MST Pharmacology Table Cumulative PDF

ANALGESICS AND ANAESTHETICS: Nocicep3ve pain: burning, aching sensa.on localised to around the site of injury and caused by excess s.mula.on of peripheral nocicep.ve neurons. Neuropathic pain: shoo.ng pain persis.ng a;er the peripheral injury has healed. Neuroplas3c pain...

ANALGESICS AND ANAESTHETICS: Nocicep3ve pain: burning, aching sensa.on localised to around the site of injury and caused by excess s.mula.on of peripheral nocicep.ve neurons. Neuropathic pain: shoo.ng pain persis.ng a;er the peripheral injury has healed. Neuroplas3c pain: non-painful s.muli are interpreted as pain due to memories of pain causing central sensi.sa.on to various s.muli. Acute pain: short-lived, o;en due to injury. Chronic pain: lasts over 12 weeks, can be nocicep.ve, o Cancer pain: associated with malignancy. o Non-cancer pain: includes various chronic condi.ons. Small diameter primary afferent fibres have sensory endings in peripheral.ssue that detect s.muli such as mechanical, thermal or chemical injuries and project to the dorsal horn of the spinal cord where they synapse on neurons projec.ng to higher centres. ANALGESIC: MECHANISM(s) of ac3on: Indica3ons and ADRs: Opioids Mimic endogenous pep.des Indica3ons: (endorphins, enkephalins, Moderate to severe pain (acute and chronic dynorphins) and bind to cancer pain). central opioid receptors, including the mu receptor Mu opioid receptors in the medulla responsible for analgesia, oblongata, specifically in the cough centres, triggering G-protein coupled play a role in suppressing the cough reflex. cascades in pre-synap.c and Drugs like codeine and dextromethorphan post-synap.c neurons. act on these receptors to reduce coughing, which is why they are commonly used in At the pre-synap.c terminal, cough medica.ons. the opioid-mu triggered- cascade will result in reduced Mu opioid receptors in the GI tract reduce cAMP levels, decreasing peristalsis and intes3nal mo3lity when calcium ion influx and ac.vated. This leads to slower movement of therefore reducing contents through the intes.nes and greater neurotransmiHer release absorp.on of water, which helps in firming between the two nerves, stools and reducing diarrhoea. Medica.ons leading to less like loperamide (Imodium), which acts on communica.on. peripheral mu receptors, exploit this mechanism for trea.ng diarrhoea without At the post-synap.c terminal, significant central nervous system effects. the opioid-mu triggered- cascade will increase K+ ADRs: efflux, hyperpolarising the Physical dependence + withdrawal upon neuron and reducing pain discon.nua.on transmission up the spinal Respiratory depression cord. Dysphoria: nega.ve mood effects. Cons.pa.on: reduced GI mo.lity. Nausea and vomi.ng: o;en CTZ-related. Seda.on: increases falls risk  Pupil constric.on (mioisis): Histamine release triggered by morphine: may cause itching, bronchospasm, and hypotension. CLINICAL CONSIDERATIONS: Tolerance: higher doses needed to achieve previous analgesic effect, can develop within 14 days of regular dosing. Physiological and psychological dependence: if there is inconsistency of administra.on or sudden drop in dose, the dependent pa.ent will experience withdrawal symptoms. A;er experiencing withdrawal once, this promotes psychological dependence through the dopaminergic mesolimbic reward system. Examples of Details of use Clinical considera3ons and indica3ons: opioids Morphine/ Codeine is morphine’s pro- Conversion of codeine to morphine is codeine drug (≈10% codeine is dependent on the availability of CYP2D6 hepa.cally converted to enzyme in the liver. Without CYP2D6, this morphine). conversion cannot occur. Codeine is 10x less potent Codeine’s lower potency means that it used than morphine when for mild-moderate pain relief usually in morphine is given in its ac.ve combina.on with an NSAID or paracetamol. form on a per milligram basis. Morphine has oral-, Codeine can be used to suppress non- injectable-slow- and quick- produc.ve cough. ac.ng forms. Oxycodone Longer half-life than morphine Fentanyl Extremely potent NOT first-line NOT used outside of severe cancer pain Methadone Long-half life, weak agonist of Used as an opioid replacement treatment in mu-opioid receptors, used as situa.ons of serious dependence due to an opioid replacement. longer half-life, reduced induc.on of euphoria, cross-tolerance as it blocks the effects of drugs like heroin, facilitates more controlled and gradual withdrawal due to longer half-life. Buprenorphine Used as an opioid BeHer for elderly pa.ents due to its ceiling replacement, comes in oral effect on respiratory depression regardless film or patch form. of increasing dose. Par.al agonist but potent. Tramadol Dirty drug (extremely non- selec.ve, inhibits serotonin and noradrenaline reuptake, impacts muscarinic and  nico.nic receptors, drug interac.ons, inter-individual variability in metabolism, uncomfortable ADRs. Tapentadol Opioid-like analgesia helps (is a treat nocicep.ve or acute noradrenaline pain. reuptake By increasing noradrenaline inhibit with levels in the synapse, opioid agonist tapentadol modulates pain ac.ons) transmission in descending pain pathways, contribu.ng to analgesia of neuropathic pain. NALOXONE: Naloxone is a mu-receptor antagonist used in the treatment of opioid overdose. Can be injected, administered via a nasal spray or taken in combina.on controlled-release oxycodone tablets. When opioids liked crushed oxycodone alone are injected, they rapidly reach the brain, causing a quick onset of effects, including euphoria. Oxycodone-naloxone tablets have been created to stop oxycodone tablets being crushed in opioid abuse situa.ons: injec.on of oxycodone-naloxone combina.on does not result in euphoria as naloxone antagonises injected oxycodone. When swallowed, naloxone undergoes extensive first-pass metabolism in the liver, meaning that a large propor.on of naloxone is inac.vated before it can enter the bloodstream and reach the brain. Therefore, orally administered naloxone has very poor bioavailability, meaning that it does not block oxycodone’s effect, but theore.cally blocks its cons.patory effects. ANALGESIC: MECHANISM(s) of ac3on: Clinical considera3ons, Indica3ons and ADRs: Paracetamol Acts on the cyclooxygenase INDICATIONS: enzyme (likely COX-3) to Mild-moderate pain. provide analgesic and an.- Fever reduc.on. pyre.c effects without an.