Pharmacology Past Paper (Semester Two)

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