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					                                                                                      Dyskinesia (oral, facial)
Parkinson's                ↑ Dopamine Function
                                                                                      Psychosis (limiting factor) → mesolimbic path, ↑ in elderly

                                                                                             N/V, Depression, Anxiety
                                                                                                 Arrythmia (α, β)                                                                 Large first-pass
                                                                                                      ..                                                                  *   CNS by ACTIVE transport
Levodopa               L-Dopa —   → Dopamine
                                  AAAD
                                                                                          orthostatic hypotension
                                                                                           …………………………………………….                                                             *   ↑ seratonin receptors
(L-Dopa)                  D1 + D2 receptor                   Treat Symptoms
                                                                                          (+) Coombs, brown secretion                                                     *   avoid non-specific MAOIs
                                                          Not alter disease course    …………………………………………………………………………………………………...........................................…


                                                                                                                 Neuroleptic                                              *   free radical = ↑ neuron dmg
                                                                      .                           …………………….


                                                                                                           Malignant Syn
                                                                early stages
                                                           (require DA neurons)
Carbidopa                                                                                minimize peripheral side
                                 (-) AAAD                                                                                                                                             Periphery only
                                                                                      effects                     ↑
                            ( ↑ L-Dopa in CNS )                                                                                                                                       NOT cross BBB
Benserazide                                                                                            t1/2 levadopa x2
                 give w/
                levadpoa                                                                                                                                                  Peripheral Only                  Short
Entacapone                                                enhance L-dopa uptake
                              (-) COMT                                                                                                                                                duration
                                                               and efficacy
                       L-dopa →3-O methyldoma                                                                                                                                      Central + Peripheral
Tolcapone                                                 ↓ "on/off" phenomenon                         Hepatotoxicity
                                                                                                                                                                                     Long Duration

Selegiline                                                                                 ↑ amphetamine = anxiety, sleep
                                (-) MAOB                     Neuroprotective ?                                                                                                  no tyramine interactions
                                                                                                 Meperidine, TCA + SSRI
                             (type B = Brain)             Delay levodopa 9-12 mo                                                                                                     DA in CNS only
Rasagiline                                                                                            interactions

                                                                                                    insomnia, HTN,                                                              FQ inhibit metabolism
Ropinirole
                                                            1st line or adjunt                    obsessive behavior                                                          * also tx restless leg synd
                               D3 > D2
                      Receptor agonists               .        Late stages                                                                                                            transdermal
Rotigotine                                                                                      has some D1 effects
                           * ↓ free radical damage           (not require DA)                                                                                                 * also tx restless leg synd
                           * reduce "on/off" effect                  .
                                                                                            insomnia, HTN, Nausea
Pramipexole                                                                                                                                                                        cimetidine = ↑ t1/2
                                                                                               renal elimination

Bromocriptine                                                                                              insomnia, HTN
                               D1 and D2
                                                             Older - not used                                                                                                       Ergot derivatives
                            Receptor agonists
Pergolide                                                                                        valvular heart disease

                                                                                                                                                                               injectable (infusion pump)
                           D1, D2, D3 Agonist                 rescue drug for                      pretreat nausea w/
Apomorphine (SubQ)                                                                                                                                                               avoid w/ (-) Seratonin-3,
                            * R-enantiomer *               "on/off" phenomenon                   trimethobensamide
                                                                                                                                                                               anti-HTN, metabisulfite allerge

                                                                                Levadopa = Gold Standard for Treatment
                                                                                On/Off phenomenon :: L-dopa has buffereing capacity (storage in striatum)
Parkinson's            other mechanisms

                        Adenosine-A2A            ↑ Motor via Indirect path         neuroprotective ?             * expressed only in striatum *
Istradefylline
                       Receptor Blocker          (-)globus pallidus→ GABA        No dyskenesia effects            Caffeine similar MAO = ↓PD

Buspirone
                        5-HT1A Agonists            Dyskinesia side effects         prolong levadopa
                          (seratonin)             Pronong L-Dopa duration          duration of action
Sarizotan

