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2012-02-16 23:47:58
neuro pharmacology

Pharmacology of the Autonomic Nervous System, anticonvulsants, anti-parkinson's drugs, drugs for headaches, anesthetics
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  1. Bethanechol
    • A muscarinic agonist that activates bowel and bladder smooth muscle
    • It is resistant to acetylcholinesterase (AChE)
    • Mnemonic: Bethany, call me if you want to activate your Bowels and Bladder
    • Used for non-obstructive urniary retention (given subcutaneously, post-operative abdominal distension (given orally), and gastric atony (given orally)
  2. Muscarinic Agonists
    • Activate muscarinic (M) receptors found on postganglionic parasympathetic fibers and on the sympathetic postganglionic sweat glands of the skin
    • Causes SLUD: Salivation, Lacrimation, Urination, and Defecation
    • Also causes sweating by increasing activity of sympathethic muscarninics
    • In general, muscarinic antagonists are resistant to cholinesterases because the have little to no nicotinic activity and tend to retain their activity at relative organ systems
  3. Acetylcholine (ACh)
    Has little or not therapeutic use because its actions are diffuse and it is rapidly degraded
  4. Methacholine
    • A muscarinic agonist that is used as a challenge test for diagnosis of asthma
    • It stimulates M3 receptors in the airway when inhaled
    • Is susceptible to AChE
  5. Pilocarpine
    • A muscarinic agonist
    • Is a potent stimulator of sweat, tears, and saliva
    • Is resistant to AChE
    • Mnemonic: You cry, drool, and sweat on your PILOw
    • Used to treat xerostomia (given orally)
    • Used as initial treatment of glaucoma (espeically narrow angle glaucoma) because it causes contraciton of the ciliary muscle of the eye (open angle) and the pupillary sphincter (narrow angle); it also increases aqueous humor drainage and relieves interaocular pressure
  6. Muscarinic antagonists
    • Block muscarinic (M) receptors and therefore block ACh action
    • Causes tachycardia, decreased secretion, depression and coma in the DNS, and bronchiole relaxation
    • Do not affect nicotinic receptors
    • Problems: These are nonspecific for M1 through M5; as a result, the effects are generalized and there is poor patient compliance with these drugs
    • Use of local administration can be used to mitigate these problems
  7. Atropine
    • A muscarinic antagonist
    • Used for IBS
    • Causes mydriasis and cyclopegia
    • Can also be used as "organophosphate rescue", but note that it will only help the parasympathetic effects and not the skeletal neuromuscular effects as these are controlled by nicotinic receptors
  8. Scopolamine
    • A muscarinic antagonist
    • Prophylactically used for motion sickness
  9. Pirenzipine
    • A muscarinic antagonist
    • Has some M1 selectivity
    • Historically used to treat peptic ulcers but now largely replaced by H. pylori therapy, H2 antagonists, and proton pump inhibitors
  10. Oxybutynin
    • A muscarinic antagonist
    • Reduces urgency in mild cystitis and reduces bladder spasms
  11. Ipratroprium
    • A muscarinic antagonist
    • Blocks all muscarinic receptors but have little effect on mucociliary clearance
    • Used in treatment of COPD and asthma
    • Mnemonic: I pray I can breathe soon!
