CNS Pharm

  1. Sedatives/Hypnotics: what are the three drug classes involved?
    • Benzodiazepines (BZ)
    • Barbiturates
    • Alcohols
  2. Sedatives/Hypnotics: General Info
    • Dose dependent CNS depression that extends from sedation to anesthesia, respiratory depression and death
    • BZ reach a plateau in CNS depression, while barbiturates and alcohols do not (making BZ safer at higher doses)
  3. Sedatives/Hypnotics: Mechanism
    • 2 complexes:
    • 1. GABAa: Cl influx, most sedatives
    • 2. GABAb: K influx
    • Activation results in membrane hyperpolarization (inhibition)
  4. Sedatives/Hypnotics: Benzodiazepines - General Info
    • BENzodiazepines: are short duration = male-like sexual response
    • -lam, -pam drugs
    • Potentiate GABA
    • GABA must be present for BZ to function
    • Increases the frequency of opening the Cl- channels, decrease REM sleep
    • No GABA mimetic activity
    • long half lives & active metabolites
    • Act through BZ receptors that are a part of the GABAa complex
    • BZ1 receptors mediate sedation
    • BZ2 receptors mediate antianxiety, impairment of cognitive function
    • Acute anxiety
  5. Sedatives/Hynpotics: Benzodiazepines
    Clinical use:
    Anxiety, spacticity, status (lorazepam/dizpema), detoxification (especailly ETOCH w/drawal), night terrors, sleepwalking, general anesthetic (amnesia, muscle relaxation), hypnotic (insomnia)
  6. Sedatives/Hypnotics: Benzodiazepines Toxicity
    • Dependence, additive CNS depression w/ ETOH, less respiratory depression and coma than barbidurates
    • OD tx: flumazenil
  7. Sedatives/Hypnotics: Benzodiazepines
    Short acting ones:
    • TOM Thumb
    • T= Triazolam
    • O = Oxazepam
    • M = Midazolam highest addictive potential
  8. Sedatives/Hypnotics: Benzodiazepine: Alprazolam
    • Indication: anxiety, panic, phobias
    • commonly prescribed
  9. Sedatives/Hypnotics: Benzodiazepine: Diazepam
    • Indication: anxiety, preop sedation, muscle relaxation, withdrawal states
    • Longest lasting
  10. Sedatives/Hypnotics: Benzodiazepine: Lorazepam
    • Indications: anxiety, preop sedation, status epilepticus (IV)
    • No active metabolites
    • Metabolism: extrahepatic congugation, thus safe in elderly and liver damage
    • Best choice of drug
  11. Sedatives/Hynpotics: Benzodiazepine: Midazolam (Versed)
    • Indications: preop sedation, anesthesia IV
    • Shortest acting
  12. Sedatives/Hypnotics: Benzodiazepine: Temazepam
    • Indications: sleep disorders
    • no active metabolites
    • Metabolism: extrahepatic congugation, thus sfae in elderly and liver damage
  13. Sedative/Hypnotics: Benzodiazepine: Oxazepam
    • Indications: sleep disorders, anxiety
    • no active metabolites
  14. Sedatives/Hypnotics: Benzodiazepine: Flunitrazepam
    • Indications: date rape drug, colonoscopy
    • causes anterograde amnesia (cant remember after administration)
  15. Sedatives/Hypnotics: Benzodiazepines that help with sleep
    • Temazepam
    • Oxaxepam

    Take a Time Out for sleep
  16. Sedatives/Hypnotics: Benzodiazepines that are good for the elderly/liver dysfunction patients:
    • Oxazepam
    • Temazepam
    • Lorazepam

    • Outside The Liver
    • extrahepatic conguation and no active metabolites
  17. Sedatives/Hypnotics: Withdrawal signs of BZ
    • rebound insomnia
    • anziety
    • seizures (when BZ are used as an antiepileptic or @ high doses)
  18. Sedatives/Hypnotics: Antidote for BZ overdose:
    • Drug: Flumazenil
    • Mechanism: nonspecific BZ receptor antagonist
    • used to reverse CNS depression caused by BZ in overdose or anesthesia settings
    • Limitation: cannot reverse the CNS depression caused by barbiturates and alcohols ONLY BZ!
  19. Sedatives/Hypnotics: Barbiturates: General Info
    • BARBiturates = longer duration = female-like sexual response
    • -tal drugs
    • Prolong GABA activity
    • increase duration of the Cl channel opening
    • Have GABA mimetic activity at high doses
    • do not act through BZ receptors
    • have their own binding sites on the GABAa complex
    • Also inhibit complex I of the electron transport chain
  20. Sedatives/Hypnotics: Barbiturates
    • Drugs: Phenobarbital (for seizures), Thiopental (induction of anesthesia)
    • Pharmacokinetics: liver metabolized, sometimes to active metabolites
    • Mechanism: general inducers of CYP-450 enzymes, increases Cl- channel opening in GABAa = less neuron firing
    • contraindicated in porphyrias
    • Drug interactions: induce metabolism of most lipid-soluble drugs (OCP, carbamazapine, phenytoin, warfarin, etc.)
    • Toxicity: dependence, additive CNS depressive effects with ETOH, respiratory or CV depression, death,
    • OD tx: symptom management (assist in respiration, and increase BP)
  21. Sedative/Hypnotics: Withdrawal signs of Barbiturates & ETOH
    • Anxiety
    • Agitation
    • life-threatening seizures (delirium tremens w/ ETOH)
    • Management: supportive and long acting BZ
    • (funny how you would use a BZ for ETOH and barbiturate withdrawal)
  22. Sedatives/Hypnotics: Tolerance to & Dependence
    • Chronic use = tolerance
    • Cross-tolerance btw BZ, barbiturates, ethanol
    • psycholog & physical dependence
    • Abuse liability BZ < barbiturates or ETOH
  23. Sedatives/Hypnotics: Drug interactions
    • GABAa drugs are:
    • Additive with other CNS depressants (respiratory depression) - like anesthetics, antihistamines, opiates, B-blockers
    • Barbiturates: induce metabolism of most lipid-sol drugs (OCP, carbamazepine, phenytoin, warfarin, etc.)
  24. Sedatives/Hypnotics: Non-BZ Drugs
    • Drugs: Zolpidem, Zaleplon, Ramelteon
    • Mechanism: BZ1 receptor agonist (Z drugs), melatonin receptor agonist (Rmaelteon)
    • Antidote to OD: flumazenil
    • Clinical Use: sleep disorders
    • less tolerance and abuse liability