                                                                               Agranulocytosis (limiting)      ↑ M-block (dryness)
Clozapine
                      Atypical Antipsych          Treat hallucinogenic               Low ↑ Prolactin           Ø EPS/TD
                     (5-HT2 + D2 >> D1)               side effects
Quietiapine

Coenzyme Q10               antioxidant                                                                             ↓mitochondrial complex 1
                                                           OTC                    high doses required
(Upiquinone)        (↑ mitochondrial function)                                                                      in substantia nigra of PD




                    Antiviral (Influenza A)                                        dizziness, lethargy
Amantadine                                       Early stages, mild cases                                             Adjunct to levadopa
                     (dopamine ? NMDA-R?)                                          anti-cholinergic




Trimethobenzamide



                                                        Muscarinic Antagonists were used before L-dopa developed
                                                          - resting tremor improved
                                                          - postural impairments not affected
                                                                * side effects = Atropine Like (sedate, dry, blurry vision)
Alzheimer's Disease :: 1) Excitotoxicity           2) Oxidative Stress + membrane peroxidation          → early :: ↓ Ach
…………………………………         .. 3) Inflammation               4) Infection                                          late :: ↓ Glut, 5-HT
                                                             ↑ cognitive scores      side effects = cholinergic
AChE Inhibitors :: ↑ Ach                                                                                              Atropine = treat toxicity
                                                            Early tx = protective       N/V, diarrhea, ↓ HR

                                                                 Early Stage
Tacrine                                                                                   Hepatotoxic L            Reversible, Non-competitive
                                                          (weak K+Channel blocker)                                     (reversible organophosphate-ish)


Donepezil                                                        ALL Stages          1x day, gradually ↑ dose               AChE > BChE

                                                                                                                   pseudoirreversible (↑duration)
                           AChE inhibitors
Rivastigmine                                                     Early Stage          GI effect = discontinue      * carbamyl clvg into active site
                                                                                                                           AChE = BChE
                                                                                                                   Reversible, competitive AChE
                                                                  Early Stage
Galantamine                                                                           Weight loss at ↑ dose        > BChE              CYP 2D6,
                                                              (Nicotinic Agonist)
                                                                                                                          3A4 Substrate
                                                             Prevent Progression       hallucinate, catatonia,
NMDA - Blockers :: ↓ Excitoxicity                                                                                   Use in Combo with Donepezil
                                                             (↑ neurotrophic BDNF)       ↑ BP, anesthesia
                                                               Advanced stage
                          NMDA-R Blocker                                             ↓ neuroleptics, barb, 5-HT3     use dependant, low affinity
Memantine                                                  PD + Vascular Dementia
                         * non-competitive *                                            ↑ morphine, L-dopa          (learn = ↑ glut, overcome block)
                                                                  Antiviral

Anti-Oxidants :: ↓ Oxidative Stress

                                                               ↑ cognitive scores
Vitamin E                     Antioxidant                                                not > 400 IU/day
                                                                ↓ progression ?

Omega 3 Fas                   Antioxidant                      ↑ cognitive scores

                    MAO-B inhibitor                                                     NO tyramin toxicity
Selegiline
                    ↓ free radical production                                                B= Brain
                     (-) Aβ protein isoprenylation                                       Rhabdomyolysis                 CYP450 Substrate
Statins                * not insert in membrane *
                                                   (-) HMG-CoA Reductase
                                                                                           muscle pain              -avoid imidazole, macrolides
                            Bind soluble Aβ
Alzhemed               (-) β sheet + amyloid fibrils
                                                           ↓ Inflammtory Response


Curcumin                  (-) Aβ formation

                                                                                     spontaneous cerebral beed
Gingko Biloba                       ?
                                                                                       - avoid anti-coagulants
Pioglitazone                PPAR-γ agonists                  ↓ inflammation in PD
Rosiglitazone         * nuclear hormone receptor                    Diabetes
Drugs to Treat other symptoms of dementia

Fluoxetine         SSRI's                             HD + AD
                                                                              Depression
Carbamazepine      Anti-epileptic                     HD + AD

Baclofen           GABA-B agonist                       ALS                                        Intrathecal administration

                   α-2 Agonist
Tizanidine                                              ALS                    Spasticity
                   … * pre-synaptic inhibition

BZs                GABA-A agonist                 ALS + AD + HD

                   (-) NMDA - R                                                                     increase ALS survival
Riluzole                                             ALS + HD              * monitor hepatic
                   … - block Voltage gated                                                               by 60 days
Chlorpromazine                                                          * ↑ mortality > 6-12 wks
                   Anti-psychs L                         AD
Haloperidol                                                              (sudden cardial death)




Huntingon's Disease :: Mitochondrial role?, Caudate of Basal Gaglia → ↓ Ach, GABA
…… * Autosomal Dominant, CAG repeat, 30-40s, Hyperkinetic, Choreiform movement, Progessive Dementia + Motor decline
Tetrabesine
                            movement                ↓ dopamine
Reserpine
Fluoxetine
                     depression + irritability
Carbamazepine
Clozapin
                       psychoisis, paranoia      treat with low dose
Carbamazepine

Benzodiazepines               Anxiety




Amyotropic Lateral Sclerosis (ALS) :: (SOD1 gene) Ventral Horn + Corticospinal Motor Tracts
…… * Rapidly progressive weakness, atrophy, fasciculations, DEATH from RESPIRATORY 2-3 years
For all DAergic drugs:
PNS - arrythmias (B1)
.        hypotension
CNS -N/V(emetic center)
.   dyskinesia, agitation .
hallucinations         (DA-
R in other parts of brain)
                       Weak Base: unionized → cross Lipid Membrane                             co-administer w/            α1-agonist = vasoconstrict
Local Anesthetics                                                                                     * remain local, prolong effects + ↓ toxicity
                       ,,,,,,,,,,,,,,,,,, ionized → Activated (require acidic env)

                                                                                                     ADMINISTRATION
Procaine                                                                                     Topical ::                                                 Short Duration.
                                                                                             Skin, Mucous Membrane, Cornea                     Infiltration, Nerve block, Spine
                                                                                                - EMLA :: mix 2+ solids = liquid                          NOT Topical
Chloroprocaine                                                                               Infiltration ::
                                                            DOC: Liver Problems              Inject SubQ tissue (dental, suture)
                                                                                               - Epi added except end-organ)                           Infiltration …..
Tetracaine                                                          Esters.                  Nerve Block :: Regional                                     Topical …...




                                                                                                                                                                                Medium Duration
                                                            Metabolized by Plasma +          Inject Peripheral nerve/plexus
                                                                  Tissue Esterases           Spinal Intrathecal ::
Benzocaine                                                                                                                                             Topical only …...
                                                                                       ……………………………………
                                                                                         Inject Subarachnoid + tilt body
                                                           Allergy via PABA metabolite ……………………………………
                                                                                           - headache from CSF leaking LP
Dibucaine                Block inactivated axonal                                          - ↓ Respiration if ascend too high                          Topical …..
                               Na+ channel                                             ……………………………………                                           * hemorrhoids + rectal * …..
(exception to "-i ")                                                                       - meningitis (rare)
                                                                                       ……………………………………
                                                                                         Epidural :: Systemic
                                     .
                                                                                       ……..…………………………..
                                                                                         Injet Lumbar or Caudal epidural                           (-) NE uptake …..
Cocaine                  (prevent depolarization)                                           - beware Cardio + Neurotoxic
                                                                                       ……………………………………                                            * vasoconstriction * …..
                                    .
                                                                                       ……………………………………                                            Class Ib antiarrythmic




                                                                                                                             Short Duration
                                    .                                                  ……..
Lidocaine                                                                                                                                     Infiltration, Epidural, Nerve block,
                                    .                                                  .. Neurotoxicity                                                  Spinal, Topical
                                    .                                                  .. CardioToxic
                                                                                                                                                     Infiltration, Topical
                                                                                       .. Allergies
Prilocaine                                                                                                                                    * toxic metabolite toluidine *
                          pain/temp ---------- motor                                                                                              (met-hemoglobinemia)
                                                                    Amides.
                         C > B > Aδ > Aβ > Aα                  Metabolized by Liver                                                           Infiltration, Epidural, nerve block,
Bupivacaine                 recovery in reverse                                                                                                       spine, NOT topical
                                                                    Amidases




                                                                                                                             Long Duration
                                                                                                                                                   Infiltration , nerve block
Etidocaine                                                                                                                                                NOT Topical

                                                                                                                                              Infiltration, Epidural, nerve block
Ropivacaine                                                                                                                                              NOT Topical
                                                                                            ↓ CV resistance,
General Anesthetics :: Inhaled ( ion channel signal transduction)
                                                                                          ↑ perfusion to brain
::   -- after IV agent = can be rapidly regulated
                                                                                            Bronchodilation
                                                                                        NO CV or Respiratory
                                                                 Analgesia                                         no metabolism                       ↓
Nitrous Oxide                                                                               depression
                              Non-Halogenated                 NOT Unconscious                                         B/G = Fast, leat potent
Gas                                                                                     megaloblastic anemia
                                                              NOT muscle relax                                          (little protein bound)
                                                                                         - oxidize cobalt in B12

                                                                                              Hepatotoxic          Slow
                                                                  Surgery                 Cardiac Arrythmia        metabolites ::
Halothane                                                                                                          - hypersensitivity = fatal in 50%
                                                            (no analgesic effect)       Malignant hyperthermia
                                                                                                                   - Hepatitis
                                Halogenated                                                         .              - use 1x per 6 months
                       .
Enflurane              ….. ↓ MAC = very potent                                             less CV toxicity
                       .                                      Muscle relaxation         more Resp depression           Medium rate of induction
Isoflurane             * less post-op N/V                                                Seizuer (high dose)
                       * dose-dependant ↓ RR, CV
                       * Uterine Relax = cesarean                                         Irritat respiratory
Desflurane
                                                                                              epithelium
                                                                                                                          Fast rate of induction
Sevoflurane                                                                                        J

     Drug/Class                 Mechanism                       Clinical Uses               Side Effects                    Miscellaneous

General Anesthetics :: IV → CNS depression :: Unconscious, Analgesic, Amnesia, Muscle relax

                                  Barbiturate                                                                                  fast-acting
Thiopental                                                Induction, short procedures    Resp & CV toxicity
                                   (GABA-A)                                                                            lipid soluble = redistribute

Midazolam                       Benzodiazepine                                                                            slower actions
                                                           pre-op sedation / anxiety    less CV + Resp effects
Diazepam                           (GABA-A)                                                                          Countered with Flumazenil

                                                                                          ↑ Itracranial Press,              medium-acting
                              (-) NMDA-Receptor              dissociative amnesia
Ketamine                                                                                  ↑ Cardiovascular            Similar to PCP-hallucinations
                                  (glutamate)                   DOC: children
                                                                                          ↑ BT, delerium                      " special K "

                                                                                                                               fast-acting
Propofol                           ? GABA ?                 Diagnostic procedures          ↓ Cardiac + CNS
                                                                                                                    not redististribute, no hangover
                                                                DOC : cardiac sx
Fentanyl               Opioid                    (μ→Gi)                                   NO cardiotoxicity                    fast-acting
                                                            twilight (w/ droperidol)
                                                             ER : rapid induction        Least effects on BP
Etomidate                        ? Histamine ?                                                                            No analgesic effects
                                                            Anesthesia + sedation             Less CV
Opioid Agonists :: Presynapse: close Ca2+                                                                                  3 receptors = Gi-coupled        ↓ NE, 5-HT, Substance P
………………………………… .. Postsynapse: open K+                                                                                          μ (pain), κ, δ             (ACh parasympathetics dominate)

Morphine
                           Pain from trauma,
                                                       EFFECT + SIDE EFFECTS are similar for all Opiods                         Leutenant's are NARCCs that work VIS.
                               cancer, MI

Codeine                                                 Antitussive (cough)                    * convert to morphine *
                                                                                                                                 L ongitude m. Relax / Circular constrict
                                                                                                                                    - Constipation (Laxative + Lubricant)
Hydrocodone (oral)                                     * with ASA/Acetominophen *                     ↓ potency
                                                                                                                                       Cramping (Anti-Spasm = M-blocker)
                                                                                               Oxycontin = slow release                     ex. Loperamide (tx diarrhea)
                           Moderate-Severe
Oxycodone      (oral)                                     * with ASA/Acetominophen *                                                 - Urinary Retention
                                Pain                                                                 ↓ potency                       - Inc. Biliary Pressure
                                                                                                                                     - Miosis (sphincter muscle = M3)
                                                  pregnancy (labor), biliary dz               ↓ smooth m (miosis, urine)
Meperidine                Acute-Severe Pain                                                                                       N ausea + Vomitting
                                                    post-anesthesia shivers                      * toxic metabolite *
                                                                                                                                      - (+) chemoreceptor trigger zone
                              Chronic Pain                                                            long acting                     - area prostrema = no BBB
Methadone       (oral)                                      Less euphoria                                                         A nalgesia ( μ – Receptor )
                               Addiction                                                      avoid rifampin + tramadol
                                                                                                                                       - dissociation = ↑ tolerance, ↓ perception
                                                                                                                                  R espiratory Depress ( μ – Receptor )
                                                                                                                                       - ↓ response to ↑ PCO2
                                                         100x more potent                                                              - DON’T give O2 ; DO give naxolone
Fentanyl
                                                   (IV, epidural, intrathecal, transdermal)                                       C ough Suppression ( NOT μ )
                             Cardiovascular                                                                                       C ircular m. Constrict
Sufentanil                                              1000x more potent                       minimal effects on ICP
                                Stability                                                                                         V asodilation, Cardiovascular (minor)
                                                                                                No Histamine release
                                                                                                           .                            - increase blood flow
Alfentanil                                                    less potent                        * muscle rigidity *                   - Hypotension (histamine)
                                                                                                                                  I tching (HS-Type I)
                                                                                                                                       - (+) histamine release
                            short procedures      * rapid onset, rapid recovery
Remifentanil (IV)                                                                                                                 S edation
                             w/ severe pain      (plasma esterase degrades)

                                                                                                                                                Contraindications :
                                                                                                                                         1) Head Injury
Partial Agonists :: precipitate withdrawl b/c antagonistic effects                                                                          - ↑ Intracranial Pressure

                                                  (-) NE + 5HT reuptake, weak μ                                                          2) Pulmonary Dysfunction
                             Mild-Moderate                                                          ↓ side-effects
Tramadol                                                                                                                                    - except edema or congestion
                                  Pain                  * with Acetaminophen *                    may cause siezure

                           Moderate-Severe                                                                                               3) Renal Failure
Pentazocine                                       κ agonist in spine + μ antagonist                                                         - glurcuronidation → M-6G
                                Pain                                                                                                                             (more acitve)

                           Moderate-Severe                                                        2-50x more potent                      4) Hepatic Failure
Buprenorphine                                              μ partial agonist
                             Addiction                                                              longer duration
                                                                                                                                         5) Adrenal / Thyroid dz
                             Acute-Severe                                                       Cardiovascular effects                      - increase response
Butorphanol     (nasal)                           κ agonist in spine + μ antagonist
                             Headache/CA                                                       ↑ pumonary a. pressure
                                                                                                                                         6) Pregnancy
                                                                                                                                            - exception : meperidine
 Short-Acting (1-2 hrs)                    Long- Acting (6-8 hrs)                 Transdermal (48 hrs)
   Fentanyl, "-tanil"     Diphenoxylate, Loperamide, Dextromethorphan < Methadone    Fentanyl patch
                                                                                                                                           Acute Toxicity Triad.
                                                                                                                                       1. Pinpoint Pupils
                                                                                                                                       2. Repsiratory Depression
                                                                                                                                       3. Coma
                                                                                                                                          Tx : Supportive + IV naxolone
Other Uses for Opioids
                                                                                                              Opiate withdrawl:
                                                                                                       1)   Yawning
Diphenoxylate                                                                Combine with atropine     2)   Tears, Sweat, Salivation
                           Diarrhea              Meperidine Derivative                                 3)   Goosbumps
                                                                                Poorly absorbed        4)   Anxiety
Leperamide                                                                                             5)   Muscle cramps + Spasm
                                                                             (P-glycoprotein pump)
                                                                                                       6)   CNS Pain
                           Diarrhea
Paregoric                                         Camphorated opium
                           Teething                                                                  Tx: Supportive + Methadone
                                                                                                     …………………... Clonidine
Dextromethorphan          Anti-Cough




Neuropathic Pain = damaged neurons (opioids not effective)

                          Diabetic
Gabapentin                                        ↑ GABA (inhibitory)
                         Neuropathy
                          …………………………………..

                          Trigeminal                   ↑ NE, 5-HT
TCAs                      Neuralgia                 (-) Na-Channels




Antagonists

Naloxone (IV)                               reverse respiratory depression
                         block opiate
                          receptors           ↓ Addiction for EtOH and
Naltrexon (PO)
                                                       opiates
not > 48 hrs or high dose
      Drug/Class                   Mechanism                      Clinical Uses                         Side Effects                                    Miscellaneous
Na Channel Blockers :: prolong inactivation of Na channel                                                Blood Dyscrasias = Always monitor CBC
…       .* ↓ axonal conductance, prevent Paroxysmal Depolarization Shift (PDS)                      Renal + Hepatotoxic = BUN/Creatinine + ALT/AST

                                                                        ADULTS                                                   (+) CYP3A4                                                                                              ↑ metabolism, ↓ [ ]
                                                                * teratogenic = cleft lip *     Minimal CNS depression         low [] = 1st order elim                                                                                    OCT, antiepileptics
Phenytoin **               Na Channel Blocker                                                                                  high [] = zero order = toxic L                                                                             digitoxin, steroids
                                                                      Partial                   .
                           .. * only target channels                                                                                                                                                                                       Vit K, anticoags
                                                                    Tonic-Clonic                (-) Folate metabolism          .............................................................................................
                           …... open at high freq
                                                                                                                                                                                                                                                ..................

                                                                                                ... - Megaloblastic Anemia     High Plasma Protein Binding                                                                                 ↓ [phenytoin]
                           .                                    Status Epilepticus
                                                                                                Hirsutism, Osteomalacia        .. - hypoalbumin, uremia= ↑Vd                                                                               Antiepileptics
                           . "voltage + use dependant"           ** supplement with
Fosphenytoin (IV)                                                                               Gingival Hyperplasia           Genetic Polymorphisms
                                                                      Vitamin K
                                                                                                                               ..- monitor serum, don't ∆ brand
                                                                                                                               ................                                                  .................................

                                                                                                Cross BBB [CSF] = [Plasma]     (+) CYP3A4, 2C,                                                                                           ↑ metabolism, ↓ [ ]

                           * Na Channel Blocker                        Partial
                                                                                                .. - acute OD → stupor, coma   .... UDP glucuronyltransferase                                                                               itself, OCT
Carbamazepine                                                                                   Aplastic anemia, leukopenia.   1st order (linear) elimination J
                                                                                                                                                                                                                                                        .


                           * Upreg. Adenosine-R                    Tonic-Clonic
                                                                                                ... - may have to stop drug
                                                                                                                                                                                                                                          ↑ [active metab]
(related to TCAs)
                                                                    Bipolar (TCA)                                              * active metabolite =
                           * (-) NE Reuptake                                                    Renal + Hepatotoxic
                                                                                                                                                                                                                                         erythro, cimetidine
                                                                CN V + IX Neuralgia                                            ….. carbamazepine epoxide                                                                             propoxyphene, fluoxetine,
                           .                                                                    Hypersensitivity Rxns
                           . "voltage + use dependant"         Anti-diuretic (↓ ADH)                                           * multiple daily dosing                                                                               isoniazid    anti-epileptics
Oxycarbazepine                                                                                  ↓ side effects

                                                                Partial, Generalized
                           * Na Channel Blocker
Topiramate                                                           Myoclonic                  * well tolerated                          metabolized by CYP3A4
                           * GABA, AMPA, Kainate                 Lennox-Gastaut

                                                                Partial, Tonic-Clonic
                                                                                                Stevens-Johnsons               Substrate Glucuronidation                                                                                   ↓ t1/2 lamotrigine
Lamotrigene                * Na Channel Blocker                 Atypical Absence                                               * phenyltriazine derivative *                                                                             Phenytoin, Phenobarb
                                                                                                DIC, ataxia, dizzy, blurry
adjunt or monotherapy      * (-) Glut release                   Juvenile Myoclonic,                                                                                                                                                         Carbamazepine
                                                                 Lennox-Gastaut                 Anti-Folate agent


T-Type Ca Blockers :: Generalized + Absence Siezures.
                                                                                                   Absence :: Ethosuximide > Valproate > Lamotrigene
(↓ pre-syn influx)……* Thalamus not relay to cortex (sensory except smell)
                                                                                                Parkinsonian-like synd
                                                                                                                               NOT induce CYP450
                                                                                                Photophobia, Rash, Lupus
Ethosuximide               Ca blocker in Thalamus             DOC: Absence Seizure
                                                                                                GI issues, CNS depression
                                                                                                                               * start low, gradually ↑dose
                                                                                                Blood dyscrasias, BMS          .. to minimize side effect


Combined Na+ + Ca2+ Channel Blockers
                                                               * teratogenic = spina bifida *                                  (-) CYP2C9, UGT                                                                                            ↓ Effectiveness
                                                                                                * used as combo drug *
Valproate                  * Na + Ca Channels                  Partial, Tonic-Clonic,                                          ..                                                                                                    Phenytoin, Phenobarb
                                                                                                Hepatotoxic, Pancreatitis                                                                                                            .

(valproic acid)            * ↑ GABA synthesis                   Myoclonic, Absence                                                                                                                                                   ↑ [ ] = Salicylates
                                                                                                Hyperammonemia
                                                                  Bipolar Disorder                                                                                                                                                   ↓ [ ] = anti-epileptics
Zonisamide                                                      Partial, Generalized
adjunt therapy             * Na + Ca Channels                        Absence
                                                                                                Metabolic Acidosis             * Sulfonamide = sulfa allergy
GABA Agonists :: increase inhibitory tone
                                                              Simple Partial
                                                                                   * Low Toxicity, Tolerance                                                                        (+) CYP
Phenobarbital **           Barbiturates                        Tonic-Clonic
                                                            Status Epilepticus     .                                                                                                can be used in Absence
                           * Prolong GABAA
                                                                                   Sedation, ataxia
                           * ↑ duration of Cl opening            Partial                                                                                                            active metab = Phenobarb
Primidone                                                      Tonic-Clonic
                                                                                   slowed cognition
                                                                                                                                                                                    * less potent
                                                        Absence, Myoclonic & Atonic      Long-Term Managment
Clonazepam                                                      in children         .            (children)

                                                                                    .
                           Benzodiazepines
Clorazepate                                                                         * lowest toxicity, Tolerance                                                                            Metabolized by liver CYP450
adjunct with other drugs
                           * potentiate GABAA-R                   Partial          ..............................................................................................
                                                                                                                                                                                         Lipophillic : cross BBB, placenta
                           * ↑ frequency Cl opening                                Arythmia, ↓CNS, mild ↓ RR
Diazepam **                                                                        Hypotension, Anxiety
                                                             Status Epilepticus
Lorazepam **

                                                          Partial, Generalized                                                                                                      Short t1/2
Gabapentin                                                                         * low side effects                                                                               ….. * multiple daily dosing
                           ↑ GABA release                        Migraine
                                                                                   * well tolerated, side effect                                                                    Lipophillic : cross BBB, placenta
adjunt or monotherapy      … - unknown mechanism           Diabetic Neuropathy
                                                                                   .. disappear in first wks                                                                        .......................................................................................................
                                                           Bipolar, herpes pain
                                                                                                                                                                                    * start low, gradually ↑dose

                                                           Partial, Generalized    Amnesia, Hypersensitivity
Vigabatrin                 (-) GABA transaminase                Refractory         Blurred vision, eye pain                                                                         NOT metabolized by CYP450
adjunt therapy             ……     * irreversible
                                                          LAST RESORT DRUG         Blue-yellow blindness

Tiagabine                                                    Refractory Partial    Facilitate GABA effects                                                                          Substrate CYP3A
adjunt therapy             (+) GAT-1 re-uptake                 Tonic-Clonic        .. * may cause Absence sz                                                                        anti-epileptics ↓ t1/2


NMDA-R :: excessive activation dispaces Mg2+ block
…… * Ca2+ influx → (+) NOS → NO synthesis → excessive Glutamate
                           * NMDA-R antagonist              Refractory Epilepsy    Aplastic Anemia (low risk)
Felbamate                                                                                                                                                                                      metabolized by CYP3A4
                           * Na + Ca Channels                (Lennox Gastaut)      Hepatotoxic (high)



Inhibit Burst Firing WITHOUT affecting normal neural activity
Levetiracetam              (-) Post-synaptic                     Partial
adjunct therapy
                                                                                   Excrete in Urine unchanged.                                                                                  NO CYP metabolism
                           ….. Binding site                    Tonic-Clonic

Status Epilepticus = **
Adjunt Therapy =
                         low [] = 1st order elim
                         high [] = zero order = toxic
                         ................
                         .................................

                         CYP3A4 Inducer
                         - anti-epileptics, OCT,
                         levadopa ..methadone, anti-
                         coag,                     -↓
                         Vitamin K, digitonin, steroids
                         ........................................................................................

                         ...                                                    *
                         CYP3A4 Inducer
                         - ↑ by itself
                         - ↓ by erythromycin, propoxyphen,
                         cimetidine, fluoxetine, isoniazid, anti-
                         epileptics
                         ....................................................

                                                                   * Increase metab of OCT
                         ...........................................




                         difference helps reduce the impact on the liver of
                         metabolizing the drug, and also prevents the
                         serious forms of anemia or agranulocytosis
                         occasionally associated with carbamazepine.




prolonged period of depolarization, called the paroxysmal depolarization shift (PDS)
                                                                                                               Respiratory Depression                      ↑ Tolerance -->↑TI
                                                                     Anitconvulsant, Euphoria, Sleep
Barbiturates                      GABAA-gated Cl channel
                                                                           (↑total sleep time)
                                                                                                             (small margin in anesthesia)                * cross tolerance w/ CNS
                                                                                                               High dose :: ↓ BP, HR                           depressants

Thiopental (IV)               * Prolong GABAA                               Induce Anesthesia                (lipid soluble→ redistribution)          General CP450 Inducer.
(very short acting)                                                         Emergency Siezure                         laryngospasm                        (avoid in porphyrias)
                              ↑ duration of Cl opening
Pentobarbital                 .                                                 Insomnia                               short-acting                 * ↑metabolism of Vit K/D, steroids/OCT,
                              note: can affect w/o GABA                      Pre-Op Sedation                                                                cholesterol, bile acids
Amobarbital                   .                                             Emergency Seizure                        medium-acting                                     .


                              * (-) excitatory AMPA-R                                                                                                     Liver glucuronidation
                                                                       Status Epilepticus, Seizure                     long-acting
Phenobarbital                 * ↑ BZ Binding
                                                                            Daytime Sedation                            slow onset
                                                                                                                                                            Secreted in Urine

Thiobarbiturates Distribution :: #1 BRAIN → Highly Perfused Tissue (skeletal m) → Poorly Perfused tissue (adipose)                                           * All Cross Placenta *
* INACTIVE METABOLITES BUT SLOW Metabolism = long half life / multiple dosing can be cumulative / residual CNS depression can last 24 hrs                   Avoid in COPD, Asthma
* Paradoxical Excitiement (Elderly), Allergy Common                                                                                                               Hypotension
                                                                                                                         Barb withdrawl:
                                 * Supportive, Gastric Lavage                                                       1) