negative symptoms in individuals diagnosed with schizophrenia at the beginning of the trial and after one year of follow-up. Minocycline is recognized for its ability to be well-tolerated in acne treatment and its capacity to cross the blood-brain barrier. Preliminary findings have indicated that it may be effective in preventing the onset of negative symptoms in schizophrenia. There have been no clinical trials conducted on the other antibiotics.

Diphenhydramine is a type of antihistamine that belongs to the first generation. It is commonly used to alleviate extrapyramidal side effects (EPSE). Unlike second generation antihistamines, first generation antihistamines have anticholinergic properties and can penetrate the blood-brain barrier, resulting in sedative effects. The anticholinergic effects of first generation antihistamines are beneficial for treating EPSE, which is believed to be caused by excessive acetylcholine due to reduced dopamine activity. Dopamine normally inhibits acetylcholine, but when dopamine activity is reduced, acetylcholine levels increase, leading to EPSE.

Extrapyramidal side-effects (EPSE’s) are a group of side effects that affect voluntary motor control, commonly seen in patients taking antipsychotic drugs. EPSE’s include dystonias, parkinsonism, akathisia, and tardive dyskinesia. They can be frightening and uncomfortable, leading to problems with non-compliance and can even be life-threatening in the case of laryngeal dystonia. EPSE’s are thought to be due to antagonism of dopaminergic D2 receptors in the basal ganglia. Symptoms generally occur within the first few days of treatment, with dystonias appearing quickly, within a few hours of administration of the first dose. Newer antipsychotics tend to produce less EPSE’s, with clozapine carrying the lowest risk and haloperidol carrying the highest risk. Akathisia is the most resistant EPSE to treat. EPSE’s can also occur when antipsychotics are discontinued (withdrawal dystonia).

Brugada syndrome typically appears in males during adulthood, usually around age 40, and sudden death may be the initial symptom. This genetic disorder is inherited in an autosomal dominant pattern. This information is sourced from the National Organization for Rare Disorders (NORD).

Lithium – Pharmacology

Pharmacokinetics:
Lithium salts are rapidly absorbed following oral administration and are almost exclusively excreted by the kidneys unchanged. Blood samples for lithium should be taken 12 hours post-dose.

Ebstein’s:
Ebstein’s anomaly is a congenital malformation consisting of a prolapse of the tricuspid valve into the right ventricle. It occurs in 1:20,000 of the general population. Initial data suggested it was more common in those using lithium but this had not held to be true.

Contraindications:
Addison’s disease, Brugada syndrome, cardiac disease associated with rhythm disorders, clinically significant renal impairment, untreated of untreatable hypothyroidism, low sodium levels.

Side-effects:
Common side effects include nausea, tremor, polyuria/polydipsia, rash/dermatitis, blurred vision, dizziness, decreased appetite, drowsiness, metallic taste, and diarrhea. Side-effects are often dose-related.

Long-term use is associated with hypothyroidism, hyperthyroidism, hypercalcemia/hyperparathyroidism, irreversible nephrogenic diabetes insipidus, and reduced GFR.

Lithium-induced diabetes insipidus:
Treatment options include stopping lithium (if feasible), keeping levels within 0.4-0.8 mmol/L, once-daily dose of the drug taken at bedtime, amiloride, thiazide diuretics, indomethacin, and desmopressin.

Toxicity:
Lithium salts have a narrow therapeutic/toxic ratio. Risk factors for lithium toxicity include drugs altering renal function, decreased circulating volume, infections, fever, decreased oral intake of water, renal insufficiency, and nephrogenic diabetes insipidus. Features of lithium toxicity include GI symptoms and neuro symptoms.

Pre-prescribing:
Before prescribing lithium, renal function, cardiac function, thyroid function, FBC, and BMI should be checked. Women of childbearing age should be advised regarding contraception, and information about toxicity should be provided.

Monitoring:
Lithium blood levels should be checked weekly until stable, and then every 3-6 months once stable. Thyroid and renal function should be checked every 6 months. Patients should be issued with an information booklet, alert card, and record book.

Amantadine and QTc Prolongation

Amantadine is a medication used to treat Parkinson’s disease and influenza. It has been associated with QTc prolongation, which can increase the risk of Torsades de points. Therefore, caution should be exercised when prescribing amantadine to patients with risk factors for QT prolongation. If a patient is already taking amantadine and develops a prolonged QTc interval, the medication should be discontinued and an alternative treatment considered. It is important to monitor the QTc interval in patients taking amantadine, especially those with risk factors for QT prolongation.