  12. Nicotine
    • Nicotine has complex, unpredictable effects that vary based on the concentration of the dose
    • In the ANS: low doses stimulate and high doses show initial stimulation followed by blockage and increased heart rate, blood pressure, and GI motility
    • In the skeletal NMJ: similar to the ANS for low and high doses, except the stimulant phase is usually obscurred by rapidly developing paralysis
    • In the CNS: serves as an effective stimulate; high doses cause stimulation then depression and central paralysis; also stimulates the chemoreceptor trigger zone and causes vomiting (this is self-limiting)
  13. Nicotinic antagonists
    • Block nicotinic receptors either at the ganglion or at the NMJ
    • Note that nicotinic receptos are found in four locations:
    • 1) The CNS
    • 2) At synaptic clefts of preganglionic and postganglionic sympathetic ganglia
    • 3) Skeletal NMJ
    • 4) At the synaptic clefts of preganglionic and postganglionic parasympathetic ganglia
  14. Hexamethonium
    • A nicotinic antagonist that is a ganglion blocking drug
    • Is incredibly state dependent, meaning that because different organs are predominantly controlled by either the parasympathetic or sympathetic system, the effects of this drug will depend on which system is blocked
    • The arterioles, veins, and sweat glands are all predominantly controlled by the sympathetic system
    • The heart, iris, ciliary muscle, GI tract, urinary bladder, and salivary glands are all predominantly controlled by the parasympathetic system
    • Genital tract is predominantly controlled by both (so hexamethonium here causes decreased stimulation)
  15. D-tubocurarine
    • A nicotinic antagonist
    • Has a long duration of action
    • Causes muscle weakness and then flaccid paralysis that first affects small, rapidly-moving muscles, then the limbs/trunk, and finally the intercostals and diaphragm
    • Does not cross the blood-brain-barrier (BBB)
    • Antidote is an anticholinesterase inhibitor (AChE I)
    • Mechanism: Binds the AChR without activating it, preventing ACh from binding
  16. Succinylcholine
    • A nicotinic antagonist that acts at the NMJ
    • It is a depolarizing agent
    • Mechanism: Binds the AChR, causing depolarization with an initial contraction (fasciculations) and then flaccid paralysis
    • Has two phases: Phase I, the prolonged depolarization phase, and Phase II, the desensitization phase where ACh binding cannot elicit an action potential as the muscle is already depolarized
    • It is rapidly degraded in the liver by butyrylcholinesterase, and so antidote is to stop applying the drug
    • AChE inhibitors exacerbate its effect
  17. Therapeutic uses of NMJ blockers (2 uses)
    • Surgery: Derivatives of tubocurarine and succinylcholine can be used to facilitate skeletal muscle relaxation and allow for operative manipulations of the muscle
    • Focal Dystonia of the face: Botox is used to persistently inhibit ACh release at specific muscles
    • Mechanism of Botox: Toxin causes clipping of SNARE proteins, which are responsible for synaptic vesicle docking and release of NT; no SNARE, no docking, no ACh release
    • This procedure must be repeated every few months as regeneration of the SNARE proteins and degradation of toxin occurs
  18. Acetylcholinesterase inhibitors (AChEI)
    Especially effective at postganglionic parasympathetic muscarinic receptors because less ACh release occurs in these regions than at the nicotinic receptors found in the parasympathetic and sympathetic ganglions
  19. Quaternary Alcohols
    • An acetylcholinesterase inhibitor (AChEI)
    • These bind using electrostatics and have a short-lived duration (2-10 minutes)
    • Ex. is Edrophonium, which is used in diagnosing myasthenia gravis:
    • If a patient is given edrophonium and their weakness increases, they are having a cholinergic crisis whereby skeletal muscle weakness is occuring because high concentrations of ACh are causing continuous depolarization of the motor endplate
    • If a patient is given Edrophonium and their weakness decreases, it is myasthenia gravis, a an autoimmune disorder where autoantibodies are directed against nicotinic ACh receptors in the motor endplate
  20. Carbamate Esters
    • An acetylcholinesterase inhibitor (AChEI)
