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.

The main requirement is a mismatch between an individual’s biological sex and their gender identity, which causes significant distress.

Gender identity is the person’s identification of lived role in society, which is separate from their biological sex. Gender can include non-binary and pangender identities, and cisgender refers to people whose gender is congruent with their biological sex. Gender identity is not the same as sexual preference, which is covered by separate diagnostic categories. The ICD-11 has redefined gender identity-related health, replacing diagnostic categories like “transsexualism” and “gender identity disorder of children” with “gender incongruence of adolescence and adulthood” and “gender incongruence of childhood”, respectively. The DSM-5 uses the term ‘gender dysphoria’ to cover the whole range of gender identity disorders, which is characterized by a marked incongruence between one’s experienced/expressed gender and their assigned gender, lasting at least 6 months, and associated with clinically significant distress of impairment in social, occupational, of other important areas of functioning.

In 1951, Charpentier in France synthesised Chlorpromazine with the aim of creating a centrally acting antihistamine to assist with general anaesthesia. Later, studies conducted by Delay and Deniker provided evidence for its effectiveness in treating schizophrenia.

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.

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.

The medication with the strongest evidence is sildenafil.

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.

In 1977, Engel introduced the term ‘biopsychosocial model’ in an article for Science, advocating for a more comprehensive approach to understanding psychiatric illness. The biomedical model, which originated in the mid 19th Century, has been widely used. Aaron Beck has promoted the diathesis-stress model of psychopathology in relation to depression. August Weismann developed genetic determinism in 1890. Brown and Stewart, among others, have advocated for patient-centred care.

The serum concentration of valproic acid may be elevated by chlorpromazine, although the reason for this is not fully understood. However, this outcome is widely acknowledged.

Chlorpromazine: Photosensitivity Reactions and Patient Precautions

Chlorpromazine, the first drug used for psychosis, is a common topic in exams. However, it is important to note that photosensitivity reactions are a known side effect of its use. Patients taking chlorpromazine should be informed of this and advised to take necessary precautions. Proper education and awareness can help prevent potential harm from photosensitivity reactions.

The middle cerebral artery is the most frequent location for cerebral infarction, resulting in contralateral paralysis and sensory loss. If the dominant hemisphere is affected, language impairment such as Broca’s of Wernicke’s aphasia may occur. Bilateral anterior cerebellar artery blockage is uncommon but can lead to akinetic mutism, which is characterized by a loss of speech and movement. Non-dominant middle cerebral artery blockage can cause contralateral neglect, as well as motor and sensory dysfunction, but language is typically unaffected. The occlusion of the posterior inferior cerebellar artery can result in lateral medullary syndrome, also known as Wallenberg syndrome, which is characterized by crossed contralateral and trunk sensory deficits and ipsilateral sensory deficits affecting the face and cranial nerves. Emboli in the ophthalmic artery can cause temporary vision loss, also known as amaurosis fugax, which is more commonly caused by emboli originating in the carotid artery.

Cerebrospinal Fluid: Formation, Circulation, and Composition

Cerebrospinal fluid (CSF) is produced by ependymal cells in the choroid plexus of the lateral, third, and fourth ventricles. It is constantly reabsorbed, so only a small amount is present at any given time. CSF occupies the space between the arachnoid and pia mater and passes through various foramina and aqueducts to reach the subarachnoid space and spinal cord. It is then reabsorbed by the arachnoid villi and enters the dural venous sinuses.

The normal intracerebral pressure (ICP) is 5 to 15 mmHg, and the rate of formation of CSF is constant. The composition of CSF is similar to that of brain extracellular fluid (ECF) but different from plasma. CSF has a higher pCO2, lower pH, lower protein content, lower glucose concentration, higher chloride and magnesium concentration, and very low cholesterol content. The concentration of calcium and potassium is lower, while the concentration of sodium is unchanged.

CSF fulfills the role of returning interstitial fluid and protein to the circulation since there are no lymphatic channels in the brain. The blood-brain barrier separates CSF from blood, and only lipid-soluble substances can easily cross this barrier, maintaining the compositional differences.

Anton’s syndrome, also known as Anton-Babinski syndrome, is a condition that results from damage to the occipital lobe. People with this syndrome are cortically blind, but they are not aware of it and deny having any problem, a condition known as anosognosia. They may start falling over furniture as they cannot see, but they believe they can still see and describe their surroundings in detail, even though their descriptions are incorrect (confabulation). This syndrome is characterized by a lack of awareness of visual impairment, which can lead to significant difficulties in daily life.

While it’s not necessary to memorize the precise sequence of all the stressful life events, it’s advisable to have knowledge of the order of the most significant three.

