Elevated troponin levels typically manifest within a few hours of myocardial injury and persist for a maximum of two weeks.

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.

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 preferred initial treatment for alcohol withdrawal syndrome is benzodiazepines.

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.

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.

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.

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.

, coma, respiratory depression (rare)

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).

With aging, there is an increase in lean body weight and body water and a decrease in the proportion of fat. As a result, water-soluble drugs are distributed to a greater extent. Lipid-soluble drugs have a lower volume of distribution in the elderly due to the lower proportion of body fat.

Prescribing medication for elderly individuals requires consideration of their unique pharmacokinetics and pharmacodynamics. As the body ages, changes in distribution, metabolism, and excretion can affect how medication is absorbed and processed. For example, reduced gastric acid secretion and motility can impact drug absorption, while a relative reduction of body water to body fat can alter the distribution of lipid soluble drugs. Additionally, hepatic metabolism of drugs decreases with age, and the kidneys become less effective, leading to potential accumulation of certain drugs.

In terms of pharmacodynamics, receptor sensitivity tends to increase during old age, meaning smaller doses may be needed. However, older individuals may also take longer to respond to treatment and have an increased incidence of side-effects. It is important to start with a lower dose and monitor closely when prescribing medication for elderly patients, especially considering the potential for interactions with other medications they may be taking.

SNRIs include duloxetine and venlafaxine.

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 given scenario follows first order kinetics, where the elimination rate of a drug depends on its concentration. A 100 mg dose of the drug is administered, with a 10% elimination rate per minute. After 1 minute, 10 mg of the drug is eliminated, leaving 90 mg. After 2 minutes, 9 mg is eliminated, leaving 81 mg. After 3 minutes, 8.1 mg is eliminated, resulting in a total of 27.1 mg eliminated.

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.

It is important to be aware of the higher likelihood of experiencing discontinuation symptoms with paroxetine compared to other selective serotonin reuptake inhibitors during exams.

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).

Sertraline use has been linked to the development of leucopenia. Patients are advised to report any signs of infection, such as fever, sore throat, of stomatitis, during treatment.

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.

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.

The liver plays a significant role in breaking down clozapine through the action of CYP450 enzymes, with CYP1A2, CYP3A4, and CYP2D6 being particularly involved in the process.

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.

Lithium is known to cause hypercalcemia and hyperparathyroidism, which can lead to various symptoms. These symptoms may include constipation (groans), kidney stones (stones), bone pain (bones), and mental health issues such as depression, lethargy, and confusion (psychic moans).

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.

Serotonin syndrome is identified by a combination of neuromuscular irregularities such as myoclonus and clonus, changes in mental state, and dysfunction of the autonomic nervous system.

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.

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.

The second generation of H1 antihistamines exhibit limited ability to cross the blood-brain barrier, leading to their non-sedating properties. Furthermore, they possess greater receptor specificity and do not produce significant anticholinergic effects. These characteristics make them a more desirable option for managing allergic conditions, as they minimize the risk of adverse effects.

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.

Although iproniazid demonstrated an antidepressant effect in clinical trials involving tuberculosis patients, it has been largely discontinued due to its link to liver damage. However, isoniazid, which shares chemical similarities with iproniazid, is still utilized as a treatment for tuberculosis.

The Maudsley Guidelines recommend the use of diazepam and clonazepam in their treatment plan for antipsychotic induced akathisia, likely because of their extended duration of action.

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.

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.

If a patient develops NMS, they may still require antipsychotic medication. However, it is recommended to stop antipsychotics for at least 5 days, and ideally longer. When restarting antipsychotics, it should be done slowly and at low doses, with close monitoring of blood pressure and temperature.

Anticholinergic drugs are believed to worsen NMS, possibly due to their effect on reducing sweating and exacerbating hyperthermia. However, there is no direct causal relationship between anticholinergics and NMS.

In cases where an alternative antipsychotic is needed, those with low dopamine affinity should be considered. These include clozapine, quetiapine, and aripiprazole.