    Z-drugs to catch some zzzzz's
  25. Sedatives/Hypnotics: Non-BZ Drugs
    • Drug: Busprione
    • No effect on GABA **
    • Mechanism: 5-HT1a partial agonist **
    • Clinical use: generalized anxiety disorders, chronic anxiety
    • non sedative effects (no CNS GABA effect)
    • Takes 1 - 2 weeks for effects
  26. Sedatives/Hypnotics: Drugs used for sleep disorders are:
    • BZ
    • Z-drugs
    • Ramelteon
  27. Sedatives/Hypnotics: Drugs used for anxiety are:
    • BZ (acute)
    • Busprione (chronic)
    • SSRI (chronic)
  28. Sedatives/Hypnotics: Alcohols: General
    all alcohols cause CNS depression, partially thru GABA mimetic activity, and metabolic acidosis
  29. Sedatives/Hypnotics: Alcohols: Ethylene Glycol
    metabolized by alcohol DH into glycoaldehyde whcih causes:

    • 1. CNS depression
    • 2. severe metabolic acidosis
    • 3. nephrotoxicity
  30. Sedatives/Hypnotics: Alcohols: Methanol
    metabolized by alcohol DH into formaldehyde which causes:

    • 1. respiratory failure
    • 2. severe anionic gap metabolic acidosis
    • 3. ocular damage (blurry/snowy vision)

    OD tx: Fomepizole: long acting inhibitor of alcohol DH, but may require hemodyalsis at high alcohol levels
  31. Sedatives/Hypnotics: Alcohols: Ethanol
    • Ethanol side effects:
    • 1. CNS depression
    • 2. metabolic acidosis (ketones)
    • 3. acetaldehyde toxicity

    • Acetaldehyde effects:
    • think hangover
    • n/v, headache, hypotension
    • combines with: folate to inactivate it
    • combines with: thiamine to decrease availability

    • Acetaldehyde DH (in mito)
    • Inhibited by disulfiram
    • tx used for alcoholics
  32. Drugs that cause disulfiram-like effects:
    • Metranidazole
    • Cefoperazone
    • Cefotetan
    • Chloropropamide
    • Grisefulvin
  33. Treatments: Mechanism of Action:
    • 1. decrease axonal conduction by preventing Na influx thru fast Na channels: carbamazepine, phenytoin
    • 2. increase inhibitory tone by facilitation of GABA-mediated hyperpolarization: barbiturates, benzodiazepines
    • 3. decrease excitatory effects of glutamic acid: lamotrigine, topiramate (blocks AMPA receptors); felbamate (blocks NMDA receptors)
    • 4. Decreases presynaptic Ca influsx thru type T channels in Thalamic neurons: ethosuximide & valproic acid
  34. Anticonvulsants and Seizure States:
    • Partial (simple/complex): valproic acid, phenytoin, carbamazapine, lamotragine
    • General (tonic-clonic): valproic acid, phenytoin, carbamazepine, lamotrigine
    • General (absence): EthoSUXimide, valproic acid
    • Status epilepticus: Lorazepam, diazepam, phenytoin, fosphenytoin

    cleanest question: Ethosuximide used for abnsce seizures

    valproic acid works for almost everything
  35. Anticonvulsants: Phenytoin
    • Mechanism: blocks axonal Na channels in their inactivated state (state dependent blockage), prevents seizure propagation
    • Clinical Use: seizure states
    • PK: variable reabsorption, nonlinear kinetics, induction of CYP450, zero order elimination
    • Side Effects: CNS depression, gingival hyperplasia, hirsuitism, osteomalacia (decreased vit D), megaloblastic anemia (decreased folate), aplastic anemia (check hematology lab results), ataxia, nystagmus, diplopia, fetal hydantoin syndrome, SLE-like rxn, P450 induction
    • Teratogenicity: cleft lip and palate
  36. Drugs that are zero order kinetics:
    • phenytoin
    • ethanol
    • aspirin
  37. Anticonvulsant: Carbamazapine
    • Mechanism: blocks axonal Na channels in their inactivated state (state dependent blockage), prevents seizure propagation
    • Clinical Use: seizure states, DOC for trigeminal neuralgia, bipolar disorder
    • PK: induces CYP450, including its own metabolism
    • Side effects: CNS depression, osteomalacia, megaloblastic anemia, exfoliative dermatitis, increases ADH secretion (SIADH), diplopia, ataxia, liver toxicity, induciton of P450, Steven Johnsons
    • Teratogenicity: cleft lip, palate, spina bifida
  38. Anticonvulsant: Valproic Acid
    • Mechanism: blocks axonal Na channels in their inactivated state, prevents siezure propagation, but also inhibits GABA transaminase and blocks the T type Ca channels
    • Uses: seizure states, mania of bipolar disorders, migraines
    • PK: inhibits CYP450
    • Side effects: hepatotoxicity (from toxic metabolite), thrombocytopenia, pancreatitis, alopecia
    • Teratogenicity: spina bifida (neural tube defects) CONTRAINDICATED IN PREGNANCY
  39. Anticonvulsant drugs that have p450 effects
    • Activator: phenytoin, carbamazapine
    • Inhibitor: valproic acid
  40. Anticonvulsant: Ethosuximide **
    • Mechanism: blocking the T type Ca channels in thalamic neurons
    • Use: absence seizures
  41. Anticonvulsant drug use: General consideration
    • are additive to CNS depressants
    • avoid abrupt withdrawal, may preciptate seizures
    • decreased efficacy of OCP via induction of CYP450
    • safest in pregnancy: Phenobarbital
  42. Anticonvulsant drug: Felbamate & Lamotrigine
    • Mechanism: block Na channels and glutamate receptors
    • Used in seizure sates (often adjunct thereapy)
    • Side effects: hepatotoxicity and aplastic anemia (felamate)
    • Steven-Johnson syndrome (lamotrigine)
  43. Anticonvulsant drug: Gabapentin
    increases GABA efects, used in neuropathic pain (ie post herpetic neuralgia)
  44. General anticonvulsant words of wisdom
    • if you don't know what to give them, give them valproic acid
    • if there are multiple types of seizures should give valproic acid
  45. Anesthesia Drugs: Classes
    • 1. Inhaled Anesthetics
    • 2. IV Anesthetics
    • 3. Local Anesthetics (most #of q from here)
    • 4. Skeletal Muscle Relaxants
  46. Anesthesia Drug: Inhaled Anesthetics: General Info
    • Anesthesia protocols include several agents in combo
    • Inhaled agest have varying potency wrt lipid solubility (need to be lipid sol to enter CNS)
    • Minimum Alveolar Concentration: MAC: the concentration of inhaled anesthetic as a % of inspired air, at which 50% of the pts do not respond to a surgical stimulus
    • - measure of potency: ED50
    • - more lipid sol = lower MAC value = more potent
    • MAC values are additive
    • MAC values are lower in elderly & in the presence of opiates or sedative-hypnotics
    • Rates of onset/recovery depend on the blood:gas ratio:
    • - more soluble the anesthetic in blood = slower anesthesia
    • - less soluble the anesthetic in blood = rapid induction and recovery times
    • - high blood:gas ratio = slower onset and recovery
    • - low blood:gas ratio = faster onset and recovery
  47. Anesthesia Drugs & Organs
    • Lungs: high rate + depth of ventilation = high gas tension
    • Blood: high blood solubility = high blood/gas partition coefficient = high solubility = more gas needed to saturate blood = slower onset of action
    • Tissue (ie brain): AV concentration gradient high = high solubility = more gas required to saturate tissue = slower onset of action
  48. Anesthesia Drug: Inhaled Anesthetic: NO
    • MAC value = 104% (less potent)
    • Blood:gas ratio = .5 (fast onset)
    • Characteristics: rapid onset/recovery, no metabolism, diffusional hypoxia, spontanous abortions
    • toxicity: not potent enough to use on own, minimal CV effects, expansion of trapped gas
  49. Anesthesia Drug: Inhaled Anesthetic: Halothane, Desflurane, Sevoflurane
    • MAC = .8% (very potent)
    • Blood:gas ratio = 2.3 (slow)
    • Characteristics: malignant hyperthermia, heptatits, cardia dysrhythmias
    • Toxicity: CV effects: sensitizes heart to catecholamines (pheo), halothane (hepatotoxicity), methyoxyflurane (neprhotoxicity), enflurane (proconvulsant), malignant hyperthermia
  50. Anesthesia Drugs: IV Anesthetics:
    • Thiopental
    • Midazolam
    • Propofol
    • Fentanyl
    • Ketamine

