Anti-Emetics, Analgesics & Anesthetics PDF

ANTI-EMETICS, ANALGESICS & ANESTHETICS Readings: Ch 22-24 in Pharmacology Revealed 1 AGENDA • Student Presentations • Take up term test #2 • Anti-Emetics • Pain & Analgesics • Local Anesthetics • General Anesthetics 2 EMESIS • Emesis = vomiting • Ubiquitous and necessary process the body uses...

ANTI-EMETICS, ANALGESICS & ANESTHETICS Readings: Ch 22-24 in Pharmacology Revealed 1 AGENDA • Student Presentations • Take up term test #2 • Anti-Emetics • Pain & Analgesics • Local Anesthetics • General Anesthetics 2 EMESIS • Emesis = vomiting • Ubiquitous and necessary process the body uses to defend itself against real or perceived pathogens • Coordinated by 2 areas of the CNS (both located in the medulla): • Vomiting Centre • Chemoreceptor Trigger Zone • Nerves afferent (towards) to these areas induce emesis • Nerves efferent (away from) these areas will stimulate the motor nerves to generate the reflex • Retrograde contractions of the small intestine couples with contractions of the diaphragm and abdominal muscles 6 VOMITING REFLEX • The vomiting reflex is triggered by stimulation of receptors in the upper GI tract, and mechanoreceptors in the wall of the GI tract, which are activated by both contraction and distension of the gut • A coordinating centre in the CNS controls the emetic response • Afferent nerves to the vomiting centre arise from abdominal splanchnic and vagal nerves and stimulate a structure in the brain called the chemoreceptor trigger zone (CTZ) • The CTZ senses activation from distension and contraction of the gut and can sense hormone variations associated with pregnancy (rising estrogen and progesterone levels) and have histamine receptors H1 receptors also thought to be key in this process • This activation sets off the vomiting reflex 7 NAUSEA & VOMITING OF PREGNANCY (NVP) • NVP has a serious impact on the lives of pregnant women • 47% feel loss of job productivity, 35% must take time off work • Negative impact on relationships • Results in feelings of anxiety and worry about the effects of symptoms on the fetus • Severe NVP has been compared to the severity of nausea caused by chemotherapy • Has been cited as a reason for elective termination of pregnancy • Hyperemesis Gravidarum lies on the extreme end of NVP – effecting 0.3-2% of pregnancies • Recognizing and treating NVP in a timely fashion may prevent the progression to HG 8 ANTI-EMETICS • Design focuses primarily on the neurotransmitters associated with the vomiting reflex • Each one will be specific to a certain type of nausea and vomiting • Drug used in Canada to treat nausea and vomiting of pregnancy (NVP) is DICLECTIN • doxylamine succinate pyridoxine hydrochloride • DICLECTIN is the first line therapy for NVP • Best studied drug in pregnancy – has been included in 25 epidemiological studies and 2 meta-analyses • Drug Class: Antihistamine (doxylamine succinate) and an anti-emetic (pyridoxine-hydrochloride, belongs to the Vitamin B complex group, specifically Vitamin B6) 9 DICLECTIN & NVP • DICLECTIN is a histamine antagonist that binds to histamine Type 1 receptors • One of the principal receptors at the CTZ are histamine type 1 receptors (H1) • This receptor is also expressed throughout the body, specifically in smooth muscles • H1 antagonists like DICLECTIN reduce or block the actions of histamine by reversible competitive binding to the H1 receptor • Work very poorly at the H2 and H3 receptors • Once bound to H1 receptors, it prevents histamine from binding and directly inhibits the action of histamine at the H1 receptor, and decreases the stimulation of the vomiting centre • Binding to histamine receptors on smooth muscle of the stomach, and intestine prevents smooth muscle contraction 10 Slide Modified from: Dr. C. Beites, Laurentian University DICLECTIN: FORMULATION & DOSAGE • Tablets have a special coating for delayed release • Should