Analgesics and Anesthetics PDF

**ANALGESICS AND ANAESTHETICS:** - **Nociceptive pain:** burning, aching sensation localised to around the site of injury and caused by excess stimulation of peripheral nociceptive neurons. - **Neuropathic pain:** shooting pain persisting after the peripheral injury has healed. -...

**ANALGESICS AND ANAESTHETICS:** - **Nociceptive pain:** burning, aching sensation localised to around the site of injury and caused by excess stimulation of peripheral nociceptive neurons. - **Neuropathic pain:** shooting pain persisting after the peripheral injury has healed. - **Neuroplastic pain:** non-painful stimuli are interpreted as pain due to memories of pain causing central sensitisation to various stimuli. - **Acute pain:** short-lived, often due to injury. - **Chronic pain:** lasts over 12 weeks, can be nociceptive, - **Cancer pain:** associated with malignancy. - **Non-cancer pain:** includes various chronic conditions. - **Small diameter primary afferent fibres** have sensory endings in peripheral tissue that detect stimuli such as mechanical, thermal or chemical injuries and **project to the dorsal horn of the spinal cord** where they synapse on neurons projecting to higher centres. +-----------------------+-----------------------+-----------------------+ | **ANALGESIC:** | **MECHANISM(s) of | **Indications and | | | action:** | ADRs:** | +=======================+=======================+=======================+ | **Opioids** | - Mimic endogenous | **Indications:** | | | peptides | | | | (endorphins, | - Moderate to | | | enkephalins, | severe pain | | | dynorphins) and | (acute and | | | bind to central | chronic cancer | | | opioid receptors, | pain). | | | including the mu | | | | receptor | - Mu opioid | | | responsible for | receptors in the | | | analgesia, | **medulla | | | triggering | oblongata**, | | | G-protein coupled | specifically in | | | cascades in | the **cough | | | pre-synaptic and | centres**, play a | | | post-synaptic | role in | | | neurons. | suppressing the | | | | cough reflex. | | | - At the | Drugs like | | | pre-synaptic | **codeine** and | | | terminal, the | **dextromethorpha | | | opioid-mu | n** | | | triggered-cascade | act on these | | | will result in | receptors to | | | reduced cAMP | reduce coughing, | | | levels, | which is why they | | | decreasing | are commonly used | | | calcium ion | in cough | | | influx and | medications. | | | therefore | | | | reducing | - Mu opioid | | | neurotransmitter | receptors in the | | | release between | GI tract reduce | | | the two nerves, | **peristalsis** | | | leading to less | and **intestinal | | | communication. | motility** when | | | | activated. This | | | - At the | leads to **slower | | | post-synaptic | movement** of | | | terminal, the | contents through | | | opioid-mu | the intestines | | | triggered-cascade | and greater | | | will increase K+ | absorption of | | | efflux, | water, which | | | hyperpolarising | helps in | | | the neuron and | **firming | | | reducing pain | stools** and | | | transmission up | reducing | | | the spinal cord. | diarrhoea. | | | | Medications like | | | | **loperamide** | | | | (Imodium), which | | | | acts on | | | | peripheral mu | | | | receptors, | | | | exploit this | | | | mechanism for | | | | treating | | | | diarrhoea without | | | | significant | | | | central nervous | | | | system effects. | | | | | | | | **ADRs:** | | | | | | | | - Physical | | | | dependence + | | | | withdrawal upon | | | | discontinuation | | | | | | | | - Respiratory | | | | depression | | | | | | | | - Dysphoria: | | | | negative mood | | | | effects. | | | | | | | | - Constipation: | | | | reduced GI | | | | motility. | | | | | | | | - Nausea and | | | | vomiting: often | | | | CTZ-related. | | | | | | | | - Sedation: | | | | increases falls | | | | risk | | | | | | | | - Pupil | | | | constriction | | | | (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 | | | | administration or | | | | sudden drop in | | | | dose, the | | | | dependent patient | | | | will experience | | | | withdrawal | | | | symptoms. After | | | | experiencing | | | | withdrawal once, | | | | this promotes | | | | psychological | | | | dependence | | | | through the | | | | dopaminergic | | | | mesolimbic reward | | | | system. | +-----------------------+-----------------------+-----------------------+ | **Examples of | **Details of use** | **Clinical | | opioids** | | considerations and | | | | indications:** | +-----------------------+-----------------------+-----------------------+ | **Morphine/\ | - Codeine is | - Conversion of | | codeine** | morphine's | codeine to | | | pro-drug (≈10% | morphine is | | | codeine is | dependent on the | | | hepatically | availability of | | | converted to | CYP2D6 enzyme in | | | morphine). | the liver. | | | | Without CYP2D6, | | | - Codeine is 10x | this conversion | | | less potent than | cannot occur. | | | morphine when | | | | morphine is given | - Codeine's lower | | | in its active | potency means | | | form on a per | that it used for | | | milligram basis. | mild-moderate | | | | pain relief | | | - Morphine has | usually in | | | oral-, | combination with | | | injectable-slow- | an NSAID or | | | and quick-acting | paracetamol. | | | forms. | | | | | - Codeine can be | | | | used to suppress | | | | non-productive | | | | cough. | +-----------------------+-----------------------+-----------------------+ | **Oxycodone** | - Longer