Holmes Rahe Stress Scale (Social Readjustment Rating Scale)

In 1967, Holmes and Rahe conducted a study on the impact of stress on illness. They surveyed over 5,000 medical patients and asked them to report whether they had experienced any of 43 life events in the past two years. Each event was assigned a Life Change Unit (LCU) value, which represented its weight for stress. The higher the score, the more likely the patient was to become ill.

The first 10 life events and their corresponding LCU values are listed below.

1. Death of spouse – 100
2. Divorce – 73
3. Marital separation – 65
4. Jail term – 63
5. Death of a close family member – 63
6. Personal illness – 53
7. Marriage – 50
8. Being fired from work – 47
9. Marital reconciliation – 45
10. Retirement – 45

This scale is known as the Holmes Rahe Stress Scale of the Social Readjustment Rating Scale. It is still widely used today to assess the impact of life events on stress levels and overall health.

Individuals who are homozygous for APOE 4 have a risk of 10-30 times higher than those who do not have this genetic variant, while those who are heterozygous have a risk that is 3 times higher.

Genetics plays a role in the development of Alzheimer’s disease, with different genes being associated with early onset and late onset cases. Early onset Alzheimer’s, which is rare, is linked to three genes: amyloid precursor protein (APP), presenilin one (PSEN-1), and presenilin two (PSEN-2). The APP gene, located on chromosome 21, produces a protein that is a precursor to amyloid. The presenilins are enzymes that cleave APP to produce amyloid beta fragments, and alterations in the ratios of these fragments can lead to plaque formation. Late onset Alzheimer’s is associated with the apolipoprotein E (APOE) gene on chromosome 19, with the E4 variant increasing the risk of developing the disease. People with Down’s syndrome are also at high risk of developing Alzheimer’s due to inheriting an extra copy of the APP gene.

Schizophrenia Risk According to Gottesman

Irving I. Gottesman conducted family and twin studies in European populations between 1920 and 1987 to determine the risk of developing schizophrenia for relatives of those with the disorder. The following table displays Gottesman’s findings, which show the average lifetime risk for each relationship:

General population: 1%
First cousin: 2%
Uncle/aunt: 2%
Nephew/niece: 4%
Grandchildren: 5%
Parents: 6%
Half sibling: 6%
Full sibling: 9%
Children: 13%
Fraternal twins: 17%
Offspring of dual matings (both parents had schizophrenia): 46%
Identical twins: 48%

Blocq’s disease, also known as astasia-abasia, is a conversion symptom characterized by an abnormal gait that is not indicative of any organic lesion. Hypochondriasis is excessive worry about having a serious illness despite the absence of a medical condition. Malingering involves fabricating symptoms for secondary gain, while somatization is a chronic condition with multiple physical complaints for which no physical cause can be found and is associated with frequent medical contact.

The DVLA has guidelines for obtaining a vocational licence for Group 2 entitlement (LGV/PCV), which state that a licence will not be granted if there has been a history of alcohol dependence within the past three years. Alcohol dependence is a condition that develops after repeated alcohol use and includes a strong desire to consume alcohol, difficulty controlling its use, continued use despite harmful consequences, increased tolerance, and sometimes physical withdrawal symptoms. Indicators of alcohol dependence may include a history of withdrawal symptoms, tolerance, detoxification, and/of alcohol-related seizures. For Group 1 entitlement (car, motorcycle), confirmed alcohol dependence requires licence revocation of refusal until a one-year period free from alcohol problems has been achieved. Abstinence and normalization of blood parameters, if relevant, will typically be required.

Understanding the Placebo Effect

In general, a placebo is an inert substance that has no pharmacological activity but looks, smells, and tastes like the active drug it is compared to. The placebo effect is the observable improvement seen when a patient takes a placebo, which results from patient-related factors such as expectations rather than the placebo itself. Negative effects due to patient-related factors are termed the nocebo effect.

Active placebos are treatments with chemical activity that mimic the side effects of the drug being tested in a clinical trial. They are used to prevent unblinding of the drug versus the placebo control group. Placebos need not always be pharmacological and can be procedural, such as sham electroconvulsive therapy.

The placebo effect is influenced by factors such as the perceived strength of the treatment, the status of the treating professional, and the branding of the compound. The placebo response is greater in mild illness, and the response rate is increasing over time. Placebo response is usually short-lived, and repeated use can lead to a diminished effect, known as placebo sag.

It is difficult to separate placebo effects from spontaneous remission, and patients who enter clinical trials generally do so when acutely unwell, making it challenging to show treatment effects. Breaking the blind may influence the outcome, and the expectancy effect may explain why active placebos are more effective than inert placebos. Overall, understanding the placebo effect is crucial in clinical trials and personalized medicine.

, coma, respiratory depression (rare)

Regression to the mean is a statistical occurrence where the natural fluctuations in repeated data can appear as actual changes. This happens because measurements that are exceptionally high of low are typically followed by measurements that are closer to the average.