- inflammatory ac.on. COMBINATION THERAPY: Can be used alongside NSAIDs, synergis.c with opioids, therefore allowing lower opioid doses to gain the same perceived level of pain relief. OVERDOSE: Can arise from inten.onal harm or accidentally. In an overdose, paracetamol metabolism cannot occur fast enough. Normally, paracetamol is safely processed in the liver through two main pathways —  glucuronida.on and sulfa.on — which convert it into non-toxic, water-soluble compounds that are excreted in the urine. However, when an overdose of paracetamol occurs, these primary pathways become saturated, and more of the drug is metabolized by the cytochrome P450 enzyme system (specifically CYP2E1) into NAPQI. Under normal condi.ons, NAPQI is rapidly detoxified by conjuga.on with glutathione, a protec.ve an.oxidant, forming a non-toxic compound that is safely excreted. In a paracetamol overdose, glutathione stores are depleted, and once depleted, NAPQI accumulates in the liver and begins to covalently bind to cellular proteins and lipids, causing oxida3ve stress. This results in cellular damage, primarily in hepatocytes, leading to liver necrosis, and in severe cases, Ac3vated Ac.vated charcoal can help by acute liver failure. Charcoal for absorbing paracetamol in the paracetamol gastrointes.nal tract, reducing the overdose: amount that enters the bloodstream and is metabolized into NAPQI. LOCAL ANAESTHETICS: Local anaesthe.cs block voltage-dependent sodium channels which are important for the ini.a.on and propaga.on of an ac.on poten.al. Normally, when a sensory, nocicep.ve nerve (A-delta and C fibres) receives a pain signal, sodium channels open to allow sodium to enter the nerve cell which generates an ac.on poten.al that transmits the local signal. By blocking voltage-dependent sodium channels, the local anaesthe.c prevents the genera3on of ac3on poten3als in the nociceptors, effec.vely stopping the transmission of pain signals from the peripheral nerves to the brain. Local anaesthe.cs also promote the efflux of potassium ions which helps to further hyperpolarise the cell membrane, making it more difficult for the nerve to reach the threshold needed to fire again. By increasing the refractory period (the.me when a neuron cannot fire again), local anaesthe.cs can prevent the transmission of pain signals. Local anaesthe.cs can be used to treat both nocicep3ve pain (caused by actual or poten.al.ssue damage, such as injury) and neuropathic pain (caused by damage or dysfunc.on to the nerves themselves. When used topically, local anaesthe.cs can block pain signals at the site of nerve damage or irrita.on. This is beneficial because they prevent the spontaneous firing of damaged nocicep.ve nerves, which is o;en responsible for chronic pain. LOCAL ANAESTHETICS SHOW USE-DEPENDENCE: Use-dependence means that local anaesthe.cs are more effec.ve at blocking sodium channels when those channels are ac3ve or open (i.e. during frequent nerve firing). Sodium channels cycle between open, closed, and inac3vated states during ac.on poten.al propaga.on. Local anaesthe.cs bind preferen.ally to the open or inac3vated channels, which are more likely to be present in frequently firing nerves (such as in cases of pain). This is important because painful s3muli o;en cause an increase in ac.on poten.als in pain-transmimng neurons. Therefore, the local anaesthe3c works becer when nerves are ac3vely transmidng pain signals. Hydrophobic pathways allow local anaesthe.cs to access these sodium channels from the inside of the cell membrane, where they block the sodium current more effec.vely. PROPERTIES OF GOOD LOCAL ANAESTHETICS: Good local anaesthe3cs are lipid soluble: hydrophobic pathways allow these local anaesthe.cs to access voltage-gated sodium channels from the inside of the cell membrane, where they block the sodium current more effec.vely. They are weak bases, meaning they are mostly ionised at physiological pH. However, in inflamed.ssues (which are more acidic), they become more ionised, reducing their effec.veness (which is why local anaesthe.cs may not work as well in inflamed or infected.ssues). Use-Dependence’s role in painful procedures: In a biopsy where there isn’t ongoing pain, the concept of use-dependence isn’t as cri.cal as it would be in a case where the pa.ent is already experiencing chronic pain or where the nerve is hyperac3ve. However, during the procedure, once the nerves begin to fire in response to 3ssue trauma, use- dependence comes into play. The local anaesthe.c will be even more effec.ve at blocking the pain signals from nerves that are repeatedly firing as the procedure progresses. TYPES OF LOCAL ANAESTHETICS: All local anaesthe.cs end in the suffix, -caine. All possess an aroma.c ring structure with an amide side chain. Local anaesthe.cs are dis.nguished by the presence of an ester bond or amide bond. TYPE OF LOCAL FEATURES: INDICATIONS: CLINICAL USE/ADRs: ANAESTHETIC: Ester bond local Metabolised by non- Local nerve block ADRs are usually anaesthe.cs (e.g. specific for procedures. associated when the cocaine, procaine) pseudocholinesterases local anaesthe3c so their ac.on is escapes the local area: shorter-las.ng Amide bond local Distributed more Restlessness (an.- anaesthe.cs (e.g. widely epilep.c, CNS- lidocaine) Metabolised by related effects, taste hepa.c CYP enzymes disturbance, so their ac.on is respiratory longer-las.ng depression). Cardiovascular effects: myocardial depression, conduc.on block, vasodila.on. Vasoconstrictor Vasoconstrictors constrict Slower absorp.on The coupling (e.g. local blood vessels at the site into the vasoconstric3on anaesthe3c + of injec.on, which bloodstream means caused by adrenaline) reduces blood flow to the that less of the adrenaline reduces area. This slows down the anaesthe3c enters local bleeding at absorp3on of the the systemic the site of the anaesthe3c into the circula3on at once, procedure. This is bloodstream. By keeping reducing the risk of especially useful for the local anaesthe.c in systemic side surgeries or minor the targeted area for effects or toxicity procedures like longer, it extends the (such as central biopsies or dental dura3on of anaesthesia, nervous system or work, where meaning the pa.ent cardiovascular side reducing blood flow remains pain-free for a effects). This allows can improve longer.me during the higher doses of visibility and make procedure. local anaesthe.c to the procedure be used if needed easier to perform. for larger procedures without causing dangerous systemic effects. if a drug name has an “I” before ”-caine” (like lidocaine), it’s an amide. Without the “I” (like procaine), it’s an ester. DRUGS USED IN AFFECTIVE DISORDERS: Affec.ve disorders primarily affect mood and include condi.ons such as depression, mania and bipolar disorder. Normal affect is regulated by a complex interplay between various brain regions including the prefrontal cortex, anterior cingulate cortex, basal ganglia, limbic system (amygdala and hippocampus), ventral tegmental area, nucleus accumbens, hypothalamus, pituitary and brainstem. Therefore, the symptoms of these disorders can occur whenever one of those par.cular brain regions is disrupted. Age, gender, stress and gene.cs act as risk factors for the development of affec.ve disorders. DEPRESSION: Can be mild, moderate or major in terms of severity. High-dose opioids can precipitate or exacerbate depression by ac.ng on receptors other than mu (e.g. delta and kappa opioid receptors) which are known to affect mood regula3on. Ac.va.on of delta opioid receptors at high doses can contribute to emo.onal blun.ng and affec.ve disturbances. Ac.va.on of the kappa opioid receptors can lead to dysphoria (anxiety, depression-like symptoms of feeling sad, isolated and uncomfortable). Symptoms of depression include low mood, significant rumina.on on the past, misery, apathy, hopelessness, preoccupa.on with guilt, inadequacy, feelings of worthlessness, suicidal intent, indecisiveness, loss of appe.te, changes in body weight and loss of libido. The chemical-imbalance model of depression implies that depression is caused by an imbalance of neurotransmiHers (e.g. serotonin 5-HT, noradrenaline and dopamine). This model is losing trac.on to a holis.c model which proposes that depression arises following the interac.on of many factors. The mul3-factorial model of depression suggests that depression is associated with disrup3on in synap3c communica3on, neuroplas3city and hemispheric func3on (involving neurotransmiHers including 5-HT, noradrenaline, dopamine