not be crushed, chewed or broken • Contain 10mg of doxylamine and 10mg of pyridoxine • Delayed release works optimally between 4-6 hours after ingestion • Client does not take as needed, but on a dosing schedule according to the timing, duration, severity and frequency of symptoms • Typical dosing is 4 tablets a day • 2 at bedtime – so that (for most people) when symptoms are worst in the morning, the drug will have appeared in the blood • 1 in the morning – to counteract any afternoon symptoms • 1 in the afternoon – to counteract any evening symptoms • This regime can be modified based on the client’s history and symptoms 11 Slide Modified from: Dr. C. Beites, Laurentian University ADVERSE REACTIONS • Due to the anticholinergic properties of antihistamines, caution should be used when DICLECTIN is taken concurrently with alcohol • Clients with epilepsy should consult their doctors, as DICLECTIN can increase the risk of seizures • No published reports of DICLECTIN use while breastfeeding – but it’s MW is small, so passage into breastmilk should be expected • Side effects include drowsiness, stomach upset, diarrhea, and headache 12 Slide Modified from: Dr. C. Beites, Laurentian University OVERDOSE • S&Sx of overdose are restlessness, dry mouth, dilated pupils, sleepiness, dizziness, mental confusion, and rapid heartbeat • Treatment for OD = gastric lavage or activated charcoal Self-Study • Case #19 – Veronica’s Vomiting • SOGC CPG 339: The management of Nausea and Vomiting of Pregnancy (on A2L) 13 PAIN • Can be acute or chronic • Classified as: • Visceral • Stretching of unmyelinated fibres in the walls of organs • Dull/aching • Somatic • Either superficial or deep • Labour • Combination of visceral and somatic • See Chapter 22 of your text for a more detailed description of the anatomy and physiology of the different types of pain 15 POSTPARTUM PAIN • Afterpains • Perineal or vaginal lacerations • Post operative pain • Breast engorgement • Normally, these pains will respond to mild analgesics or nonpharmacologic interventions 16 NSAIDS FOR POSTPARTUM PAIN • Diclofenac (oral) and Naproxen (oral) • Both inactivate cyclooxygenase (COX) • COX1 is constitutively active and not associated with inflammation • COX2 is produced in response to inflammatory stimuli • Preferred to inhibit this enzyme when it comes to pain control 17 Diclofenac • Oral formulation prescription-only analgesic in Canada (VOLTAREN) • VOLTAREN ointment available OTC • Diclofenac is more specific for COX2 than COX1, but still acts upon both to some degree • Because COX2 is more targeted, there is less of an effect on platelet aggregation compared to ibuprofen and ASA • Important consideration for postpartum bleeding • Metabolism and excretion of diclofenac: • Mainly metabolized by the liver • t1/2 is about 3h, given every 8h • Clinical use: • Post surgical pain relief and inflammation • Good for reducing perineal pain and swelling from operative delivery and episiotomy 18 Slide Modified from: Dr. C. Beites, Laurentian University Diclofenac Adverse Effects • Used acutely for post-operative pain there are few side-effects • Diclofenac is excreted in the breast milk; however, the doses given post-operatively should yield tiny doses to the newborn • RID unknown • Don’t give to someone with cardiovascular disease (although <100 mg is likely fine) • Contraindicated in pregnancy: teratogenic; associated with oligohydramnios, premature closure of DA, bleeding problems; avoid if hypersensitivity • NSAIDS should be avoided in clients with hypertension Drug Interactions • Because there may be antiplatelet effect of diclofenac other anticoagulants and antiplatelet drugs should be avoided => no ibuprofen or ASA • There are no drugs in the midwifery legislation 19 Slide Modified from: Dr. C. Beites, Laurentian University Naproxen • An NSAID used for its anti-inflammatory/analgesic properties postpartum • Available