    • Bind covalently and last longer (up to 6 hr)
    • Neostigmine: Has no CNS penetration; used to treat postoperative and neurogenic ileus and urinary retention, myasthenia gravis, and reversing NMJ blockade
    • Physostigmine: Crosses blood-brain-barrier (BBB); used to treat Glaucoma and atropine overdose (it PHYxes overdose); it can also be used prophylactically to minimize the damage caused by a nerve gas attack
    • Pyridostigmine: Does not penetrate CNS; used to treat myasthenia gravis (gets RID of muscle weakness)
  21. Organophosphates
    • An acetylcholinesterase inhibitor (AChEI)
    • Extremely stable molecules that undergo a seondary conversion when binding AChE that leads to irreversible binding (termed aging)
    • Echothiophate: Can be used to treat glaucoma
    • Melathion
    • Parathion
  22. 3 Sources for AChE Inhibitor Exposure
    • Accidental exposure like insecticide spraying (common in the US)
    • Warfare agents: Sarin (a volatile substance acquired by inhalation), Vx (a persistant organophosphate absorbed mostly by skin exposure and that can survive on skin/terrain for extended periods), and Soman (moderately volatile, absorbed by inhalation/skin contact, and notable for very rapid aging, within minutes)
    • Side effects from AChE inhibitor therapy: DUMBBELSS (Diarrhea, Urination, Myosis, Bronchospams (from bronchoconstriction and secretion), Bradycardia, Excitement of the CNS and skeletal muscle, Lacrimation, Sweating, and Salivation
  23. Prophylaxis and Treatment of Toxicity (4 ways)
    • Pyridostigmine: Used prophylactically to reversible bind a small reserve of AChE such that if the remaining AChE are compromised (i.e. via a nerve gas attack as in the Gulf War), there is enough left to maintain body functions
    • Heroic doses (200 mg) of atropine: Counteract the parasympathetic effects (won't work on skeletal neuromuscular effects as these utilize nicotinic receptors)
    • Pralidoxime: "Regenerates" AChE by binding organophosphate and weakening its covalent bond; can cause complete reversal of all symptoms; only effective if aging has not occurred
  24. Catecholamines
    • Adrenergic agonists
    • Have a rapid onset of action but a brief duration of action
    • Are metabolized by catcheol-O-methyl transferase (COMT) and monoamine oxidase (MAO)
    • Not given orally
    • Have poor penetration into the CNS
    • Includes epinephrine, norepinephrine, dopamine, isoproterenol, and dobutamine
  25. Non-catecholamines
    • Adrenergic agonists
    • Have a slow onset of action but a long duration of action
    • Can be given orally
    • Can penetrate the CNS
  26. Sympathetomimetics
    Are adrenergic agonists
  27. Sympatholytics
    Are adrenergic antagonists
  28. Phenylephrine
    • An alpha1 selective adrenergic agonist
    • a1 > a2 >>>> b
    • Causes pupillary dilation, vasoconstriction, and nasal decongestion (causes decreased mucosa volume)
    • Used as a mydriatic agen for retinal examination, for minor allergic hyperemia (arterioles and venules utilize the alpha1 receptor)
    • Care must be taken in patients that are hypertensive, have prostatic enlargement, are on MAO inhibitors (usually for depression) and in cardiovascular/cerebrovascular diseases as can exacerbate these diseases because of the vasoconstrictive properties
  29. Methoxamine
    • An alpha-1 selective adrenergic agonist
    • a1 > a2 >>>> b
    • Used to treat the hypotension caused by blocking sympathetic preganglionic fibers in spinal anesthesia
  30. Midodrine
    • A prodrug that when activated becomes an alpha-1 selective adrenergic agonist
    • a1 > a2 >>>> b
    • Used for chornic orthostatic hypotension
  31. Clonidine
    • An alpha-2 selective adrenergic agonist
    • a2 > a1 >>> b (alpha2 receptors are found in CNS)
    • Acts on central alpha2 receptors to decrease central adrenergic outflow and therefore decrease blood pressure
    • Used to treat hypertension, especially that found with renal disease as it does not decrease the blood flow to the kidney
  32. Isoproterenol
    • A nonselective beta-adrenergic agonist
    • B1 = B2 >>>> a
    • Is a catecholamine used to stimulate the heart in emergency situations (AV block)
    • Causes bronchodilation (B2), increased heart rate/contractile force/cardiac output/systolic blood pressure (all B1), and vessel dilation of skeletal muscle (B2)