and glutamate and brain-derived neurotrophic factor BDNF and endocrine dysfunc3ons such as chronically elevated CRH+cortsiol) alongside inflamma3on and gene3c factors. There are TWO types of depression: 1) REACTIVE DEPRESSION: triggered by external events (≈75%), some.mes labelled as adjustment disorder in clinical prac.ce. 2) ENDOGENOUS DEPRESSION: no apparent external trigger. MANIA: Mania is a mental state of excessive exuberance, impulsiveness, euphoria, talka.veness, distrac.bility, self-confidence, grandiose ideas, racing thoughts, increased libido and increased motor ac.vity. Bipolar Disorder is an alterna3on between depressive and manic states, o;en first presen.ng in adolescence or young adulthood, and associated with high rates of comorbidity and suicide. THE BIOLOGIC AMINE HYPOTHESIS: The chemical-imbalance model of depression is the basis for the biogenic amine hypothesis. The biogenic amine hypothesis suggests that depression occurs when there is an insufficient amount of one or more of these neurotransmiHers (serotonin, noradrenaline, dopamine) in the synap.c cle;s (the gaps between nerve cells where neurotransmiHers send signals). This deficiency results in faulty communica.on between neurons, leading to the mood disturbances, fa3gue, lack of interest, and other symptoms typical of depression. However, not all people with depression have obvious deficiencies in serotonin, noradrenaline or dopamine levels. Furthermore, an.-depressants o;en take weeks to exert therapeu.c effects despite rapid changes in transmiHer levels, sugges.ng that other brain processes are involved in depression recovery (e.g. neuroplas3city). Current medica.ons for depression are largely based on the biogenic amine hypothesis and so most an.-depressants work by modula.ng the levels or ac.vity of these neurotransmiHers. MECHANISMS OF ACTION (MOA) OF ANTIDEPRESSANTS: 1. Inhibi3on of Presynap3c Reuptake Pumps: An.depressants like SSRIs and SNRIs inhibit the reuptake pumps on the presynap.c terminal. By blocking these reuptake transporters, they increase the amount of serotonin (5-HT) and/or noradrenaline (NA) in the synap.c cle;, prolonging their ac.on on the postsynap.c receptors. 2. Blocking Presynap3c Autoreceptors: Presynap.c autoreceptors normally inhibit the release of neurotransmiHers like serotonin when they detect enough of it in the synap.c cle;. Some an.depressants block these autoreceptors, which leads to an increase in neurotransmiHer release from the presynap.c neuron. 3. Inhibi3on of Monoamine Oxidase (MAO): MAOIs inhibit monoamine oxidase, an enzyme found in mitochondria that breaks down neurotransmiHers such as serotonin, norepinephrine, and dopamine. By blocking this enzyme, MAOIs prevent the breakdown of these neurotransmiHers, thereby increasing their levels in the brain. 4. Changes in Postsynap3c Receptor Sensi3vity: Over.me, chronic use of an.depressants may lead to changes in postsynap.c receptor sensi.vity. This can either enhance the responsiveness of these receptors to neurotransmiHers or downregulate receptor numbers to balance the synap.c environment. TREATMENT OF DEPRESSIVE SYMPTOMS: The main strategy to treat depression focuses on correc3ng abnormal synap3c processes. Most modern an.depressant medica.ons aim to improve synap.c responsiveness by increasing the availability of neurotransmicers in the synap3c clel and improving the sensi3vity of neurons to these neurotransmicers. Most an3depressants take up to 8 full weeks for clinical effects to manifest: these drugs may be modifying neuronal connec.vity, changing receptor numbers, and some drugs s.mulate release of BDNF in this.me. The delay in clinical improvement is suggested to occur because in response to an increase in neurotransmiHer levels within the synapse, caused by, for example, reduced uptake, the postsynap3c receptors (the receptors on the receiving neuron) undergo a compensatory adjustment where the number of postsynap3c receptors may decrease (a process known as downregula.on) in response to the elevated neurotransmiHer levels. Ini.ally, with too many receptors, the heightened neurotransmiHer concentra.on might not immediately translate to improved mood, but over.me, as the receptors adjust and reduce in number, the system reaches a new balance. A;er several weeks, the brain may adapt to the higher levels of neurotransmiHers through changes in receptor sensi.vity or number, and this new equilibrium could contribute to the improvement in mood and depression symptoms. Class of Mechanism of ac3on Clinical considera3ons and ADRs: an3depressant and examples Selec.ve Selec.vely block 5-HT First-line for depressive and anxiety serotonin reuptake. symptoms. reuptake Does not affect breastmilk. inhibitors (SSRIs) ADRs include: (e.g. Sertraline, Insomnia, nausea, dizziness, anxiety, Escitalopram) increased suicide risk during early phase of treatment, serotonin syndrome Serotonin syndrome results from excessive accumula3on of serotonin in the CNS, and occurs when people take medica.ons that increase serotonin levels, par.cularly when mul3ple serotonin-enhancing drugs are used together. Some migraine medica.ons and some opioids will also increase 5-HT ac.vity. Serotonin- Block reuptake of 5-HT, Can be problema.c to gradually withdraw Noradrenaline noradrenaline and from. Reuptake dopamine. Duloxe.ne is used in the treatment of Inhibitors neuropathic pain, par.cularly for diabe.c (SNRIs) peripheral neuropathy. (e.g. Venlafaxine, ADRs include: Duloxe.ne) Hypertension, hypercholesterolaemia, nausea, dizziness, insomnia. Tricyclic Inhibit reuptake of ADRs include: An3depressants noradrenaline and 5-HT, An.-cholinergic effects (cons.pa.on, dry (e.g. increasing the concentra.on eyes, dry mouth, orthosta.c hypertension, amitriptyline) of both in the synap.c cle;. confusion, seda.on) and cardiac arrythmias (can be lethal in overdose). Tetracyclic Blocking pre-synap3c alpha- ADRs include: An3depressants 2 adrenoceptors inhibits Seda.on at lower doses (e.g. autoregula.on, leading to Increased appe.te mirtazapine) increased release of noradrenaline, enhancing neurotransmission and improving mood. Monoamine Inhibit MAOIs, preven.ng Non-selec.ve MAOIs (Monoamine Oxidase Oxidase neurotransmiHer Inhibitors) are less popular because they Inhibitors breakdown. require dietary restric3ons to avoid (MAOIs) poten.ally dangerous side effects, such as (e.g. irreversible hypertensive crises (dangerously high phenelzine, blood pressure). reversible moclobemide) Non-selec.ve MAOIs inhibit both MAO-A and MAO-B, enzymes that break down monoamines like serotonin, dopamine, and tyramine (a compound found in certain foods). Tyramine is normally broken down by MAO-A in the gut. When MAO-A is inhibited, tyramine can build up in the bloodstream. Elevated tyramine levels can cause excessive release of noradrenaline, leading to severe hypertension (a hypertensive crisis), which can be life-threatening. Foods rich in tyramine include: Aged cheeses Cured meats (e.g., salami, sausages) Fermented foods (e.g., soy sauce, sauerkraut) Alcohol (especially red wine and beer) ADRs: Sleep disturbance, dizziness, nausea, dietary restric.on required. Vor3oxe3ne Inhibits reuptake and enhances 5-HT availability Has direct receptor ac.vity Agomela3ne Melatonin agonist, weak 5- HT serotonin antagonist  Complementary St John’s Wort: St John’s Wart ADRs: medicines Herbal remedy thought to Dry mouth inhibit 5-HT, noradrenaline Photosensi.vity and dopamine reuptake, Headache modulate serotonin Palpita.ons receptors, inhibit MAO and modulate GABA and glutamate. Selec3ve Noradrenaline Selec3ve Noradrenaline Reuptake Inhibitor Reuptake Inhibitor: (e.g. ADRs: Reboxe3ne) Dizziness Primarily blocks Insomnia noradrenaline reuptake. GENERAL CLINICAL CONSIDERATIONS: Pa.ent adherence to therapy is important due to delayed onset of clinical effects. Increased suicide risk during early treatment stages. Concerns about use of an.