CNS Drugs

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bshin
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83162
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CNS Drugs
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2011-12-12 14:59:51
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CNS Drugs
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CNS Drugs
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  1. CNS effects of increasing Doses of Sedative Hypnotic
    • Paradoxical disinhibition
    • Sedation, anxiolysis, anticonvulsant + muscle relax
    • Hypnosis
    • Anesthesia (BDZs start plateau here)
    • Meduallary depression-->resp depression
    • Coma
    • Death
  2. GABAa receptor
    • Ligand gated Cl- channel
    • 5subunits
    • alpha- GABA
    • beta- Barbituates
    • gamma-Benzodiazepines
  3. GABAb receptor
    • GPCR--> K+ efflux
    • (just like M2 in SA and AV node!)
    • only agonist- Baclofen
  4. Flumazeni
    • BDZ overdose antidote!
    • -block both BZ1 and BZ2 receptor sites! (both GABAa receptor gamma subunit subtypes)

    does NOT reverse Barbituate or Alcohol overdose
  5. Benzodiazepines
    • Sedative-hypnotic
    • Potentiate GABA (GABAa)
    • (shift sigmoid log-response curve to Left!)
    • Increase frequency of Cl channel opening
    • Decrease REM sleep
    • most have long half-lives, active metabolites
    • less risk of resp depression than Barbituates, alcohol

    • USE- Anxiety, Spasticity
    • Status epilepticus (Lorazepam, Diazepam)
    • Detox for alcohol withdrawal
    • night terrors, sleepwalking
    • General anesthetic (amnesia, muscle relax)
    • Hypnotic (insomnia)

    • BZ1--> sedation
    • BZ2-->antianxiety, anterograde amnesia

    SE- dependence, additive CNS depression with alcohol
  6. BDZs with NO active metabolites
    • Oxazepam
    • Temazepam
    • Lorazepam
  7. BDZs with short Half lifes
    • Temazepam
    • Oxazepam
    • Midazolam (shortest, only IV)

    • Good for insomnia!
    • But has Highest addiction potential
  8. BDZs that can use IV
    • Diazepam
    • Lorazepam
    • Midazolam

    Good for emergency withdrawal states (alcohol) and Seizures (except Midazolam)!
  9. Alprazolam
    • BDZ, Potentiate GABA
    • (shift sigmoid log-response curve to Left!)
    • Increase frequency of Cl channel opening
    • Has active metabolite, long half life

    USE- Anxiety, Panic, Phobias

    SE- dependence, additive CNS depression with alcohol
  10. Diazepam
    • BDZ, Potentiate GABA
    • (shift sigmoid log-response curve to Left!)
    • Increase frequency of Cl channel opening
    • Has many active metabolites, so long acting
    • Diazepam-->Nordiazepam-->Oxazepam
    • has IV!

    • USE- Anxiety, preOp sedation, muscle relaxant (UMN-spasticity)
    • Withdrawal states (esp. Alcohol)
    • can use for Seizures (but prefer Lorazepam)

    SE-dependence, additive CNS depression with alcohol
  11. Lorazepam
    • BDZ, Potentiate GABA
    • (shift sigmoid log-response curve to Left!)
    • Increase frequency of Cl channel opening
    • NO active metabolites, but still long acting
    • has IV!

    • USE- anxiety, preOP sedation,
    • Status Epilepticus (IV)!!

    SE-dependence, additive CNS depression with alcohol
  12. Midazolam
    • BDZ, Potentiate GABA
    • (shift sigmoid log-response curve to Left!)
    • Increase frequency of Cl channel opening

    Shortest Half life (mins)!! so use only IV!

    USE- PreOP sedation, Anesthesia IV

    • SE-dependence, additive CNS depression with alcohol
  13. Temazepam
    • BDZ, Potentiate GABA
    • (shift sigmoid log-response curve to Left!)
    • Increase frequency of Cl channel opening

    • Short half life! No active metabolites
    • so good for insomnia!

    USE- sleep disorders

    SE-dependence, additive CNS depression with alcohol
  14. Oxazepam
    • BDZ, Potentiate GABA
    • (shift sigmoid log-response curve to Left!)
    • Increase frequency of Cl channel opening

    • Short half life! NO active metabolites
    • so good for insomnia!

    USE- sleep disorders

    SE-dependence, additive CNS depression with alcohol
  15. Triazolam, Chlordiazepoxide
    BDZ (see other cards)
  16. Barbituates
    • Sedative-hypnotic
    • Prolong GABA activity (GABAa)
    • Increase duration of Cl- channel activity
    • Bind gamma subunit
    • GABA mimetic activity at HIGH DOSE --> resp depression-->coma-->death
    • Inhibit Complex I on ETC--> decr ATP
    • INDUCE Cyp450!! (incr Vmax!)

    USE- Sedative for Anxiety, Seizures, Insomnia, Induction of Anesthesia (Thiopental)

    • SE- dependence, additive CNS depression with Alcohol, Resp/CV depression-->coma/death, Induce Cyps!!
    • DO NOT USE IN PORPHYRIAS!! -activate D-ALA synthase, worsen the buildup of metabolites in Porphyrias (enzyme deficiency downstream of ALA-synthase)
  17. Tolerance & dependence of Sedative Hypnotics
    • Chronic use-->tolerance
    • Cross-tolerance between BDZ, Barbituates, Ethanol
    • Psychologic (craving) + Physical dependence
    • Abuse liability BDZ< Barbituates or Ethanol
  18. Withdrawal Signs of BDZ
    • Rebound insomnia
    • Rebound anxiety
    • Seizures (if Lorazepam or Diazepam was used as antiepileptic)
  19. Withdrawal signs of Barbituates and Ethanol
    • Anxiety
    • Agitation
    • Life-threatening Seizures!
    • Delirium (w/ alcohol)

    Manage withdrawal with long acting BDZs (Diazepam, Lorazepam)
  20. Drug interactions of GABAa agonists
    Additive with other CNS depressants! (anesthetics, antihistamines, opiates, beta-blockers, alpha-agonists)

    Barbituates INDUCE Cyps-->induce breakdown of lipid soluble drugs (OPC, Cabamazepine, Phenytoin, Warfarin..)
  21. Phenobarbitol
    • Barbituate
    • Prolong GABA activity
    • Increase duration of Cl- channel activity
    • GABA mimetic activity at HIGH DOSE --> resp depression-->coma-->death
    • Inhibit Complex I on ETC--> decr ATP
    • INDUCE Cyp450!! (incr Vmax!)
    • LONG ACTING

    USE- Seizures, safe in pregnancy!

    • SE- dependence, additive CNS depression with Alcohol, Resp/CV depression-->coma/death,
    • Induce Cyps!!
    • DO NOT USE IN PORPHYRIAS!! -activate D-ALA synthase, worsen the buildup of metabolites in Porphyrias (enzyme deficiency downstream of ALA-synthase)
  22. Thiopental
    • Barbituate
    • Prolong GABA activity
    • Increase duration of Cl- channel activity
    • GABA mimetic activity at HIGH DOSE --> resp depression-->coma-->death
    • Inhibit Complex I on ETC--> decr ATP
    • INDUCE Cyp450!! (incr Vmax!)
    • Short acting!

    USE- Induction of Anesthesia

    • SE- dependence, additive CNS depression with Alcohol, Resp/CV depression-->coma/death,
    • Induce Cyps!!
    • DO NOT USE IN PORPHYRIAS!! -activate D-ALA synthase, worsen the buildup of metabolites in Porphyrias (enzyme deficiency downstream of ALA-synthase)
  23. Pentobarbital, Secobarbital
    • Barbituates
    • Prolong GABA activity
    • Increase duration of Cl- channel activity
    • GABA mimetic activity at HIGH DOSE --> resp depression-->coma-->death
    • Inhibit Complex I on ETC--> decr ATP
    • INDUCE Cyp450!! (incr Vmax!)

    USE- Sedative for Anxiety, Seizures, Insomnia

    • SE- dependence, additive CNS depression with Alcohol, Resp/CV depression-->coma/death,
    • Induce Cyps!! DO NOT USE IN PORPHYRIAS!! -activate D-ALA synthase, worsen the buildup of metabolites in Porphyrias (enzyme deficiency downstream of ALA-synthase)
  24. Zolpidem (Ambien), Zaleplon
    • Non-BDZ hypnotics
    • BZ1 agonist! -->sedation
    • Less effect on cognition/memory (BZ2)
    • Less addictive
    • Short duration

    USE- Sleep disorders only

    • SE-ataxia, headache, confusion
    • modest day-after psychomotor depression
  25. Ezopiclone (Lunesta)
    • Non-BDZ hypnotics
    • BZ1 agonist! -->sedation
    • Less effect on cognition/memory (BZ2)
    • Less addictive
    • Short duration

    USE- Sleep disorders only

    SE-ataxia, headache, confusionmodest day-after psychomotor depression
  26. Buspirone
    • Non-BDZ hypnotic
    • 5-HT1A partial agonist
    • partial agonist (agonist alone, blocker w/ full agonist)
    • NO effect on GABA
    • nonsedative!! no addition, no tolerance, no interaction with alcohol!