    • Result is a large decrease in peripheral resistance and diastolic blood pressure
  33. Dobutamine
    • A nonselective beta-adrenergic agonist
    • B1 = B2 >>>> a
    • Is a catecholamine that shows some a1 selectivity
    • Increases cardiac output but has little effect on the heart rate and vasculature
    • Used to stimulate the heart in congestive heart failure or acute myocardial infarctions
  34. Beta-2 selective agents
    • Used to treat asthma (because it causes the B2R to be internalized and destroyed, it is used in conjunction with glucocorticoids, which promote B2R production)
    • Decreased rik of cardic side effects because there is less B1 activity
    • Can also be used to decrease uterine contractions in premature labor
    • Side effects include anxiety, tremor, headache, cardiac arrhythmias, seizures, and hypokalemia*** (big question on Boards)
    • Examples are albuterol and ritodrine
  35. Albuterol
    • A B2 selective adrenergic agonist
    • Used to treat acute asthma
  36. Ritodrine
    • A B2-selective adrenergic agonist
    • Used to reduce premature uterine contractions
  37. Epinephrine
    • An endogenous cathcholamine
    • a1 = a2; B1 = B2 (activates all receptors)
    • Effects: lungs (bronchodilation), vasculature (high doses affect a1=vasoconstriction; low doses affect B2 = vessel dilation in skeletal muscle), heart (increases contractile force, cardiac output, and systolic blood pressure)
    • *Because a1 increases peripheral resistance, heart rate goes down; B2 decreases peripheral resitance, so heart rate increases
    • Therapeutic uses: Lungs (anaphylaxis and acute asthma), vasculature (amphylaxis, limits local absorption of anesthetic, topical homeostasis), heart (cardiac arrest)
    • Side effects: Anxiety, tremor, headaches, cerebral hemorrhage (from increased systolic blood pressure), cardiac arrhythmias, and hypokalemia
    • Used
  38. Anaphylaxis
    • Caused by respiratory distress (laryngeal edema and intense bronchospasm) and cardiovascular collapse (severe hypotension)
    • Initial treatment includes epinephrine because it causes bronchodilation (B2; decreased mucosa volume) and vasoconstriction (a1; increased blood pressure); also suppresses release of mast cell mediators
  39. Effect of epinephrine on absorption of local anesthetics
    • Epinephrine increases duration of action by preventing blood carrying
    • It also causes vasoconstriction, thereby decreasing blood flow to the area (reduces bleeding)
    • Can be applied topically for epistaxis (watch for rebound vasodilation) or for homeostasis in oral, facial, and nasal surgery
  40. Epinephrine and Cardiac Arrest
    Epinephrine increases vascular resistance, causes redistribution of blood flow to the coronaries and brain, and facilitates defibrillation
  41. Norepinephrine
    • An endogenous catecholamine
    • a1 = a2; B1 >> B2 (very little B2 activity, which really alters how it can be used therapeutically)
    • Effects: Lungs (little effect), vasculature (a1 = vasoconstriction, a dominant effect that results in increased peripheral resistance and increased systolic and diastolic blood pressure), and heart (cardiac output with either unchanged or decreased because of increased peripheral resistance; heart rate is decreased becaue of increased vagal reflex activity)
    • Therapeutic uses: Lungs (none), vasculature (used to treat septic shock by increasing peripheral resistance), and heart (none)
    • Side effects: Anxiety, tremor, headache, cerebral hemorrhage (from increased blood pressure), cardiac arrhythmias, and reduced blood flow to the kidneys because of vasoconstriction
  42. Dopamine
    • An endogenous catecholamine
    • D1 = D2 >> B >> a
    • Low doses vasodilate the renal vasculature, causing increased perfusion and glomerular filtration rate (GFR)
    • Moderate doses act on B1 to increase heart rate and contractility force
    • High doses act on a1 and cause vasoconstriction (may be used for septic shock treatment)
  43. Cocaine
    • An indirect sympathomimetic
    • Mechanism: Blocks monoamine reuptake transporters for dopamine, norepinephrine, and serotonin (5-HT), resulting in increased monoamine concentration in the synaptic cleft
    • Once used as a local anesthetic for its sympathomimetic actions
    • Side effects: seizures, hypertensive crisis (cerebral hemorrhage), cardiac arrythmias, and myocardial ischemia
    • Causes vasoconstriction and local anesthesia
  44. Amphetamine
    • An indirect sympathomimetic
    • Mechanism: alters vesicular storage of monoamines (norepinephrine) and dopamine by displacing them, causing increased extravesicular/intracellular levels of the monoamines; these monoamines are them pumped out by reverse action of the uptake transporters (resulting in increased monoamine concentration in the synaptic cleft)
    • Used for depression of appetite (obesity), narcolepsy (modanifil), and ADD (methylphenidate AKA ritalin)
    • Side effects: euphoria, psychosis, dependence, and arrythmias (hypertension resulting from norepinephrine release)
  45. Snake alpha-bungarotoxin
    Competitively binds AChR in NMJ and causing it to remain in a closed state
  46. Ondansetron
    • Used an an antiemetic agent to block 5-HT3 receptors in the chemoreceptor trigger zone
    • Mneumonic: "You will not vomit with Ondansetron, so you can go ON DANcing"
  47. Benzodiazepines
    • Increase the frequency of the GABAa receptor channel openings (ultimately causing increased intracellular [Cl])
    • Result is that GABAa affects are increased (these act as sedatives and hypnotics)
    • Mneumonic: Frenzodiazepines increase frequency
  48. Barbituates
    • Increase the duration of how long the GABAa receptor is open
    • Results in increased intracellular [CL]
    • Mneumonic: BarbiDURATes increase duration
  49. Strychnine
    • Found in rat poison
    • Is an antagonic of the Glycine receptor, meaning it will prevent inhibition and cause tetanic convulsions
    • Note that strychnine has no effect on glycine binding as a co-factor to NMDA receptors because they lack a binding site for strychnine
  50. Magnesium
    Treatment of choice for eclampsia because Mg blocks NMDA receptors, giving it its anticonvulsant effects
  51. Phencyclidine (PCP, angel dust, ozone, rocket fuel)
    • Blocks the port of NMDA receptors that stimulate thalamic GABAergic neurons
    • Produces signs of schizophrenia in normal individuals
    • May also trigger rapid behavioral antidepressant effects
  52. Ketamine
    • An intravenous anesthetic used in Peds and in drug abuse
    • Blocks NMDA receptors that stimulate thalamic GABAergic neurons (results in increased glutamate concentrations)
  53. Carbachol
    • A muscarinic agonist
    • Has high nicotinic receptor activity as well so is not used very much
  54. Alpha-latrotoxin
    • Black widow toxin
    • Stimulates release of excess ACh
    • First symptom is acute pain at the site of bit, then muscle cramps, abdominal pain, weakness, tremor, twitching, pain, and paralysis
  55. Botulinum toxic
    • Clips the SNARE protein so synaptic vesicles cannot fuse to membrane (prevents vesicular release)
    • Causes flaccid paralysi, dry eyes, dry mouth, and GI ileus
  56. Tetanus toxin
    • Blocks glycine and GABA release (blocking inhibitory stimuli)
    • Causes tetanic paralysis, with drooling, sweating, and inability to control defecation and urination
  57. Snake beta-bungarotoxin
    Prevents presynaptic release of vesicles
  58. Anesthetics
    • Have a very narrow margin of safety, which is important when describing the depth of anesthesia:
    • Stage I is analgesia and subsequent amnesia
    • Stage II is excitement, including delirium, combative behavior, increase in blood pressure and increase in respiratory rate (To avoid this stage, a short-acting IV
    • anesthetic is usually given before)
    • Stage III is surgical anesthesia, characterized by regular respiration, skeletal muscle relaxation, decrease in eye reflexes and movements, and fixed pupils (Loss of motor and autonomic responses to pain: in order to ensure the patient is deeply anesthetized, no signs of blood pressure fluctuation must be visible; Surgical
    • anesthesia is determined with EEG-based techniques; this is the stage you want (you want to bypass Stages I and II))
    • Stage IV is medullary paralysis, resulting in depression of respiratory and vasomotor centers and ultimately death
    • Many of these stages are not seen with the rapidly acting modern agents; they are also obscured by use of IV agents during pre-medication, induction and use of mechanical ventilator