-depressants in people under 25 due to ongoing brain development. Non-pharmacological treatments should be emphasised for mild-moderate depression. Drugs used in Mechanism of ac3on Clinical considera3ons and ADRs: mania An3-psycho3c An3-psycho3cs antagonise and an3- dopamine and 5-HT (e.g. epilep3c olanzapine, que.apine, medicines carbamazepine and (first-line valproate) treatment) An3-epilep3cs possess an.- convulsant ac.vity. Lithium Subs.tutes itself for sodium Used for the prophylaxis of difficult to treat carbonate ions, altering ac.on bipolar disorder. poten.als and neuronal Takes around two weeks to become signalling to reduce effec.ve. transmiHer release. Narrow margin of safety (highly toxic drug). ADRs include: Cardiac dysrhythmia Convulsions Hypothyroidism Diarrhoea ANXIETY DISODERS: Anxiety is the normal response to perceived threats, associated with autonomic reflexes, arousal, alertness, cor.costeroid secre.on, and nega.ve emo.ons. Anxiety disorders occur when responses to stress are triggered, in an.cipa.on of, or without, an external stressor, leading to persistent interference with daily func3oning. Anxiety disorders are associated with a consistent percep3on of the threat of harm to oneself or others resul.ng in debilita3ve emo3onal, behavioural and motor responses out of propor.on with the actual threat. Anxiety is associated with autonomic nervous system ac3va3on, altered muscle tone, ritualised behaviour, sleep disorders, altered acen3on and concentra.on, alongside the co-morbidi3es of depression, substance abuse, poor health and social func.oning. Emo.onal s.muli are processed through the sensory thalamus, cor.ces and hippocampus. In anxiety disorders, the amygdala may process these s.muli directly, bypassing the cor.ces and hippocampus, leading to exaggerated responses. Examples of anxiety disorders include generalised anxiety disorder (GAD), panic disorder, social anxiety disorder, agoraphobia and specific phobias. Note that PTSD and OCD are no longer classified as anxiety disorders in the DSM-5. NEUROTRANSMISSION IN THE CNS AND ITS RELATIONSHIP WITH ANXIETY: Glutamate is an excitatory neurotransmiHer with its specific receptors being: N-methyl-D-aspartate receptors (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazoleprionic acid receptors (AMPA), kainite receptors, and metabotropic glutamate receptors (mGluR). Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmiHer with its specific receptors being: GABA-A ionotropic receptor and GABA-B G-protein coupled receptor. MEDICATING ANXIETY DISORDERS: First-line treatment is cogni.ve behavioural therapy (CBT) and/or SSRIs. Note that 50% of pa.ents who complete a CBT program of 6-12 weeks no longer sa.sfy the diagnos.c criteria for anxiety and this posi.ve effect lasts for two years. 80% of pa.ents who complete a CBT program experience some benefit. Second-line treatment is SNRIs and TCAs. Benzodiazepines should only be used acutely (short-term). Other op.ons include an3-psycho3cs, beta-blockers (not evidenced-based, only used in social anxiety semngs with more of a placebo effect), an3-seizure drugs (for difficult to control anxiety).  Benzodiazepines Mechanism of ac3on Clinical considera3ons and ADRs: Benzodiazepines Benzodiazepines bind Effects of benzodiazepines: include allosterically to the GABA-A Anxioly.c effect, addressing in-the-moment diazepam ionotropic receptor. Once anxiety for 1-3 days and useful when (Valium) bound, benzodiazepines star.ng SSRIs that might cause an ini.al temazepam, and enhance the effect of GABA anxiety flare. clonazepam by increasing the frequency Induc.on of sleep and relaxa.on with which the Cl- channel An.-convulsant (seizure inhibi.on) opens when GABA is Muscle relaxant by inhibi.ng signals to present, allowing more Cl- muscle, preven.ng muscle spasms ions to enter the neuron. Paradoxical aggression and irritability This causes greater hyperpolarisa.on which Clinical considera3ons: further inhibits neuronal Highly lipid soluble firing, leading to enhanced Well-absorbed orally inhibitory effects. Can cross the BBB Hepa.cally metabolised, some.mes to ac.ve metabolites which extend the half- life and dura.on even further. Some benzodiazepines and their metabolites are renally cleared, which can lead to drug accumula3on and increased risk of adverse effects in pa.ents with renal impairment. Benzodiazepines with shorter half-lives or those that are not extensively renally cleared are preferred in pa.ents with renal impairment to avoid drug accumula.on and prolonged seda.on. ADRs of benzodiazepines: CNS depression: drowsiness, confusion, amnesia, impaired co-ordina.on and the hangover effect. Tolerance and dependence: develop quickly as a result of down-regula.on of GABA-A receptors and is correlated to dura.on and magnitude or receptor occupancy. Withdrawal needs to be done slowly, is associated with heightened anxiety, rebound REM sleep (hence, disturbed sleep), tremor,.nnitus, and weight loss. Withdrawal from benzodiazepines is more difficult than from opioids. Interac.ons between benzodiazepines and other CNS depressants or alcohol can be dangerous. When an overdose of benzodiazepines occurs, flumazenil (a compe..ve antagonist at the GABA-A receptor) is prescribed and administered. INSOMNIA: Insomnia is a sleep disorder characterised by difficulty falling asleep, staying asleep, or waking up too early and not being able to go back to sleep. It can lead to day3me fa3gue, impaired cogni3ve func3on, mood disturbances, and reduced quality of life. Insomnia can be acute (short-term) or chronic (las.ng for weeks or more), and it may be caused by factors such as stress, medical condi3ons, psychiatric disorders, or lifestyle habits. Drugs used in Mechanism of ac3on Clinical considera3ons and ADRs: the treatment of insomnia Z-drugs (e.g. Both drugs act on brain Used exclusively for sleep. zolpidem and GABA-A receptors, Dependence refers to the body’s adapta.on zoplicone) enhancing the ac.vity of to a drug. Over.me, the brain and body may GABA, the brain’s primary become physically reliant on the drug to inhibitory neurotransmicer. func.on normally. When zolpidem or This leads to a seda3ve effect zopiclone are taken regularly, the brain by increasing chloride ion becomes accustomed to their effects. If the influx, which hyperpolarises drug is suddenly stopped, the person might neurons and decreases the experience withdrawal symptoms (such as poten.al for an ac.on rebound insomnia, anxiety, or restlessness). poten.al to occur because This is why they are generally prescribed for the inside of the cell is now short-term use, usually for no more than a farther from the threshold few weeks at a.me. poten3al. The neuron’s ac.vity is suppressed, leading to an overall inhibitory effect in the CNS. Melatonin Melatonin receptor agonists Generally quite well-tolerated especially in receptor work by mimicking the comparison to other sleep aids like agonists (e.g. ac3on of melatonin, a benzodiazepines or