in 225mg dose over the counter (ALEVE) • Higher doses can be prescribed (NAPROSYN) • Not as specific for COX2 as diclofenac Metabolism: • Mainly by the liver; metabolites excreted in urine • t1/2 is about 14h (administered PO, q12h) Adverse Effects: • When used acutely for post-operative pain there are little side-effects • Naproxen is excreted in the breast milk however the doses given postoperatively should yield tiny doses to the newborn • RID = 3.3%, M:P = 0.01 • Contraindicated in pregnancy: teratogenic; associated with oligohydramnios, premature closure of DA, bleeding problems; avoid if hypersensitivity • NSAIDS should be avoided in clients with hypertension 20 Slide Modified from: Dr. C. Beites, Laurentian University Naproxen Drug Interactions: • Because there is an antiplatelet effect of naproxen, other anticoagulants and antiplatelet drugs should be avoided => no ibuprofen or ASA • There are no drugs in the midwifery legislation which will have significant interactions with naproxen particularly in the modest doses given to control post-partum pain What’s the difference between naproxen and ibuprofen for post-partum pain? • The half-life for ibuprofen is only 2h compared to 14h for naproxen 21 Slide Modified from: Dr. C. Beites, Laurentian University LOCAL ANESTHESIA • Definition: The loss of sensation in an area of the body without the loss of consciousness • Local anesthetics work by blocking open sodium channels • Several different forms: • Topical • At a mucous membrane • Infiltrational • Skin, superficial tissues and organs – not targeting a specific nerve • Field block • Beneath the cutaneous layers – targets specific nerves • Nerve block • Larger region of anesthesia than a field block • Injections of LA near specific peripheral nerves • E.g., pudendal block • Regional • A type of nerve block, but is higher than individual nerves • E.g., epidural, spinal 23 LOCAL ANESTHETICS FOR PERINEAL REPAIR • Lidocaine (XYLOCAINE) • Amide local anesthetic • By far the most common • Bupivacaine (MARCAINE) • Amide local anesthetic • Slightly slower acting, longer lasting • Chloroprocaine (NESACAINE) • Ester local anesthetic • Rapid acting, shorter lasting • More likely to cause hypersensitivity 24 Slide Modified from: Dr. C. Beites, Laurentian University CLASSES (AND SPELLING) OF LAs “THE RULE OF “i”” Amides Esters (no I before ‘caine’) • Lidocaine • Procaine • Bupivacaine • Chloroprocaine • Levobupivacaine • Tetracaine • Ropivacaine • Benzocaine 25 Slide Modified from: Dr. C. Beites, Laurentian University METABOLISM OF LAs Amides Esters • Primarily hepatic, broken down slower, last longer • Hydrolysis in the plasma by esterases • Plasma concentration may accumulate with repeated doses • Negligible potential for accumulation due to esterases • Toxicity usually only results from direct IV injection 26 Slide Modified from: Dr. C. Beites, Laurentian University FAMILIES OF LAs - ESTERS + H+ Chloroprocaine (free base- uncharged and lipophilic) H+ Chloroprocaine (charged and hydrophilic) Ester LAs are rapidly broken down in the blood by esterases so their half-lives are short. For example, procaine (NOVOCAIN) and chloroprocaine (NESACAINE) typically provides anesthesia for less than 30 minutes. Slide courtesy of B Wainman 27 FAMILIES OF LAs - AMIDES PLT Demo CH3 CH3 H N C CH3 N O Lidocaine as a free base (uncharged and lipid soluble) + H + H H+ C N N CH3 O Lidocaine as a cation (charged and water soluble) The amide LAs are broken down in the liver thus they last longer than ester-based LAs. Lidocaine provides anesthesia for 30-60 min and bupivacaine 2-4 hr. Slide courtesy of B Wainman 28 Propagation of the Wave of Depolarization along an Axon Sodium ions (Na+) Voltage-Gated Sodium Channel 3. Voltage-gated sodium channels Potassium ions (K+) continue to open thus a wave of Voltage-Gated depolarization moves Potassium Channel down the excitable membrane 4. Voltage-gated potassium channels open bringing the potential back down to below the RMP 1. Voltage increased to -55mv 2. Voltagegated sodium channels open 29 Slide courtesy of B Wainman THE ACTION POTENTIAL Image Sourced from: HyperPhysics.com 30 -80 -55 Volt meter (mV) -80 -55 Volt meter (mV) -80 -55 Volt meter (mV) 31 Slide courtesy of B Wainman -80 -55 Volt meter (mV) -80 -55 Volt meter (mV) -80 -55 Volt meter (mV) 32 Slide courtesy of B Wainman AXON SENSITIVITY TO LAs LAs will first block: 1. 2. 3. 4. Visceral and deep somatic pain: C fibers, thin and unmyelinated Sympathetic nerves: B fibers are thin and myelinated Superficial somatic pain: A-delta fibers are thinner and have less myelin than A-alpha Somatic motor nerves: A-alpha fibers are thick and myelinated; e.g. can maintain motor control after pain is blocked • E.g., epidural will block deep somatic and visceral pain first, then sympathetic nerves of blood vessels (what does this cause?), maintains motor control 33 BUPIVACAINE • Onset of action in 5-10 min with a blockade for 2-4 hr • Provides pain control for about 2X longer than lidocaine 3X longer than chloroprocaine • The onset of action is faster for lidocaine • Used routinely in epidural and spinal anesthesia • Because it affects relatively more visceral and somatic pain fibres than motor fibres Adverse Effects • Bupivacaine toxicity includes cardiac arrest and ventricular arrhythmia refractory to treatment • The onset of a toxic reaction is often preceded by tongue paresthesia and light-headedness • Most of the serious side-effects will only occur secondary to direct intravascular injection because the absorption into systemic circulation is very slow when given subcutaneously • Hypersensitivity reactions to lidocaine and bupivacaine (both amides) are extremely rare 34 Slide Modified from: Dr. C. Beites, Laurentian University CHLOROPROCAINE • The proper name is 2-chloroprocaine • Marketed in Canada as NESACAINE • Onset of action in 3-5 min with a maximum duration of blockade about 30-60 min • Removed from the Canadian market in 2012 Adverse Effects • Allergic reactions are more common with ester LAs because they are derivatives of p-aminobenzoic acid (PABA- a well known allergen) 35 Slide Modified from: Dr. C. Beites, Laurentian University SUMMARY: PAIN PATHWAYS 1. 2. 3. 4. 5. Specific pain nerve fibers in tissues stimulated by inflammatory mediators (histamine, PGs) released when tissues are damaged => NSAIDs block PG synthesis Passage of pain impulses depend on action potentials => blocked by LAs Integration of pain and touch fibers and descending messages in dorsal horn of spinal cord, “pain gate” => opioids act here Pain pathways in brainstem activate SNS and increase respiration, HR, BP, emesis, perspiration => anesthetic gases and opioids act in brainstem Pain pathways in cerebral cortex activated => opioids act in cerebral cortex 36 Slide Modified from: Dr. C. Beites, Laurentian University PHYSIOLOGY OF PAIN IN LABOUR • 1st stage of labour – mostly visceral • (from viscera) caused by dilation of the cervix and distention of the lower uterine segment • Dull, aching and poorly localized • Slow conducting, visceral C fibers, enter spinal cord at T10 to L1 • 2nd stage of labor – mostly somatic • Distention of the pelvic floor, vagina and perineum as baby pushes down • Sharp, severe and well localized • Rapidly conducting A-delta fibers, enter spinal cord at S2 to S4 37 Slide Modified from: Dr. C. Beites, Laurentian University REGIONAL ANESTHESIA IN LABOUR • Regional anesthesia refers to the use of local anesthetic solution(s) to produce circumscribed areas of loss of sensation; • Regional anesthesia is a generic term including conduction, nerve block, spinal, epidural, field block, infiltration, and topical anesthesia • Approximately 64% of women in labour at Ontario hospitals will have some form of regional anesthesia • Almost all will be epidural or intrathecal (“spinal”) anesthesia • Injections of local anesthetics into epidural or intrathecal space • Opioids do not provide regional anesthesia, but they are excellent pain control agents; but do not provide a complete blockade of nervous signals • Regional anesthesia at level of lumbar spine will affect sympathetic nervous system because part of SNS emerges from lumbar spine • Blockade of sympathetic motor neurons removes input to smooth muscle in blood vessel • What happens? • Prevention? 