Condensed NP2 .docx

Pharmacology of movement disorders (9 BP Qs) Parkinsonism : Characterized by a combination of bradykinesia (slow movements) with at least one of the following: rigidity, tremor (at rest), and postural instability (instability of balance can lead to falls). The basal ganglia consists of the: stri...

Pharmacology of movement disorders (9 BP Qs) Parkinsonism : Characterized by a combination of bradykinesia (slow movements) with at least one of the following: rigidity, tremor (at rest), and postural instability (instability of balance can lead to falls). The basal ganglia consists of the: striatum (Str) caudate nucleus putamen globus pallidus (GP) internal (GPi) external parts (GPe) subthalamic nucleus (STN) substantia nigra (SN) reticular part compact part Which dopamine pathway is affected by PD? – Dopaminergic input into striatum is lost Nigrostriatal pathway (from substantia nigra to caudate-putamen (striatum)) – motor control death results in Parkinson’s Disease. Symptoms appear when 50-60% of neurons lost and the DA in str is reduced by 70-80% the numbers don’t match because there is a greater amount of DA lost than cell body that is lost. Terminals die first then cell bodies retrograde loss Direct and Indirect pathways NORMALLY: The cortex will stimulate D1 and D2 receptors in the striatum. D1 plays a role in the direct pathway which facilitates movement. D2 plays a role in the indirect pathway which inhibits movement. We use Levodopa (L-DOPA) to supplement dopamine. However, only 1-3% of levodopa actually enters the brain due to the action of the DOPA decarboxylase enzyme in the periphery, which converts levodopa to Dopamine. Peripheral dopa-decarboxylase inhibitor: Levodopa + Carbidopa (Sinemet) Carbidopa/L-dopa is the most effective medication for symptomatic treatment; minimum amount of carbidopa to prevent conversion outside of CNS: 75mg/day Reserve for later tx if possible bc of narrowing therapeutic window 25/100mg TID Protein restriction – diets high in protein may decrease absorption of levodopa due to competition with AAs for intestinal transporters Adverse Effects of Sinemet: Psychotic disorder: Anxiety, agitation, insomnia, hallucinations, delusions, nightmares, mood changes, Compulsive behaviors; drowsiness, dyskinesias (nigrostriatal), nausea Monitoring Parameters: mental status, abnormal involuntary movements, nausea Problems with Sinemet: Long-term “wearing off” can ensue at any time after treatment with LDOPA/Sinemet, but typically after 3-5 years. It is characterized by predictable fluctuations in motor function (akinesia, bradykinesia). How can we combat this? Reduce fluctuations in L-DOPA (increase frequency of dosing) Why does this occur? Progression of the disease Increase frequency of carbidopa/L-dopa doses; *** add either COMT inhibitor or MAO-B inhibitor or dopamine agonist Add or switch to extended-release carbidopa/L-dopa (Rytary) Use L-dopa inhalation or apomorphine SQ or SL* The “On-Off Phenomenon” represents the end-stage of L-DOPA therapy and is characterized by severe, unpredictable fluctuations in motor function. Patients fluctuate from normal function (on) and akinesia/bradykinesia (off); during “on” periods, patient can exhibit dyskinesias Dyskinesia Tx Add amantadine as adjunctive therapy** Lower Sinemet dose to try to counteract dyskinesias Why does this occur? “plastic” changes of the striatum due to wide fluctuations in dopamine levels Amantadine most commonly used adjunctively for L-dopa induced dyskinesia in patients experiencing “off” episodes “delayed on” or “no on” Tx: Give carbidopa/L-dopa on empty stomach Use ODT, avoid SR Use L-dopa inhalation or apomorphine SQ or SL* Freezing Tx Increase carbidopa/L-dopa dose Add dopamine agonist or MAO-B inhibitor Utilize physical therapy along w/ assistive walking devices or sensory cues Peak dose dyskinesia Tx Provide smaller doses of carbidopa/L-dopa at the same or increased dosing frequency*** Reduce dose of adjunctive dopamine agonist Add amantadine** Catechol-O-Methyltransferase COMT degrades L-DOPA to 3-O-methyldopa. Inhibition of peripheral dopa decarboxylase is associated with compensatory increase in peripheral COMT activity. COMT