non-benzodiazepine agomela.ne) natural hormone produced seda.ve-hypno.cs. by the pineal gland that regulates the sleep-wake Common ADRs: cycle (circadian rhythm). Dizziness These drugs bind to Fa.gue or drowsiness melatonin receptors in the Headache brain, specifically the MT1 Nausea and MT2 receptors, to Worsening of sleep if not used properly promote sleep onset and help regulate circadian rhythms. Suvorexant An orexin receptor Works by reducing wakefulness rather than antagonist. Orexin is a seda.ng the pa.ent. neurotransmiHer produced Low risk of dependence or withdrawal in the hypothalamus that symptoms helps regulate the sleep- wake cycle. It s.mulates Common ADRs: wakefulness and arousal by Daylight drowsiness ac.va.ng orexin receptors Headache (OX1R and OX2R) in the Abnormal dreams or nightmares brain. By antagonizing Sleep paralysis (blocking) the orexin Sleep-related behaviours receptors, suvorexant Depression or suicidal thoughts reduces wakefulness, thereby promo.ng sleep onset and sleep maintenance. SEIZURES AND ANTI-CONVULSANTS: Seizures are episodic, abnormal, high-frequency discharges of impulses in the brain, star.ng in a specific group of neurons called a focus and poten.ally spreading to other areas of the brain. Seizures are hypothesised to be associated with (a) enhanced excitatory amino acid transmission, (b) impaired inhibitory transmission and (c) abnormal electrical proper.es of affected neurons The symptoms of a seizure depend on which area of the brain is affected. Seizures can be idiopathic or triggered by brain lesions, tumours, chemical imbalances, drugs, alcohol, stress, sleep depriva3on or infec3ons. An.-convulsant drugs are effec.ve in 70-80% of cases of epilepsy, although some severe cases require surgical interven.on to amend defec.ve neurons. TYPES OF SEIZURES: Focal Onset Seizures: commence locally and remain localised. 1) Simple par3al seizures with awareness: These seizures affect a specific part of the brain, but the person remains fully aware of their surroundings during the episode. The seizure may cause unusual sensa.ons, movements, or feelings, such as.ngling, visual disturbances, or muscle twitching, but the person can s.ll interact normally during the seizure. These types of seizures do not cause a loss of consciousness. 2) Complex par3al seizures with impaired awareness In this type, the seizure also starts in a localized part of the brain, but the person’s awareness is impaired or lost. They may seem confused or unable to respond to others during the seizure. The person might also perform automa.c movements, such as lip-smacking, chewing, or repe..ve hand movements, which they may not be aware of or remember a;erwards. Generalised Onset Seizures: the abnormal electrical ac.vity begins in one area of the brain (the focus) but quickly spreads to affect the en.re brain. This widespread involvement of both hemispheres typically leads to a loss of consciousness. These seizures are divided into two main categories based on their characteris.cs: 3) Motor (Tonic-Clonic): These are what most people think of when they hear the term “seizure.” Motor/Tonic-Clonic seizures have two dis.nct phases: The Tonic phase: During this phase, the body becomes rigid and s.ff due to a sudden, intense contrac.on of muscles. The person may fall or be unable to move. The Clonic phase: This is when convulsions or rhythmic jerking movements begin. These convulsions are typically rapid and uncontrolled, involving various parts of the body like the arms, legs, and face. A;er the seizure, the person o;en feels exhausted, confused, or disoriented. This period, called the pos.ctal state, can last for minutes to hours, leaving the person physically and mentally drained.  4) Non-Motor Seizures (Absence Seizures): These seizures involve brief lapses in consciousness, o;en so subtle that they can go unno.ced. They are characterised by short periods (a few seconds) where the person stares blankly or seems disconnected from their surroundings. During the seizure, they may display minor physical symptoms like lip-smacking and eyelid fluHering. Absence seizures are less disrup.ve in the moment than tonic-clonic seizures, but because they can occur frequently, they can interrupt ac.vi.es and affect concentra.on and learning, especially in children. Panel A: Normal EEG This panel shows normal brain ac.vity, with rela.vely regular waveforms that correspond to different brain regions. F, T, and O represent electrodes placed in the frontal (F), temporal (T), and occipital (O) regions of the brain. The waveforms here are low amplitude and regular, indica.ng a normal, non-seizure state. Panel B: Generalized Tonic-Clonic Seizure (Grand Mal) This shows an EEG during a generalized tonic-clonic seizure. In these seizures, the en3re brain is involved. The seizure progresses in phases, with the first part showing high-frequency, chao3c, and sharp electrical discharges as the seizure begins (tonic phase). The later phase shows rhythmic, larger-amplitude spikes during convulsions (clonic phase). This type of seizure is characterised by unconsciousness and violent muscle contrac.ons. Panel C: Generalised Absence Seizure (Pe3t Mal) This panel shows the EEG paHern during a generalized absence seizure, also known as pe.t mal seizures. The waves in this EEG are spike-and-wave discharges (short, rapid spikes followed by slow waves), which are characteris.c of absence seizures. In this type of seizure, there is a brief loss of consciousness, and the person may appear to “zone out” for a few seconds, o;en with subtle movements like eyelid fluHering or lip smacking. This type of ac.vity o;en resolves quickly, as shown by the brief dura.on of the seizure in the EEG. Part D: Par3al Seizure: This panel shows the EEG during a par.al (focal) seizure. These seizures start in a specific part of the brain and may or may not spread to other areas. The EEG shows irregular electrical ac3vity in a localized region, different from the global brain ac.vity seen in generalized seizures. The localized spikes correspond to the focus of the seizure ac.vity, which does not involve the en.re brain. Depending on the loca.on of the focus, the symptoms could vary (e.g., muscle twitching in one part of the body, or sensory changes). ANTI-CONVULSANTS HAVE THREE MECHANISMS OF ACTION: 1. Enhance GABA ac3vity: GABA is inhibitory; therefore, increasing its ac.vity is consistent with the goal of reducing impulse transmission. 2. Inhibit sodium-channel signalling: carbamazepine, phenytoin, lamotrigine. 3. Block calcium channels: ethosuximide, gabapen.n, pregabalin. Therefore, an.-convulsant medica.ons work by targe.ng specific channels and neurotransmiHers in the brain to prevent abnormal electrical discharges that lead to seizures. Common adverse effects of these drugs include seda3on, confusion and skin rashes and teratogenicity. An3-convulsant drug: Mechanism of ac3on: Clinical considera3ons and ADRs Carbamazepine Blocks sodium channels of Undergoes hepa.c metabolism to form neurons that are firing an ac.ve metabolite which also has an.