    B.B. King on OPIATES PROPOses FOOLishly
  51. Anesthesia Drug: IV Anesthetic: Thiopental
    • A barbiturate
    • use: induction of anesthesia & short surgical procedures
    • characteristic: highly lipid soluble: rapid onset, short acting due to redistribution, but remains in the fat for up to 9 hours, decreases cerebral BF

    remember Barbs don't have an antidote
  52. Anesthesia Drug: IV Anesthetic: Midazolam
    • A benzodiazepine
    • Use: preoperative sedation, anterograde amnesia, induction, outpatient surgery, endoscopy, often used with gaseous anesthetics & narcotics
    • toxicity: depresses respiratory function post-op, decreases BP, amnesia
    • OD tx: flumazenil

    antidote = flumazenil
  53. Anesthesia Drug: IV Anesthetic: Propofol
    • Use: induction and maintenance of anesthesia, rapid in and out
    • antiemetic, CNS and cardiac depressant
    • Potentiates GABAA

    Ie: eye surgery is very nauseating, thus this would be a good choice
  54. Anesthesia Drug: IV Anesthetic: Fentanyl/Morphine
    • An opiate
    • use: induction and maintenace of general anesthesia, depresses respiratory function

    antidote: naloxone
  55. Anesthesia Drug: IV Anesthetic: Ketamine** (an Arylcyclohexylamine)
    • Dissociative anesthetic: catatoric, no sensory input
    • Mechanism: NMDA receptor antagonist
    • Use: induction of anesthesia
    • emergent delirium, hallucinations, CV stimuation, increases intracranial pressure, good for asthmatics (little effect on respiration)
    • Toxocity: CV stimulation, disorientation, bad dreams, increases cerebral BF
  56. Anesthesia Drug: Local Anesthetics **
    very common Q!
    • Use: regional anesthesia
    • Drugs: Esters & Amides (each have their own card)
    • Mechanisms: nonionized form crosses axonal membrane (most of the body is acidic thus ionized drug more common), from w/in, ionized form blocks the inactivated Na channel by binding on the inner part of the channel, slows recovery and prevents propagation of action potentials
    • Most effective in rapidly firing neurons
    • 3* amine local anesthetics penetrate membrane in uncharged form, then bind to ion channesl as a charged form
  57. Anestheia Drug: Local Anesthetics Drugs: PRINCIPLE
    An infected (acidic) tissue, alkaline anesthetics are charged and cannot penetrate the membrane effectively. More anethetic is needed in these cases
  58. Anesthesia Drug: Local Anesthetics Drugs
    Esters: procaine, cocaine, benzocaine ...all metabolized by plasma and tissue esterases

    one eyed ester has allergies: any of the local anesthetics that have one letter "i" in their name is an ester and allergies are more common

    Amides:
    lidocaine, bupivacaine, mepivacaine... all metabolized by liver amidases

    more than one letter "i" in the drug it is an amide
  59. Anesthesia Drug: Local Anesthetics: Nerve Fibre Sensitivity
    • Small-diameter fibres > lg-diameter
    • Myelinated fibres > non-myelinated
    • Overall size predominants over myelination --small myelinated > small unmyelinated > large myelinated > large unmyelinated

    Order of loss: pain (lose first) > temperature > tough > pressure (loose last)