Understanding the Placebo Effect

In general, a placebo is an inert substance that has no pharmacological activity but looks, smells, and tastes like the active drug it is compared to. The placebo effect is the observable improvement seen when a patient takes a placebo, which results from patient-related factors such as expectations rather than the placebo itself. Negative effects due to patient-related factors are termed the nocebo effect.

Active placebos are treatments with chemical activity that mimic the side effects of the drug being tested in a clinical trial. They are used to prevent unblinding of the drug versus the placebo control group. Placebos need not always be pharmacological and can be procedural, such as sham electroconvulsive therapy.

The placebo effect is influenced by factors such as the perceived strength of the treatment, the status of the treating professional, and the branding of the compound. The placebo response is greater in mild illness, and the response rate is increasing over time. Placebo response is usually short-lived, and repeated use can lead to a diminished effect, known as placebo sag.

It is difficult to separate placebo effects from spontaneous remission, and patients who enter clinical trials generally do so when acutely unwell, making it challenging to show treatment effects. Breaking the blind may influence the outcome, and the expectancy effect may explain why active placebos are more effective than inert placebos. Overall, understanding the placebo effect is crucial in clinical trials and personalized medicine.

M1 receptors are found in the sympathetic postganglionic neurons.

To prevent bias in the study, the researchers are implementing patient blinding to prevent performance bias, as knowledge of whether they are taking venlafaxine of a placebo, of which arm of the study they are in, could impact the patient’s behavior. Additionally, investigators must also be blinded to avoid measurement bias.

When two individuals who are heterozygous for an autosomal recessive condition have a child, there is a 25% chance that the child will be affected by the condition, a 50% chance that the child will be a carrier of the condition, and a 25% chance that the child will be neither a carrier nor affected by the condition.

Inheritance Patterns:

Autosomal Dominant Conditions:
– Can be transmitted from one generation to the next (vertical transmission) through all forms of transmission observed (male to male, male to female, female to female).
– Males and females are affected in equal proportions.
– Usually, one parent is an affected heterozygote and the other is an unaffected homozygote.
– If only one parent is affected, there is a 50% chance that a child will inherit the mutated gene.

Autosomal Recessive Conditions:
– Males and females are affected in equal proportions.
– Two copies of the gene must be mutated for a person to be affected.
– Both parents are usually unaffected heterozygotes.
– Two unaffected people who each carry one copy of the mutated gene have a 25% chance with each pregnancy of having a child affected by the disorder.

X-linked Dominant Conditions:
– Males and females are both affected, with males typically being more severely affected than females.
– The sons of a man with an X-linked dominant disorder will all be unaffected.
– A woman with an X-linked dominant disorder has a 50% chance of having an affected fetus.

X-linked Recessive Conditions:
– Males are more frequently affected than females.
– Transmitted through carrier females to their sons (knights move pattern).
– Affected males cannot pass the condition onto their sons.
– A woman who is a carrier of an X-linked recessive disorder has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers.

Y-linked Conditions:
– Every son of an affected father will be affected.
– Female offspring of affected fathers are never affected.

Mitochondrial Inheritance:
– Mitochondria are inherited only in the maternal ova and not in sperm.
– Males and females are affected, but always being maternally inherited.
– An affected male does not pass on his mitochondria to his children, so all his children will be unaffected.

Omega 3 fatty acids, which are found in high amounts in oily fish, have been shown in some studies to improve depressive symptoms and can be safely combined with SSRIs. However, St John’s wort, which inhibits serotonin reuptake at nerve terminals, should not be taken with drugs that have a predominantly serotonergic action. Brewer’s yeast may cause a tyramine reaction with an MAOI, while evening primrose oil and ginkgo biloba have no interaction with SSRIs.

Freud’s The Psychopathology of Everyday Life was written in 1901, while The Interpretation of Dreams was written in 1899, Mourning and Melancholia in 1917, and The Ego and the Id in 1923. Man and Superman was a play written by George Bernard Shaw in 1903 and is unrelated to Freud’s works.

Electroencephalography

Electroencephalography (EEG) is a clinical test that records the brain’s spontaneous electrical activity over a short period of time using multiple electrodes placed on the scalp. It is mainly used to rule out organic conditions and can help differentiate dementia from other disorders such as metabolic encephalopathies, CJD, herpes encephalitis, and non-convulsive status epilepticus. EEG can also distinguish possible psychotic episodes and acute confusional states from non-convulsive status epilepticus.

Not all abnormal EEGs represent an underlying condition, and psychotropic medications can affect EEG findings. EEG abnormalities can also be triggered purposely by activation procedures such as hyperventilation, photic stimulation, certain drugs, and sleep deprivation.