38 LUMBAR SPINE ANATOMY • Spinal cord ends L1 (i.e. lumbar vertebra number 1) • Below L1 the spine continues as spinal nerves called the cauda equina • At the cauda equina the nerves spread out and are not solidly packed like in the spinal cord so if you get near the nerves with a needle they move out of the way Slide courtesy of Dr B Wainman 39 LUMBAR SPINE ANATOMY 40 Slide courtesy of Dr B Wainman EPIDURAL ANESTHESIA • Injection of drug into the fat-filled epidural space • e.g., MARCAINE (local anaesthetic) is bupivacaine HCl - anaesthetizes whatever peripheral nerves in contact with drug; with opiate fentanyl • Some of the anaesthetic diffuses into the arachnoid space but if the injection is small enough and caudally applied then anaesthesia is mostly on the nerve roots passing through the epidural space i.e. the somatic sensory fibres • Can be patchy or incomplete if anesthetics do not reach all nerves 41 Slide Modified from: C. Osepchook, Ryerson University SUBARACHNOID ANESTHESIA • The subarachnoid injection is often called a “spinal”; also, intrathecal injection • The injection of a local anaesthetic into the space below L2 (spinal cord ends and cauda equine begins and less likely to damage nerves) • Advantages: • Clear end point: withdraw syringe and see CSF leaves little doubt in intrathecal space • Unlikely to fail to provide anesthesia because drugs into CSF which bathes the nerves → less drug required • Reliable for Caesarean delivery • Less morbidity and mortality than general anesthesia • Works within a few minutes vs. 10-15 min with epidural 42 EPIDURAL vs. SPINAL Epidural injection The outer needle in an epidural set is like a lumbar puncture needle. The catheter with the drug(s) is passed through the middle of the needle and into the appropriate area. The outer needle can then be removed, and the catheter left indwelling. Spinal injection Uses smaller needle and usually no catheter 43 EPIDURAL vs. SPINAL 44 Slide courtesy of Dr B Wainman OPIATES FOR PAIN CONTROL • Opiates work in number locations in CNS and PNS • Nociception begins at stimulation of peripheral nerves • Opiates can bind to opiate receptors on the free nerve endings → decrease firing of nerves • See Figs. 23-7 & 23.8 • Stimulation (pain) at free nerve endings in viscera initiates action potential • Action potentials travel towards CNS • Opiates bound to opiate receptors leads to hyperpolarization of nerve endings (more negatively charged) • Hyperpolarization decreases firing (pain message) 45 OPIATE ACTION ON THE SPINAL CORD 2 main mechanisms: 1. Bind to presynaptic receptors in the dorsal horn of the spinal cord • Results in inhibition of the release of stimulatory neurotransmitters (e.g., glutamate – which binds to its receptor NMDA and opens sodium channels which would propagate the pain message) 2. Bind to postsynaptic receptors causing hyperpolarization • Opiates bind to receptors and open potassium channels (K+ leaves the cell) causing increased negative charge and decreased neuronal excitability • Fig 23.8 46 OPIOIDS IN SPINALS AND EPIDURALS Benefits: • Allows less LA to be used • Results in less motor blockade • Thus, better mobility and better proprioception • Touch maintained to a greater extent • Allows for better position changes in labour and more effective second stage (pushing) Limitations: • Less effective at preventing somatic pain associated with second stage • Do not