    • type B/C (pain)> type Adelta (pain/temp)> type Abeta/gamma(touch/pressure)> typeAalpha (muscle)
    • recovery is in reverse order
  60. Anesthesia Drug: Local Ansthetics: Absorption
    Coadministered with alpha1 agonists: to decrease local anesthetic absorption into systemic circulation and prolong effects/decrease toxicity
  61. Anesthesia Drug: Local Anesthetics: Side effects:
    • neurotoxicity-CNS excitation
    • CV toxicity (bupivicaine), hyper/hypotension, arrythmias (cocaine)
    • Allergies (esters via PABA formation) if allergic then give amides
    • Note: Amides are not metabolized into PABA
  62. Anesthesia Drug: Skeletal Muscle Relaxants General
    • Physiology: nicotinic ACh receptor has 2 alpha subunits that need to be bound in order to open up the Na channel to depolarize the muscle
    • Use: ICU or anesthesia protocols that require muscle relaxation/immobility Mechanism: interact w/ nicotinic ACh receptors at the NMJ (more selective for NMJ vs. autonomic receptors)
  63. Anesthesia Drug: Skeletal Muscle Relaxant: Nondepolarizing (competitive)
    • Mechanism: nicotinic antagonists
    • D-Tubocurarine is the prototype
    • reversible with AChE inhibitors (neo-, pyridostigmine) to increase ACh binding to alpha subunits
    • causes: progressive paralysis (face, limbs, respiratory muscle), no effects n cardiac or smooth muscle, no CNS effects
    • Drugs: Atracurium, Mivacurium, succinylcholine, BZ, baclofen
  64. Anethesia Drug: Skeletal Muscle Relaxant: Nondepolarizing (competitive)
    • Atracurium
    • Rapid recovery
    • safe in hepatic or renal impairment
    • spontaenous inactivation due to laudanosine
    • Laudanosine can cause seizures

    • Mivacurium
    • very short acting
    • metabolized by plasma cholinesterases

    • Other drugs: tubocurarine, pancuronium, vecuroniu, rocuronium
    • Reversal of blockade: neostigmine, edrophonium, other cholinesterase inhibitors
  65. Anesthesia Drug: Skeletal Muscle Relaxant: Depolarizing (non-competitive)
    • drug: Succinylcholine (ACh-ACh)
    • nicotinic agonist
    • 2 phases:
    • phase I: prolonged depolarization, fasciculation, prolong depolarization, flaccid paralysis (due to receptor sensitization). no antidote, block potentiated by cholinesterase inhibitors
    • Phase II: desensitization
    • AChE inhibitors increase phase I and no effect on phase II. repolarized, but blocked, antidote consists of cholinesterase inhibitors (ie neostigmine)
    • Metabolized: by pseudocholinesterase: short duration
    • Caution: atypical pseudocholinesterase (genetic polymprphism), hyperkalemia, hypercalcemia, malignant hyperthermia
  66. Anesthesia Drug: Centrally Acting Skeletal Muscle Relaxants
    • Drugs: BZ thru GABAa receptors, Baclofen thru GABAb receptors
    • Use: spasticity

    there is less excessive muscle tone or spasm injury and CNS muscle dysfunction
  67. Malignant Hyperthermia
    Defn: a life threatening syndrome characterized by muscle rigidity, hyperthermia, hypertension, acidosis, and hyperkalemia

    Associated with use of: skeletal muscle relaxants, especially succinyl CoA

    Genetic susceptibility: mutations in the ryanodine receptor and/or protein part of the L-type Ca channel in muscle

    • Treatment: Dantrolene
    • Mechanism: blocks the Ca release from SR in skeletal muscle and decreases muscle rigidity (as seen in malignant hyperthermia or neuroleptic malignant syndrome)

    3 drugs that cause malignant hyperthermia: succinylcholine, halothane, tubocurarine
  68. Opioid Analgesics General
    • Endogenous opiate peptides: endorphins, enkephalins, dynorphins
    • 3 receptor families: mu, kappa, delta
    • Mu pharm is most NB

    • Mechanism: Act as agonists at these opioid receptors
    • Mu = morphine
    • Kappa = dynorphin
    • delta =enkephalin
    • All act to modulate synaptic transmission = inhibit the release of ACh, NEp, 5HT, glutamate, substance P
  69. Contraindications/Caution for opioids:
    • Head injuries: possible increased intracranial pressure
    • Pulmonary dysfunction: except pulmonary edema
    • Hepatic/renal dysfunction: possible accumulation
    • Adrenal/thyroid deficiencies: exaggerated responses
    • Pregnancy: possible neonatal depression/dependence, except meperidine
  70. Side effects from opioid analgesics:
    • Acute toxicity: Classic Triad:
    • 1. pinpoint pupils
    • 2. respiratory depression
    • 3. coma

    Management of acute toxicity: supportive, IV naloxone
  71. Opiate-related drugs w/ specific indications:
    • Loperamide: for diarrhea, OTC, no abuse potential bc does not cross BBB
    • Dextromethorphan: for cough, works centrally to elevate the threshold for coughing
    • Benzonatate: is a non-opioid used for cought that anesthetizes cough/stretch receptors in lung
  72. Abuse liability of opioid analgesics:
    • Tolerance: pharmacodynamic; occurs to all effects (except miosis & constipation)
    • Dependence: physical and psychologic
    • Withdrawal: yawning, lacrimation, rhinorrhea, salivation, anxiety, sweating, goose bumps, muscle cramps, spasms, CNS-originating pain
    • Management of withdrawal: supportive, mehadone, clonidine
  73. Butorphanol
    • Mechanism: partial agonist at opioid mu receptors, agonist at kappa receptors
    • Clinical use: pain; less respiratory depression than full agonists
    • Toxicity; causes w/drawal if on full opioid agonist
  74. Tramadol
    • Mechanism: very week opioid agonist, also inhibits serotonin, NEp reuptake (works on multiple NT = tram it all!
    • Clinical use: chronic pain
    • Toxicity: similar to opioids, decreases seizure threshold
  75. Opioid Analgesics: Morphine
    • prototype mu agonist
    • mechanism: presynaptically 0 decreased Ca influx & substance P release, post synaptically increase K efflux = hyperpolarization (similar to M2 effects on heart)
    • Pharmacology: analgsia: increases pain tolerance and decreases perception/reaction to pain (less NT), sedation
    • Side Effects: respiratory depression if OD: decreased response to hi pCO2
    • OD tx: naloxone
    • Side effects: CV: minimal on heart, vasodilation (avoid in head trauma)
    • Side effects SM: longitudinal relaxes, circular constricts: GI = decreased peristalsis, constipation, cramping, GU = urinary retention, urgency to void, Biliary: increased pressue (stones/colic), pupils: miosis
    • Other actions: cough suppression (antitussive agent), stimulates the CTZ = n/v, increases histamine release
    • PK: glucuronidation, morphine-6-glucuronide is highly active, caution renal function
  76. Opioid: Full Agonist: Meperidine
    • Characertistics: antimuscarinic, no miosis or spasm of GI/GU/gallbladder
    • tachy
    • CYP450 metabolism to form normeperidine
    • serotonin reuptake inhibitor
    • normeperidine can cause serotonine syndrome & seizures
  77. Opioid Full Agonist: Methadone
    Characteristics: used in maintenance of opiate addict
  78. Opioid Full Agonist: codeine
    Characteristics: cough suppressant, analgesia, used in combo with NSAIDS
  79. Other Opioid Full Agonists:
    • heroin
    • morphine
  80. Opioid: Partial Agonist: Buprenorphine
    Characteristics: precipitation of withdrawal
  81. Opioid: Mixed Agonist/Antagonist: Nalbuphine, pentazocine
    Kappa agonist: spinal analgesia, dysphoria