- excessively during seizures seizure proper.es. to reduce neuronal excitability and therefore Common ADRs: prevent high-frequency Bone marrow suppression discharges, helping to control epilep.c events. Phenytoin Blocks sodium channels of Highly protein-bound (≈90%), par.cularly neurons that are firing to plasma albumin, leaving only 10% free excessively during seizures to exert its therapeu.c effect. Changes in to reduce neuronal protein levels such as in kidney or liver excitability and therefore disease can drama.cally affect the levels prevent high-frequency of ac.ve, free phenytoin, leading to discharges, helping to either toxicity or sub-therapeu.c levels. control epilep.c events. Exhibits dose-dependent (non-linear) pharmacokine3cs meaning that small increases in dosage can result in dispropor.onately large increases in blood levels of the drug.  CYP450 metabolism which can vary greatly between individuals, influenced by gene.cs, age, and liver func.on. Declining in use due to ADRs and unpredictable pharmacokine.cs which requires precise dose adjustments due to satura.on at higher doses. Common ADRs: Known teratogen. Gum hyperplasia Lamotrigine Blocks sodium channels of neurons that are firing excessively during seizures to reduce neuronal excitability and therefore prevent high-frequency discharges, helping to control epilep.c events. Ethosuximide Affects T-type calcium Used in first-line treatment for absence channels, which help seizures, par.cularly in children and propaga.on absence adolescents. seizures. Valproate Affects T-type calcium Used in second-line treatment for channels, further controlling absence seizures. seizure ac.vity by limi.ng calcium influx. Common ADRs: Known teratogen Weight gain Gabapen3n and These drugs reduce calcium Commonly used for neuropathic pain but pregabalin entry into nerve terminals, can also help with seizures. Common thereby decreasing the drug of abuse. release of neurotransmiHers. By Excreted by the kidneys and can inhibi.ng the trafficking of accumulate in pa.ents with renal calcium channels to the impairments. Doses o;en need plasma membrane, they adjustment in such cases to avoid toxicity. help control seizures by reducing neuronal excitability. Cannabinoids Cannabis-derived product. Offers an emerging treatment op.on for pa.ents who may not respond well to tradi.onal an.-seizure medica.ons. DRUGS IN DEGENERATIVE DISEASE: Degenera.ve disorders are brain disorders characterised by a progressive loss of neurons in one or more regions of the brain, leading to a deteriora.on of func.on. ALZHEIMER’S DISEASE: Form of demen.a that gradually progresses into adulthood without any known cause, affec.ng 2% of the total popula.on and 20% of people in their later 80s. Involves misfolded or mutated proteins, resul.ng in the development of amyloid plaques (consis.ng of beta-amyloid protein) and neurofibrillary tangles (consis.ng of tau protein). Normally, misfolded proteins are removed by intracellular degrada.on. However, in neurodegenera.ve disorders, these proteins accumulate, leading to loss of cholinergic neurons, especially in the hippocampus and frontal cortex, consistent with overall brain 3ssue loss, enlarged ventricles and reduced gyri. SIGNS AND SYMPTOMS Ini.al short-term memory loss and carelessness about personal appearance. Loss of remote long-term memory. Impaired verbal expression. Incon.nence and loss of independence. Difficulty with ac.vi.es of daily living (ADLs). AHempts to compensate for symptoms. An3-Alzheimer’s Mechanism of ac3on: Clinical considera3ons and ADRs drugs: An3cholinesterases Prolong acetylcholine Used in mild-moderate disease. (e.g. Donepezil). ac.vity by inhibi.ng its breakdown by ADRs: cholinesterase. GI issues, increasing with dose. NMDA receptor In Alzheimer’s disease, Used in later stages of demen.a. antagonists (e.g. excessive amounts of Meman.ne) glutamate can overs.mulate ADRs: NMDA receptors, leading to Headache neurotoxicity and cell Drowsiness damage. Meman.ne blocks Dizziness these receptors, preven.ng Cons.pa.on prolonged and excessive s.mula.on while s.ll allowing normal glutamate ac.vity that is essen.al for memory and learning. PARKINSON’S DISEASE: Parkinson’s disease is a movement disorder primarily seen in older people. Arises from the aggrega3on of misfolded proteins, especially in the basal ganglia. This leads to loss of dopaminergic neurons between the corpus striatum and substan3a nigra. Cholinergic interneurons in the striatum release acetylcholine, a neurotransmiHer that generally promotes the ac.vity of the indirect pathway, leading to the inhibi3on of movement. Dopamine normally inhibits these cholinergic interneurons, thereby reducing the inhibitory effect of the indirect pathway and allowing smoother and more coordinated movement.  In condi.ons like Parkinson’s disease, where dopaminergic neurons in the substan.a nigra degenerate, the loss of dopamine leads to a reduc.on in inhibi.on of cholinergic neurons. As a result, cholinergic ac.vity increases, which over-ac.vates the indirect pathway, contribu.ng to the rigidity, bradykinesia (slowness of movement), and tremors seen in Parkinson’s pa3ents. This is why an.cholinergic medica.ons (which reduce acetylcholine ac.vity) are some.mes used in Parkinson’s disease treatment to help restore the balance between cholinergic and dopaminergic ac.vity. SYMPTOMS OF PARKINSON’S DISEASE: Bradykinesia: suppression of voluntary movements due to muscle rigidity and partly an iner.a of the motor system, leading to difficulty ini.a.ng and stopping movement. Tremor at rest, most obvious in the hands. Shuffling gait and difficulty stopping or changing direc.on. Masked facial expressions Hallucina.ons and depression MAIN TREATMENT APPROACHES FOR PARKINSON’S DISEASE: There are several treatments used to treat Parkinson’s disease, and o;en they are used in combina.on, increasingly so as the disease progresses. MECHANISMS OF DRUGS USED IN PARKINSON’S DISEASE: Dopamine replacement Dopamine mimicry S.mula.on of dopamine release Reduc.on of dopamine levels/dopamine agonist breakdown Blocking of central muscarinic receptors Non-drug receptors Ul.mately, all drugs used in trea.ng Parkinson’s disease will either enhance dopaminergic ac3vity or inhibit cholinergic ac3vity. Drugs used in Mechanism of ac3on: Clinical considera3ons and its ADRs: Parkinson’s disease: Levodopa Is a dopamine precursor that O;en combined with DOPA crosses the blood-brain-barrier, decarboxylase inhibitors ac.ng as a dopamine replacement. (cardbidopa or benzerazide) and COMPT inhibitors (entacapone). This is because Levodopa faces a treacherous journey from the mouth into the brain. MAO in the intes.nal wall deac.vates Levodopa, and Levodopa has a two- hour half-life. In that.me, enzyma.c conversion to dopamine is 95-99% of the original Levodopa dose that was swallowed, so only 1% of Levodopa arrives at the brain.  