Inhibitors (-capone) include tolcapone, opicapone (Ongentys), and entacapone (Comtan). These drugs doubles half-life of L-DOPA and allow more access of L-DOPA to CNS. Stalevo is the combination of levodopa + carbidopa + entacapone. Adverse effects: increased incidence of dyskinesias (bc more levodopa in brain), nausea, confusion; diarrhea, fatigue, drowsiness, hallucinations, discolored urine Tolcapone: hepatotoxic Adenosine receptor antagonist (-ine) In addition to the degeneration of dopaminergic neurons, there is also an increased density of A2A receptors The resulting overactivity of the indirect “STOP” pathway may further impact motor functionality A2A receptor antagonist = Istradefylline Adverse effects: Dyskinesias; constipation and nausea; dizziness, insomnia; abnormal behaviors, hallucinations, delusions, impulse control disorder Monoamine Oxidase Inhibitors -giline (suicide inhibitors) Selegiline and rasagiline are irreversible inhibitors of MAOB. Two types of MAO: MAOA metabolizes NE and 5-HT MAOB metabolizes DA – fewer drug interactions compared to A subtype Thought to have some neuroprotection but no great evidence to support For mild functional impairment Adverse effects: can enhance motor and cognitive effects of L-DOPA, headache, dyskinesias (R), orthostatic hypotension, nausea, vomiting, indigestion, weight loss, insomnia (S); BBW: Suicidal thoughts in children & adolescents (S) Take selegeline in the morning to avoid insomnia Potential drug interactions: Cheese effect: hypertensive crisis resulting from interaction with sympathomimetic agents (tyramine-mediated) – too much NE release/activation of sympathetic nervous system Serotonin Syndrome: hyperthermia, rigidity, myoclonus, mental and vital sign changes, seizures, coma with 5-HT drugs Dextromethorphan – psychosis, bizarre behavior Opioid drugs- potentiate CNS/respiratory depression Dopamine Receptor Agonists (-ine, -ole) include apomorphine (Apokyn), bromocriptine (D2 agonist), pergolide (D1 and D2 agonist), and Pramipexole (Mirapex), Ropinorole (Requip) – titrate, Rotigotine (Neupro) Usually start with this drug Delays the time for needing levodopa Monotherapy provides greater symptomatic benefit for patients with mild-to-moderate impairment/early disease Less effective in severe disease (>Stage 3) Can be used as adjunctive therapy with other agents For rapid relief of acute off episodes (SQ or SL) during “delayed on” or “no on” During end-of-dose “wearing off” (motor fluctuation) Carbidopa/Ldopa often needs to be reduced Adverse effects: impairs impulse control, daytime sleepiness/drowsiness, orthostatic hypotension, dizziness, dyskinesias (can be reduced by lowering dose), headache, nausea/vomiting, confusion, hallucinations, lower extremity edema, delusions; application site reactions - rotigotine (Neupro) Apomorphine (Apokyn): orthostatic hypotension AE: Severe n/v, QT syndrome, hypotension, hallucinations Monitor: blood pressure, dizziness upon standing Premedicate with trimethobenzamide (because n/v are common AE); AE SQ & SL (Can’t use ondansetron due to the profound hypotension and loss of consciousness when administered with apomorphine Reduce dose in renal impairment Pramipexole (Mirapex) and Ropinirole (Requip) – titrate dose slowly and take with food Monitor: mental status, lower extremity swelling, mental behavior status, nausea, BP/dizziness upon standing Muscarinic receptor antagonists: include benztropine, trihexyphenidyl, biperiden, orphenadrine, procyclidine DOC for tremor MOA: Dopamine provides negative feedback to Ach neurons in striatum, so degeneration of dopamine neurons affect cholinergic activity. These are anticholinergic drugs. Improve tremor & rigidity, but not bradykinesia Adverse effects: “dry as a bone, blind as a bat, red as a beet, mad as a hatter” – anticholinergic effects (dry mouth, urinary retention, flushing, agitation, blurry vision, confusion, drowsiness) Monitoring Parameters: Dry mouth, mental status, constipation, urinary retention, vision AVOID IN OLDER ADULTS and in those with history of constipation, memory impairment, urinary retention Amantadine RA Mechanism of action unclear: may influence synthesis, release, or