half-life | | | | than morphine | | +-----------------------+-----------------------+-----------------------+ | **Fentanyl** | - Extremely potent | | | | | | | | - NOT first-line | | | | | | | | - NOT used outside | | | | of severe cancer | | | | pain | | +-----------------------+-----------------------+-----------------------+ | **Methadone** | - Long-half life, | - Used as an opioid | | | weak agonist of | replacement | | | mu-opioid | treatment in | | | receptors, used | situations of | | | as an opioid | serious | | | replacement. | dependence due to | | | | longer half-life, | | | | reduced induction | | | | 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 | - Better for | | | replacement, | elderly patients | | | comes in oral | due to its | | | film or patch | ceiling effect on | | | form. | respiratory | | | | depression | | | - Partial agonist | regardless of | | | but potent. | increasing dose. | +-----------------------+-----------------------+-----------------------+ | **Tramadol** | - Dirty drug | | | | (extremely | | | | non-selective, | | | | inhibits | | | | serotonin and | | | | noradrenaline | | | | reuptake, impacts | | | | muscarinic and | | | | nicotinic | | | | receptors, drug | | | | interactions, | | | | inter-individual | | | | variability in | | | | metabolism, | | | | uncomfortable | | | | ADRs. | | +-----------------------+-----------------------+-----------------------+ | **Tapentadol**\ | - Opioid-like | | | (is a noradrenaline | analgesia helps | | | reuptake inhibit with | treat nociceptive | | | opioid agonist | or acute pain. | | | actions) | | | | | - By increasing | | | | noradrenaline | | | | levels in the | | | | synapse, | | | | tapentadol | | | | modulates pain | | | | transmission in | | | | descending pain | | | | pathways, | | | | contributing 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 combination 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 situations: injection of oxycodone-naloxone combination 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 proportion of naloxone is inactivated 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 theoretically blocks its constipatory effects. +-----------------------+-----------------------+-----------------------+ | **ANALGESIC:** | **MECHANISM(s) of | **Clinical | | | action:** | considerations, | | | | Indications and | | | | ADRs:** | +=======================+=======================+=======================+ | **Paracetamol** | - Acts on the | **INDICATIONS:** | | | cyclooxygenase | | | | enzyme (likely | - Mild-moderate | | | COX-3) to provide | pain. | | | analgesic and | | | | anti-pyretic | - Fever reduction. | | | effects without | | | | anti-inflammatory | **COMBINATION | | | action. | THERAPY:** | | | | | | | | - Can be used | | | | alongside NSAIDs, | | | | synergistic with | | | | opioids, | | | | therefore | | | | allowing lower | | | | opioid doses to | | | | gain the same | | | | perceived level | | | | of pain relief. | | | | | | | | **OVERDOSE:** | | | | | | | | - Can arise from | | | | intentional harm | | | | or accidentally. | | | | | | | | - In an overdose, | | | | paracetamol | | | | metabolism cannot | | | | occur fast | | | | enough. | | | | | | | | - Normally, | | | | paracetamol is | | | | safely processed | | | | in the liver | | | | through two main | | | | pathways | | | | ---glucuronidatio | | | | n | | | | and sulfation --- | | | | 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 | | | | conditions, NAPQI | | | | is rapidly | | | | detoxified by | | | | conjugation with | | | | glutathione, a | | | | protective | | | | antioxidant, | | | | 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 | | | | oxidative | | | | stress.** This | | | | results in | | | | cellular damage, | | | | primarily in | | | | hepatocytes, | | | | leading to liver | | | | necrosis, and in | | | | severe cases, | | | | acute liver | | | | failure. | +-----------------------+-----------------------+-----------------------+ -------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------------------------------------------- -- **Activated Charcoal for paracetamol overdose:** Activated charcoal can help by absorbing paracetamol in the gastrointestinal tract, reducing the amount that enters the bloodstream and is metabolized into NAPQI. -------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------------------------------------------- -- **LOCAL ANAESTHETICS:** - Local anaesthetics **block voltage-dependent sodium channels** which are important for the initiation and propagation of an action potential. - Normally, when a sensory, nociceptive nerve (A-delta and C fibres) receives a pain signal, sodium channels open to allow sodium to enter the nerve cell which generates an action potential that transmits the local signal. - By blocking voltage-dependent sodium channels, the local anaesthetic **prevents the generation of action potentials in the nociceptors**, effectively stopping the transmission of pain signals from the peripheral nerves to the brain. - Local anaesthetics 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 time when a neuron cannot fire again), local anaesthetics can prevent the transmission of pain signals. - Local anaesthetics can be used to treat both **nociceptive pain** (caused by actual or potential tissue damage, such as injury) and **neuropathic pain** (caused by damage or dysfunction to the nerves themselves. - When used **topically**, local anaesthetics can block pain signals at the site of nerve damage or irritation. This is beneficial because they prevent the spontaneous firing of damaged nociceptive nerves, which is often responsible for chronic pain. **LOCAL ANAESTHETICS SHOW USE-DEPENDENCE:** - Use-dependence means that local anaesthetics are more effective at **blocking sodium channels** when those channels are **active** or **open** (i.e. during frequent nerve firing). - Sodium channels cycle between **open, closed, and inactivated** states during action potential propagation. - Local anaesthetics bind preferentially to the **open or inactivated channels**, which are more likely to be present in **frequently firing nerves** (such as in cases of pain). This is important because **painful stimuli** often cause an increase in action potentials in pain-transmitting neurons. Therefore, the **local anaesthetic works better when nerves are actively transmitting pain signals.** - **Hydrophobic pathways** allow local anaesthetics to access these sodium channels from the inside of the cell membrane, where they block the sodium current more effectively. **\ ** **PROPERTIES OF GOOD LOCAL ANAESTHETICS:** - **Good local anaesthetics** are **lipid soluble:** hydrophobic pathways allow these local anaesthetics to access **voltage-gated sodium channels** from the **inside of the cell membrane**, where they block the sodium current more effectively. - They are weak bases, meaning they are mostly ionised at physiological pH. However, in inflamed tissues (which are more acidic), they become more ionised, reducing their effectiveness (which is why local anaesthetics may not work as well in inflamed or infected tissues). **Use-Dependence's role in painful procedures:** - In a biopsy where there **isn't ongoing pain**, the concept of use-dependence isn't as critical as it would be in a case where the patient is already experiencing **chronic pain** or where the nerve is **hyperactive**. - However, **during the procedure, once the nerves begin to fire in response to tissue trauma, use-dependence** comes into play. The local anaesthetic will be even more effective at blocking the pain signals from nerves that are repeatedly firing as the procedure progresses. **TYPES OF LOCAL ANAESTHETICS:\ ** - All local anaesthetics end in the suffix, -caine. - All possess an aromatic ring structure with an amide side chain. - Local anaesthetics are distinguished by the presence of an **ester bond** or **amide bond.** +-----------------+-----------------+-----------------+-----------------+ | **TYPE OF LOCAL | **FEATURES:** | **INDICATIONS:* | **CLINICAL | | ANAESTHETIC:** | | * | USE/ADRs:** | +=================+=================+=================+=================+ | **Ester bond** | - Metabolised | - Local nerve | **ADRs are | | local | by | block for | usually | | anaesthetics | non-specifi | procedures. | associated when | | (e.g. cocaine, | c | | the local | | procaine) | pseudocholi | | anaesthetic | | | nesterases | | escapes the | | | so their | | local area:** | | | action is | | | | | shorter-las | | - Restlessnes | | | ting | | s | | | | | (anti-epile | | | | | ptic, | | | | | CNS-related | | | | | effects, | | | | | taste | | | | | disturbance | | | | | , | | | | | respiratory | | | | | depression) | | | | |. | | | | | | | | | | - **Cardiovas | | | | | cular | | | | | effects:** | | | | | myocardial | | | | | depression, | | | | | conduction | | | | | block, | | | | | vasodilatio | | | | | n. | +-----------------+-----------------+-----------------+-----------------+ | **Amide bond** | - Distributed | | | | local | more widely | | | | anaesthetics | | | | | (e.g. | - Metabolised | | | | lidocaine) | by hepatic | | | | | CYP enzymes | | | | | so their | | | | | action is | | | | | longer-last | | | | | ing | | | +-----------------+-----------------+-----------------+-----------------+ | **Vasoconstrict | **Vasoconstrict | Slower | The | | or | ors | absorption into | **vasoconstrict | | coupling (e.g. | constrict blood | the bloodstream | ion** | | local | vessels** at | means that | caused by | | anaesthetic + | the site of | **less of the | adrenaline | | adrenaline)** | injection, | anaesthetic | reduces **local | | | which reduces | enters the | bleeding** at | | | blood flow to | systemic | the site of the | | | the area. This | circulation** | procedure. This | | | slows down the | at once, | is especially | | | **absorption of | reducing the | useful for | | | the | risk of | surgeries or | | | anaesthetic** | **systemic side | minor | | | into the | effects** or | procedures like | | | bloodstream. By | **toxicity** | **biopsies** or | | | keeping the | (such as | **dental | | | local | central nervous | work**, where | | | anaesthetic | system or | reducing blood | | | **in the | cardiovascular | flow can | | | targeted area | side effects). | improve | | | for longer**, | This allows | **visibility** | | | it extends the | higher doses of | and make the | | | **duration of | local | procedure | | | anaesthesia**, | anaesthetic to | easier to | | | meaning the | be used if | perform. | | | patient remains | needed for | | | | pain-free for a | larger | | | | longer time | procedures | | | | during the | without causing | | | | procedure. | 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:** - Affective disorders primarily affect mood and include conditions 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 particular brain regions is disrupted. - Age, gender, stress and genetics act as **risk factors** for the development of affective disorders. **\ ** **DEPRESSION:** - Can be mild, moderate or major in terms of severity. - High-dose opioids can precipitate or exacerbate depression by acting on receptors other than mu (e.g. delta and kappa opioid receptors) which are known to affect **mood regulation.