Therapeu.c effec.veness of Levodopa declines with.me, and so higher and higher doses are needed with.me. Common ADRs: As dose increases, ADRS increase. Psychosis Nausea On-off phenomenon where during “on” periods, the pa.ent experiences a good response to Levodopa and Parkinson’s symptoms are well controlled. During “off” periods, the pa.ent’s motor symptoms worsen o;en suddenly or unexpectedly because the effect of levodopa wear off before the next dose is due. Adjuncts to Levodopa include: DDC inhibitors (e.g. carbidopa, benserazide) COMT inhibitors (e.g. entacapone) Dopamine receptor Mimic dopamine’s ac.on by ac.ng Useful when the “on-off” agonists (e.g. on D2 receptors, also inhibi.ng phenomena from Levodopa bromocrip.ne and prolac.n release from the anterior treatment is becoming pramipexole) pituitary. troublesome. Bromocrip3ne ADRs: Nausea Somnolence Fibrosis Pramipexole ADRs: Nausea Somnolence Compulsive behaviours Amantadine Amantadine aims to release Common ADRs: dopamine from whatever Dizziness func.oning dopaminergic neurons Confusion remain. By increasing dopamine Hallucina.ons availability, amantadine helps to Dry mouth alleviate motor symptoms such as Leg oedema bradykinesia (slowness of Livedo re.cularis movement), rigidity, and tremors. Amantadine also works by In pa.ents with cogni.ve impairment, inhibi3ng the reuptake of or the elderly, the central nervous dopamine into pre-synap.c system side effects, such as confusion  neurons which allows more and hallucina.ons, can be more dopamine to remain in the synap.c pronounced. cle;, making it more available to s.mulate the post-synap.c dopamine receptors which enhances motor func.on. Amantadine is an NMDA receptor antagonist, the receptor involved in regula.ng glutamate, a neurotransmiHer associated with excitotoxicity. By blocking excessive glutamate ac.vity, amantadine may help reduce dyskinesias, the involuntary movements that can occur as a side effect of long-term levodopa therapy. MAO-B Inhibitors Inhibit the enzyme monoamine ADRs: (e.g. selegiline, oxidase type B (MAO-B) responsible Nausea rasagiline and for breaking down dopamine in the Headache safinamide). brain. This slows down the Insomnia degrada.on of dopamine, Dizziness increasing the amount of dopamine Orthosta.c hypotension available in the brain. This is Hallucina.ons par.cularly helpful in Parkinson’s No dietary restric.ons required at disease where dopamine levels are lower doses depleted due to the degenera.on of dopaminergic neurons in the substan.a nigra. May slow disease progression through neuroprotec3ve proper3es where they protect neurons from degrada.on by reducing the forma.on of toxic byproducts of dopamine metabolism such as hydrogen peroxide and free radicals. An3cholinergic Normally, dopamine and ADRs: drugs acetylcholine work in balance to Cogni.ve impairment regulate motor func.on. Dopamine Delirium facilitates movement, while Hallucina.ons acetylcholine tends to inhibit Seda.on movement. When dopamine levels Dry mouth decrease (as in Parkinson’s disease), Blurred vision the rela.ve ac.vity of acetylcholine Cons.pa.on becomes excessive, contribu.ng to Urinary reten.on tremors, rigidity, and bradykinesia Tachycardia (slowness of movement). Dry skin An3cholinergic drugs work by reducing the overac3vity of cholinergic neurons, par.cularly in the basal ganglia, to restore  balance between acetylcholine and dopamine. An3cholinergic drugs block the ac.vity of acetylcholine by aHaching to muscarinic acetylcholine receptors (specific sites on neurons that acetylcholine binds to in order to act). By blocking acetylcholine, these drugs reduce its overac.vity. This helps restore balance between acetylcholine and dopamine in the brain. As a result, this reduces some of the motor symptoms of Parkinson’s disease, such as tremor and muscle rigidity. ANTI-PSYCHOTICS: Psychosis is a debilita.ng mental illness characterised by a distorted sense of reality, hallucina.ons, delusions, disorganised thought and speech and disorganised or agitated behaviours. There are two types of psychosis: schizophrenia (e.g. slow onset, lifelong, affec.ng 1% of the popula.on equally among males and females; emerges at the ages of 15-30 years old). SCHIZOPHRENIA: Includes posi3ve and nega3ve symptoms. Posi3ve symptoms are greater or more grandiose than normal degrees of thoughts and behaviours including delusions, hallucina.ons, paranoia, and disordered thoughts. Nega3ve symptoms are lesser or less grandiose than normal degrees of thoughts and behaviours including flat affect, social withdrawal, isola.on, cogni.ve deficits in aHen.on and memory. Stronger evidence that familial predisposi3on and use of illicit drugs (notably THC in cannabis) increase the likelihood of developing schizophrenia. Weaker evidence that season of birth, vitamin D exposure, socioeconomic status, complica.ons at birth, increased inflammatory mediators and in-utero infec.ons increase the likelihood of developing schizophrenia. Long-3me theory rests on dopamine drive pathology: it is now clear that mul.ple receptor/transmiHer systems are involved, including both dopamine, 5-HT and glutamate. A simplis.c view is that increased dopamine/5-HT results in psychosis while decreased dopamine/5- HT results in depression. THE DOPAMINE HYPOTHESIS OF PSYCHOSIS: The mesolimbocor.cal pathway controls behaviours and emo.ons. The dopamine hypothesis of psychosis states that overac3vity of dopamine in certain pathways in the brain, specifically the mesolimbic pathway, plays an important role in the development of psycho3c symptoms. This is because dopamine regulates emo.on, mo.va.on, pleasure and movement. In this context, excessive dopamine ac3vity, especially in the mesolimbic pathway, is associated with hallucina3ons, delusions and other psycho3c behaviours, which are symptoms seen in schizophrenia. 5-HT and dopamine interact; the serotonin-dopamine interac3on theory suggests that 5-HT may also contribute to psycho.c symptoms and that drugs affec.ng both 5-HT and dopamine can help manage these symptoms. GABA and glutamate are also implicated in the overall balance of brain func.on and psychosis. Abnormali.es in these systems may contribute to cogni.ve and sensory processing issues seen in schizophrenia. STRUCTURAL CHANGES IN SCHIZOPHRENIA: Brain regions involved in cogni.on and percep.on show changes in individuals with schizophrenia. This could mean that certain parts of the brain either shrink or enlarge, affec.ng how the person experiences the world. There is enlargement of the brain’s ventricles sugges.ng neuroanatomical changes in schizophrenia. LANGUAGE CHANGES IN SCHIZOPHRENIA: Schizophrenia o;en involves language difficul3es with decreased sophis.ca.on in communica.on and poten.al dysfluency. This contributes to the social and cogni.ve impairments seen in schizophrenia. Schizophrenia is associated with a higher propor3on of lel-handed individuals or ambidexterity which suggests that brain lateralisa3on (how func.ons are divided between the two hemispheres) might be atypical in people with this condi3on. DRUGS USED TO TREAT SCHIZOPRHENIA AND OTHER PSYCHOTIC STATES: Are also called neurolep.cs, an.-schizophrenia drugs, an.-psycho.c drugs and tranquilisers. Seek to produce depressed motor ac.vity, emo.onal quie.ng, relief of distress, normalisa.on of thought, mood and behaviour and reduced tendencies. Neuroimaging shows that an.