Specific waveforms are seen in an EEG, including delta, theta, alpha, sigma, beta, and gamma waves. Delta waves are found frontally in adults and posteriorly in children during slow wave sleep, and excessive amounts when awake may indicate pathology. Theta waves are generally seen in young children, drowsy and sleeping adults, and during meditation. Alpha waves are seen posteriorly when relaxed and when the eyes are closed, and are also seen in meditation. Sigma waves are bursts of oscillatory activity that occur in stage 2 sleep. Beta waves are seen frontally when busy of concentrating, and gamma waves are seen in advanced/very experienced meditators.

Certain conditions are associated with specific EEG changes, such as nonspecific slowing in early CJD, low voltage EEG in Huntington’s, diffuse slowing in encephalopathy, and reduced alpha and beta with increased delta and theta in Alzheimer’s.

Common epileptiform patterns include spikes, spike/sharp waves, and spike-waves. Medications can have important effects on EEG findings, with clozapine decreasing alpha and increasing delta and theta, lithium increasing all waveforms, lamotrigine decreasing all waveforms, and valproate having inconclusive effects on delta and theta and increasing beta.

Overall, EEG is a useful tool in clinical contexts for ruling out organic conditions and differentiating between various disorders.

Erik Erikson and Daniel Levinson expanded the understanding of adult development. Erikson proposed a life-span model of human development consisting of eight successive psychosocial stages, each associated with an inherent conflict of crisis that the individual must encounter and successfully resolve to proceed with development. Levinson proposed a developmental theory consisting of universal stages of phases that extend from the infancy state to the elderly state, based on biographical interviews of 40 men in America. Both theorists maintained that personality develops in a predetermined order and builds upon each previous stage, and that failure to successfully negotiate a stage can result in a reduced ability to complete further stages and therefore a more unhealthy personality and sense of self. However, Levinson’s theory is age-based rather than event-based, and his model proposed a ‘life sequence’ consisting of a series of alternating stable (structure-building) periods and cross-era transitional (structure-changing) periods, with transitional periods typically lasting 5 years.

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.

Tourette’s syndrome, also known as combined vocal and motor tic disorder, is characterized by multiple motor tics and one of more vocal tics. Inattention may be present but is not a defining symptom. Coprophagia, of the act of eating feces, is not associated with Tourette’s syndrome and is more commonly seen in individuals with learning difficulties of chronic psychotic disorders. Glossolalia, of speaking in tongues, is not related to psychopathology and is not a feature of Tourette’s syndrome.

Methylphenidate commonly causes a decrease in appetite, while the other listed side-effects are considered rare of uncommon.

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.

Functions of the Hypothalamus

The hypothalamus is a vital part of the brain that plays a crucial role in regulating various bodily functions. It receives and integrates sensory information about the internal environment and directs actions to control internal homeostasis. The hypothalamus contains several nuclei and fiber tracts, each with specific functions.

The suprachiasmatic nucleus (SCN) is responsible for regulating circadian rhythms. Neurons in the SCN have an intrinsic rhythm of discharge activity and receive input from the retina. The SCN is considered the body’s master clock, but it has multiple connections with other hypothalamic nuclei.

Body temperature control is mainly under the control of the preoptic, anterior, and posterior nuclei, which have temperature-sensitive neurons. As the temperature goes above 37ºC, warm-sensitive neurons are activated, triggering parasympathetic activity to promote heat loss. As the temperature goes below 37ºC, cold-sensitive neurons are activated, triggering sympathetic activity to promote conservation of heat.

The hypothalamus also plays a role in regulating prolactin secretion. Dopamine is tonically secreted by dopaminergic neurons that project from the arcuate nucleus of the hypothalamus into the anterior pituitary gland via the tuberoinfundibular pathway. The dopamine that is released acts on lactotrophic cells through D2-receptors, inhibiting prolactin synthesis. In the absence of pregnancy of lactation, prolactin is constitutively inhibited by dopamine. Dopamine antagonists result in hyperprolactinemia, while dopamine agonists inhibit prolactin secretion.

In summary, the hypothalamus is a complex structure that regulates various bodily functions, including circadian rhythms, body temperature, and prolactin secretion. Dysfunction of the hypothalamus can lead to various disorders, such as sleep-rhythm disorder, diabetes insipidus, hyperprolactinemia, and obesity.

René Spitz coined the term anaclitic depression to describe the negative impact on children who are separated from their primary caregiver, such as during a hospital stay. In extreme cases, this can lead to hospitalism. Although this type of depression can hinder a child’s development, recovery is likely if the separation from the mother does not exceed three months. Ainsworth is known for her work on the strange situation procedure, while Bowlby focused on attachment and maternal deprivation. Main is associated with the adult attachment interview, and Rutter distinguished between privation and deprivation, with the former referring to a failure to form attachments.