reuptake of DA? May increase D2 receptor expression May delay disease progression (inhibition of microglia (resident immune cells) and increased GDNF- in culture)? Adverse effects: dizziness, nausea, restlessness, depression, irritability, insomnia, agitation, hallucinations, confusion, orthostatic hypotension, livedo reticularis Monitoring parameters: renal function, lower extremity examination, ankle edema Useful add-on agent to attenuate L-dopa-induced dyskinesias or “off” periods Primavanserin – FDA-approved for psychosis in PD Other medications used to treat psychosis with PD: Clozapine and Quetiapine (D2 blocking effects, so not worsening the motor symptoms) Nonpharmacologic treatments of PD: exercise, physiotherapy, yoga, Tai Chi, and dance supports improvement in PD sx Huntington’s Disease Autosomal dominant disorder Characterized by chorea “dance” - uncontrolled movements, loss of intellectual faculties, and emotional disturbance Degeneration of neurons within striatum (movement) and cortex (thought, perception, and memory) Drugs that impair dopaminergic neurotransmission often alleviate chorea Reserpine (Serpasil) and tetrabenazine (Xenazine) deplete dopamine and other monoamines from the axon terminus by preventing intraneuronal storage Reserpine: depression, GI distress (n/v/d), dizziness, vertigo, drowsiness Tetrabenazine: depression, drowsiness, fatigue, Parkinsonism, insomnia, restlessness, nausea AE: Depression and Suicidal thoughts May also use DA receptor antagonists or BZs Adverse effects for these drugs include: Restless Legs Syndrome – abnormal regulation if nigrostriatal pathway Unpleasant sensations in the legs and an uncontrollable urge to move them for relief Sensations such as burning, creeping, tugging, or like insects crawling inside the legs may be related to aberrant regulation of nigrostriatal pathway Treatments Symptoms may resolve with correction of coexisting iron- deficiency anemia May respond to DA agonists, levodopa, GABA enhancing drugs, gabapentin, or opioids Ropinirole (Requip), rotigotine and pramipexole – Dopamine agonists Alzheimer’s disease pharmacology (4 BP Q’s) Alzheimer’s Disease pathology Neurofibrillary tangles made of tau protein and plaques made of Beta amyloid plaques Early Alzheimer’s Disease pathology: Some of the first neurons lost are cholinergic neurons in the septum and nucleus basalis (important in short term to long term memory then long term memory storage) Cholinesterase Inhibitors/Anticholinesterases: donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne). Tx in mild to moderate disease Slows the breakdown of acetylcholine In moderate to severe disease, consider adding NMDA antagonist (Memantine) for behavioral issues The key limiting adverse effects are: nausea/vomiting/diarrhea, loss of appetite, weight loss Titrate slowly GI toxicity If switching, stop for 1 week before titrating another Donepezil: bradycardia How might glutamate and NMDA-Rs be misregulated by ϐ amyloid? Excess Ca2+ excitotoxicity (too much activity of glutamate at NMDA receptors). Under normal conditions, APP inhibits NMDA receptors and enhances glutamate transport activity removing glutamate from the synaptic cleft. This is opposite when APP is falsely processed by Beta-amyloid (increasing glutamate concentrations in the synaptic cleft -- > may even drive glutamate transporters into reversed uptake mode). Memantine (Namenda) RA Tx in moderate-severe disease MOA: Blocks glutaminergic transmission, non-competitive NMDA antagonist, 5-HT3 antagonist, weak nicotinic receptor antagonist. Can be used alone or in combination with anticholinesterase Side effects: confusion, dizziness, headache, hypertension/hypotension, drowsiness, nausea/vomiting, risk of seizure, TIA, stroke How does NMDA antagonism help with AD symptoms? NMDA antagonism will prevent excess calcium and excitotoxicity = prevent neuronal death Sustained activation of NMDA receptors lead to excessive calcium Combo Therapy (memantine + cholinesterase inhibitor) in moderate to severe AD: Namzaric = donepezil + memantine Decrease in rate of progression of dementia in patients who received memantine with donepezil vs donepezil alone Anti-Amyloid