    • Anesthetics can be divided into two categories:
    • General (via inhalation or intravenous)
    • Local (via Esters or Amides)
  59. Inhalational anesthetics
    • Cause: decreased metabolic rates, CNS depression, decreased cerebral vascular resistance, decreased renal and liver blood flow, decreased uterine contraction (except NO), decreased peripheral resistance (isoflurane/sevoflurane), decreased blood pressure, bronchodilation, decreased mucociliary function, and decreased ventillary response to hypoxia
    • Pharmacokinetics:
    • 1. Alveolar wash-in
    • 2. Uptake from lungs
    • 3. blood solubility (a low blood/gas coefficient is good)
    • NO < sevoflurane < Isoflurane
    • 4. Tissue uptake
    • 5. Elimination
    • Mechanism of action: Depressed neuronal activity in many regions by binding hydrophibic pockets of ion channels (increases GABA-a/Gly receptors and potassium channel activity; inhibits nAChR)
    • The dorsal horn neurons in the spinal cord are first depressed (analgesia), followed by frontal cortex neurons (sedation), then the thalamus/ARAS/midbrain reticular formation (hypnosis), and finally the ventral horn of the spinal cord (immobility)
    • Note: Because inhaled anesthetics bind at calcium receptors in the sarcolemma, they can cause malignant hyperthermia (this is treated with dantrolene)
    • Note: Drugs that block NMDA-R are strong analgesics but poor anesthetics (and vice versa)
  60. Isoflurane
    • The most commonly inhaled anesthetic
    • 99% is excreted unchanged via the lungs
    • There is NO organ toxicity
    • Works by dilating coronaries and decreased myocardial oxygen consumption (SAFE to use in patients if they have ischemic heart disease)
  61. Sevoflurane
    • An inhaled anesthetic
    • 97% is excreted unchanged by the lungs (3% is metabolished by the liver)
    • Preferred for outpatient surgery
    • Used in kids because it has low potency and doesn't cause airway irritation
    • Is a POTENT bronchodilator
  62. Nitrous Oxide
    • An inhaled anesthetic
    • Blocks NMDA-R (meaning it is a strong analgesic but poor anesthetic)
    • Often used as an adjuvant with other anesthetics to decrease their side effects
    • Causes nausea and vomitting but NOT respiratory depression or muscle relaxation
    • Can cause diffusional hypoxia by diffusing out of arterioles into the lungs and replacing nitrogen in body cavities (because NO is more soluble), increasing pressure, and creating the possibility of an obstructed bowel loop or pneumothorax
  63. Barbituates
    • An intravenous anesthetic
    • Prototype: Thiopental (sodium pentothal, the "truth drug")
    • Has high lipid solubility and is fast acting because it rapidly enters the CNS (but also rapidly exits and perfuses to other tissues)
    • Used for deep sedation and inducing anesthesia
    • Causes decreased cerebral metabolism and blood flow (good to use if a patient has cerebral swelling coupled with decreased cardiac output, decreased blood pressure, and respiratory depression)
    • NOT a good anesthetic as is short acting
    • Works by increasing the length (duration) of time the GABA-a channels are open
  64. Benzodiazepines
    • An intravenous anesthetic
    • Prototype: Midazolam (AKA Verced), used for endoscopy
    • Used as an adjuvant to produce anxiolysis, amnesia, and sedation, especially when general anesthesia isn't needed (like in GI surgery or in the ICU)
    • May cause severe postoperative respiratory depression, decreased blood pressure, and amnesia
    • Midazolam doesn't cause venous irritation, has rapid onset, and shorter duration of action
    • Works by increasing the frequency that GABA-a channels open
  65. Propentol
    • An intravenous anesthetic
    • Prototype: Propentol is the prototype
    • Used for rapid anesthetic induction and short procedures because of its rapid onset (recovery is faster than benzodiazepines)
    • Causes less nausea than thiopental
    • Potentiates the GABAa receptor
    • Causes respiratory depression, decreased myocardial contraction, decreased intracranial pressure, and decreased peripheral resistance
    • NOT a good analgesic
    • Note: It is formulated as an emulsion so bacterial contamination can occur
  66. Gabazine
    A GABA-a antagonist