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.

Alternative Routes of Administration for Antidepressants

While most antidepressants are taken orally, there are a few alternative routes of administration available. However, it is important to note that these non-oral preparations should only be used when absolutely necessary, as they may not have a UK licence.

One effective alternative route is sublingual administration of fluoxetine liquid. Buccal administration of selegiline is also available. Crushed amitriptyline has been shown to be effective when administered via this route.

Intravenous administration is another option, with several antidepressants available in IV preparations, including citalopram, escitalopram, mirtazapine, amitriptyline, clomipramine, and allopregnanolone (which is licensed in the US for postpartum depression). Ketamine has also been shown to be effective when administered intravenously.

Intramuscular administration of flupentixol has been shown to have a mood elevating effect, but amitriptyline was discontinued as an IM preparation due to the high volumes required.

Transdermal administration of selegiline is available, and suppositories containing amitriptyline, clomipramine, imipramine, and trazodone have been manufactured by pharmacies, although there is no clear data on their effectiveness. Sertraline tablets and doxepin capsules have also been given rectally.

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.

Agonists and Antagonists in Pharmacology

In pharmacology, an agonist is a substance that binds to a receptor and triggers a biological response. On the other hand, an antagonist is a substance that blocks the effects of an agonist. A partial agonist produces a response but cannot produce the maximum response even at high doses.

Competitive antagonists bind to the receptor in a reversible way without affecting the biological response. They make the agonist appear less potent. Inverse agonists, on the other hand, have opposite effects from those of full agonists. They are not the same as antagonists, which block the effect of both agonists and inverse agonists.

Full agonists display full efficacy at a receptor. Some substances can act as an agonist at certain receptors and as an antagonist at others. Such a substance is called an agonist-antagonist. Understanding the differences between agonists and antagonists is crucial in drug development and treatment.

Individuals of African and African-American descent exhibit the greatest prevalence of deficient CYP2D6 metabolism, resulting in a higher likelihood of being poor metabolisers. Codeine is classified as a prodrug, necessitating initial metabolism (specifically by CYP2D6) before it can produce pain-relieving effects.

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.

Modafinil shares similarities in its mechanism of action with amphetamine, and its effects are relatively brief with a half-life of approximately 8-12 hours. Additionally, the side effects of modafinil are comparable to those of amphetamine.

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.

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).

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.

Reboxetine is classified as a selective inhibitor of noradrenaline reuptake (NRI), which means it works by preventing the reuptake of noradrenaline and increasing its levels in the body. This medication is typically prescribed as a secondary option for treating acute depressive episodes of major depression when SSRIs are ineffective of not well-tolerated.

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.

Both lithium carbonate and citrate are used for the treatment and prevention of various mental health conditions, including mania, bipolar disorder, recurrent depression, and aggressive of self-harming behavior. Lithium carbonate is available in tablet form, while lithium citrate is a liquid medication.

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.

Pseudocholinesterase Deficiency

Pseudocholinesterase deficiency, also known as butyrylcholinesterase deficiency, is a medical condition that can lead to increased sensitivity to certain drugs. This condition affects approximately 1 in 3200 to 1 in 5000 people, with higher prevalence in certain populations such as the Persian Jewish community and Alaska Natives. Interestingly, this condition does not cause any noticeable symptoms until an abnormal drug reaction occurs.

It is important for individuals with pseudocholinesterase deficiency to avoid certain drugs, including donepezil, galantamine, procaine, succinylcholine, and pilocarpine. By avoiding these drugs, individuals with this condition can reduce their risk of experiencing adverse reactions.

Alternative Routes of Administration for Antidepressants

While most antidepressants are taken orally, there are a few alternative routes of administration available. However, it is important to note that these non-oral preparations should only be used when absolutely necessary, as they may not have a UK licence.

One effective alternative route is sublingual administration of fluoxetine liquid. Buccal administration of selegiline is also available. Crushed amitriptyline has been shown to be effective when administered via this route.