Medications – know that they target beta amayloid Aducanumab-avwa (Aduhelm) is a monoclonal antibody against aggregated amyloid-beta. It reduces plaques in a dose- and time-dependent manner. AE: hives/angioedema; abnormal MRI- edema and hemosiderin deposition EMERGE and ENGAGE Dose-response effect on brain amyloid at 78 weeks Lecanemab-irmd (Leqembi) is a monoclonal antibody against amyloid-beta protofibrils (precursor to the plaque, gets to soluble and insoluble). It reduces plaques in a dose- and time-dependent manner. Side effects: headache, infusion reactions, reduced lymphocytes, hypersensitivity reactions, angioedema Black box warning for amyloid-related imaging abnormalities Donanemab (expected FDA approval by end of 2023) BBW for antipsychotics in dementia: increased risk for mortality in older adults with dementia related psychosis; Mortality mostly CV or infectious pneumonia Meds to avoid in dementia: antipsychotics, benzodiazepines, anticholinergics Opioid analgesics & antagonists (9 BP Qs) Some terms… Narcosis is a state of drugged sleep. Nociception -pain reception Nociceptor - pain receptor Opioid vs. opiate: Opioid - more general (anything that binds and activates the opioid receptor; synthetic); Opiate - naturally occurring, more selective as a term) Opioid receptors (unfortunately all drugs hit the mu receptor, ideally, would want to only bind to delta and kappa) Mu receptors: Distributed throughout nervous system, concentrated in areas involved in nociception and reward Mediate analgesia, reward (euphoria), sedation, respiratory depression, miosis, inhibition of GI motility, modulation of hormone release Delta receptors: Similar distribution as μ receptors, with some distinctions Mediate analgesia and modulation of hormone release Not as tied to reward Kappa receptors: Unique anatomical distribution and unique pattern of physiologic action Produce analgesia, dysphoria, psychotomimesis, sedation, and slow GI transit Orphanin FQ or nociceptin – bind ORL1 Endogenous opioid peptides All peptides bind all receptors with some affinity The endorphins bind mu receptors preferentially The pentapeptide enkephalins bind delta receptors preferentially (met or leu) The dynorphins bind kappa receptors preferentially All opioid receptors are metabotropic (INHIBITORY) Linked to several signal transduction pathways, including: inhibition of adenylate cyclase, which results in less cAMP activation of K+ channels, which results in hyperpolarization/IPSP inactivation of voltage-gated Ca2+ channels, which results in less NT release How do opioid receptors modulate nociceptive pathways in the spinal cord? All 3 major receptor are present in high concentrations in the dorsal horn of the spinal cord Mu opioid receptor: open K+ which increases IPSP, decrease AP Delta & kappa are present (analgesia) In the brain? Brain to spinal cord: modulates activity, primarily of the secondary neuron within the dorsal horn of spinal cord How do opioid receptors modulate descending inhibition? By inhibiting inhibitor to activate/increase descending inhibition Opioids enhance descending inhibition; opioids are inhibitors, so double negative = positive Opioids tell GABA to stop inhibiting the descending inhibitory pathway, which stimulates more APs in the descending inhibitory neuron pathway Common opioid analgesics New drug! Oliceridine is an IV only, µ receptor, G protein-pathway selective (µ-GPS) modulator In theory, improves analgesia and less opioid-related adverse effects The drugs differ with regards to: Receptor specificity Mu vs. kappa (no clinically useful pure delta agonists) Efficacy and potency Pharmacokinetics Lipophillicity (how well and how quickly are they in the brain) ½ life Agonist or antagonist properties Some are partial agonists- possibly useful with addiction liability Route of administration Common opioid analgesics Mu agonists: (know strong vs moderate agents) Strong Morphine Classic (prototypical) mu agonist, some kappa activity Oxymorphone: Strong mu agonist Methadone: mu only, long acting Meperidine: antimuscarinic effects, seizures Fentanyl, sufentanil: very potent, short acting Mild to moderate Oxycodone/Hydrocodone: orally active Codeine: low efficacy, used for minor pain and cough Tramadol: used for moderate pain, SNRI Buprenorphine: partial mu agonist, kappa antagonist Oliceridine: mu G protein-pathway selective agonist LESS adverse effects, selecting for G-protein pathway diphenoxylate and loperamide: limited CNS activity, used for diarrhea Kappa agonists: Pentazocine: Kappa agonist, partial mu agonist, can be used orally, low abuse risk Butorphanol: Kappa agonist, partial mu agonist, used IV or intranasally Heroin (diacetylmorphine) is potent and fast acting Methadone: mu agonist only, NMDA antagonist used for treatment of addiction (slow absorption prevents euphoria, and it suppresses withdrawal) highly variable kinetics (CYP3A4 and CYP2B6) and long half life Meperidine has significant antimuscarinic effects, negative inotropic action on the heart, potential for producing seizures Tramadol – Weak mu agonist, SERT/NET inhibitor How does NET inhibition help with pain? Buprenorphine: potent and long acting partial mu agonist, kappa antagonist May be used for opioid dependence Butorphanol and pentazocine: Kappa agonist, partial mu agonist What side effects would you expect due to kappa agonism? Opioid antagonists Naloxone, Naltrexone Naloxone: usually given IV, short duration of action (1-2 hrs) Naltrexone: can be given orally, but has first pass effects, half life 10 hrs Oxycodone + naltrexone (Troxyca ER) Buprenorphine + Naloxone (Suboxone) Physiological effects Analgesia Euphoria/dysphoria: which receptor causes which? Dysphoria: kappa, Euphoria: Mu Sedation Respiratory depression Cough suppression Miosis Nausea and vomiting Temperature: mu- hyperthermia, kappa- hypothermia Cardiovascular – bradycardia (ex. meperidine- tachycardia) GI tract – Inhibition of GI motility, constipation Biliary tract – contraction of the biliary sphincters Renal function is depressed (due to decreased renal blood flow), contraction of bladder sphincters- urinary retention Uterus- may reduce uterine tone Neuroendocrine- Stimulate the release of ADH, prolactin, and GH, but inhibit LH Pruritus- produce flushing and warming of skin, sometimes accompanied by sweating and itching Interactions Sedative-hypnotics, Antipsychotics: increased sedation, variable respiratory depression effects MAO inhibitors: High incidence of hyperpyrexic coma hypertension Toxicity/adverse effects Respiratory Depression is the chief reason for overdose deaths. Nausea and vomiting, Constipation, Increased intracranial pressure, Urinary retention, Itching, Pinpoint pupils, At extremely high doses, can cause seizures Tolerance With frequently repeated does of opioids, there is a gradual loss of effectiveness (tolerance) Which effects are LEAST affected by tolerance? Miosis, constipation, convulsions Physical dependence Failure to continue administering opioid can result in withdrawal Runny nose, lacrimation, yawning, chills, goosebumps, hyperventilation, hyperthermia, pupil dilation, muscular aches, vomiting, diarrhea, anxiety, hostility Hyperalgesia – increased sensation of pain Mechanism: Dopamine pathways that were “disinhibited” by opioids become more inhibited; Norepinephrine pathways that were inhibited by opioids become more active How does lofexidine, which is a alpha-2 receptor agonist help? Decrease in calcium influx leads to a decrease in NT release Skeletal muscle relaxants (4 BP Qs) Spasticity is a condition in which certain muscles are continuously contracted. Symptoms of spasticity: hypertonicity (increased muscle tone), muscle weakness, exaggerated deep tendon reflexes, muscle spasms, scissoring (involuntary crossing of the legs), fixed joints, abnormal function of bowel and bladder Somatic motor neurons are controlled by the corticospinal (pyramidal) and brainstem (extrapyramidal) pathways that project from the brain to the spinal cord. In spasticity, our somatic motor neurons are being overactivated, which is causing the muscles to contract abnormally. Hence, strategies would be to decrease their activation via 1) reducing the activity of afferents (sensory neurons), 2) reducing activity of descending pathways that activate the motor neurons, or 3) increase the activity of inhibitory interneurons within the spinal cord. Diazepam Produces sedation at doses required to reduce muscle tone MOA: enhances GABAA receptor activity post-synaptically, which is providing inhibition of the somatic motor neuron (GABA released by interneurons is more effective in providing inhibition) Baclofen (p-Chlorophenyl-GABA) MOA: GABAB (pre/post-synaptic) receptor agonist Acts both pre- and post-synaptically to decrease activity of somatic motor neurons (inhibits somatic motor neurons and decreases presynaptic neurotransmitter release by corticospinal neurons) Intrathecal and oral administration Adverse effects: drowsiness (tolerance can develop to this), dizziness, constipation, fatigue, increased seizure activity in epileptic patients Tizanidine (similar to clonidine, but less CV effects) MOA: alpha2 (inhibitory) receptor agonist comparable in efficacy to diazepam and baclofen Adverse effects: drowsiness, dry mouth, dizziness, asthenia (low energy) hypotension, rare but serious hepatotoxicity Dantrolene (used in malignant hypothermia) MOA: blocks the ryanodine receptor that causes Ca2+ release from the SR comparable in efficacy to diazepam, baclofen, and tizanidine Main adverse effect is generalized muscle weakness (will not select for just muscles that are having spasms) Carisoprodol (Soma) Mechanism of action unclear- Centrally acting skeletal muscle relaxant – appears to act in the brain stem (not spinal cord) GABAA receptors Metabolized to meprobamate (old sedative/hypnotic) Adverse effects: Biggest concern is drug abuse/drug dependence-withdrawal, which is why it should only be used short-term Cyclobenzaprine (Flexeril) Centrally acting (brain) skeletal muscle relaxant – brain stem appears to be primary site of action Structurally related to Amitriptyline (anti-histamine, anti-cholinergic effects); significant sedation Metaxalone (Skelaxin) Centrally acting skeletal muscle relaxant Adverse effects: drowsiness, dizziness, headache, nervousness or “irritability”, nausea, vomiting, gastrointestinal upset Take as directed, patients experience increasing drug concentrations under fed conditions Methocarbamol Centrally acting skeletal muscle relaxant; unknown mechanism (potential inhibitor of carbonic anhydrase enzyme) IM, IV, oral Adverse effects: dizziness, headache, lightheadedness, somnolence Local anesthetics (7 BP Qs) Local anesthetics Block impulse conduction along nerve axons following local application Can affect both motor and sensory fibers Completely reversible When applied properly, systemic toxicity is uncommon BLOCK voltage-gated Na+ channel Voltage-gated sodium channels enter their activated state when depolarized Inactivated when depolarized Local anesthetics preferentially bind and block sodium channels in their activated and inactivated states. The relative voltage of the membrane at the time when voltage-gated sodium channels are most vulnerable to local anesthetic block are when they are depolarized During an action potential, neurons exhibit the membrane potential that subjects voltage-gated Na+ channels to be most vulnerable to local anesthetic block Increased rate of firing of axons are extremely sensitive to local anesthetic block Nerve fibers differ in susceptibility to local anesthetics on the basis of size and degree of myelination Smaller diameter = increased sensitivity No (type C) or lighter (Type B) myelination = more sensitive Local anesthetic chemistry Consist of a lipophillic group (aromatic ring) connected by an alklyl chain to a hydrophillic domain, usually a tertiary amine; have to get local anesthetic across the membrane, once inside prefers the protonated form Protonation of the tertiary amine depends on the pKa of the compound and the local pH log Cationic form = pKa - pH Uncharged form The uncharged form of the LA crosses membranes (and gain access to its receptor), but the protonated form has a higher affinity for the Na+ channel. How might an infection (high acidic environment) affect the ability of the local anesthetic to work? In acidic environments, protonated form can’t cross the membrane. In acidic environment, LA will be protonated, but you need the unprotonated form to cross The alkyl chain is either an