provide surgical anesthesia (LA must be added for Caesarean section) 47 OPIOID SIDE EFFECTS • Pruritis • Nausea and vomiting • Respiratory depression Adverse Effects of Neuraxial Anesthesia (Epidural) • Inadequate anaesthesia • Incomplete or “patchy” epidural – 20% • Block failure – 5% • Mild headache (due to sympathetic blockade – vasodilation) • Spinal headache • • • • Caused by leakage of CSF Very severe positional headache Occurs in 1-5% of users Treated with blood patch • Backache reported in 20% • Physical nature of the injection (e.g. bruising) • Less than 1% possibility of infection 48 GENERAL ANESTHETICS • Causes an absence of all perception • Therapeutic indices of 2-4 => thus, monitored continuously to avoid adverse effects • 2 types: • Parenteral GAs: given by injection often to induce GA • Inhalational GAs: to maintain anesthetized state for longer procedure (more than a few minutes) • Goal is to provide absence of pain, involuntary movement and autonomic reflexes → number of drugs necessary 50 PARENTERAL GENERAL ANESTHETICS • Small lipophilic molecules • Rapid onset of action • Short half-life • E.g., thiopental, propofol, ketamine • Mode of action: inhibition of neuronal firing through alteration of ligand-gated ion channels • E.g., ketamine blocks NMDA receptor • E.g., barbituates and benzodiazepenes (lorazepam, diazepam) antagonize the GABA receptor • Given via IV, rapidly distributed to tissues such as brain and spinal cord 51 INHALATIONAL GENERAL ANESTHETICS • For long-lasting surgical anesthesia • E.g., enflurane, halothane, isoflurane; nitrous oxide only effective as analgesic • Potency is correlated to their lipophilicity and thus penetration and removal from tissues; e.g., N2O less lipophilic and does not penetrate tissues as well • Mechanism of action is unclear • Appears to include disruption of lipid bilayer and thus structure of receptors that mediate neuronal stimulation e.g., GABA rec, NMDA rec 52 Nitrous oxide (ENTONOX) • 50% Nitrous Oxide, 50% oxygen in a compressed gas cylinder • Very lipid soluble • Effects start 25-30 seconds after administration and persist for about 60 seconds after inhalation stops • Client needs to self-administer: why? • Counsel them to breathe normally, slowly, and deeply but do not hyperventilate • Increased ventilation increases delivery of gas to blood • They will also exhale too much CO2 which can lead to: • Maternal hypoventilation and vasoconstriction of placental arteries which can lead to hypoxia in fetus • Cerebral vasoconstriction → dizzy 53 Nitrous oxide (ENTONOX) Four stages of analgesia (due to gradual suppression of brain activity) 1. Analgesia during contractions (reduces pain) 2. Delirium: vivid dreams, hallucinations (may occur transiently), pleasurable sensations leading to overuse in labour 3. Surgical anesthesia is possible (but would need really high concentrations of N2O and usually something else) 4. Depression of vital centers of medulla: very high concentrations lead to medullary paralysis (and can lead to death of infant) Adverse effects in clients: • Dangerous if client has a preexisting respiratory disease (like pulmonary hypertension); this could make it worse • Can exacerbate any existing placental insufficiencies • If fetal heart rate is abnormal, do not use 54 GENERAL ANESTHETIC PROBLEMS • Low therapeutic index - continuous monitoring by anesthesia required • Hypotension due to vasodilation and negative inotropy • Nausea and vomiting -> chance of aspiration • Toxicity due to halogens – metabolites are toxic • Malignant hyperthermia: reaction to halogenated gases • Hypermetabolic state: muscles generate +++heat causing rapid increase body temp destroying muscle, death if not treated • A main cause of mortality = failed intubation • intubation failure rate of 1:250 for pregnant people (10x higher than the general population) • 25% mortality of GAs is due to failed intubation 55