    Mu antagonist: precipitation of withdrawal

    can precipitate a withdrawal
  82. Should you give a mixed agonist/antagonist to a pt on a full agonist?
    NO!!!!!!

    it can lead to immediate state of withdrawal
  83. Opioid Antagonists: Naloxone, Naltrexone, Methylnatrexone
    • Naloxone: shorter half-life, IV, reversal for respiratory depression
    • Naltrexone: longer half-life, PO (bc TREX is like TRIX and you eat that cereal), decreases cravings for alcohol and sed in opiate addiction
    • Methylnaltrexone: treatment of opioid-induced constipation (does not cross BBB and won't precipitate a withdrawal)
  84. What are the 4 DA neural pathways?
    • Nigrostriatal: cell bodies in substantia nigra project to striatum and release DA, in Parkinson's these DA neurons are lost = excessive ACh
    • Mesolimbic-mesocortical tract: cell bodies in the midbrain project to the cerebrocortical and limbic structures, involved in reinforcement
    • Tuberoinfundibular: cell bodies in the hypothalamus project to ant. pit. and release DA (decrease PRL release)
    • Chemoreceptor trigger zone: activation by DA = increases emesis
  85. What are the DA receptors?
    • D1-like = Gs coupled
    • D2-like = Gi coupled:
    • D2A = nigrostriatal (Parkinson's dz)
    • D2C = mesolimbic (Schizophrenia)
  86. What are the signs and symptomas of Parkinson Disease?
    • Bradykinesia
    • Muscle rigidity (cogwheel)
    • Resting tremor (low freq)
    • postural instability
  87. Pathology of Parkinson Disease:
    degeneration of nigrostriatal DA tracts w/ imbalance between DA (lo) and ACh (hi)

    schizophrenia is opposite
  88. Strategies in Parkinson Disease:
    • Agonize DA receptors: Bromocriptine, pergolid, pramipexol, ropinrole
    • Increase DA: Amantadine, L-dopa/carbidopa
    • Prevent DA breakdown: selegiline, entacoapone, tolcapone
    • curb excess cholinergic activity: Benztropine
  89. Parkinsons Drugs: Bromocriptine
    • other drugs: pergolide (ergot alkaloid and partial DA agonist), pramipexole, ropinirole (non-ergot), *non-ergots are preferred
    • Mechanism: DA-receptor agonist
    • Use: hyhperprolactinemia, acromegaly
    • Side effects: dyskinesia & psychosis
  90. Parkinsons Drugs: Amantadine
    • Mechansim: may increase DA release, blocks muscarinic receptors and increases DA release
    • Side effects: atropine-like, livedo reticularis (purple skin discolouration), ataxia, edema, hallucinations
    • Use: Parkinsons, influenza A, rubella
    • Toxicity: ataxia
  91. Parkinsons Drugs: L-Dopa/Carbidopa
    • Mechanism: levodopa can cross the BBB and turns into DA, prodrug converted to DA by aromatic amino decarboxylase (AAAD), usually given as carbidopa (periphreal decarboxylase inhibitors that increases bioavailibility in the CNS and decreases it peripherally)
    • Side Effects: dyskinesias, 'on-off' effects = off (akinesia) & on (better mobility), psychosis (increased DA), hypotension, vomitind (DA is emetic), arrhythmias due to peripheral conversion to DA, decreased effectiveness w/ high protein meals (need to take long before you eat), dosage needs to increase w/ time
  92. Parkinsons Drugs: Selegiline
    other drugs: toclcapone/entacopone (COMT-inhibitor that prevent Ldopa degredation = increased DA availability) ...has to be used w/ Ldopa

    Mechanism: selective-MAOB inhibitor (no tyramine interactions), preferentially metabolizes DA over NE and 5-HT, thus increasing bioavailibility of DA (essentially prevents L-dopa breakdown)

    • Selegiline is the initial tx & adjunct to levodopa
    • Side effects: dyskinesias, psychosis, insomnia (metabolized to amphetamine), enhances the side effects of L-dopa
  93. Parkinsons Drugs: Benztropine
    • Other drugs: trihexylphenidyl, diphenhydramine (both antimuscarinic)
    • Mechanism: antimuscarinie (decreases ACh activity), DA agonist
    • Use: improves tremor and rigidity but little effect on bradykinesia
    • Side effects: atropine-like effects (dry picture), less dyskinesia, makes dementia/psychosis/autonomic instability worse

    Park your Mercedes-Benz
  94. Parkinsons Drugs: Beta-blockers
    can be used for essential or familial tremors
  95. Parkinsons Drugs: Tolcapone/entacapone
    • Mechanism: inhibits the COMT (prevents the breakdown of levodopa into 3-O-methyldopa, increases levodopa into the CNS
    • Side effects: tolcapone = hepatoxic
  96. Schizophrenia Positive SXS
    • Thought disorders
    • Delusions
    • Hallucinations
    • Paranoia

    often seen with older drugs
  97. Schizophrenia Negative SXS
    • Amotivation
    • Social withdrawal
    • Flat affect
    • Poverty of speech

    often seen with newer drugs
  98. Dopamine Hypothesis for Schizophrenia
    • Symptoms arise bc of excessive dopaminergic activity in mesolimbic system
    • DA agonists cause psychosis
    • DA antagonists have antipsychotic actions

    typical mechanism of treatment: block DA and 5HT2 receptors
  99. Serotonin Hypothesis for Schizophrenia
    more atypical theory
  100. Typical Tx for Schizophrenia
    • Mechanism: blocks DA and/or 5HT2receptors
    • Same tx can be used in: schizoaffective states, bipolar disorder, Tourettes syndrome, Huntingtons, drug / radiation emesis
    • Side effects of DA blockade:
    • Dyskinesia: EPS:
    • Acute-pseudoparkinsonism, dystonia, akathisia
    • Acute management- antimuscarinic drugs (benztropine/diphenhydramine)
    • Chronic- tardiv dykinesia
    • Chronic management-discontinuation, switch to atypical
    • Dysphoria:
    • Endocrine dysfunction: temp regulation problems (neuroleptic malignant syndrome, treated with dantrolene and bromocriptine), increased PRL, increased eating behaviours (weight gain)
    • Side effects from muscarinic blockade: tachy, decreased seizure threshold
    • Side effects from alpha blockade: hypotension
  101. TYPICAL ANTIPSYCHOTICS
    • Drugs: haloperidol, trifluoperazine, fluphenazine, thioridazine, chlopromazine
    • Mechanism: all block D2 receptors = increases cAMP1
    • Clinical use: schizoprenia (positive symptoms), pscyhosis, acute mania, Tourette's
    • Toxicity:
    • 1. highly lipd soluble and stored in body fat, slowly removed from body
    • 2. EPS
    • 3. endocrine side effects
    • 4. receptor blocking side effects: muscarinic (dry), alpha (hypotension), histamine (sedation)
    • Neuroleptic Malignant syndrome-rigidity, myoglobinuria, autonomic instability, hyperpyrexia, tx: dandrolene, bromocriptine
    • Tardive dyskinesia-stereotypic oral-facial movts due to LT antipsychotic use, often reversible
  102. Evolution of EPS side effects
    • 4 hour: acute dystonia (muscle spasm, stiffness, oculogyric crisis)
    • 4 days: akinesia (parkinsonian symptoms)
    • 4 weeks: akathisia (restlessness)
    • 4 months: tardive dyskinesia
  103. Antipsychotic Drugs (neuroleptics) TYPICALS: Chloropromazine
    • Haloperidol + '-azines'
    • Muscarinic block
    • H1 (sedation) block
    • Alpha block (mostly alpha1)
  104. Antipsychotic Drugs (neuroleptics): TYPICALS: Thioridazine
    • Muscarinic block
    • H1 (sedation) block
    • alpha block (mostly alpha1)
    • cardiotoxicity (Torsades, quinidine-like), retinal deposits
  105. Antipsychotic Drugs (neuroleptics): TYPICALS Fluphenazine
    EPS (pseudoparkinsons)
  106. Antipsychotic Drugs (neuroleptics): TYPICALS Haloperidol
    • EPS (pseudoparkinsons)
    • Other: most likely the cause of neuroleptic malignant syndrome (NMS) and TD
  107. Neuroleptic Malignant Syndrome (NMS)
    think FEVER:

    • Fever
    • Encephalopathy
    • Vitals unstable
    • Elevated enzymes
    • Rigidity of muscle

    Muscle rigidity, myoglobinuria, autonomic instability, hyperpyrexia

    Treatment: Dantrolene: prevents the release of Ca ions from the SR in skeletal muscle
  108. ATYPICAL ANTIPSYCHOTIC DRUGS
    Drugs: olanzapine, clozapine, quetiapine, risperidone, aripiprazole, ziprasidone

    it's atypical for old closets to quietly risper from A to Z

    • Clinical use: schizophrenia (+ and - symptoms), Olanzapine can be used in OCD, anxiety, depression, mania, Tourettes
    • Toxicity: fewer EPS & anticholinergic side effects than typicals, all atypicals cause hyperglycemia = weight gain & insulin resistance
  109. Antipsychotic Drugs (neuroleptics): ATYPICALS Clozapine
    • EPS (may or may not)
    • muscarinic block
    • alpha block
    • D2C receptors block
    • 5HT2 receptors block
    • H1 receptor block
    • no TD
    • Agranulocytosis: weekly WBC count needed
    • weight gain
    • increased salivation (wet pillow syndrome)
    • seizures
  110. Antipsychotic Drugs (neuroleptics) ATYPICALS Olanzapine
    • EPS (may or may not)
    • Receptors blocked: alpha1, 5HT2
    • Improves negative symptoms
    • no TD
    • Clinical use: OCD, anxiety disorder, depression, mania, Tourette's
    • always pick this one bc it is a better drug
  111. Antipsychotic Drugs (neuroleptics) ATYPICALS Risperidone
    • EPS
    • receptors blocked: H1, alpha 1 5HT2, maybe Muscarinic
    • improves negative symptoms
  112. Antipsychotic Drugs (neuroleptics) ATYPICALS Aripiprazole
    • EPS, maybe muscarinic, H1, alpha block, parital agonist of D2 receptors, blocks 5HT2 receptors
    • improves negative symptoms
  113. Lithium
    • Mechanism: not established, possibly inhibition of posphoinostitol cascade
    • Clinical use: mood stabilizer for bipolar, blocks relapse and acute manic events, SAIDH
    • Toxicity: tremor, sedation, edema, heart block, hypothyroidism, polyuria (ADH antagonist causing nephrogenic DI), teratogenesis, narrow therapeutic window thus requires close monitoring