    USE- generalized anxiety disorders (takes 1-2wks to work)
  27. All alcohols (ethylene glycol, methanol, ethanol) cause:
    -2
    • CNS depression
    • metabolic acidosis
  28. Ethylene glycol metabolism + poisoning
    Ethylene glycol--->Alcohol dehydrogenase-->Aldehyde dehydrogenase-->Oxalic acid

    • CNS depression
    • Severe anion gap metabolic acidosis
    • Acute tubular necrosis + Oxalate crystals


    Rx- Fomepizole (block alcohol dehydrogenase)
  29. Methanol (metabolism + posioning)
    • (wood alcohol contaminant)
    • Methanol-->alcohol dehydrogenase-->Formaldehyde-->aldehyde dehydrogenase-->Formic acid

    • CNS depression, respiratory failure
    • Severe anion gap metabolic acidosis
    • Blindness!

    Rx-Fomepizole
  30. Ethanol (metabolism) and Acetaldehyde toxicity
    • Ethanol-->alcohol dehydrogenase (cytoplasm)-->Acetaldehyde->acetaldehyde dehydrogenase (mitochon)-->Acetic Acid-->Acetyl-CoA--> glycerol-3P
    • NADH made every step!
    • Build up of Acetaldehyde--> hangover!
    • Acetaldehyde dehydrogenase needs Thimine and Folate!
    • -headache, hypotension, inactivate Folate, decrease Thiamine
  31. Acute Ethanol Posioning
    • CNS depression
    • Metabolic acidosis
    • Acetaldehyde toxicity

    steps: incr sociability-->gait-->delay rxn time-->ataxia-->impaired mental status-->coma-->death
  32. Chronic Ethanol Poisoning
    Alcohol damages Liver, Pancrease, Heart and Brain!

    • Fasting hypoglycemia
    • -Acetaldehyde-->decrs Thiamine-->decrs Gluconeogenesis
    • -incres NADH-->make Pyruvate-->lactic acid, so deprive Pyruvate for gluconeogenesis.
    • Faty liver + lipemia (mallory bodies)
    • -Incrs NADH, Acetyl-CoA
    • Acute, Chronic Pancreatisis
    • Muscle wasting (low glu--> incrs proteolysis)
    • Gout (lactate competes with urate for excretion)
    • Mallory Weis, Borhaaves' Syndrome
    • Beri Beri
    • Wernicke Korsakoff
    • Dilated Cariomyopathy
    • Risk of squamous cell carcinoma of esophagus
    • Risk of Linitis Plastica

    • Note: Give IV Thiamine before giving glucose!
    • b/c Thiamine cofactor for carb-metabolism->fiving just glucose may cause hyperosmolar coma!
  33. Disulfram
    Acetaldehyde dehydrogenase blocker

    • USE-given to increase neg feedback for alcoholics
    • build up of acetaldehyde-->make you feel like shit (hangover)

    Disulfram-like effects: headache, hypotension, nausea, vomit
  34. Drugs that cause Disulfram-like effects
    -azoles

    • Metronidazole
    • Cephalosporines (Cefoperazone. Cefotetan)
    • Chlorpropamide (sulfonylurease)
    • Griseofulvin (antifungal)
  35. Various mechanisms of Anticonvulsants
    • Decrs axon conduction by blocking Na influx
    • -Phenytoin, Carbamazapine
    • Increase inhibition by GABA
    • -Barbituates, BDZ
    • Decrease excitation by Glutamate
    • -Lamotrigine, Topiramate, Felbamate
    • Decrease presynaptic T-type Ca channel (in thalamus)- Ethosuximide, Valproic Acid
  36. Seizure states + drugs of choice
    • Partial: simple or complex
    • -no loss of consciousness
    • USE- Valproic Acid, Phenytoin, Carbamazepine

    • General- global brain, all lose consciousness
    • General- Tonic Clonic
    • -Grand mal seizure
    • USE- Phenytoin, Carbamazepine, Valproic acid

    • General-Absence
    • -moment of CNS depression!
    • CNS depressants like BDZ, Barbituates will worsen it!
    • USE- Ethosuximide, Valproic acid

    • Status Epilepticus
    • -epilepsy prolongs over 30 mins-->danger of glutamate toxicity, hydroping braing swelling, respiratory compromise
    • -need IV-anticonvulsants!
    • USE- IV BDZ: Lorazepam, Diazepam
    • -prophylactic: Phenytoin or Fosphenytoin(parenteral, water soluble)
  37. Phenytoin
    • anticonvulsant
    • -block axonal Na channels (inactivated state, like Class Ib antiarrhythmics)
    • -increase refractory period, inhibit glutamate release
    • -prevent seizure prolongation

    • USE- 1st line for Tonic Clonic seizure! (any seizures except absence!!)
    • -prophylaxis for Status Epilepticus

    Zero-order kinetics! (constant amount cleared per time-->nonlinear kinetics of dose vs plasma conc) reach toxic dose faster

    • SE-Induce Cyps (don't use in Porphyria), Gingival hyperplasia +hirsutism, Nystagmus, ataxia, diplopia, sedation, SLE-like syndrome.
    • -Osteomalacia (decrs Vit D), megaloblastic anemia (decr GI conjugase-->decr Folate absorp), Aplastic anemia (SLE-like HST rxn)
    • Teratogenic!-cleft lip, palate (fetal hydantoin syndrome)
  38. Carbamazepine
    • anticonvulsant
    • -block axonal Na channels (inactivated state, like Class Ib antiarrhythmics)
    • -increase refractory period, inhibit glutamate release
    • -prevent seizure prolongation

    • USE- 1st line for Tonic Clonic seizure (any seizure except absence!)
    • - Trigeminal neuralgia (DOC!)
    • - manic phase of Bipolar

    • SE-Induce Cyps (incrs its own metabolism-may req higher doses later)
    • -Exfoliative Dermatitis (Steven-Jphnson's syndrome) + incrs ADH secretion (dilutional hyponatremia!-SIADH)
    • -Osteomalacia + Megaloblastic anemia + Aplastic anemia
    • Teratogenic- clepft lip/palate, spina bifida
  39. Valproic acid
    • anticonvulsant
    • -block inactivated Na channels (like Phenytoin)
    • -block GABA tansaminase (block GABA breakdown)
    • -blocke T-type Ca-channel

    • USE- any seizures including Absence seizures!
    • -Mania of Bipolar, Migraines

    • INHIBIT Cyps (opposite of Phenytoin, Carbamazapine..)
    • SE-Hepatotoxicity, Thrombocytopenia
    • Pancreatitis , Alopecia (hair loss- opposite of Phenytoin), weight gain, tremor
    • Teratogenic- Spina bifida (Phenytoin-cleft lip/palate)
    • do NOT use in pregancy!
  40. Ethosuximide
    • anticonvulsant
    • -block T-type Ca channels in thalamus

    USE- Absence seizures! (DOC)

    • SE-GI distress, fatigue, headache, urticaria,
    • Stevens-Johnson Syndrome!
  41. Stevens-Johnson Syndome
    Prodrome of malaise + fever--> rapid onset red rash (oral, ocular, genital)

    rash progresses to epidermal necrosis and sloughing
  42. General features of anticonvulsant drugs
    • anticonvulsants are additive with other CNS depressants! -alcohol, opiates, antihistamines..
    • Avoid abrupt withdrawal-->ppt seizures
    • Decrs efficacy of OPCs (b/c most induce Cyps)-use Valproic acid that inhibits Cyps if on OPCs
    • Phenobarbital-safe during pregnancy
  43. Lamotrigine, Felbamate
    • anticonvulsant
    • block vol-Na channels AND glutamate receptors

    USE- adjunct to other seizure drugs

    • SE- Hepatotoxicity + aplastic anemia (Felbamate)
    • - Stevens-Johnson syndrome (Lamotrigine)
  44. Gabapentin
    • anticonvulsant
    • -GABA analog (enhance GABA effects)
    • -inhibit HVA Ca-channels

    • USE- Seizures, neuropathic pain (peripheral neuropathy)
    • -Bipolar


    SE- Sedation, ataxia
  45. Topiramate
    • anticonvulsant
    • -block Na channels
    • -enhance GABA

    USE- Partial seizures and Tonic Clonic

    SE- Sedation, Mental-dulling, Kidney stones, weight loss
  46. Phenobarbital (for seizure)
    • Barbituate, anticonvulsant
    • Prolong GABA activity

    • INDUCE Cyp450!! (incr Vmax!)
    • LONG ACTING

    USE- Seizures, safe in pregnancy!