SNRIs are a type of antidepressant medication that work by blocking the reuptake of both serotonin and norepinephrine, providing two mechanisms to help with the antidepressant effect. They are particularly effective at inhibiting the norepinephrine transporter compared to the serotonin transporter. Examples of SNRIs include Venlafaxine, Desvenlafaxine, Duloxetine, and Milnacipran. Bupropion is a different type of antidepressant that works by inhibiting the reuptake of norepinephrine and dopamine (NDRI). Escitalopram is a selective serotonin reuptake inhibitor (SSRI), while Mirtazapine is a noradrenergic and specific serotonin antidepressant (NaSSA). Nefazodone is a serotonin antagonist/reuptake inhibitor (SARI).

For individuals with hepatic impairment, it is advisable to use low dose haloperidol. Amisulpride and paliperidone are eliminated through the kidneys, but there is no clinical data to support their safety in this population. Aripiprazole, olanzapine, quetiapine, and risperidone undergo significant liver metabolism. Chlorpromazine has a high potential for liver toxicity. Clozapine should not be used in individuals with active liver disease.

The development of tardive dyskinesia is thought to be caused by an increased sensitivity of postsynaptic D2 receptors in the nigrostriatal pathway. Therefore, clozapine is recommended as a treatment option since it has minimal binding affinity for D2 receptors.

Tardive Dyskinesia: Symptoms, Causes, Risk Factors, and Management

Tardive dyskinesia (TD) is a condition that affects the face, limbs, and trunk of individuals who have been on neuroleptics for months to years. The movements fluctuate over time, increase with emotional arousal, decrease with relaxation, and disappear with sleep. The cause of TD remains theoretical, but the postsynaptic dopamine (D2) receptor supersensitivity hypothesis is the most persistent. Other hypotheses include the presynaptic dopaminergic/noradrenergic hyperactivity hypothesis, the cholinergic interneuron burnout hypothesis, the excitatory/oxidative stress hypothesis, and the synaptic plasticity hypothesis. Risk factors for TD include advancing age, female sex, ethnicity, longer illness duration, intellectual disability and brain damage, negative symptoms in schizophrenia, mood disorders, diabetes, smoking, alcohol and substance misuse, FGA vs SGA treatment, higher antipsychotic dose, anticholinergic co-treatment, and akathisia.

Management options for TD include stopping any anticholinergic, reducing antipsychotic dose, changing to an antipsychotic with lower propensity for TD, and using tetrabenazine, vitamin E, of amantadine as add-on options. Clozapine is the antipsychotic most likely to be associated with resolution of symptoms. Vesicular monoamine transporter type 2 (VMAT2) inhibitors are agents that cause a depletion of neuroactive peptides such as dopamine in nerve terminals and are used to treat chorea due to neurodegenerative diseases of dyskinesias due to neuroleptic medications (tardive dyskinesia).

Anticholinergic side effects, such as dry mouth, urinary retention, and dry skin, are commonly associated with Amitriptyline and other tricyclic antidepressants.

Amantadine and QTc Prolongation

Amantadine is a medication used to treat Parkinson’s disease and influenza. It has been associated with QTc prolongation, which can increase the risk of Torsades de points. Therefore, caution should be exercised when prescribing amantadine to patients with risk factors for QT prolongation. If a patient is already taking amantadine and develops a prolonged QTc interval, the medication should be discontinued and an alternative treatment considered. It is important to monitor the QTc interval in patients taking amantadine, especially those with risk factors for QT prolongation.

Treating akathisia is a challenging task, as there are limited options available. In many cases, the only viable solution is to decrease the use of antipsychotic medication.

Extrapyramidal side-effects (EPSE’s) are a group of side effects that affect voluntary motor control, commonly seen in patients taking antipsychotic drugs. EPSE’s include dystonias, parkinsonism, akathisia, and tardive dyskinesia. They can be frightening and uncomfortable, leading to problems with non-compliance and can even be life-threatening in the case of laryngeal dystonia. EPSE’s are thought to be due to antagonism of dopaminergic D2 receptors in the basal ganglia. Symptoms generally occur within the first few days of treatment, with dystonias appearing quickly, within a few hours of administration of the first dose. Newer antipsychotics tend to produce less EPSE’s, with clozapine carrying the lowest risk and haloperidol carrying the highest risk. Akathisia is the most resistant EPSE to treat. EPSE’s can also occur when antipsychotics are discontinued (withdrawal dystonia).

Amantadine and QTc Prolongation

Amantadine is a medication used to treat Parkinson’s disease and influenza. It has been associated with QTc prolongation, which can increase the risk of Torsades de points. Therefore, caution should be exercised when prescribing amantadine to patients with risk factors for QT prolongation. If a patient is already taking amantadine and develops a prolonged QTc interval, the medication should be discontinued and an alternative treatment considered. It is important to monitor the QTc interval in patients taking amantadine, especially those with risk factors for QT prolongation.