** - Activation of delta opioid receptors at high doses can contribute to emotional blunting and affective disturbances. - Activation 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 rumination on the past, misery, apathy, hopelessness, preoccupation with guilt, inadequacy, feelings of worthlessness, suicidal intent, indecisiveness, loss of appetite, changes in body weight and loss of libido. - The **chemical-imbalance model of depression** implies that depression is caused by an imbalance of neurotransmitters (e.g. serotonin 5-HT, noradrenaline and dopamine). This model is losing traction to a holistic model which proposes that depression arises following the interaction of many factors. - The **multi-factorial model of depression** suggests that depression is associated with **disruption in synaptic communication, neuroplasticity and hemispheric function** (involving neurotransmitters including 5-HT, noradrenaline, dopamine and glutamate and **brain-derived neurotrophic factor** BDNF and **endocrine dysfunctions such as chronically elevated CRH+cortsiol**) alongside **inflammation** and **genetic factors.** There are **TWO** types of depression: 1. **REACTIVE DEPRESSION:** triggered by external events (≈75%), sometimes labelled as adjustment disorder in clinical practice. 2. **ENDOGENOUS DEPRESSION:** no apparent external trigger. **MANIA:** - Mania is a mental state of excessive exuberance, impulsiveness, euphoria, talkativeness, distractibility, self-confidence, grandiose ideas, racing thoughts, increased libido and increased motor activity. - **Bipolar Disorder** is an **alternation** between **depressive and manic states**, often first presenting 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 neurotransmitters (serotonin, noradrenaline, dopamine) in the synaptic clefts (the gaps between nerve cells where neurotransmitters send signals). This **deficiency** results in faulty communication between neurons, leading to the **mood disturbances**, **fatigue**, **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, anti-depressants often take **weeks** to exert therapeutic effects despite rapid changes in transmitter levels, suggesting that **other brain processes are involved in depression recovery (e.g. neuroplasticity).** - Current medications for depression are largely based on the biogenic amine hypothesis and so most anti-depressants work by modulating the levels or activity of these neurotransmitters. **MECHANISMS OF ACTION (MOA) OF ANTIDEPRESSANTS:** 1. **Inhibition of Presynaptic Reuptake Pumps:** Antidepressants like SSRIs and SNRIs inhibit the reuptake pumps on the presynaptic terminal. By blocking these reuptake transporters, they increase the amount of serotonin (5-HT) and/or noradrenaline (NA) in the synaptic cleft, prolonging their action on the postsynaptic receptors. 2. **Blocking Presynaptic Autoreceptors:** Presynaptic autoreceptors normally inhibit the release of neurotransmitters like serotonin when they detect enough of it in the synaptic cleft. Some antidepressants block these autoreceptors, which leads to an increase in neurotransmitter release from the presynaptic neuron. 3. **Inhibition of Monoamine Oxidase (MAO):** MAOIs inhibit monoamine oxidase, an enzyme found in mitochondria that breaks down neurotransmitters such as serotonin, norepinephrine, and dopamine. By blocking this enzyme, MAOIs prevent the breakdown of these neurotransmitters, thereby increasing their levels in the brain. 4. **Changes in Postsynaptic Receptor Sensitivity:** Over time, chronic use of antidepressants may lead to changes in postsynaptic receptor sensitivity. This can either enhance the responsiveness of these receptors to neurotransmitters or downregulate receptor numbers to balance the synaptic environment. **TREATMENT OF DEPRESSIVE SYMPTOMS:** - **The main strategy to treat depression focuses on** **correcting abnormal synaptic processes.** - Most modern antidepressant medications aim to improve synaptic responsiveness by **increasing the availability of neurotransmitters in the synaptic cleft** and **improving the sensitivity of neurons to these neurotransmitters.\ ** - Most **antidepressants take up to 8 full weeks for clinical effects to manifest:** these drugs may be modifying neuronal connectivity, changing receptor numbers, and some drugs stimulate release of BDNF in this time. - The delay in clinical improvement is suggested to occur because in response to an increase in neurotransmitter levels within the synapse, caused by, for example, reduced uptake, the **postsynaptic receptors** (the receptors on the receiving neuron) undergo a **compensatory adjustment** where the **number of postsynaptic receptors may decrease** (a process known as downregulation) in response to the elevated neurotransmitter levels. Initially, with too many receptors, the heightened neurotransmitter concentration might not immediately translate to improved mood, but over time, as the receptors adjust and reduce in number, the system reaches a new balance. After several weeks, the brain may adapt