Intravenous administration is another option, with several antidepressants available in IV preparations, including citalopram, escitalopram, mirtazapine, amitriptyline, clomipramine, and allopregnanolone (which is licensed in the US for postpartum depression). Ketamine has also been shown to be effective when administered intravenously.

Intramuscular administration of flupentixol has been shown to have a mood elevating effect, but amitriptyline was discontinued as an IM preparation due to the high volumes required.

Transdermal administration of selegiline is available, and suppositories containing amitriptyline, clomipramine, imipramine, and trazodone have been manufactured by pharmacies, although there is no clear data on their effectiveness. Sertraline tablets and doxepin capsules have also been given rectally.

The mechanism of action of heroin involves attaching to opiate receptors, which are G-coupled. This attachment results in the suppression of cellular activity through stimulation.

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.

In zero order kinetics, the elimination of a drug occurs at a constant rate regardless of its concentration in the plasma. This results in a linear relationship between the plasma concentration and time from peak concentration. Unlike drugs that follow first order kinetics, drugs that follow zero order kinetics do not have a fixed half-life.

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.

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.

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.

Porphyria: The Little Imitator

Porphyria is a medical condition that is often referred to as the little imitator because it can mimic various common psychiatric presentations. This condition can be triggered by the use of certain psychotropic drugs, including barbiturates, benzodiazepines, sulpiride, and some mood stabilizers.

Porphyria can manifest in different ways, and it is important to be aware of the symptoms. These may include abdominal pain, mental state changes, constipation, vomiting, and muscle weakness.

Antipsychotics can be classified in various ways, including by chemical structure and generation. The two main generations are typical (first generation) and atypical (second generation) antipsychotics. Risperidone is an atypical antipsychotic and belongs to the benzisoxazole class. It works as an antagonist for dopamine D2, 5-HT 2a, histamine-1 receptor, and alpha 1-adrenoceptor. Other antipsychotics belong to different structural categories, such as butyrophenones (e.g. haloperidol), dibenzodiazapines (e.g. clozapine), dibenzothiazapines (e.g. quetiapine), Thienobenzodiazepine (e.g. olanzapine), phenothiazines (e.g. chlorpromazine, trifluoperazine, thioridazine), thioxanthenes (e.g. flupentixol), diphenylbutylpiperidine (e.g. pimozide), substituted benzamides (e.g. sulpiride), and arylpiperidylindole (quinolone) (e.g. aripiprazole).

It is not recommended to combine MAOIs with SSRIs, clomipramine, of ephedrine.

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).

, coma, respiratory depression (rare)

Stevens-Johnson syndrome is a severe skin condition that can be caused by medication use of infection. Anticonvulsants, particularly lamotrigine, are often the cause. Symptoms include fever, sore throat, fatigue, and the appearance of ulcers and lesions in the mucous membranes. A rash of round lesions also appears on the face, trunk, arms, legs, and soles of the feet. It is a life-threatening condition that requires immediate medical attention.

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.

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

To obtain an accurate measurement of the QT interval, it is recommended to measure it in lead II of leads V5-6. The Bazett formula may not provide accurate corrections for heart rates above 100 bpm of below 60 bpm, but it can be used to estimate the QT interval at a standard heart rate of 60 bpm through the corrected QT interval (QTc).

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.

The inhibition of sexual behavior is caused by the activation of 5-HT2 receptors. However, this effect can be reversed by using 5-HT2 antagonists like cyproheptadine and 5-HT1a agonists like buspirone. These drugs are effective in treating sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs).

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.

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.

Varenicline is a medication that helps people quit smoking by partially activating specific nicotine receptors in the body.

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.

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.

Taste disturbance is known as Dysgeusia in medical terminology and can be caused by various medications. Lithium is a frequently encountered culprit, but other drugs such as certain antidepressants, benzodiazepines, z-drugs, and opiates can also lead to this condition. Additionally, any medication that causes dry mouth may result in taste disturbance. This information is sourced from D Kaufman’s book, Clinical neurology for psychiatrists, published in 2007 on page 38.