-psycho.c drugs can change regional volumes in some brain areas, and that structural areas affected by treatment correlate with those disrupted by the condi.on. ANTI-PSYCHOTIC DRUGS USED MECHANISMS OF ADRs: FOR SCHIZOPHRENIA: ACTION: Typical (1st genera.on) Block dopamine D2 Acute dystonia is an EPS associated with an.psycho.cs – compe33ve receptors, affec3ng motor side effects including involuntary antagonists of dopamine (D2) the nigrostriatal movements, restlessness, muscle spasms, receptors and fixed upward gaze, neck muscle spasm, tuberohypophyseal protruding tongue, and is accompanied Low potency (e.g. pathways. by symptoms of Parkinson’s disease chlorpromazine, including tremor, rigidity and drooling. prochlorperazine, thioridazine) Tardive dyskinesia (o;en abbreviated as High potency (e.g. TD) is a long-term side effect that can fluphenazine, haloperidol, develop a;er prolonged use of dopamine thiothixene) receptor antagonists, par.cularly first- genera3on an3psycho3cs (also known as typical an.psycho.cs) and, less commonly, some second-genera3on an3psycho3cs (atypical an.psycho.cs). It involves involuntary, repe33ve movements, primarily affec.ng the face, mouth, and limbs. This includes involuntary chewing movements, movements of the face, tongue, trunk and limbs, Endocrine disturbances: increased prolac.n release causing gynecomas.a, amenorrhoea and galactorrhoea. Dry mouth, blurred vision, cons.pa.on, urinary reten.on, seda.on, orthosta.c hypotension, tachycardia. Atypical (2nd genera.on) Antagonise 5-HT 2nd genera3on an3-psycho3cs exhibit an.psycho.cs – compe..ve and dopamine reduced EPS due to 5-HT receptor antagonists of 5-HT receptors receptors. antagonism. (5HT2A) and to a lesser extent, Blocking 5-HT dopamine (D2) receptors reduces 5-HT’s The therapeu.c effects may be delayed ability to inhibit by weeks and side effects can occur dopamine immediately. secre.on in the Nega.ve symptoms respond poorly to nigrostriatal most drugs. pathway. Posi.ve symptoms respond more than Therefore, more nega.ve symptoms. dopamine means Pa.ent adherence is crucial. less EPS. Olanzapine (Zyprexia) Weight gain is a major ADR (30% of pa.ents gain more than 15kg). Diabetes risk increases. Que3apine (Seroquel) Less weight gain than from Olanzapine. Associated with suicidality in children. Diabetes risk increases. QT prolonga.on. Ziprasidone (Geodon) No weight gain Increased diabetes risk QT prolonga.on Aripiprazole (Abilify) Weight gain (but less than from Olanzapine and Que.apine) Diabetes risk increases Low risk for EPS or TD with no agranulocytosis risk DIURETICS: Diuresis refers to the increased produc3on and excre3on of urine by the kidneys. It can occur naturally or be induced by diure3cs, which are medica.ons that help the body eliminate excess fluid. Diuresis can occur for various reasons, including increased fluid intake, hormonal changes, or condi.ons such as diabetes or kidney disease. It plays a key role in regula.ng fluid balance, blood pressure, and electrolyte levels in the body. Diure.cs are used to increase the excre3on of sodium, and therefore, water, from the body via ac.ons on the kidneys. Water generally follows sodium. Therefore, sodium lost equals water lost. Losing water is the goal of diure.cs treatment. Diure.cs are commonly used to manage condi3ons associated with fluid overload such as conges.ve heart failure (CHF), cirrhosis, chronic kidney disease and hypertension. Diure3cs MECHANISMS OF Clinical Considera3ons and ADRs: ACTION: Loop diure.cs (e.g. Act on the thick Used in the management of salt/water Furosemide) ascending limb of overload, CHF, cirrhosis with ascites, CKD, the Loop of Henle, acute pulmonary oedema when inhibi.ng the administered intravenously to act as Na+/K+/2Cl- co- vasodilators transporter on the apical (luminal) ADRs include: membrane of the Electrolyte imbalances (hypokalaemia and epithelial cells, hypomagnesemia) resul.ng in Alkalosis significant sodium Impaired excre.on or urate, resul.ng in and water hyperuricaemia excre.on by Dose-related hearing loss further blocking sodium, exacerbated by any drug that affects the ear potassium and Hypovolaemia chloride ion Hypotension reabsorp.on. Urinary urgency Inhibit the passive paracellular Mon3or K+ levels: hypokalaemia can cause transport of arryhthmias, cons.pa.on and neurological magnesium, symptoms of drowsiness, confusion, muscle calcium, weakness and drug interac3ons. potassium and sodium. Loop diure.cs can increase the effects and toxicity of digoxin. As more sodium stays in the filtrate, water Most of the.me, co-supplement the Loop follows due to diure3c with a K+ supplement or another osmosis, leading to an medicine that retains K+ such as an ACE increased volume of inhibitor. urine produc.on. Hypomagnesemia can lead to leg cramps and is exacerbated by PPIs such as pantoprazole which reduces Mg2+ absorp.on. Thiazide diure3cs (e.g. Binds to the Used in the management of hypertension hydrochlorothiazide and chloride-binding and mild oedema. indapamide) site of the distal Hydrochlorothiazide is shorter-ac.ng. tubular Na/Cl co- Indapamide is longer-ac.ng. transporter, When used alone, thiazide are mild blocking its ac.on diure3cs. and leading to When used alongside a Loop diure.c, there sodium and is synergis3c ac3vity because the Loop chloride loss in the diure.c delivers a higher concentra.on of urine. Na+ towards the thiazide’s site of ac.on, where it is yet again blocked from reabsorp.on.  ADRs: Erec.le dysfunc.on Hypotension Impaired glucose tolerance due to these medicines inhibi.ng insulin secre.on Electrolyte imbalances (hyponatremia, hypokalaemia, hypomagnesemia, hypercalcaemia) Hypercalcaemia is caused by the decreased excre.on of calcium by increasing its reabsorp.on in the DCT. This effect is some.mes considered beneficial in pa.ents at risk of osteoporosis, but it requires careful monitoring to avoid complica.ons associated with elevated calcium levels. Potassium-sparing diure3cs Have limited Can be given alongside a Loop diure.c or (e.g. amiloride/triamterene, diure.c Thiazide diure.c to maintain K+ balance. spironolactone/epleronone) effec.veness Spironolactone is also used as an adjunct because there is an.-hypertensive when the pa.ent’s only a small hypertension has been resistant to other frac.on of Na+ treatments. that gets to this part of the AMILORIDE/TRIAMTERENE: nephron. Block sodium channels in the collec.ng duct, directly reducing sodium reabsorp.on and Spironolactone indirectly reducing potassium excre.on, antagonises leading to potassium reten.on (weak aldosterone, potassium-sparing). reducing sodium reabsorp.on and SPIRONOLACTONE/EPLERNONE: increasing Commonly referred to as aldosterone potassium antagonists or mineralocor.coid receptor reten.on, ac.ng in antagonists (MRAs) which are used to the Collec.ng Duct balance K+ loss from Loop diure.cs and where only limited Thiazide diure.cs. sodium reabsorp.on Spironolactone structurally resembles occurs. aldosterone and binds to the same Aldosterone binds mineralocor3coid receptors in the kidney. By to its receptors in occupying these receptors, spironolactone the cells of the blocks aldosterone from exer3ng its effects. distal convoluted As a result: tubule and collec.ng ducts, Sodium reabsorp.on is reduced, leading to promo.ng the increased sodium and water excre.on (mild reabsorp.on of diuresis). sodium (Na⁺) and water back into Potassium excre.on is decreased, thus the bloodstream sparing potassium in the body, which is why and the excre.on spironolactone is called a potassium-sparing of potassium (K⁺) diure.c. into the urine. This process helps regulate blood Reduc3on in blood pressure: By inhibi.ng the pressure and fluid ac.on of aldosterone, spironolactone prevents balance. excessive sodium and water reten.on, helping to reduce blood volume and thus lowering blood pressure. This makes it useful in trea.ng condi.ons like hypertension, heart failure, and hyperaldosteronism (excess aldosterone produc.on). ADRs include: Hyperkalaemia Gynecomas.a Menstrual disorders Tes.cular atrophy due to ac.ons on progesterone and androgen receptors POTASSIUM RETENTION: Seen when using Amiloride, Triamterene and Spironolactone. Amiloride/triamterene block lumen-side Na+ pump. The flow on effect is the reduc.on in K+ loss from the other side of the cell. Spironolactone/epleronone go a step further by blocking aldosterone’s promo.on of Na+ reten.on AND reducing K+ loss via both the Na+ channel and the Na+/K+ pump.