to the higher levels of neurotransmitters through changes in receptor sensitivity or number, and this new equilibrium could contribute to the improvement in mood and depression symptoms. +-----------------------+-----------------------+-----------------------+ | **Class of | **Mechanism of | **Clinical | | antidepressant and | action** | considerations and | | examples** | | ADRs:** | +=======================+=======================+=======================+ | Selective serotonin | - Selectively block | - First-line for | | reuptake inhibitors | 5-HT reuptake. | depressive and | | **(SSRIs)** | | anxiety symptoms. | | | | | | **(e.g. Sertraline, | | - Does not affect | | Escitalopram)** | | breastmilk. | | | | | | | | **ADRs include:** | | | | | | | | - Insomnia, nausea, | | | | dizziness, | | | | anxiety, | | | | increased suicide | | | | risk during early | | | | phase of | | | | treatment, | | | | serotonin | | | | syndrome | | | | | | | | - Serotonin | | | | syndrome results | | | | from **excessive | | | | accumulation** of | | | | **serotonin** in | | | | the CNS, and | | | | occurs when | | | | people take | | | | medications that | | | | increase | | | | serotonin levels, | | | | particularly when | | | | **multiple** | | | | **serotonin-enhan | | | | cing | | | | drugs** are used | | | | together. Some | | | | migraine | | | | medications and | | | | some opioids will | | | | also increase | | | | 5-HT activity. | +-----------------------+-----------------------+-----------------------+ | Serotonin-Noradrenali | - Block reuptake of | - Can be | | ne | 5-HT, | problematic to | | Reuptake Inhibitors | noradrenaline and | gradually | | **(SNRIs)** | dopamine. | withdraw from. | | | | | | (e.g. Venlafaxine, | | - Duloxetine is | | Duloxetine) | | used in the | | | | treatment of | | | | neuropathic pain, | | | | particularly for | | | | diabetic | | | | peripheral | | | | neuropathy. | | | | | | | | **ADRs include:** | | | | | | | | - Hypertension, | | | | hypercholesterola | | | | emia, | | | | nausea, | | | | dizziness, | | | | insomnia. | +-----------------------+-----------------------+-----------------------+ | **Tricyclic | - Inhibit reuptake | **ADRs include:** | | Antidepressants** | of noradrenaline | | | (e.g. amitriptyline) | and 5-HT, | - Anti-cholinergic | | | increasing the | effects | | | concentration of | (constipation, | | | both in the | dry eyes, dry | | | synaptic cleft. | mouth, | | | | orthostatic | | | | hypertension, | | | | confusion, | | | | sedation) and | | | | cardiac | | | | arrythmias (can | | | | be lethal in | | | | overdose). | +-----------------------+-----------------------+-----------------------+ | **Tetracyclic | - Blocking | **ADRs include:** | | Antidepressants\ | **pre-synaptic | | | **(e.g. mirtazapine) | alpha-2 | - Sedation at lower | | | adrenoceptors** | doses | | | inhibits | | | | autoregulation, | - Increased | | | leading to | appetite | | | **increased | | | | release of | | | | noradrenaline**, | | | | enhancing | | | | neurotransmission | | | | and improving | | | | mood. | | +-----------------------+-----------------------+-----------------------+ | **Monoamine Oxidase | - Inhibit MAOIs, | - Non-selective | | Inhibitors (MAOIs)** | preventing | **MAOIs** | | | neurotransmitter | (Monoamine | | (e.g. irreversible | breakdown. | Oxidase | | phenelzine, | | Inhibitors) are | | reversible | | less popular | | moclobemide) | | because they | | | | require **dietary | | | | restrictions** to | | | | avoid potentially | | | | dangerous side | | | | effects, such as | | | | **hypertensive | | | | crises** | | | | (dangerously high | | | | blood pressure). | | | | | | | | - Non-selective | | | | 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 | | | | restriction | | | | required. | +-----------------------+-----------------------+-----------------------+ | **Vortioxetine** | - Inhibits reuptake | - | | | and enhances 5-HT | | | | availability | | | | | | | | - Has direct | | | | receptor activity | | +-----------------------+-----------------------+-----------------------+ | **Agomelatine** | - Melatonin | - | | | agonist, weak | | | | 5-HT serotonin | | | | antagonist | | +-----------------------+-----------------------+-----------------------+ | **Complementary | **St John's Wort:** | **St John's Wart | | medicines** | | ADRs:** | | | - Herbal remedy | | | | thought to | - Dry mouth | | | inhibit 5-HT, | | | | noradrenaline and | - Photosensitivity | | | dopamine | | | | reuptake, | - Headache | | | modulate | | | | serotonin | - Palpitations | | | receptors, | | | | inhibit MAO and | **Selective | | | modulate GABA and | Noradrenaline | | | glutamate. | Reuptake Inhibitor | | | | ADRs:** | | | **Selective | | | | Noradrenaline | - Dizziness | | | Reuptake Inhibitor: | | | | (e.g. Reboxetine)** | - Insomnia | | | | | | | - Primarily blocks | | | | noradrenaline | | | | reuptake. | | +-----------------------+-----------------------+-----------------------+ **GENERAL CLINICAL CONSIDERATIONS:** - Patient **adherence** to therapy is important due to **delayed onset of clinical effects.** - Increased **suicide risk** during **early treatment stages.