  67. Etomidate
    • An intravenous anesthetic
    • Used to induce anesthesia in hypotensive patients because it causes minimal cardiovascular and respiratory depression
    • Causes vomitting, pain on injection, myoclonus, and decreases plasma concentrations of hydrocortisone
    • Potentiates GABA-a receptors
  68. Opioids
    • An intravenous anesthetic
    • Prototype: Fentanyl
    • Has three uses: 1. To induce and maintain IV anesthesia; 2. in conjuction wit hlocal anesthetics in epidural anesthesia; 3. For conscious and deep sedation in the ICU
    • Causes respiratory depression with chest wall rigidity, decreased ventillation, and decreased heart rate/blood pressure
  69. Ketamine
    • A dissociative intravenous anesthetic that blocks the pores of NMDA-R
    • Usually used in kids and young adults for short procedures, but should NOT be used in neonates and babies as it causes neurodegeneration
    • Causes catatonia, amnesia, and analgesia without the loss of consciousness
    • Has minimal effect on respiratory depression, leaving the upper airway reflexes intact
    • Also causes increased intracranial pressure, which leads to post-operative hallucinations
    • Blocking NMDA-R results in schizophrenia-like symptoms in normal individuals
    • Note: Ketamine can block transcription of rabies virus and serve as a treatment
  70. Local Anesthetics
    • Includes esters and amides
    • Mechanism: Blocks sodium channels by binding receptors on the inner surface of the channel; preferentially binds to activated sodium channels (i.e. those firing with high frequency) and decreases action potential propagation, causing nerve conduction to fail
    • This effect is pH dependent: local anesthetics cross the membrane in an uncharged form and then bind in the charged form
    • This is important because infected tissue is typically acidic, and so local anesthetics will remain in their charged form, unable to cross the membrane; this is overcome by administering more of the anesthetic or giving bicarbonate
    • The order of the nerve blockade depends on the nerve's firing frequency; in general, small fibers are blocked before larger fibers, and myelinated before unmyelinated, with the size rule predominating:
    • Pain is blocked before temperature is blocked before touch is blocked before pressure is blocked before motor
    • C fibers (small, unmyelinated fibers that carry pain) are blocked before A-delta fibers (small unmyelinated that carry temperature and sharp pain) before A-beta fibers (large, myelinated fibers that carry pressure) before A-alpha fibers (large, myelinated that carry motor)
    • Local anesthetics are typically given with epinephrine to enhance their effects because epinephrine limits their absorption away from the site by blocking the release of Substance P (i.e. epinephrine causes decreased bleeding and increased anesthesia by activating alpha-2 receptors)
    • Clinical uses:
    • 1. Topical for opthamology, derm, ENT (has a risk of toxic reaction because they are absorbed rapidly)
    • 2. Infiltration for wound surgeries and biopsies
    • 3. Nerve block
    • 4. Bier block
    • 5. Spinal anesthesia
    • 6. Epidural anesthesia
    • Adverse effects: Restlessness, tremor, decreased cardiac excitability
    • Adverse effects at high doses: convulsions, respiratory depression, arteriolar dilation, cardiovascular collapse, allergies (espically to esters), and tissue damage (especially at sites where local circulation is limited, like the toes and fingers)
  71. Esters
    • A local anesthetic
    • Prototypes: Procain and tetracain
    • Hydrolized by plasma esterases
    • Lipophilic agents are more potent and longer lasting
  72. Amides
    • A local anesthetic
    • Protoypes: Lidocaine and Bupivacaine (amides have *two* I's)
    • Metabolized in the liver
    • Have a longer duration of action than esters
    • Lipophilic agents are more potent and longer lasting
  73. Opioid Analgesics
    • Used for pain, antitussive, diarrhea, acute pulmonary edema, and maintanence programs for addicts
    • Mechanism: Act as opioid receptor agonists (mew, delta, and kappa) that modulate synaptic transmission by opening potassium channels, closing calcium channels, and causing decreased transmission
    • They also inhibit ACh, NE, 5-HT, Glu, and Substance P release