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.

Hyperprolactinemia is a potential side effect of antipsychotic medication, but it is rare with antidepressants. Dopamine inhibits prolactin, so dopamine antagonists, such as antipsychotics, can increase prolactin levels. The degree of prolactin elevation is dose-related, and some antipsychotics cause more significant increases than others. Hyperprolactinemia can cause symptoms such as galactorrhea, menstrual difficulties, gynecomastia, hypogonadism, and sexual dysfunction. Long-standing hyperprolactinemia in psychiatric patients can increase the risk of osteoporosis and breast cancer, although there is no conclusive evidence that antipsychotic medication increases the risk of breast malignancy and mortality. Some antipsychotics, such as clozapine and aripiprazole, have a low risk of causing hyperprolactinemia, while typical antipsychotics and risperidone have a high risk. Monitoring of prolactin levels is recommended before starting antipsychotic therapy and at three months and annually thereafter. Antidepressants rarely cause hyperprolactinemia, and routine monitoring is not recommended. Symptomatic hyperprolactinemia has been reported with most antidepressants, except for a few, such as mirtazapine, agomelatine, bupropion, and vortioxetine.

Pregnant women who take valproate have a high risk of giving birth to children with congenital malformations, with rates ranging from 6-11%. The North American Antiepileptic Drug Registry found that 10.7% of children born to women taking valproate monotherapy had major malformations, while the UK Epilepsy and Pregnancy Register reported a rate of 6.2%. The most common malformations are heart and facial defects, as well as neural tube, urogenital, and skeletal defects. While folic acid supplementation may help reduce the risk of malformations, it is strongly recommended that women avoid taking valproate during pregnancy.

Pharmacological Treatments for Alcohol Dependence

Acamprosate, when used in conjunction with counselling, has been found to be effective in helping alcohol-dependent patients with strong cravings maintain abstinence. Bupropion hydrochloride, which is primarily used as an antidepressant, has also been shown to be effective in maintaining smoking cessation. Disulfiram, on the other hand, causes an unpleasant systemic reaction when alcohol is consumed due to the buildup of acetaldehyde. Nalmefene has recently been licensed for the reduction of alcohol consumption in alcohol-dependent patients with a high drinking risk level who do not have physical withdrawal symptoms and do not require immediate detoxification. Finally, naltrexone, an opioid-receptor antagonist, may be used in the treatment of alcohol dependence after successful withdrawal.

Buspirone is a type of anti-anxiety medication that belongs to the azapirone (azaspirodecanedione) class of drugs. It is used to treat the same conditions as benzodiazepines. Unlike benzodiazepines, buspirone is a partial agonist of the serotonin 5HT1A receptor and does not cause sedation, physical dependence, of psychomotor impairment. However, it may cause side effects such as dizziness, headache, excitement, and nausea. Other less common side effects include dry mouth, tachycardia/palpitations/chest pain, drowsiness/confusion, seizures, fatigue, and sweating. Buspirone is not recommended for individuals with epilepsy, severe hepatic impairment, moderate to severe renal impairment, during pregnancy, of while breastfeeding.

Hyponatraemia is a condition where the serum sodium level in a patient falls below 135 mmol/L, with severe hyponatraemia being defined as a level below 120 mmol/L. The causes of hyponatraemia can be classified based on the patient’s fluid status, which can be hypovolaemic, euvolemic, of hypervolaemic. Hypovolaemic hyponatraemia occurs when there is a reduction in extracellular fluid volume and serum sodium levels, often due to gastrointestinal losses. Euvolemic hyponatraemia is the most common type and occurs when the extracellular fluid volume is normal. This type can be caused by conditions such as SIADH, hypothyroidism, primary polydipsia, and medications. Hypervolaemic hyponatraemia is associated with increased extracellular volume and occurs when fluid retention is greater than sodium retention, often due to cardiac and renal failures of liver cirrhosis.