** - Concerns about use of anti-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 | **Clinical | | mania** | action** | considerations and | | | | ADRs:** | +=======================+=======================+=======================+ | **Anti-psychotic and | - **Anti-psychotics | | | anti-epileptic | ** | | | medicines (first-line | antagonise | | | treatment)** | dopamine and 5-HT | | | | (e.g. olanzapine, | | | | quetiapine, | | | | carbamazepine and | | | | valproate) | | | | | | | | - **Anti-epileptics | | | | ** | | | | possess | | | | anti-convulsant | | | | activity. | | +-----------------------+-----------------------+-----------------------+ | Lithium carbonate | - Substitutes | - Used for the | | | itself for sodium | prophylaxis of | | | ions, altering | difficult to | | | action potentials | treat bipolar | | | and neuronal | disorder. | | | signalling to | | | | reduce | - Takes around two | | | transmitter | weeks to become | | | release. | effective. | | | | | | | | - 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, corticosteroid secretion, and negative emotions. - Anxiety disorders occur **when responses to stress are triggered**, in anticipation of, or without, an external stressor, leading to **persistent interference with daily functioning.** - Anxiety disorders are associated with a **consistent perception of the threat of harm to oneself or others** resulting in **debilitative emotional, behavioural and motor responses** out of proportion with the actual threat. - Anxiety is associated with **autonomic nervous system activation**, altered muscle tone, ritualised behaviour, **sleep disorders**, **altered attention** and concentration, **alongside the co-morbidities** of depression, substance abuse, poor health and social functioning. - Emotional stimuli are processed through the sensory thalamus, cortices and hippocampus. In anxiety disorders, the amygdala may process these stimuli directly, bypassing the cortices 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 neurotransmitter 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 neurotransmitter with its specific receptors being: **GABA-A ionotropic receptor** and **GABA-B G-protein coupled receptor.** **MEDICATING ANXIETY DISORDERS:** - **First-line** treatment is cognitive behavioural therapy **(CBT) and/or SSRIs.** Note that 50% of patients who complete a CBT program of 6-12 weeks no longer satisfy the diagnostic criteria for anxiety and this positive effect lasts for two years. 80% of patients who complete a CBT program experience some benefit. - **Second-line** treatment is **SNRIs and TCAs.** - **Benzodiazepines** should only be **used acutely (short-term).** - Other options include **anti-psychotics**, **beta-blockers** (not evidenced-based, only used in social anxiety settings with more of a placebo effect), **anti-seizure drugs** (for difficult to control anxiety). +-----------------------+-----------------------+-----------------------+ | **Benzodiazepines** | **Mechanism of | **Clinical | | | action** | considerations and | | | | ADRs:** | +=======================+=======================+=======================+ | Benzodiazepines | - Benzodiazepines | **Effects of | | include diazepam | bind | benzodiazepines:** | | (Valium) temazepam, | **allosterically* | | | and clonazepam | * | - Anxiolytic | | | to the GABA-A | effect, | | | ionotropic | addressing | | | receptor. Once | in-the-moment | | | bound, | anxiety for 1-3 | | | benzodiazepines | days and useful | | | **enhance the | when starting | | | effect of GABA** | SSRIs that might | | | by **increasing | cause an initial | | | the frequency | anxiety flare. | | | with which the | | | | Cl- channel opens | - Induction of | | | when GABA is | sleep and | | | present,** | relaxation | | | allowing more Cl- | | | | ions to enter the | - Anti-convulsant | | | neuron. This | (seizure | | | causes greater | inhibition) | | | hyperpolarisation | | | | which further | - Muscle relaxant | | | inhibits neuronal | by inhibiting | | | firing, leading | signals to | | | to enhanced | muscle, | | | inhibitory | preventing muscle | | | effects. | spasms | | | | | | | | - Paradoxical | | | | aggression and | | | | irritability | | | | | | | | **Clinical | | | | considerations:** | | | | | | | | - Highly lipid | | | | soluble | | | | | | | | - Well-absorbed | | | | orally | | | | | | | | - Can cross the BBB | | | | | | | | - Hepatically | | | | metabolised, | | | | sometimes to | | | | active | | | | metabolites which | | | | extend the | | | | half-life and | | | | duration even | | | | further. | | | | | | | | - Some | | | | benzodiazepines | | | | and their | | | | metabolites are | | | | **renally | | | | cleared**, which | | | | can lead to | | | | **drug | | | | accumulation** | | | | and increased | | | | risk of **adverse | | | | effects** in | | | | patients with | | | | **renal | | | | impairment**. | | | | Benzodiazepines | | | | with **shorter | | | | half-lives** or | | | | those that are | | | | **not extensively | | | | renally cleared** | | | | are preferred in | | | | patients with | | | | renal impairment | | | | to avoid drug | | | | accumulation and | | | | prolonged | | | | sedation. | | | | | | | | **ADRs of | | | | benzodiazepines:** | | | | | | | | - CNS depression: | | | | drowsiness, | | | | confusion, | | | | amnesia, impaired | | | | co-ordination and | | | | the hangover | | | | effect. | | | | | | | | - Tolerance and | | | | dependence: | | | | develop quickly | | | | as a result of | | | | down-regulation | | | | of GABA-A | | | | receptors and is | | | | correlated to | | | | duration and | | | | magnitude or | | | | receptor | | | | occupancy. | | | | | | | | - Withdrawal needs | | | | to be done | | | | slowly, is | | | | associated with | | | | heightened | | | | anxiety, rebound | | | | REM sleep (hence, | | | | disturbed sleep), | | | | tremor, tinnitus, | | | | and weight loss. | | | | Withdrawal from | | | | benzodiazepines | | | | is more difficult | | | | than from | | | | opioids. | | | | | | | | - Interactions | | | | between | | | | benzodiazepines | | | | and other CNS | | | | depressants or | | | | alcohol can be | | | | dangerous. | +-----------------------+-----------------------+-----------------------+ When an **overdose** of benzodiazepines occurs, **flumazenil** (a competitive 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 **daytime fatigue**, **impaired cognitive function**, **mood disturbances**, and **reduced quality of life**. Insomnia can be **acute** (short-term) or **chronic** (lasting for weeks or more), and it may be caused by factors such as **stress**, **medical conditions**, **psychiatric disorders**, or **lifestyle habits**. +-----------------------+-----------------------+-----------------------+ | **Drugs used in the | **Mechanism of | **Clinical | | treatment of | action** | considerations and | | insomnia** | | ADRs:** | +=======================+=======================+=======================+ | Z-drugs **(e.g. | - Both drugs act on | - Used exclusively | | zolpidem and | brain **GABA-A | for sleep. | | zoplicone)** | receptors**, | | | | enhancing the | - **Dependence** | | | activity of | refers to the | | | **GABA**, the | body's adaptation | | | brain's primary | to a drug. Over | | | **inhibitory | time, the brain | | | neurotransmitter* | and body may | | | *. | become | | | This leads to a | **physically | | | **sedative | reliant** on the | | | effect** by | drug to function | | | increasing | normally. When | | | **chloride ion | **zolpidem** or | | | influx**, which | **zopiclone** are | | | hyperpolarises | taken regularly, | | | neurons and | **the brain | | | decreases the | becomes | | | potential for an | accustomed to | | | action potential | their effects.** | | | to occur because | If the drug is | | | the inside of the | suddenly stopped, | | | cell is now | the person might | | | farther from the | experience | | | **threshold | **withdrawal | | | potential**. The | symptoms** (such | | | neuron's activity | as rebound | | | is | insomnia, | | | **suppressed**, | anxiety, or | | | leading to an | restlessness). | | | overall | This is why | | | **inhibitory | **they are | | | effect in the | generally | | | CNS.** | prescribed for | | | | short-term use**, | | | | usually for no | | | | more than a few | | | | weeks at a time. | +-----------------------+-----------------------+-----------------------+ | Melatonin receptor | - **Melatonin | - Generally quite | | agonists (e.g. | receptor | well-tolerated | | agomelatine) | agonists** work | especially in | | | by **mimicking | comparison to | | | the action of | other sleep aids | | | melatonin**, a | like | | | natural hormone | benzodiazepines | | | produced by the | or | | | **pineal gland** | non-benzodiazepin | | | that regulates | e | | | the **sleep-wake | sedative-hypnotic | | | cycle** | s. | | | (circadian | | | | rhythm). These | **Common ADRs:** | | | drugs bind to | | | | **melatonin | - Dizziness | | | receptors** in | | | | the brain, | - Fatigue or | | | specifically the | drowsiness | | | **MT1** and **MT2 | | | | receptors**, to | - Headache | | | promote **sleep | | | | onset** and help | - Nausea | | | regulate | | | | **circadian | - Worsening of | | | rhythms**. | sleep if not used | | | | properly | +-----------------------+-----------------------+-----------------------+ | Suvorexant | - An orexin | - Works by | | | receptor | **reducing | | | antagonist. | wakefulness** | | | **Orexin** is a | rather than | | | neurotransmitter | sedating the | | | produced in the | patient. | | | hypothalamus that | | | | helps regulate | - Low risk of | | | the sleep-wake | dependence or | | | cycle. It | withdrawal | | | stimulates | symptoms | | | wakefulness and | | | | arousal by | **Common ADRs:** | | | activating orexin | | | | receptors (OX1R | - Daylight | | | and OX2R) in the | drowsiness | | | brain. By | | | | antagonizing | - Headache | | | (blocking) the | | | | orexin receptors, | - Abnormal dreams | | | suvorexant | or nightmares | | | reduces | | | | wakefulness, | - Sleep paralysis | | | thereby promoting | | | | sleep onset and | - Sleep-related | | | sleep | behaviours | | | maintenance. | | | | | - Depression or | | | | suicidal thoughts | +-----------------------+-----------------------+-----------------------+ **SEIZURES AND ANTI-CONVULSANTS:** - Seizures are **episodic**, **abnormal**, **high-frequency** discharges of impulses in the brain, starting in a specific group of neurons called a focus and potentially 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 properties 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 deprivation or infections.** - Anti-convulsant drugs are effective in 70-80% of cases of epilepsy, although some severe cases require surgical intervention to amend defective neurons. **TYPES OF SEIZURES:** - **Focal Onset Seizures:** commence locally and remain localised. 1. **Simple partial 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 sensations, movements, or feelings, such as tingling, visual disturbances, or muscle twitching, but the person can still interact normally during the seizure. These types of seizures do not cause a loss of consciousness. 