    • Toxicity: Addiction, respiratory depression, constipation, miosis, additive CNS depression with other drugs
    • Note: Use Naloxone or Naltrexone to treat toxicity (they are mew receptor antagonists)
    • Because of first pass elimination, opioid analgesics may not be effective if administered orally
    • Thus, the efficacy of opioids is based on their oral:parenteral ratio (O/P ratio); high ratios mean there is high first pass elimination and these drugs should not be given orally; contrastly, low ratios mean there is little first pass elmination and these drugs can be given orally
  74. Phenanthrenes
    • A subclass of opioid analgesics
    • Strong agonists: Morphine (low O/P ratio), hydromorphone (low O/P ratio), oxymorphone (low O/P ratio), and oxycontin (medium O/P ratio)
    • All used for chronic and severe pain (NOT for sharp, intermittent pain)
    • Morphine and hydromorphone are metabolized via chemical conversion with glucuronic acids to M3G/M6G (H3G); these are active metabolites that can become toxic at high concentrations
    • Mild and moderate agonists: Codeine (high O/P ratio), oxycodone (medium O/P ratio), and hydrocodone (medium O/P ratio)
    • Used in combo with aspirin (i.e. percocet, which is oxycodone plus aspirin) or acetominophren
    • Have adverse effects that limit the maximum tolerated dose available
    • Codeine is metabolized by CYP2D6 and then demethylated to morphine (its active component)
    • Oxycodone and hydrocodone are metabolized by CYP2D6 but their metabolites exert little effects
    • Mixed receptor agonists:
    • 1. Nalbuphine: a strong kappa agonist that has mew antagonist effects; it is resistant to nalaxone reversal; given parenterally and causes less respiratory depression than morphine
    • 2. Buprenorphine: Kappa antagonists and mew agonist with slow dissociation from receptors; also resistant to naloxone reversal; sublingual administration is preferred
  75. Phenylpiperidines
    • A subclass of opioid analgesics
    • Strong agonists: Fentanyl (low O/P ratio) and meperidine (medium O/P ratio)
    • Mild and medium agonists: Loperamide (used for diarrhea but because it cannot cross the blood brain barrier it is being considered for peripheral neurotic pain)
    • Metabolism:
    • Remifentinal (given parenterally only) via common tissue esterases
    • Heroin (diacetylmorphine) is degraded by common tissue esterases to monoacetylmorphine, and from there to morphine, then to M3G and M6G
    • Fentanyl is degraded into inactive metabolites via hepatic N-dealkylation by CYP3A4
  76. Benzomorphan
    • A subclass of opioid analgesics
    • Pentazocine (medium O/P ratio) has mixed receptor action and is a kappa agonsist/mew antagonist
  77. Phenylheptylamine
    • A subclass of opioid analgesics
    • Methadone (high O/P ratio) is a strong mew agonists and is metabolized via CYP3A4 and CYP2D6
  78. Lithium
    • A naturally occurring monovalent ion that has unclear mechanism of action (Na channels and 2nd messengers)
    • It is 1st line treatment for acute mania and maintenance in BPAD
    • Has multiple side effects
    • Can be lethal in overdose and blood levels (.4-1.5) must be monitored for toxicity
  79. Valproate (aka Depakote)
    • An anticonvulsant with undefined effects on the GABA system
    • 2nd line to Lithium
    • Effective in acute mania and prophylaxis for bipolar disorder
    • Side effects: GI, sedation, tremor, hair loss, weight gain
    • Can cause pancreatitis
    • Blood levels are 50-100
    • Metbolized by the liver
  80. Carbamazepine (Tegretol)
    • An anticonvulsant with unknown mechanism in BPAD
    • Useful for acute mania and bipolar prophylaxis
    • Good alternative for people who don't respond to lithium and can also be combined with lithim or valproate
    • Side effects: GI, sedation, hepatits, rash
    • Risk of aplastic anemia and agranulocytosis
    • Causes *auto-induction* (induces liver metabolism, decreasing drug concentrations)
  81. Formepizole
    • Inhibits alcohol dehydrogenase
    • Is an antidote for methanol or ethylene glycol poisoning
  82. Disulfiram (Antabuse)
    Inhibits acetaldehyde dehydrogenase, causing acetaldehyde to accumulate and contribute to hangover symptoms (facial flushing, nausea, vomiting, dizziness, and headache)