    • LMNOP
    • Lithium side effects: Movement, Nephrogenic diabetes insipidis, hypOthyroidism, Pregnancy problems
  114. Methylphenidate (Ritalin)
    Mechanism: increases NEp vesicular release (like amphetamies), but the actual mechanism of alleviating ADHD is unknown
  115. Buspirone
    • Mechanism: Stimulates 5HT1a receptors
    • Clinical use: generalized anxiety disorder, does not cause sedation, addiction, tolerance, does not interact with alcohol (vs. barbs and benzos)
  116. Antidpressant Drugs:
    • MAO Inhibitors
    • TCAs
    • SSRI
    • Others: Trazodone, Venlafaxine, Buproprion, Mitrazapine
  117. Antidepressant Drugs: MAO Inhibitors
    • Drugs: Penelzine, tranylcypromine, isocarboxazid, selegiline (selective MAO-B inhibitor)
    • Mechanism: nonselecitve MAO inhibition = increases amine NT
    • Clinical use: atypical depression, anxiety, hyochondriasis
    • Toxicity: hypertensive crisis w/ tyramine ingestion (ie wine and cheese) and B-agonists; CNS stimulation
    • Drug interactions:
    • hi NEp = Hypertensive Crissi: hi BP, arrhythmias, excitation, hyperthermia. caused by - releasers (ie tyramine), TCA, alpha1 agonists
    • hi 5HT = Serotonin Syndrome: sweating, rigidity, myoclonus, hyperthermia, ANS instability, seizures. caused by - SSRI, TCA, meperidine
  118. Antidepressant Drugs: Tricyclic Antidepressants
    • Drugs: imipramine, amitriptyline, desipramine, nortriptyline, clomipramine, doxepin, amoxapine
    • Mechanism: block reuptake of NEp & serotinin
    • Clinical use: major depression, enuresis (mipramine), OCD (clomipramine), fibromyalgia, neuropathic pain
    • Side effects: sedation, alpha-blocking effect, atropine like effects (tachy, urinary retention), specific TCA drug effects
    • Toxicity: Tri-C's: Convulsions, Coma, Cardiotoxicity (arrhythmias), respiratory depression, hyperyrexia, confusion/hallucinations in elderly due to anticholinergic effecs (should use nortriptyline), tx: NaHCO3 for CV toxicity
    • Drug interactions: MAOI (hypertensive crisis), SSRI, MAOI, meperidine (Serotonin syndrome), alpha2 agonists, guanethidine (antihypertensive action)
  119. Antidepressant Drug: TCA: Amytriptyline
    • 3* TCA
    • more anitcholinergic effects than 2* TCA (nortriptyline)
  120. Antidepressant Drug: TCA: Nortriptyline
    use in elderly to avoid confusion and hallucinations
  121. Antidepressant Drug: TCA: Desipramine
    Least sedating TCA, has lower seizure threshold
  122. Antidepressant: SSRI
    • Drugs: fluxetine, paroxetine, sertraline, citalopram
    • Mechanism: serotonin-specific reuptake inhibitors
    • Clinical use: depression, OCD< bulimia, social phobias, slow onset anxiety, premenstrual dysphoric disorder
    • Toxicity: fewer than TCA, GI distress, sexual dysfunction (anorgasmia), Serotonin syndrome (with any drug that increases 5HT like MAOI = hyperthermia, muscle rigidity, CV collapse, flushing, diarrhea, seizures. Tx: cyprohetadine (5HT2 receptors antagonist)
    • Duration of onset: 2 - 3 weeks to have an effect
    • Benefits over other Rx: less sedative and cause initial weight loss
  123. Antidepressants: Other: SNRI:
    • Drugs: venlfaxine, duloxetine
    • Mechanism: inhibit serotonin and NEp reuptake
    • Clinical use: depression. Venlfaxine - generalized anxiety disorder. Duloxetine more NEp effect
    • Toxicity: increased BP is most common; also stimulant effects, sedation, nausea
    • Benefit: nonselective reuptake blocker; avoids ANS side effects
  124. Antidepressants: Atypical: Buproprion
    • aka Wellbutrin
    • Clinical use: depression, smoking cessation
    • Mechanism: DA reuptake inhibitor
    • Toxicity: stimulant effects (tachy, insomnia), headache, seizure in bulimia, no sexual side effects
  125. Antidepressants: Atypical: Mirtazapine
    • Mechanism: alpha2 antagonist (increases NEp release and serotonin, potent 5-HT2 & 5-HT3 receptor antagonist
    • Toxicity: sedation, increased appetite, weight gain, dry mouth
  126. Antidepressants: Atypical: Maprotiline
    • Mechanism: blocks NEp reuptake
    • Toxicity: sedation, orthostatic htn
  127. Antidepressants: Atypical: Trazadone
    • Mechanism: mostly serotonin reuptake
    • Use: insomnia, high doses are needed for antidepressant effects
    • Toxicity: sedation, nausea, pripaism, postural hypotension
  128. Drugs of Abuse: CNS Stimulant: COCAINE
    • NT: NE, DA, 5HT
    • Mechanism of action: blocks the NT reuptake in CNS; local anesthetic action from Na channel blockade
    • Effects: NE: sympathomimetic, DA: psychotic episodes, paranoia, hallucinations, dykinesia, endocrine disturbances. 5HT: behavioural changes, aggressiveness, dyskinesias, decreased appetite
    • Toxicity: NE: cardiac arrhythmias, generalized ischemia w/ possible MI & stroke; acute renal & hepatic failure. DA: major psychoseis, cocaine delirium. 5HT; possible serotonin syndrome. convulsion, hyperpyrexia, death
    • Withdrawal: craving, severe depression, anhedonia, anxiety; manage with antidepressants
  129. Drugs of Abuse: CNS Stimulant: AMPHETAMINES
    • NT: NE, DA, 5HT
    • Mechanism: blockage of reuptake of NE and DA, release amines form mobile pool, weak MAO inhibitor
    • Effects: NE: sympathomimetic, DA: psychotic episodes, paranoia, hallucinations, dykinesia, endocrine disturbances. 5HT: behavioural changes, aggressiveness, dyskinesias, decreased appetiteToxicity: NE: cardiac arrhythmias, generalized ischemia w/ possible MI & stroke; acute renal & hepatic failure. DA: major psychoseis, cocaine delirium. 5HT; possible serotonin syndrome. convulsion, hyperpyrexia, deathWithdrawal: craving, severe depression, anhedonia, anxiety; manage with antidepressants
  130. Drugs of Abuse: CNS Depressant: BENZODIAZEPINES
    • NT: GABA
    • Mechanism: potentiation of GABA interaction with GABAa receptors involves the BZ1 and BZ2 binding sites
    • Effects: light to moderate CNS depression
    • Toxicity: sedation, anterograde amnesia; in severe OD (or IV use), reverse with flumazenil
    • Withdrawal: rebound insomnia, reboud anxiety
  131. Drugs of Abuse: CNS Depressants: BARBITURATES & ETHANOL
    • NT: GABA
    • Mechanism of action: prolongation of GABA, GABAmimetic at high doses on GABAa receptors
    • Effects: any plane of CNS depression
    • Toxicity: severe CNS depression, respiratory depression, death
    • Withdrawal: agitation, anxiety, hyperreflexia, life-threatening seizure + ethanol withdrawal delusions/hallucinations - delerium tremens (DTs)
  132. Drugs of Abuse: Opiods: Morphine, Heron, Methadone, Fentanyls, other opoids:
    • NT: NE, DA, 5HT, GABA, many others
    • Mechanism: activate opioid mu, kappa, delta receptors, potent mu receptor activation = most intense abuse / dependence liability,possibley effects via an increase in DA tranmission in mesolimbic tracts
    • Effects: euphoria, analgesia, sedation, cough suppression, constipation; strng miosis (except meperidine)
    • Toxicity: severe respiratory depression (reverse with naloxone), nausea, vomiting
    • Withdrawal: lacrimation, yawning, sweating, restlessness, rapidly followed with centrally originating pain, muscle cramping, diarrhea; not life-threatening
  133. Drugs of Abuse: Hallucinogens: MARIJUANA
    • NT: many
    • Mechanism of action: interaction of THC with CB1 & CB2 cannabinoid receptors in CNS and periphery
    • Effects: sedation, eurphoria, increased HR, delusions, hallucinations
    • Toxicity: associated with smoking, possible flashbacks
    • Withdrawal: irritability, anxiety
  134. Drugs of Abuse: Hallucinogens: HALLUCINOGENS
    • NT: 5HT
    • Mechanism of action: interaction with several subtypes of 5HT receptors
    • Effects: hallucinogen, sympathomimetic, causes dysethesias
    • Toxicity: poorly described, flashbacks likely
    • Withdrawal: poorly characterized
  135. Drugs of Abuse: Miscellaneous: PCP
    PCP: NMDA-receptor antagonist; extremely toxic; horizontal and vertical nystagmus, paranoid, rhabdomyolysis; OD is common with convulsions & death
  136. Drugs of Abuse: Miscellaneous: Ketamine
    similar to, but milder than PCP; hallucinations, glutamate receptor antagonist
  137. Drugs of Abuse: MIscellaneous: Anticholinergics
    scopolaime, atropine-like
  138. Drugs of Abuse: Miscellaneous: MDMA "Ecstasy", MDA, MDEA
    amphetamine-like strong 5HT pharmacology, hallucinogenic, neurotoxic
  139. Drugs of Abuse: Miscellaneous: Inhalants
    solvent use, multiple organ damage
  140. Alzheimer's Drugs: Memantine
    • Mechanism: NMDA receptor antagonist, helps prevent excitotoxicity (mediated by Ca)
    • Toxocity: Dizziness, confusion, hallucinations
  141. Alzheimer's Drugs: Donepezil, galantamine, rivastigmine
    • Mechanism: AChE inhibitor
    • Toxicity: nausea, dizziness, insomnia
  142. Huntington's Drugs
    • Huntington's Dz: increased DA, decreased GABA + ACh
    • Reserpine + tetrabenzaine: amine depletion
    • Haloperidol: DA receptor antagonist
  143. Migraine Drug: Sumatriptan
    • Mechanism: 5-HT1B/1D agonist, VC, inhibition of trigeminal activation and VIP, half life is < 2 hours
    • Clinical use: acute migraine, cluster headaches
    • Toxicity: coronary vasospasm, contracindicated in pts with CAD/Prinzmetal's angina), mild tingling