ester or an amide: amides all have an “i” before the “caine” The esters: procaine/chloroprocaine (short duration) and benzocaine (surface only) The amides: Lidocaine, Bupivacaine, Prilocaine The esters are metabolized via esterases. The metabolic product of procaine is chloroprocaine. The amides are metabolized by CYP enzymes. Local anesthetic absorption and distribution don’t determine onset but duration of action and toxicity. Absorption is dependent on vascularity of the area where LA is applied. Why might you use a vasoconstrictor (like epinephrine) with your local anesthetic? Reduce systemic absorption of LAs to prolong duration of action and reduce toxicity How do LAs work to block the primary nociceptor? Prefers small and unmyelinated neurons Uses Surface anesthesia means the LA can be applied directly to mucous membranes, the cornea, or the skin (lidocaine/benzocaine spray for sunburn) Infiltration anesthesia means the LA is injected into tissue without regard for location of nerve tracts. (dental procedures, inject area where you are getting tooth worked on) A nerve block is an injection of LA into or adjacent to peripheral nerves and plexuses. All areas distal to site of injection will be “numb”. Spinal (or intrathecal) anesthesia is where the LA is injected into CSF. This may be used to anesthetize a large fraction of lower body with a dose that produces minimal plasma levels. (injection is through the dura (part of meninges) Epidural anesthesia is where the LA is injected or infused into the space above the dura. The LA may be absorbed into the bloodstream. Toxicity is rare when administered correctly. Cardiovascular: bradycardia, hypotension GI: taste, nausea/vomiting CNS: drowsiness, dizziness, nervousness, blurred vision CNS/Neural toxicity High concentrations: twitching followed by tonic-clonic convulsions (inhibition of descending inhibitory pathways) Cardiovascular toxicity Slow conduction in atria and ventricles and reduce excitability of cardiac muscle, can cause cardiac arrest With the exception of cocaine, local anesthetics also depress the strength of cardiac contraction and cause arteriolar dilation General anesthetics (7 BP Qs) William T.G. Morton is credited with the invention of general anesthesia. General anesthesia exists when 5 descriptors are satisfied. What do these include? Hypnosis (asleep) Analgesia (no pain) Amnesia (no memory) Muscle relaxation Homeostasis Usually administered by intravenous (none of IV meds are full anesthetics injection or by inhalation) In 1920, Guedel described four stages of ether anesthesia: Stage of analgesia: analgesia without amnesia, then includes amnesia Stage of excitement/delirium: amnesia accompanies delirium, respiration is irregular, vomiting may occur if patient is stimulated Stage of surgical anesthesia: recurrence of regular respiration *This is the desired stage* Stage of medullary depression: severe depression of vasomotor center and respiratory center, death Inhaled anesthetics Halothane, isoflurane, enflurane, sevoflurane, desflurane = all complete anesthetics Nitrous oxide is incomplete MAC = minimum alveolar concentration The alveolar concentration that prevents purposeful movement in HALF of subjects in response to a painful stimulus 1.2-1.3 times the MAC is often necessary to ensure adequate anesthetic depth MACs can be additive between drugs MAC is higher in babies (newborns: 1.2x that of a 30yr old; 6 mo: 1.5x that of a 30 yr old – might be related to lipid content of brain at that age) Uptake and distribution of inhaled anesthetics (study ICE) The rate at which therapeutic concentrations are achieved in the brain depends on: Solubility of anesthetic in the blood Increased solubility or increase blood gas partition coefficient --> decreases equilibration rate Things that are less soluble are quicker to equilibrate Its concentration of anesthetic in inspired air As we increase conc of inspired air, increase rate (direct relationship) The volume of pulmonary ventilation Increase volume, increase rate (direct relationship) Pulmonary ventilation rate: as the rate increases, equilibration rate also increases Larger partition coefficient = slower onset/offset Elimination