    • SE- dependence, sedation, tolerance, Induce Cyps!!
    • DO NOT USE IN PORPHYRIAS!!
  47. Diazepam, Lorazepam
    • Benzodiazepines
    • Potentiate GABA (incrs frequency of open)

    • USE- DOC for Status Epilepticus!
    • -b/c IV
    • -seizures of eclampsia (1st line is MgSO4)
    • -Lorazepam has simpler kinetics (no active metabolite and long acting)

    SE- Sedation, tolerance, dependence (see Benzos)
  48. Tiagabine
    • anticonvulsant
    • -inhibit GABA reuptake

    USE- Partial seizures
  49. Vigabatrin
    • anticonvulsant
    • -irreversibly inhibit GABA transaminase-> incr GABA

    USE- Partial seizures
  50. Levetiracetam
    • anticonvulsant
    • -unknown mech

    USE- Partial seizure , Tonic clonic
  51. Inhaled anesthetic principle:
    1.CNS drugs must be:
    • Lipid soluble (cross BBB) or be Actively transported.
    • -inhaled anesthetics potency depends on Lipid solubility!
  52. MAC= minimum alveolar anesthetic concentration
    • MAC= amount req to anesthetize 50% patients
    • -measure of potency
    • -Drugs w/ LOW solubility in blood (less lipid soluble) = more protein bound, less free "gas' form= rapid induction, recovery (ex) N2O

    -Drugs with HIGH solubility in blood (more lipid soluble)= low MAC, high potency. Slower induction!

    • - more lipid soluble= lower MAC, greater potency
    • -MAC values are additive (why use combo)
    • -MAC lower in elderly! so use lower dose
    • -MAC lower in combo with opiates, sedative hypnotics.
  53. Blood:Gas Ratio
    • Blood:Gas
    • Blood= protein bound drug
    • Gas= free, active drug (goes to brain)

    higher blood solubility= slower anesthesia (b.c more protein bound)

    • Low B/G--> fast onset, fast recovery! (ex) N2O
    • High B/G --> slow onset, slow recovery! -likes to accumulate. (ex) Haloethane
  54. Organ & Mech of Action
    -Lungs: high rate + depth of ventilation= high gas tension

    -Blood: high solubility= high Blood/Gas partition coefficient= high solubility= More gas req to saturate blood= slower onset!

    -Tissue (ex. Brain): high AV concentration gradient= high solubility= high gas req to saturate tissue= slower onset!
  55. Nitrous Oxide N2O
    • inhaled anesthetic
    • -HIGH MAC (104%) = LOW potency
    • -LOW bood:gas ratio (low protein bound)
    • -LOW blood and lipid solubility
    • -fast induction and recovery
    • -NO metabolism. Just breath out

    USE- Great induction of anesthesia

    SE- Diffusional hypoxia (Henry's law: dec partial-P O2), spontaneous abortions, expansion of trapped gas
  56. Haloethane
    other "fluranes"- Desflurane, Sevoflurane, Enflurane, Isoflurane, Methoxyfurane
    • inhaled anesthetic
    • -LOW MAC (0.8%)= HiGH potency
    • -HIGH blood: gas ration (high protein bound)
    • -High lipid, blood solubility
    • -slow induction, slow recovery
    • -likes to build up! (slow metabolism)

    USE- anesthesia: heart depression, resp depression, nausea/emesis, incr cerebral blood flow (decrease cerebral metabolic demand)

    • SE- CV: sensitize heart to NE, EPI--> arrhythmias
    • Hepatotoxicity (additive!) Malignant hyperthermia
    • (see next cards)
  57. SE of Methoxyflurane
    • Nephrotoxicity
    • Malignant hyperthermia
  58. SE of Enflurane
    • Proconvulsant
    • Malignant hyperthermia
  59. Thiopental (as anesthetic)
    • Barbituate, IV-anesthetic
    • -highly lipid soluble, high potenty
    • -rapid entry to brain- rapid onset
    • -short acting due to redistribution!

    • USE- INDUCTION of anesthesia
    • -short surgery
    • -decrease cerebral blood flow
  60. Midazolam (as anesthetic)
    • BDZ, IV-anesthetic
    • Potentiate GABA
    • -Shortest Half life BDZ (mins)!!
    • so use only IV!

    • USE- preOP sedation, Adjunctive to Gaseous anesthetic & narcotics
    • -most commonly used drug for ENDOSCOPY
    • (b/c sedation + amnesia)

    • SE- severe post-op resp depression, additive CNS depression with alcohol
    • -RX overdose with Flumazenil!
  61. Propofol
    • IV anesthetic
    • -looks like milk!
    • -Potentiate GABAa
    • -CNS, Cardiac depressant
    • -rapid onset

    • USE- rapid induction + maintenance anesthesia
    • -short procedures
    • -antiemetic! less postop nausea than thiopental
  62. Fentanyl
    • IV- anesthetic, Opiate
    • depress respiratory function
    • -has central analgesic fuction! (different from anesthesia)

    • USE- Inuduction + maintenance of anesthesia
    • -used with other anesthetics dur general anesthesia

    SE- resp depression
  63. Ketamine
    • arylcyclohexylamine, IV-anesthetic
    • -PCP (phencyclinidine) analog "angel dust"
    • -block NMDA-receptor

    • USE- dissociative anesthetic
    • -Induction of anesthesia, esp used alot in Kids

    • SE- CV stimulation, delirium, hallucinations, disorientation, Nightmares, incerase ICP (increase cerebral blood flow)
    • DO NOT use in head trauma.
  64. Local anesthetics
    -structure
    -mechanism
    • Provide regional anesthesia
    • -are ALL weak bases (R-NH2--> R-NH3+)
    • MECH:
    • 1. unionized weak base diffuse into nerve terminal
    • (need alkaline pH to be unionized & lipid soluble)
    • 2. gets ionized by acidic environment inside the cell
    • 3. block inactivated Vol-Na channel (like Class Ib antiarrhythmic)

    NOTE: infected tissue is more acidic! so must use MORE anesthetic b/c they'll be ionized and less will get in the nerve terminals
  65. Local Anesthetic: 2 types
    • Esters: Cocaine, Procaine, Benzocaine, Tetracaine
    • -NO "i" before "-caine"
    • -metabolized by esterases in tissue, plasma
    • -must worry about slow vs fast metabolizers

    • Amides: Lidocaine, Bupivacaine, Mepivacaine
    • -"i" before "-caine"
    • -metabolized by liver amidases
    • -pt must have good liver function
  66. Local anesthetic: nerve fiber sensitivity
    • -smaller diameter & high firing rate fibers are more sensitive to local anesthetics!
    • (reach effective conc faster, more inactivated channels)
    • small diameter> larger diameter (size matters more)
    • myelinated> unmyelinated

    • B, C fibers> A-delta> A-beta, gamma> A-alpha
    • small myelinated> small unmyelinated> large myelinated> large unmyelinated

    • B= preganglionic autonomic
    • C= dull pain
    • A-delta= sharp pain
    • Pain> temp> touch> pressure (lose last)
  67. Local anestheics: SE?
    • Neurotoxicity (CNS excitation)
    • Cardiotoxicity (esp. Bupivacaine)
    • Arrhythmia (esp. cocaine)
    • Hypertension, Hypotension
    • Allergies with Ester anesthetics! (PABA-drugs)
    • -like Sulfonamide hypersensitivity, PABA-drugs cause skin allergies.
    • -use Amide locals if pt has PABA allergy!!!