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.

Sulpiride belongs to the substituted benzamide class of drugs.
Chlorpromazine falls under the phenothiazine category.
Flupentixol is classified as a thioxanthene medication.
Haloperidol is a butyrophenone compound.
Pimozide is a diphenylbutylpiperidine 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

Debrisoquine hydroxylase is the primary enzyme responsible for metabolizing several antidepressants, such as tricyclics, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, and others. Approximately 5 out of 100 individuals are poor metabolisers, which can lead to increased side effects from medications that rely on CYP2D6 for metabolism. Conversely, ultra-rapid metabolisers may require higher than average doses of these medications due to their highly active forms of the enzyme.

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.

Although only gluteal injection is approved for olanzapine, deltoid injection is not as effective. Smoking and carbamazepine can induce the metabolism of olanzapine, resulting in lower concentrations. However, the increase in olanzapine clearance is only slight to moderate, and the clinical implications are likely limited. Clinical monitoring is recommended, and an increase in olanzapine dosage may be necessary. While test doses are not required for olanzapine embonate, the Summary of Product Characteristics (SPC) recommends treating patients with oral olanzapine before administering ZYPADHERA to establish tolerability and response.

, coma, respiratory depression (rare)

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.

Antidepressants: Minimum Effective Doses

According to the Maudsley 13th, the following are the minimum effective doses for various antidepressants:

– Citalopram: 20 mg/day
– Fluoxetine: 20 mg/day
– Fluvoxamine: 50 mg/day
– Paroxetine: 20 mg/day
– Sertraline: 50 mg/day
– Mirtazapine: 30 mg/day
– Venlafaxine: 75 mg/day
– Duloxetine: 60 mg/day
– Agomelatine: 25 mg/day
– Moclobemide: 300 mg/day
– Trazodone: 150 mg/day

Note that these are minimum effective doses and may vary depending on individual factors and response to treatment. It is important to consult with a healthcare professional before starting of changing any medication regimen.

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.

Pemoline, a central nervous system stimulant that was once used to treat ADHD, is now known to cause severe liver failure that can be fatal. Due to this dangerous side effect, it was taken off the market in the UK in 1997. Although this information may no longer be applicable in a clinical setting, we have kept the question in our database as it may still appear in exams.

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.

Modafinil shares similarities in its mechanism of action with amphetamine, and its effects are relatively brief with a half-life of approximately 8-12 hours. Additionally, the side effects of modafinil are comparable to those of amphetamine.

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.

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.

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).

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).

Lofexidine is administered to relieve the symptoms of withdrawal from heroin and opiates. Alprazolam and lormetazepam belong to the benzodiazepine class of drugs and are likely to cause physical dependence with prolonged use. Codeine is an analgesic opiate and frequent use can result in significant physical dependence. Phenobarbitone is a potent barbiturate with anaesthetic properties and its regular use can lead to the development of physical dependence.

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.

Antipsychotic medications change the tension of the bladder of urethral sphincter, which can result in the backward flow of semen into the bladder during ejaculation. This effect is believed to be caused by blocking the 1-adrenergic receptor.

Antipsychotics: Common Side Effects and Relative Adverse Effects

Antipsychotics are medications used to treat various mental health conditions, including schizophrenia and bipolar disorder. However, they can also cause side effects that can be bothersome of even serious. The most common side effects of antipsychotics are listed in the table below, which includes the adverse effects associated with their receptor activity.

Antidopaminergic effects: These effects are related to the medication’s ability to block dopamine receptors in the brain. They can cause galactorrhoea, gynecomastia, menstrual disturbance, lowered sperm count, reduced libido, Parkinsonism, dystonia, akathisia, and tardive dyskinesia.

Anticholinergic effects: These effects are related to the medication’s ability to block acetylcholine receptors in the brain. They can cause dry mouth, blurred vision, urinary retention, and constipation.

Antiadrenergic effects: These effects are related to the medication’s ability to block adrenaline receptors in the body. They can cause postural hypotension and ejaculatory failure.