2. **Complex partial 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 automatic movements, such as lip-smacking, chewing, or repetitive hand movements, which they may not be aware of or remember afterwards. - **Generalised Onset Seizures:** the abnormal electrical activity begins in one area of the brain (the focus) but quickly spreads to affect the entire 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 characteristics: 3. **Motor (Tonic-Clonic):** These are what most people think of when they hear the term "seizure." Motor/Tonic-Clonic seizures have two distinct phases: 4. **Non-Motor Seizures (Absence Seizures):** These seizures involve **brief lapses in consciousness**, often so subtle that they can go unnoticed. 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 fluttering. Absence seizures are less disruptive in the moment than tonic-clonic seizures, but because they can occur frequently, they can interrupt activities and affect concentration and learning, especially in children.  **\ Panel A: Normal EEG** This panel shows normal brain activity, with relatively 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**, indicating 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 entire brain is involved**. The seizure progresses in phases, with the first part showing **high-frequency, chaotic, 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 contractions. **Panel C: Generalised Absence Seizure (Petit Mal)\ **This panel shows the EEG pattern during a generalized absence seizure, also known as petit mal seizures. The waves in this EEG are **spike-and-wave discharges** (short, rapid spikes followed by slow waves), which are characteristic 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, often with subtle movements like eyelid fluttering or lip smacking. This type of activity often resolves quickly, as shown by the brief duration of the seizure in the EEG. **Part D: Partial Seizure:** **\ **This panel shows the EEG during a partial (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 activity in** a localized region, different from the global brain activity seen in generalized seizures. The localized spikes correspond to the focus of the seizure activity, which does not involve the entire brain. Depending on the location 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 activity:** GABA is inhibitory; therefore, increasing its activity is consistent with the goal of reducing impulse transmission. 2. **Inhibit sodium-channel signalling:** carbamazepine, phenytoin, lamotrigine. 3. **Block calcium channels:** ethosuximide, gabapentin, pregabalin. Therefore, anti-convulsant medications work by targeting specific channels and neurotransmitters in the brain to prevent abnormal electrical discharges that lead to seizures. Common adverse effects of these drugs include **sedation, confusion and skin rashes and teratogenicity.** +-----------------------+-----------------------+-----------------------+ | **Anti-convulsant | **Mechanism of | **Clinical | | drug:** | action:** | considerations and | | | | ADRs** | +=======================+=======================+=======================+ | **Carbamazepine** | - Blocks sodium | - Undergoes hepatic | | | channels of | metabolism to | | | neurons that are | form an active | | | firing | metabolite which | | | excessively | also has | | | during seizures | anti-seizure | | | to reduce | properties. | | | neuronal | | | | excitability and | **Common ADRs:** | | | therefore prevent | | | | high-frequency | - Bone marrow | | | discharges, | suppression | | | helping to | | | | control epileptic | | | | events. | | +-----------------------+-----------------------+-----------------------+ | **Phenytoin** | - Blocks sodium | - Highly | | | channels of | protein-bound | | | neurons that are | (≈90%), | | | firing | particularly to | | | excessively | plasma albumin, | | | during seizures | leaving only 10% | | | to reduce | free to exert its | | | neuronal | therapeutic | | | excitability and | effect. Changes | | | therefore prevent | in protein levels | | | high-frequency | such as in kidney | | | discharges, | or liver disease | | | helping to | can dramatically | | | control epileptic | affect the levels | | | events. | of active, free | | | | phenytoin, | | | | leading to either | | | | toxicity or | | | | sub-therapeutic | | | | levels. | | | | | | | | - Exhibits | | | | **dose-dependent | | | | (non-linear) | | | | pharmacokinetics* | | | | * | | | | meaning that | | | | small increases | | | | in dosage can | | | | result in | | | | disproportionatel | | | | y | | | | large increases | | | | in blood levels | | | | of the drug. | | | | | | | | - CYP450 metabolism | | | | which can vary | | | | greatly between | | | | individuals, | | | | influenced by | | | | genetics, age, | | | | and liver | | | | function. | | | | | | | | - Declining in use | | | | due to ADRs and | | | | unpredictable | | | | pharmacokinetics | | | | which requires | | | | precise dose | | | | adjustments due | | | | to saturation 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 epileptic | | | | events. | | +-----------------------+-----------------------+-----------------------+ | **Ethosuximide** | - Affects T-type | - Used in | | | calcium channels, | **first-line | | | which help | treatment** for | | | propagation | **absence | | | absence seizures. | seizures**, | | | | particularly in | |