    NOTE: Sulfonamides actually also have PABA structure! both Sulfa- and PABA- allergy!!
  68. Local anestheic: how do you prolong action & minimize systemic spread?
    • locals administerd with Alpha-agonists--> vasoconstrict
    • - decrease local anestheic spread into systemic
    • -prolong effects + decrease toxicity

    NOTE: do NOT need alpha-agonist adjuvant with Cocaine!- inhibit Na-channel + inhibit reuptake of NE--> indirect alpha-agonist--> vasoconstrict
  69. Tetrodotoxin ( TTX)
    • natural Vol-Na channel blocker
    • -in Puffer fish
    • -block activated channels--> block Na entry

    NOTE: "TTX-sensitive channel" = classic vol-Na channel!
  70. Saxitoxin
    • natural Vol-Na channel blocker
    • -in algae! "red-tide" in southern cali
    • -block activated channels--> block Na entry
    • -can aerosolize
  71. Skeletal muscle relaxants:
    -mechanism, types
    -use
    • neuromuscular blocking agents!
    • -block Nicotinic receptor (Nm- only SKM)
    • -Two Ach bind each to two alpha subunits to open Na channel--> depol
    • -2 types:
    • 1. Nondepolarizing: competative-
    • D-Tubocurarine, Atracurium, Mivacurium, Pancuronium, Vecuronium, Rocuronium
    • 2. Depolarizing: non-competative- Succinylcholine

    USE-anesthesia protocols, intubation
  72. Nondepolarizing muscle relaxants
    • Competative nicotinic blocker
    • -"-curium"
    • -prototype: D-Tubocurarine
    • -reversible with AchE inhibitors (Neostigmine)
    • -Progressive paralysis (face, limbs, resp muscle)
    • -NO CNS effects

    NOTE: b/c need 2 Ach binding to open the nicotinic channel, we only need ONE molecule of drug to prevent channel opening.
  73. D-Tubocurarine
    • -skeletal muscle relaxant
    • Prototype of nondepolarizing , competative nicotinic receptor blocker
    • -reversible with AchE inhibitors (Neostigmine)
    • -Progressive paralysis (face, limbs, resp muscle)
    • -NO CNS effects
  74. Atracurium
    • skeletal muscle relaxant
    • -depolarizing , competative nicotinic receptor blocker
    • -reversible with AchE inhibitors (Neostigmine)
    • -Progressive paralysis (face, limbs, resp muscle)
    • -NO CNS effects (SKM only)

    • -rapid recovery
    • -safe in liver or renal disease, b/c spontaneously breakdown to Laudanosine. (Hoffmann degredation)

    SE- Laudanosine can cause seizures!
  75. Mivacurium
    • skeletal muscle relaxant
    • -nondepolarizing , competative nicotinic receptor blocker
    • -reversible with AchE inhibitors (Neostigmine)
    • -Progressive paralysis (face, limbs, resp muscle)
    • -NO CNS effects (SKM only)

    • -very short duration
    • -metabolized by plasma cholinesterases

    SE- watch out for slow metabolizers!
  76. Pancuronium, Vecuronium, Rocuronium
    • skeletal muscle relaxants
    • -nondepolarizing , competative nicotinic receptor blocker
    • -reversible with AchE inhibitors (Neostigmine)
    • -Progressive paralysis (face, limbs, resp muscle)
    • -NO CNS effects (SKM only)
  77. Succinylcholine
    • Skeletal muscle relaxant
    • -Depolarizing, non-competative nicotinic receptor agonist!
    • -2 phases:
    • I: depol--> fasciculation-->prolonged depol--> flaccid paralysis
    • II: desensitization

    • -cannot reverse with AchE-inhibitors- actually worsen phase I, no effect on II.
    • -Short duration, hydrolzyed by pseudocholinesterases

    • SE-watch for slow metabolizers
    • -Hypercalcemia
    • -Hyperkalemia-->worsen depol
    • -Malignant hyperthermia (Rx w/ Dantrolene)
  78. Malignant hyperthermia
    life-threatening syndrome assoc w/ use of SKM relaxants, esp. Succinylcholine and inhalation anesthetics (except N2O)

    Succinylcholine-->depol muscle-->contract, need lot of ATP-->increase ETC, O2consumption, metabolic rate--> metabolic acidosis + heat!!--> trigger SNS to cool--> tachycardia, arrhythmia, hyperkalemia, HTN

    Genomic susceptability:
    mutation in Ryanodine receptor or L-type Ca channel in SKM--> abnormal high Ca storage--> massive response to Succinylcholine.

    Rx- Dantrolene
  79. Dantrolene
    antidote for Malignant Hyperthermia, Neuroleptic malignant syndrome

    -block Ca release from SER of SKM

    • USE- malignant hyperthermia (inhalant anesthetic, succinycholine toxicity)
    • -neuroleptic malignant syndrome (antipsychotic toxicity)
  80. Baclofen
    • centrally acting SKM relaxant
    • GABA-b agonist
    • GPCR--> K+ efflux (just like M2 in SA and AV node!)

    USE- Spasticity
  81. Endogenous opioids & receptors
    • 3 receptors: Mu, Kappa, Delta--> Gi--> open K+, close Ca channels--> decrease synaptic transmission
    • -decrease release of ACh, NE, 5-HT, Glutamate, Substance-P

    • 3 endogenous opioids:
    • -Endorphins -->mu
    • -Dynorphins--> kappa
    • -Enkephalins--> delta
  82. Opioids USES
    • Pain
    • Cough suppression (dextromethorphan)
    • Diarrhea (Loperamide, Diphenoxylate)
    • Acute pulm. edema
    • Maintenance programs (Methadone)

    SE- Addiction, Resp depression, constipation, miosis, additive CNS depression with other drugs
  83. Morphine
    • Opioid (central analgesic)
    • Prototype mu-agonist --> decr NE release

    • ACTIONS-analgesia (dissociative)
    • -CNS sedation
    • -Resp. sedation (block brain response to high CO2)-->pt breathes under hypoxic drive only
    • -NO effect on heart
    • -Histamine release--> vasodilate
    • -GI- relax longitudinal, constrict circular--> constipation, urinary retention, constrict all sphincters (biliary)--> GI/gallbladder spasm
    • -Miosis
    • -NOT mu-mediated: Suppress cough, Nausea/vomit (CTZ D2 receptors)

    KINETICS: glucuronidated to a more potent metabolite (Morphine6glucuronide), be careful with renal disease pts!!

    DO NOT give O2 to pts on Opioids unless they're on a ventilator!!! may stop breathing
  84. Contraindications for Opioid use
    • Head injuries (increase ICP)
    • Pulm disease (except Pulm edema)
    • Liver/Kidney disease (accumulate metaboite)
    • Adrenal/ Thyroid deficiencies (exaggerated response)
    • Pregnancy (neonatal depression/dependence)- except Meperidine
  85. Meperidine (Pethidine "demerol")
    • Opioid
    • Full-mu agonist
    • anti-muscarinic!

    • USE- central analgesic
    • -NO miosis, NO GI/gallbladder spasm

    • SE-tachycardia
    • -metabolized by Cyp450--> Normeperidine (SSRI) can cause Serotonin syndrome + seizures!
  86. Methadone
    • Opioid
    • Full mu-agonist
    • -slower kinetic, long half-life (1-3 days)

    • USE- maintenance of opioid addict
    • -slower, tapers off--> prevents opioid withdrawal.

    SE- takes long time to reach steady state (b/c long half-life)--> pt may overdose
  87. Codeine
    • Opioid
    • Full mu-agonist
    • morphine-like, but much much weaker!

    • USE- Cough suppressant, Analgesia
    • (used in combo w/ NSAIDS)

    SE-Addiction, Resp depression, constipation, miosis, additive CNS depression with other drugs
  88. Buprenorphine
    • Opioid
    • Partial mu-agonist

    USE- IV mild/moderate pain (safer)

    • SE- b/c partial agonist (blocker in presence of a full agonist), may ppt withdrawal on some already on a full opioid!!!
    • Addiction, Resp depression, constipation, miosis, additive CNS depression with other drugs
  89. Butorphanol
    • Opioid
    • Mixed- partial mu-agonist, kappa-agonist

    USE- analgesia (less resp. depression than full agonists), dysphoria

    SE- ppt withdrawal if pt is on full opioid!
  90. Tramadol
    • Very weak opioid agonist +inhibits 5-HT, NE reuptake!
    • -works on multiple NT "tram it all"in

    USE- chronic pain

    SE-Lower seizure threshold, Addiction, Resp depression, constipation, miosis, additive CNS depression with other drugs
  91. Nalbuphine
    • Opioid
    • Mixed agonist (kappa) + antagonist (mu)

    • USE- Kappa-> spinal analgesia (decr subP), dysphoria (NOT euphoria)
    • Mu block--> may ppt withdrawal!
  92. Pentazocine
    • Opioid
    • Mixed agonist (kappa) + antagonist (mu)

    • USE- Kappa-> spinal analgesia (decr subP), dysphoria (NOT euphoria)
    • Mu block--> may ppt withdrawal!
  93. Naloxone
    • Opioid receptor antagonist
    • IV only

    USE- IV reversal of opioid-induced respiratory depression
  94. Naltrexone
    • Opioid receptor antagonist
    • PO

    USE- decrease craving for Alcohol and Opioid addiction (nothing to do w/reversal!)
  95. Methylnaltrexone
    • Opioid receptor antagonist
    • -does NOT cross BBB

    USE- opioid-induced constipation! (often used in end-stage cancer pts on heavy opioid analgesics)
  96. Opioid toxicity triad, management
    • Acute opioid toxicity:
    • -Pinpoint pupils (except Meperidine)
    • -Resp depression
    • -Coma

    Rx- Supportive, give Naloxone (IV)
  97. Dependence and Tolerance to Opioids
    Dependence: Physical + Psychologic

    • Unique pharmacodynamic tolerance!
    • -NOT receptor downregulation/desensitization
    • -at level of Gi signal transduction-- increased cAMP cancels effects of Gi-> decr cAMP
    • -tolerance occurs to all effects except miosis, constipation.
  98. Opioid withdrawal
    • -Sympathetic surge! (upregulated alpha-1, beta-1 receptors due to decrease NE release with an opioid is now overstimulated)
    • -Reverse effects of Opioids

    • -Yawning
    • -lacrimate, salivate, rhinorrhea (from anxiety, agitation)
    • -Anxiety, sweating, goose bumps
    • -Diarrhea, incontinence
    • -muscle cramps, spasm, CNS-ongoing pain

    • Rx-Clonidine (alpha-2 agonist--> decr NE release)
    • -Methadone maintenance.
  99. Loperamide
    • Opioid related
    • OCT as Imodium

    USE- diarrhea
  100. Dextromethorphan
    • Opioid related
    • OTC
    • similar to Ketamine

    USE- cough suppressant

    SE- high abuse potential, high dose--> status epilepticus
  101. Dopaminergic pathways
    • Nigrostriatal path (D 2A-->Gi) - SN-->Striatum (DA inhibit GABA-ergic neruons)
    • -DA initiate movement
    • DA agonist--> diskinesia (hyperkinetic)
    • DA antagonist--> bradykinesia (extrapyramidal dysfunction)

    • Mesolimbic-mesocortical (D 2C--> Gi)
    • - midbrain-->cortex, limbic sys.
    • -affect, reward, cog fxn, sensory.
    • -increased in psychosis.
    • DA-agonist-->reward, high dose-->psychosis
    • DA-blocker-->decr cog fxn, Rx. psychosis

    • Tuberoinfundibular
    • -hypothalamus-->ant pituitary-->DA--> decr Prolactin, GH
    • -DA controls temp, cause anorexia (w/ NE)
    • DA-agonist--> Rx hyperprolactinemia
    • DA-antagonist-->gynecomastia, amennorrhea/galactorrhea, hyperthermia, weight gain

    • Chemoreceptor trigger zone
    • DA--> emesis
    • DA-agonist-->emetic (Apomorphine)
  102. DA receptors
    5 subtypes, divided into 2 families

    • D1--> Gs
    • D2--> Gi

    • D2A- nigrostriatal (movement)
    • D2C- mesolimbic (mood)

    Subtype specificity important! ex. Clozapine
  103. Parkinson's disease
    • 2% pop (70's)
    • oxidative damage to SN-->degeneration of DA-->imbalance, low DA, high Ach

    • -bradykinesia (dec DA)-shuffling gate
    • -Muscle rigidity (incr Ach, cogwheel rigidity)
    • -Resting tremor (incr Ach, NOT intention tremor as in cerebellar damage or alcoholics)

    • Direct/Excitatory pathway:
    • SN-->DA-->D1 (caudate/putamen)-->Gs-->stimulate excitatory pathway-->incr motion.
    • (loss of DA decrease excitatory pathway!)

    • Indirect/Inhibitory pathway:
    • SN-->DA-->D2 (caudate/putamen)-->Gi-->block GABAergic neuron-->inhibit inhibitory pathway-->incr motion
    • (loss of DA activates inhibitory pathway!)
  104. Levodopa/ Carbidopa
    • Levodopa- prodrug-->AAAD--> DA
    • -DA cannot cross BBB, Levodopa can.
    • -converted to DA by brain AAAD
    • -AAAD exists in both brain and CNS

    • Carbidopa irreversibly inhibits peripheral AAAD
    • -Carbidopa should NOT cross BBB (we need CNS AAAD!)
    • -noncompetative-->decr Vmax
    • -maximize amount of Levodopa to go into brain

    USE- Parkinson's disease

    • SE- Dyskinesia (DA there all the time), On-Off effects, Psychosis
    • -Hypotention (D1 on BV-->vasodilate). Arrythmia
    • -Vomit (D2 on CTZ)
    • -decrease prolactin
  105. Tolcapone, Entacapone
    • COMT inhibitor
    • -COMT in both periphery and CNS convert DA, Levodopa-->3-O-methyldopa (partial agonist of D receptors-->compete w/ DA!)
    • Entacapone (peripheral COMP)
    • Tolcapone(central)!!

    • USE-Parkinson's disease, adjunct to Levodopa
    • -inhibit COMT--> increase Levodopa, DA available.
    • -Tolcapone, Entacapone must cross BBB to inhibit all COMPT!

    SE- hepatotoxic
  106. Selegiline
    • Selevtive MAOb inhibitor
    • -MAOb breakdown DA (not NE, 5-HT) and Levodopa
    • -so NO tyramine interactions (NO HTN crisis!)
    • (MAOa inhibitors-->Tyramine worry)

    • USE- Parkinson's disease, Adjunct to Levodopa
    • -allow Levodopa, DA to last longer

    • SE- dyskinesia, psychosis
    • -metabolized to amphetamine!!! (hyper, insomnia, agitation)
  107. Bromocriptine (Pergolide)
    Full DA receptor agonist (ergot)

    • USE-hyperprolactinemia, acromegaly
    • (b/c DA--> inhibit Prolactin, GH release from ant. pituitary)
    • -NOT used in Parkinson's b/c too much SE

    SE- Dyskinesia, Psychosis
  108. Pramipexole
    • non-ergot DA receptor agonist
    • weaker than ergots
    • -also antioxidants!!!

    USE- Parkinson's disease
  109. Ropinirole
    • non-ergot DA receptor agonist
    • weaker than ergots
    • -also antioxidants!!!

    USE- Parkinson's disease
  110. Benztropine
    antimuscarinic

    • USE- Parkinson's disease, improves tremor, rigidity
    • NO effect on Bradykinesia (must incr DA)

    • SE-atropine-like! (dry, mydriasis, constipated, blurred vision, mad)
    • -do NOT use in glaucom, BPH!
    • -3C's of antimuscarinic toxicity: cardiotoxicity (torsades), Convulsions, Coma
  111. Trihexyphenidyl
    antimuscarinic

    • USE- Parkinson's disease, improves tremor, rigidity
    • NO effect on Bradykinesia (must incr DA)

    • SE-atropine-like! (dry, mydriasis, constipated, blurred vision, mad)
    • -do NOT use in glaucom, BPH!
    • -3C's of antimuscarinic toxicity: cardiotoxicity (torsades), Convulsions, Coma
  112. Diphenhydramine
    • antihistamine
    • (all antihistamines are strong antimuscarinics too!)

    USE- Parkinson's disease, IV to decrease tremor, rigidity (incr Ach effects)
  113. Amantadine
    • Antiviral
    • -also blocks M receptors, increase DA release, decrease DA reuptake!

    • USE- Parkinson's disease
    • -antiviral against Influenza A, Rubella

    SE- atropine-like, Livedo reticularis !! (pale skin rash,with purple dilated BVs)
  114. use what for essential, familial tremors?
    Propranolol
  115. Schizophrenia
    • + symptoms: due to stimulation (too much DA)
    • - symptoms: due to 5-HT
  116. Antipsychotics
    -mechanism
    -general uses
    • block DA and/or 5-HT2 receptors
    • atypicals- block both DA, 5-HT2 receptors

    D2- in mesolimbic sys--> decrease excess DA in psychosis (Gi)-->improve positive symptoms

    • 5-HT2 (presynaptic receptor in mesolimbic) like
    • alpha-2-->block-->decr neg feeback--> increase 5-HT in synapse--> improve negative symptoms

    USE- Schizophrenia, Schizoaffective, Bipolar, Tourette syndrome (Pimozide), Huntington's disease, anti-emetic!
  117. SE of DA blockade (typical Antipyschotics- neuroleptics)
    • highly lipid soluble, goes to fat, slow clearance
    • 1. Extrapyramidal symptoms (EPS, dyskinesia)
    • acute EPS- blocking DA in nigrostriatal
    • Hrs~days: pseudoparkinsonism, dystonia (ex. torticolis)
    • weeks: sensitization of D2 (incr affinity, lower Km)--> akathisia (compelling need to move!)
    • Rx- antimuscarinics (Benztropine, Diphenhydramine)

    • Chronic EPS: irreversible, chronic adaptation
    • months: D-receptors upregulate (incr #, Vmax)--> Tardive dyskinesia (Chorea, oral-facial, Hungtinton-like signs)-irreversible...
    • Rx- switch to atypical