Histaminergic effects: These effects are related to the medication’s ability to block histamine receptors in the brain. They can cause drowsiness.

The Maudsley Guidelines provide a rough guide to the relative adverse effects of different antipsychotics. The table below summarizes their findings, with +++ indicating a high incidence of adverse effects, ++ indicating a moderate incidence, + indicating a low incidence, and – indicating a very low incidence.

Drug Sedation Weight gain Diabetes EPSE Anticholinergic Postural Hypotension Prolactin elevation
Amisulpride – + + + – – +++
Aripiprazole – +/- – +/- – – –
Asenapine + + +/- +/- – – +/-
Clozapine +++ +++ +++ – +++ +++ –
Flupentixol + ++ + ++ ++ + +++
Fluphenazine + + + +++ ++ + +++
Haloperidol + + +/- +++ + + +++
Olanzapine ++ +++ +++ +/- + + +
Paliperidone + ++ + + + ++ +++
Pimozide + + – + + + +++
Quetiapine ++ ++ ++ – + ++ –
Risperidone + ++ + + + ++ +++
Zuclopenthixol ++ ++ + ++ ++ + +++

Overall, it is important to discuss the potential side effects of antipsychotics with a healthcare provider and to monitor for any adverse effects while taking these medications.

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.

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.

Pharmacokinetics in Pregnancy

During pregnancy, there are significant changes in maternal physiology that can affect the pharmacokinetics of drugs. These changes are most pronounced in the third trimester. One of the most notable changes is an increase in plasma volume, which can lead to haemodilution and a decrease in the concentration of plasma albumin. As a result, the total plasma concentrations of albumin-bound drugs may decrease during pregnancy. Additionally, lipophilic drugs may have an increased volume of distribution due to the increase in plasma volume.

Progesterone levels are also elevated during pregnancy, which can lead to delayed gastric emptying and reduced small intestine motility. This may affect the absorption of drugs, but the overall impact on bioavailability is likely to be relatively small.

The activity of hepatic drug-metabolizing enzymes can also change during pregnancy. Estrogens and progesterone can induce some CYP enzymes and inhibit others, leading to altered drug metabolism.

Finally, renal blood flow and the glomerular filtration rate increase during pregnancy, which can enhance the elimination of some drugs. The GFR can increase by up to 50% during pregnancy. These changes in pharmacokinetics during pregnancy must be taken into account when prescribing drugs to pregnant women.

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.

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.

Taking paracetamol with MAOIs is safe, but other medications and certain foods and drinks should be avoided to prevent the cheese reaction. The list of high-tyramine foods is provided in the drug’s leaflet. MAOIs are not commonly prescribed in primary care.

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.

According to Gillman (1998), it is recommended to avoid using the antihistamines brompheniramine and chlorpheniramine as they act as serotonin reuptake inhibitors (SRIs). However, all other antihistamines are considered safe for use. Gillman’s study focused on the history and risk of serotonin syndrome.

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 presentation is indicative of post-injection syndrome related to olanzapine embonate.

, coma, respiratory depression (rare)

Diplopia is a frequently occurring side-effect, while the other options are infrequent of extremely infrequent side-effects of carbamazepine.

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.

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).

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.

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.

The liver contains a significant number of Cytochrome P450 proteins, which are primarily located in the endoplasmic reticulum membrane. These enzymes are responsible for metabolizing various compounds, both naturally occurring and foreign. Additionally, these proteins can be found in other cellular compartments, including the cell surface and mitochondria, and are present in other areas of the body beyond the liver.

Understanding Biotransformation: A Metabolic Process for Excretion

Biotransformation is a metabolic process that occurs primarily in the liver, but also in other organs such as the kidneys, intestine, adipose, skin, and lungs. Its main function is to facilitate the excretion of both exogenous and endogenous substances by altering their chemical structures through a series of reactions. Enzymes found in the cytoplasm, endoplasmic reticulum, and mitochondria of cells catalyze these reactions, which can cause the substrate to become inactive, active, of even toxic.

Biotransformation is divided into three phases. Phase I reactions involve oxidation, reduction, of hydrolysis of the drug, yielding a polar, water-soluble metabolite that is often still active. Phase II reactions consist of adding hydrophilic groups to the original molecule, a toxic intermediate, of a nontoxic metabolite formed in phase I, to increase its polarity. The most common method is conjugation with glucuronic acid, but other groups such as sulphate, amino acids, acetate, and methyl can also be added. Phase III reactions occur post-phase II, where a chemical substance can undergo further metabolism and excretion through active transport into the urinary of hepatobiliary system.

Understanding biotransformation is crucial in pharmacology and toxicology, as it affects the efficacy and toxicity of drugs and other substances. By facilitating the excretion of these substances, biotransformation helps maintain homeostasis in the body and prevent accumulation of potentially harmful compounds.

The previously assumed higher risk is now uncertain and may not actually exist. We include this question to ensure that you are aware of the past association, as it may still be present in exam materials that have not been revised.

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.

Citalopram can moderately prolong QTc (>10 msec), while aripiprazole and paliperidone have no effect. Haloperidol and pimozide have a high effect, and quetiapine and amisulpride have a moderate effect. Clozapine, risperidone, and olanzapine have a low effect (<10 msec prolongation). Lamotrigine, mirtazapine, and SSRIs (excluding citalopram) do not have an effect on QTc interval.

If there are no T wave abnormalities on the ECG, the Maudsley guidelines deem a QTc of 460 ms acceptable for women.

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.

Duloxetine is also licensed for the treatment of generalised anxiety disorder.

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

EPSE’s result from the blocking of dopaminergic D2 receptors, so theoretically, dopamine agonists could alleviate them. However, they are not typically prescribed because they could worsen the underlying psychotic condition. Amantadine is an exception, as it is believed to work by stimulating dopamine receptors. It should be noted, however, that amantadine has complex effects and may exacerbate psychotic symptoms in certain patients.

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).

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.

Bupropion is classified as a noradrenaline dopamine reuptake inhibitor (NDRI) and functions by elevating the levels of neurotransmitters such as noradrenaline and dopamine. It has been utilized as an antidepressant and a smoking cessation aid.

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.

Studies have demonstrated that memantine possesses neuroprotective properties for individuals with Alzheimer’s disease and those who have suffered from traumatic brain injury.

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.

When apomorphine is withdrawn, it results in a decrease in dopamine activity in the brain, similar to the effect of starting an antipsychotic medication that blocks dopamine receptors.

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.

The question pertains to a classic case of atypical depression, which is best treated with phenelzine, a MAOI. While imipramine and other TCAs have some evidence for treating atypical depression, they are not as effective as MAOIs. Nowadays, SSRIs are commonly used as a first-line treatment, but they have a weaker evidence base compared to MAOIs and TCAs. Vortioxetine is a new antidepressant that has complex effects on the 5HT system, but it has not been studied for its efficacy in treating atypical depression. Similarly, venlafaxine has not been studied for this indication either.

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.

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.

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.

For centuries, individuals from the East coast of Africa have been chewing khat, which produces effects that stem from two phenylalkylamines, cathinone and cathine, both of which are structurally similar to amphetamine. The physical effects of khat include dry mouth, dizziness, impotence, cirrhosis, tachycardia, and tachypnoea.

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.

Aripiprazole does not affect the QTc interval and has minimal risk of extrapyramidal side effects, sedation, of weight gain. Amisulpride, citalopram, and quetiapine have a moderate effect on the QTc interval, which requires ECG monitoring due to a prolongation of >10 msec. Haloperidol has a high effect on the QTc interval, which mandates ECG monitoring due to a prolongation of >20 msec.