    A SUMo wrestler TRIPs ANd falls on your HEAD
  144. Epilepsy Drug: Phenytoin

    see chart on p. 428 in FA!!
    • Mechanism: use-dependent blockade of Na channels, increases the refractory period; inhibition of glutamate release from excitatory presynaptic neuron
    • Clinical use: tonic clonic sizures, status prophylaxis, class 1B antiarrhythmic
    • Toxicity: nystagmus, ataxia, diplopia, sedation, SLE-like syndrome, induction of CYP450, chronic use = gingival hyperplasia in children, periphearly neuropathy, hirsuitism, megaloblastic anemia (decreased folate absorption), teratogenic Fetal Hydantoin Syndrome
    • Note: fosphenytoin is the IV parenteral form
  145. Epilepsy Drug: Benzodiazepene (diazepam, lorazepam)
    • Type of seizure: acute use in status
    • Mechanism: increase GABAA action
    • Clinical use: seizures of preeclampsia (first line is MgSO4)
    • Toxicity: sedation, tolerance dependence
  146. Epilepsy Drug: Carbamazepine
    • Type of seizure: first line in tonic, clonic, simple and complex partial, makes absence seizures worse
    • Mechanism: increases Na channel activation
    • Use: 1st line for trigeminal neuralgia
    • Toxicity: diplopia, ataxia, blood dyscrasia (agranulocytosis, aplastic anemia), liver toxicity, teratogenesis, induction of CYP450, SIADH, Stevens-Johnsons syndrome
  147. Epilepsy Drug: Ethosuximide
    • Type of seizure: absence seizure
    • Mechanism: blocks thalamic T-type Ca channels
    • Toxicity: GI distress, fatigue, headache, urticaria, Steven-Johnsons syndrome

    EFGH; Ethosuximide, Fatigue, Gi distress, Headache
  148. Steven Johnson's syndrome
    prodrome of malaise and fever, followed by fapid onset of erythamtous/purpuric macules (oral, ocular, genital), skin lesions progress to epidermal necrosis and sloughing. more common in African Americans
  149. Epilepsy Drug: Phenobarbital
    • Type of seizure: partial simple and complex, toninc clonic, 1st line in PREGNANCY
    • Mechanism: increases GABAa action
  150. Epilepsy Drugs: Valproic Acid
    • Type of seizure: first line in tonic-clonic, parital simple and complex, in absence (not if reproductive age), myoclonic seizures
    • Mechanism: increases Na channel inactivation, increases GABA concentration)
    • Toxicity: GI distress, rare but fatal hepatotoxicity (measure LFTs), neural tube defects (spina bifida), tremor, weight gain, contraindicated in pregnancy
  151. Epilepsy Drugs: Lamotragine
    • Type of seizure: partial simple and complex, tonic clonic
    • Mechanism: blocks voltage-gated Na channels
    • Toxicity: Steven Johnsons, decreased BCP levels
  152. Epilepsy Drugs: Gabapentin
    • Type of seizure: partial simple and complex, tonic clonic
    • Mechanism: GABA analogue, but mostly inhibits the HVA Ca channels
    • Clinical use: peripheral neuropathy, bipolar disorder
  153. Epilepsy Drugs: Topirimate
    • type of seizure: simple partial and complex and tonic clonic
    • Mechanism: blocks Na channels, increases GABA action
    • Toxicity: sedation, mental dulling, kidney stones, weight loss
  154. Seizures and their tx:
    • Tonic Clonic: pheytoin, carbamazepine, valproic acid
    • Status: phytoin for prophylaxis, benzo for acute use
    • Absense: ethosuximide, then valproic acid

    • Partial Simple: all, but mostly carbamazapine, lamotrigine
    • Partial Complex: all of them
Author
Boards
ID
75188
Card Set
CNS Pharm
Description
CNS Pharm
Updated