Generally, a mirror image of uptake and distribution Increased solubility in the blood (increased blood gas partition coefficient) decreased rate (will take longer to come out of anesthesia); quick on, quick off Agents are mainly eliminated via exhalation (this is desirable bc metabolism of agents can be associated with toxicities) Metabolism is minor; but, halothane is the most metabolized anesthetic, and metabolism utilizes CYP enzymes in the liver. Mechanism of action direct relationship between lipid solubility and anesthetic potency Led to the idea that general anesthetics stabilize/incorporation into the membrane of cells and inhibit ion fluxes Recent advances in understanding the MOA: Isoflurane reduces numbers of APs in post-synaptic neurons in a frequency-dependent manner Strongest effect on higher frequency impulses that are required for functions such as cognition or movement Minimal effect on low frequency impulses that control life-supporting functions, such as breathing Decreases NT release, probably due to decreased activation of calcium channels and decreased vesicular exocytosis Adverse Effects: Cardiovascular All (except N2O) decrease mean arterial pressure (MAP) Halothane is the worst (greatest increase in right atrial pressure) Respiratory All (except N2O) decrease in minute ventilation rate Increase the partial pressure of carbon dioxide in the blood Ventilatory response to hypoxia is profoundly decreased by all modern agents Brain Uncouple flow and metabolic demand – result is increase in cerebral blood flow and intracranial pressure Seizure activity may be seen with Enflurane and Sevoflurane Hepatotoxicity: Halothane, desflurane, and isoflurane all are metabolized to trifluoroacetate, which can cause hepatotoxicity. Halothane is the worst because it is the most metabolized. Nephrotoxicity may be associated with methoxyflurane and sevoflurane. Malignant hyperthermia: rapid onset of tachycardia and hypertension, muscle rigidity, hyperthermia, acidosis Genetic disorder - occurs following general anesthesia or neuromuscular blockade (succinylcholine) This is caused by an increase in calcium in muscle cells. The treatment is dantrolene, which blocks the RYR on the sarcoplasmic reticulum (prevents calcium release). Intravenous anesthetics (none alone can meet all 5) Can be used as sole anesthetics or in combination with an inhaled Barbiturates (-al) Rapid onset, provide hyponsis and amnesia, but no analgesia or muscle relaxation (so add something else) With continuous infusion, decrease MAP and CO Respiratory depressants: transient apnea, lowered sensitivity to pCO2 Benzodiazepines (-am) Diazepam (t1/2 = 43 hr) and midazolam (t1/2= 2 hr) Used for sedative, anxiolytic, and amnestic properties, but no analgesia, insufficient muscle relaxation Flumazenil is an antagonist to accelerate recovery from BZD Opioid analgesics (but not others) – agonists of mu opioid receptors Morphine, fentanyl, sufentanil Potent analgesics, but no muscle relaxation or amnesia Side effects: respiratory depression, constipation, urinary retention, nausea, drowsiness, miosis (constricted pupils), itching Etomidate (can’t use continuous IV bc inhibits production of adrenal corticosteroids) Potentiates GABAA receptor action – inhibitory (ionotropic: Cl- channel, IPSP) Rapid action – hypnosis, muscle relaxation, amnesia, but no analgesia Minimal cardiovascular and respiratory depression Myoclonic activity and postoperative nausea is a concern Why is prolonged etomidate not recommended? Adrenal steroidogenesis inhibition Propofol/Fospropofol Potentiates GABAA receptor action Rapid action with more rapid recovery – hypnosis, muscle relaxation, amnesia, no analgesia Reduces blood pressure by decreasing vascular resistance, respiratory depression Reduces cerebral blood flow, metabolic rate, and intracranial pressure Less post-operative nausea Ketamine Produces dissociative anesthesia (catatonia, amnesia, and analgesia with or without consciousness) MOA: NMDA antagonist (ionotropic permeable to Na+ and Ca+), may act on opioid receptors Can increase HR, MAP, and CO Marked increase in cerebral blood flow and intracranial pressure Decreases respiratory rate