Understanding Biotransformation: A Metabolic Process for Excretion

Biotransformation is a metabolic process that occurs primarily in the liver, but also in other organs such as the kidneys, intestine, adipose, skin, and lungs. Its main function is to facilitate the excretion of both exogenous and endogenous substances by altering their chemical structures through a series of reactions. Enzymes found in the cytoplasm, endoplasmic reticulum, and mitochondria of cells catalyze these reactions, which can cause the substrate to become inactive, active, of even toxic.

Biotransformation is divided into three phases. Phase I reactions involve oxidation, reduction, of hydrolysis of the drug, yielding a polar, water-soluble metabolite that is often still active. Phase II reactions consist of adding hydrophilic groups to the original molecule, a toxic intermediate, of a nontoxic metabolite formed in phase I, to increase its polarity. The most common method is conjugation with glucuronic acid, but other groups such as sulphate, amino acids, acetate, and methyl can also be added. Phase III reactions occur post-phase II, where a chemical substance can undergo further metabolism and excretion through active transport into the urinary of hepatobiliary system.

Understanding biotransformation is crucial in pharmacology and toxicology, as it affects the efficacy and toxicity of drugs and other substances. By facilitating the excretion of these substances, biotransformation helps maintain homeostasis in the body and prevent accumulation of potentially harmful compounds.

Antidepressants: Minimum Effective Doses

According to the Maudsley 13th, the following are the minimum effective doses for various antidepressants:

– Citalopram: 20 mg/day
– Fluoxetine: 20 mg/day
– Fluvoxamine: 50 mg/day
– Paroxetine: 20 mg/day
– Sertraline: 50 mg/day
– Mirtazapine: 30 mg/day
– Venlafaxine: 75 mg/day
– Duloxetine: 60 mg/day
– Agomelatine: 25 mg/day
– Moclobemide: 300 mg/day
– Trazodone: 150 mg/day

Note that these are minimum effective doses and may vary depending on individual factors and response to treatment. It is important to consult with a healthcare professional before starting of changing any medication regimen.

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.

Antidepressants typically interfere with the natural pattern of sleep, especially by reducing REM sleep. However, Agomelatine has been found to enhance disrupted sleep-wake cycles in individuals with major depressive disorder.

Agomelatine: A New Drug for Depression Treatment

Agomelatine is a recently developed medication that is used to treat depression. Its mechanism of action involves acting as an agonist at melatonin M1 and M2 receptors, while also acting as an antagonist at 5HT2C receptors. The effects of melatonin appear to promote sleep, while the 5HT2C antagonism leads to the release of dopamine and norepinephrine in the frontal cortex. Interestingly, serotonin levels do not appear to be affected by this medication.

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).

Agomelatine (Valdoxan) is a novel antidepressant that functions as an agonist at both MT1 and MT2 receptors, while also acting as a 5HT2C antagonist. Unlike most other antidepressants, it does not affect monoamine uptake.
First-generation antipsychotics work by antagonizing D2 receptors.
Benzodiazepines exert their effects by potentiating GABA.
Noradrenaline reuptake inhibition is a common mechanism of action for many antidepressants, including SNRIs and tricyclics.
SSRI (and other) antidepressants function by inhibiting the reuptake of serotonin.

Lamotrigine is prescribed to enhance the effectiveness of clozapine in treating schizophrenia that is resistant to clozapine. However, it is important to note that lamotrigine can cause Stevens-Johnson syndrome, a serious skin condition that requires immediate medical attention. Therefore, if a rash appears, treatment with lamotrigine should be discontinued promptly.

Although fluoxetine was the first SSRI to be approved and marketed in the United States, it took over seven years of clinical trials (Phase I-Phase III) to do so. Meanwhile, Astra AB introduced zimeldine (Zelmid®), the first SSRI, to the European market in March 1982. However, zimeldine, which was derived from pheniramine, was taken off the European market in September 1983 due to severe side effects such as hypersensitivity reactions and Guillain-Barre syndrome, an acute peripheral neuropathy. The hypersensitivity reactions were similar to a flu-like syndrome and included fever, joint/muscle pain, headaches, and hepatic effects.

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.