    • 2. Dysphoria (decr DA)-worsen neg symptoms
    • 3. increase Prolactin (galactorrhea, gynecomastia, amenorrhea)
    • 4. eat more, weight gain
    • 5. neuroleptic malignant syndrome! (central thermostat screwed->hyperthermia) -Rx w/ Bromocriptine (D-agonist)
    • 6. histamine blockade, Sedation
    • 7. muscarinic blockade (3 Cs)
    • 8. alpha-blockade (hypotension)
    • - like Quinidine!
  118. Evolution of EPS
    4 hrs- acute dystonia (muscle spasm, stiffness, oculogyric crisis)

    4 days- akinesia, parkinsonian symptoms

    4 weeks- akathisia (restlessness- D2receptor sensitization)

    4 months- Tardive dyskinesia (D2 receptor upregulation)
  119. Neuroleptic malignant syndrome
    • Fever
    • Encephalopathy
    • Vials unstable
    • Elevated enzymes
    • Rigidity

    Rx- Dantrolene + Bromocriptine
  120. Typical antipsychotics
    • Phenothiazines..
    • Block D2 (Gi)--> increase cAMP in mesolimbic system

    • -treat positive symptoms of psychosis
    • -acute mania, tourette's syndrome

    must worry about EPS, high Muscarinic block, Alpha block, Sedation...
  121. Atypicals antipsychotics
    Block 5-HT2, DA, alpha, H1 receptors

    -treat both positive + negative symptoms

    • -fewer EPS and antimuscarinic effects that typicals
    • more weight gain?
  122. Chlorpromazine (Thorazine)
    • prototype traditional antipsychotic
    • -Block D2 (Gi)--> increase cAMP in mesolimbic
    • -low potency
    • -high M, alpha, Histamine blockade, sedation

    USE- + symptom psychosis

    SE- orthostatic hypotension, blue skin, photosenstivity, lower EPS, high M, Alpha, Histamine block! high sedation. corneal deposits
  123. Thioridazine (Mellaril)
    • traditional antipyschotic
    • -Block D2 (Gi)--> increase cAMP in mesolimbic
    • -low potency
    • -strongest M, alpha blockade of all!!
    • -most Quinidine like!
    • -LOW EPS! (b/c antimuscarinic, autotreat its EPS)

    USE- + symptom psychosis

    SE- high antimuscarinic effect (3C's- cardiotoxic, convulsion, coma), Retinal deposits (Retinitis pigmentosa)
  124. Loxapine (Loxitane)
    • Traditional antipsychotic
    • -block D2 (Gi)--> incr cAMP in mesolimbic
    • -mid potency
    • -metabolite is an antidepressant!

    USE- + symptom psychosis

    SE- higher risk for seizure
  125. Thiothixene (Navane)
    • traditional antipsychotic
    • -Block D2 (Gi)--> incr cAMP in mesolimbic
    • -mid potency

    USE- + symptom psychosis

    • SE- ocular pigment changes
    • EPS, anti-His, adr, musc effects
  126. Trifluoperazine (Stelazine)
    • traditional antipsychotic
    • mid potency

    USE- +symptom psychosis, anxiety

    SE- EPS, anti-His,Adr, Musc effects
  127. Perphenazine (Trilafon)
    • traditional antipsychotic
    • -Block D2 (Gi)-->incr cAMP in mesolimbic
    • -mid potency

    USE- +symptom psychosis

    SE- EPS, anti-His, Adr, Musc effects
  128. Fluphenazine (Prolixin)
    • traditional antipyschotic
    • -Block D2 (Gi)--> increase cAMP in mesolimbic
    • -high potency
    • -HIGH EPS!! (b/c vey potent D2 blocker)

    • USE-+ symptom psychosis
    • (has parenteral formulations)

    SE- HIGH EPS! less M, Alpha, His block, sedation than Chlorpromazine, Thioridazine
  129. Haloperidol (Haldol)
    • traditional antipyschotic
    • -Block D2 (Gi)--> increase cAMP in mesolimbic
    • -high potency
    • -HIGH EPS!! (b/c very potent D2 blocker)
    • -MOST likely to cause TD and neuroleptic malignant syndrome

    • USE- + symptom psychosis
    • (has parenteral formulations)

    SE- HIGHest EPS! less M, Alpha, His block, sedation than Chlorpromazine, Thioridazine
  130. Pimozide (Orap)
    • traditional antipsychotic
    • high potency

    USE- + symptom psychosis

    SE- high EPS, less seation,hypotension, anticholinergic effects, heart block, v-tach!
  131. Clozapine
    • Prototype Atypical antipsychotic
    • UNIQUE:
    • -block D2C (NOT D2A- in nigrostrital)- NO EPS!
    • -block D-HT2 (presynaptic)-->incr 5-HT

    USE-both + and - schizophrenia

    • SE- NO EPS!!
    • - Agranulocytosis! (hypersensitivity against WBCs, do weekly WBC count)
    • -salivation! (from 5-HT) 'wet pillow syndrome'
    • -weigh gain, seizures
  132. Olanzapine
    • Atypical antipsychotic
    • -block D-HT2 (presynaptic)-->incr 5-HT

    • USE- both + and - schizophrenia
    • -OCD, anxiety disorder, depression, mania, Tourettes'

    SE- weight gain!! less EPS, M, alpha, histamine block than traditionals.
  133. Risperidone
    • Atypical antipsychotic
    • -block D-HT2 (presynaptic)-->incr 5-HT

    USE- both + and - schizophrenia

    SE- less EPS, M, alpha, histamine block than traditionals.
  134. Aripiprazole
    • Atypical antipsychotic
    • -partial agonits of D2 (won't be as potent for + signs)
    • -block 5-HT2 (presynaptic)-->incr 5-HT
    • -LEAST weigh gain!

    USE- both + and - schizophrenia

    SE- less EPS, M, alpha, histamine block than traditionals. LEAST weight gain!!
  135. Quetiapine
    • Atypical antipsychotic
    • -block 5-HT2 (presynaptic)-->incr 5-HT

    USE- both + and - schizophrenia (good for young pts?)

    SE- less EPS, M, alpha, histamine block than traditionals.
  136. Ziprasidone
    • Atypical antipsychotic
    • -block 5-HT2 (presynaptic)-->incr 5-HT

    USE- both + and - schizophrenia

    SE- less EPS, M, alpha, histamine block than traditionals.
  137. Memantine
    • alzheimer's drug
    • NMDA-blocker
    • -decrease excitotoxicity (med by Ca)

    USE- Alzheimer's disease

    SE-dizziness, confusion, hallucinations
  138. Donepezil
    AchE-inhibitor

    USE- alzheimer's disease

    SE- nausea, dizziness, insomnia
  139. Galantamine
    AchE-inhibitor

    USE- alzheimer's disease

    SE- nausea, dizziness, insomnia
  140. Rivastigmine
    AchE-inhibitor

    USE- alzheimer's disease

    SE- nausea, dizziness, insomnia
  141. Treating Huntington's disease
    disease- high DA, low GABA + Ach

    Rx- Reserpine + tetrabenzine (deplete amine)

    Haloperidol- DA-blocker
  142. Sumatriptan
    • 5-HT1B/1D- agonist
    • -vasoconstrict
    • -inhibit trigeminal activation + vasoactive peptide release
    • -short half life

    USE- acute migraine, cluster headache attacks

    • SE- coronary vasospasm, fatigue, chest pain, mild tingling
    • do NOT use in CAD or Prinzmetal angina!!
  143. Lithium
    • mood stabilizer
    • -unknown mech (inhibit PIP cascade?)
    • -also block ADH receptor
    • -narrow T.I
    • - req close monitoring of serum levels
    • -almost exclusive excretion by kidney
    • -most reabsorbed at PCT like Na!
    • -TZD (not loops), ACE inhibitors, NSAIDs, volume depleteion (cirhhosis, heart failure)->reabsorb more Lithium at PCT-->toxicity!

    • USE- mood stabilizer for bipolar
    • -block relapse and acute manic events
    • -SIADH

    • SE- tremor, sedation, edema, heart block, ataxia, chorea!
    • -hypothyroidism, polyuria
    • -ADH antagonist--> nephrogenic DI!!
    • -teratogenesis! fetal cardia defects- Ebstein anomaly, malform great vessels
  144. Withdrawal from antidepressants
    • dizziness
    • headaches
    • nausea
    • insomnia
    • malaise
  145. Acute mechanism of antidepressant
    -based on "amine hypothesis'
    Increase NE and 5-HT

    • but, it takes several weeks to take effect!!
    • (changes in gene expression)
  146. Phenelzine, Tranylcypromine, isocarboxazid
    • MAO-inhibitors (nonselective)
    • block MAOa-->incr NE, 5-HT
    • block MAOb-->incr DA

    USE- atypical depression (refractory to SSRI), anxiety, hypochondriasis

    • SE- drug interactions!
    • NE-> Hypertensive crisis (HTN, arrhythmia, hyperthermia)
    • -w/ Tyramine (releaser), TCA (block NE reuptake), amphetamines, ephedrine (releasers), alpha1-agonist (vasoconstrict), Levodopa (alpha)

    • 5-HT--> serotonin syndrome
    • (sweating, rigidity, myoclonus, hyperthermia, seizures)
    • -w/ SSRIs, TCAs, Dextromethorphan, St. John's wart (SSRI effect), Meperidine (opiate+antimuscarinic, but metabolite is SSRI-Normeperidine)
  147. Amitriptyline (Elavil)
    • TCA
    • -nonspecific blocker of 5-HT and NE reuptake

    • USE- major depression (old)
    • -neuropathic pain! (Trigeminal, shingles)
    • -migrainesm, insomnia

    • SE-sedation
    • muscarinic and alpha blockade! (more than nortriptyline)
    • 3C's- coma, convulsions, cardiotoxicity
    • confusion, hallucination
    • -Hypertensive crisis w/ MAO-inhibitors
    • -Serotonin syndrome w/ SSRIs, Meperidine, MAO inhibitors, Dextromethorphan, St. John's wort
    • -cancel anti-HTN drugs Alpha2-agonists and Guanethidine
  148. Imipramine (tofranil)
    • TCA
    • -nonspecific blocker of 5-HT and NE reuptake

    • USE- major depression (old)
    • -Enuresis! (decrease phase4 sleep before REM when kids wet bed)
    • -Panic DO

    • SE-sedation
    • muscarinic and alpha blockade!
    • 3C's- coma, convulsions, cardiotoxicity
    • confusion, hallucination
    • -Hypertensive crisis w/ MAO-inhibitors
    • -Serotonin syndrome w/ SSRIs, Meperidine, MAO inhibitors, Dextromethorphan, St. John's wort
    • -cancel anti-HTN drugs Alpha2-agonists and Guanethidine
  149. Clomipramine (Anafranil)
    • TCA
    • -nonspecific blocker of 5-HT and NE reuptake
    • -most serotonin specific!

    • USE- major depression (old)
    • -OCD !

    • SE-sedation
    • muscarinic and alpha blockade!
    • 3C's- coma, convulsions, cardiotoxicity
    • confusion, hallucination
    • -Hypertensive crisis w/ MAO-inhibitors
    • -Serotonin syndrome w/ SSRIs, Meperidine, MAO inhibitors, Dextromethorphan, St. John's wort
    • -cancel anti-HTN drugs Alpha2-agonists and Guanethidine
  150. Doxepin (Sinequan)
    TCA (tertiary amine)

    USE- chronic pain, sleep aid (low dose)
  151. Nortriptyline (Pamelor, Aventyl)
    • TCA
    • -nonspecific blocker of 5-HT and NE reuptake
    • -no muscarinic blockade!
    • -least likely to cause ortho hypotension

    • USE- major depression (old)
    • -good for elderly b/c no anticholinergic effects
    • -chronic pain!

    • SE-sedation
    • alpha blockade! (more than nortriptyline)
    • -Hypertensive crisis w/ MAO-inhibitors
    • -Serotonin syndrome w/ SSRIs, Meperidine, MAO inhibitors, Dextromethorphan, St. John's wort
    • -cancel anti-HTN drugs Alpha2-agonists and Guanethidine
  152. Desipramine (Norpramin)
    • TCA
    • -nonspecific blocker of 5-HT and NE reuptake
    • -least sedation, but lowest seizure threshold!
    • -least anticholinergic!

    USE- major depression (old)

    • SE-muscarinic and alpha blockade!
    • 3C's- coma, convulsions, cardiotoxicity (lowest seizure threshold!)
    • confusion, hallucination
    • -Hypertensive crisis w/ MAO-inhibitors
    • -Serotonin syndrome w/ SSRIs, Meperidine, MAO inhibitors, Dextromethorphan, St. John's wort
    • -cancel anti-HTN drugs Alpha2-agonists and Guanethidine
  153. Doxepin, amoxapine
    • TCA
    • -nonspecific blocker of 5-HT and NE reuptake

    USE- major depression (old)

    • SE-sedation
    • muscarinic and alpha blockade!
    • 3C's- coma, convulsions, cardiotoxicity
    • confusion, hallucination
    • -Hypertensive crisis w/ MAO-inhibitors
    • -Serotonin syndrome w/ SSRIs, Meperidine, MAO inhibitors, Dextromethorphan, St. John's wort
    • -cancel anti-HTN drugs Alpha2-agonists and Guanethidine
  154. TCA SE
    • highly protein bound, lipid soluble
    • -antihistamine- sedation, wt gain
    • -antiadrenergic- hypotension, reflex tachy, arrhythmias, widening QRS, QT, PR, dizzy
    • -antimuscarinic- dry mouth, constipation, urinary retention, blurred vision, tachy, exacerbate narrow-angle glaucoma

    Overdose: agitation, tremor, ataxia, delirum, hyperreflexia, seizures, coma, seizures, myoclonus
  155. TCA toxicity
    • 3 C's
    • Convulsions
    • Coma
    • Cardiotoxicity (torsades)

    • resp depression
    • hyperpyrexia
    • confusion + hallucinations from anticholinergic (use nortriptyline)

    Rx- NaHCO3 (for cardiotoxicity)
  156. Fluoxetine (prozac)
    • SSRI
    • -selective 5-HT reuptake inhibitor
    • -less toxic than TCAs!
    • -longest half-life w/active metabolites; no need to taper
    • -safe in pregnancy, approved for kids

    • USE- major depression (1st line), OCD
    • Bulimia, Anxiety disorder
    • PMS (takes few weeks to work)

    • SE- anxiety, agitation initially! (give with Alprazolam initially)
    • -can elevated levels of neuroleptics-->incr SE
    • -Bruxism (teeth grinding), sexual dysfunction (anorgasmia), weight loss
    • -Serotonin syndrome (w/ MAO inhibitors, Meperidine, TCAs)
  157. Paroxetine (Paxil)
    • SSRI
    • -selective 5-HT reuptake inhibitor
    • -less toxic than TCAs!
    • -high protein bound!
    • -shoter half-life-->withdrawal if not taken consistently

    • USE- major depression (1st line),OCD
    • Bulimia, Anxiety disorder
    • PMS (takes few weeks to work)

    • SE-more anticholinergic SE (sedation, constipation, wt gain)
    • -anxiety, agitation initially! (give with Alprazolam initially)
    • -Bruxism (teeth grinding), sexual dysfunction (anorgasmia), weight loss
    • -Serotonin syndrome (w/ MAO inhibitors, Meperidine, TCAs)
  158. Sertraline (Zoloft)
    • SSRI
    • -selective 5-HT reuptake inhibitor
    • -less toxic than TCAs!
    • -highest risk for GI SE!!
    • -more common sleep changes

    • USE- major depression (1st line), OCD
    • Bulimia, Anxiety disorder
    • PMS (takes few weeks to work)

    • SE- anxiety, agitation initially! (give with Alprazolam initially)
    • -Bruxism (teeth grinding), sexual dysfunction (anorgasmia), weight loss
    • -Serotonin syndrome (w/ MAO inhibitors, Meperidine, TCAs)
  159. Citalopram (Celexa)
    • SSRI
    • -selective 5-HT reuptake inhibitor
    • -fewest drug interactions
    • -fewer sexual SE?

    • USE- major depression (1st line), OCD
    • Bulimia, Anxiety disorder
    • PMS (takes few weeks to work)

    • SE- anxiety, agitation initially! (give with Alprazolam initially)
    • -Bruxism (teeth grinding), sexual dysfunction (anorgasmia), weight loss
    • -Serotonin syndrome (w/ MAO inhibitors, Meperidine, TCAs)
  160. Escitalopram (Lexapro)
    • -SSRI
    • -levo-enantiomer of citalopram (similar efficacy, possibly fewer SE)
    • -more expensive than citalopram
  161. SE of SSRIs
    • -fewer SE than TCAs and MAOIs b/c serotonin selective
    • -much safer in overdose
    • -SEs mostly resolve within few weeks

    • -GI: nausea, diarrhea (food helps)
    • -Sexual dysfunction (25-30%, usu doesn't resolve)
    • -Insomnia, vivid dreams
    • -headaches
    • -anorexia, weight loss
    • -restlessness (akathisia-like state)
    • -seizures (0.2%)
    • -can increase levels of Warfarin (monitor when starting/stopping)
  162. Serotonin syndrome
    • hyperthermia
    • tremor, myoclonic jerks ,hyperreflexia
    • hypertonicity, rhabdomyolysis
    • CV collapse, tachycardia
    • flushing, diarrhea
    • delirium
    • seizures
    • renal failure--> death

    RX- Cyproheptadine (5-HT2 receptor blocker)
  163. Venlafaxine (Effexor)
    • SNRI
    • -nonselective reuptake blocker of NE, 5-HT
    • -less autonomic SE! (NO antimuscarinic, alpha-1 blockade)
    • -has XR form

    USE- depression, generalized anxiety disorder

    • SE-HTN, sedation, nausea, stimulant effects
    • do NOT use in BP-labile pts!!
  164. Duloxetine (Cymbalta)
    • SNRI
    • -nonselective reuptake blocker of NE, 5-HT
    • -expensive!

    USE- Depression + neuropathic pain/ fibromyalgia

    • SE- more dry mouth, constipation!
    • HTN, sedation, nausea, stimulant effects
    • more liver SE!
  165. Bupropion (Wellbutrin)
    • atypical antidepressant
    • - NE, DA-reuptake blocker

    • USE- atypical antidepressant
    • - Smoking cessation, adult ADHD

    • SE- no sexual SE!!
    • stimulant effects (tachycardia, insomnia)
    • -seizures!
    • -psychosis (at high doses)
    • do NOT give to pt w/seizure, eating DO, taking MAOI
  166. Mirtazapine (Remeron)
    • atypical antidepressant
    • -alpha-2 blocker
    • potent 5-HT2, 5-HT3 agonist!
    • increase NE

    • USE- atypical antidepressant, refractory major depression
    • -good for anorexic pts! (cause weigh gain)

    • SE- sedation, increase appetite, weight gain, dry mouth,constipation
    • rarely agranulocytosis
    • (unusual b/c SSRIs cause weight loss..)
  167. Maprotiline (Ludiomil)
    • tetracyclic antidepressant
    • NE-reuptake inhibitor

    USE- atypical antidepressant

    • SE- seizure, arrhythmia, sedation, orthostatic hypotension
    • fatal in overdose!
  168. Amoxapine (Asendin)
    • tetracyclic antidepressant
    • -metabolite of antipsychotic loxapine

    SE- EPS, similar SE as typical antipsychotics.
  169. Trazodone (Desyrel)
    Nefazodone (Serzone)
    • atypical antidepressant
    • 5-HT receptor agonist
    • -has strong alpha-1 blockade (vasodilate)
    • USE- insomnia, refractory depression
    • -high doses req for antidepressant effects

    SE- arrhythmia, priapism (bc vasodilate), hypotension, sedation!
  170. Methylphenidate
    Dextroamphetamine
    • -increase catecholamines in synaptic cleft
    • -increase esp NE, DA

    USE- ADHD, narcolepsy, appetite control
  171. what class of drug is PCP, LSD, Marijuana?
    Hallucinogens
  172. PCP
    hallucinogen

    • effects
    • - Belligerence, impulsiveness, psychomotor agitation
    • -fever
    • -vertical, horizontal nystagmus
    • -tachycardia
    • -homicidality, psychosis, delirium
    • -depression, anxiety, restlessness, anergia
    • -disturbed sleep
  173. LSD
    hallucinogen

    • effecs:
    • -makred anxiety or depression
    • -delusions
    • -visual hallucinations
    • -flashbacks
    • -mydriasis
  174. Marijuana
    Hallucinogen

    • effects:
    • -Euphoria
    • -anxiety, paranoid delusions
    • -perception of slowed time
    • -impaired judgement
    • -social withdrawl
    • -increased appetite, dry mouth
    • -hallucinations

    • longterm effects:
    • -irritability, depression, insomnia, nausea
    • -anorexia
    • -most sympootms peak in 48 hrs, last upto 5~7 days

    -can be detected in urine upto 1 month after last use
  175. Heroin addiction
    • users at risk for hepatitis, abseceses, overdose
    • hemorroids, AIDS, R-side endocarditis
    • (look for track marks)

    • Methadone - long acting oral opiate
    • - used for heroin detox or long-term maintenance

    • Suboxone- Naloxone + Buprenorphine (partial agonist)
    • -long acting w/ fewer withdrawl symptoms than methadone.
    • -Naloxone NOT ative when taken orally, so withdrawal symptoms only if injected (less abuse potential)
  176. Alcoholism
    physiologic tolerance, dependence w/ symptoms of withdrawal if stopped

    Withdrawal: tremor, tachycardia, HTN, malaise, nausea, DTs

    Complications- Alcoholic cirrhosis, hepatitis, pancreatitis, peripheral neuropathy, testicular atrophy
  177. Wernicke- Korsakoff syndrome
    Wernicke- confusion, opthalmoplegia, ataxia

    Korsakoff- irreversible memory loss, confabulation, personlaity change (psychosis)

    • -caused by Thimine deficiency
    • -assoc w/ periventricular hemorrhage/ necrosis of Mammillary bodies

    • Rx- IV vit B1 (thiamine)
    • -give thiamine w/ glucose when giving glucose!!
  178. Delirium Tremens (DTs)
    • life-threatening alcohol withdrawal syndrome
    • -peak 3-5 days after last drink

    • symptoms in order of appearance:
    • -autonomic systemic hyperacticity
    • (tachycardia, tremors, anxiety, seizures)
    • -psychotic symptoms (hallucinations, delusion)
    • -confusion

    RX- benzodiazepines!
  179. How do you treat alcohol withdrawal?
    Benzodiazepines
  180. How do you treat Anorexia/ Bulimia?
    -SSRIs
  181. How do you treat Anxiety?
    • Benzodiazepines
    • Buspirone
    • SSRIs
  182. How do you treat ADHD?
    • Methylphenidate (Ritalin)
    • Amphetamine (Dexedrine)
  183. How do you treat atypical depression?
    • MAO inhibitors
    • SSRIs
  184. How do you treat Bipolar disorder?
    • Mood stabilizers:
    • Lithium
    • Valproic acid
    • Carbamazepine

    Atypical antipsychotics
  185. How do you treat Depression?
    • SSRIs
    • SNRIs
    • TCAs
  186. How do you treat depression with insomnia?
    Mirtazapine
  187. How do you treat Obsessive- compulsive disorder?
    • SSRIs
    • Clomipramine
  188. How do you treat Panic disorder?
    • SSRIs
    • TCAs
    • Benzodiazepines
  189. How do you treat PTSD?
    SSRIs
  190. How do you treat Schizophrenia?
    Antipsychotics
  191. How do you treat Tourette's syndrome?
    Antisychotics (haloperidol)
  192. How do you treat Social phobias?
    SSRIs
  193. Depressants
    Intoxication vs Withdrawal
    overdose: mood elevation, decreased anxiety, sedation, behavioral disinhibition, resp depression

    withdrawal: anxiety, tremor, seizures, insomnia
  194. Alcohol
    overdose vs withdrawal
    • overdose: emotional lability, slurred speech, ataxia, coma, blackouts. GGT, AST> ALT
    • Rx- Naltrexone

    • withdrawal: anxiety, tremor, seizures, insomnia, delirium tremens
    • Rx- BDZ
  195. Opiods
    overdose vs withdrawal
    • overdose: CNS depression, nausea, vomiting, constipation, miosis, seizures (overdose lifethreatening)
    • Rx- Naloxone, Naltrexone

    withdrawal: sweating, mydriasis, piloerection, fever, rhinorrhea, nausea, stomach cramps, diarrhea (flu-like) Rx- Methadone, Naltrexone, Buprenorphene
  196. Barbituates
    Overdose vs withdrawal
    • overdose: low safety margin. Marked respiratory depression
    • Rx- assist resp, pressors

    withdrawal: delirium, life-threatening CV collapse!
  197. Benzodiazepines
    overdose vs withdrawal
    • Overdose: greater safety margin. Ataxia, minor resp depression
    • Rx- Flumazenil
  198. Stimulants
    overdose vs withdrawal
    overdose: mood elevation, psychomotor agitation, insomnia, cardia arrhythmias, tachycardia, anxiety

    withdrawal: post-use crash- depression, lethargy, weight gain, headache
  199. Amphetamine
    overdose vs withdrawal
    overdose: impaired judgement, mydriasis, prolonged wakefulness, attention, delusions, hallucinations, fever

    withdrawal: stomach cramps, hunger, hypersomlemnence
  200. Cocaine
    overdose vs withdrawal
    • overdose: impaired judgement, mydriasis, hallucinations, paranoia, angina, sudden cardiac death
    • Rx- BDZ

    withdrawal: suicidality, hypersomnolence, malaise, severe craving
  201. Caffeine
    overdose
    overdose: restlessness, increase diuresis, muscle twitch
  202. Nicotine
    overdose
    overdose: restlessness

    • withdrawal: irritability, anxiety, craving
    • Rx- nicotine patch, gum, lozenges, bupropion, varenicline

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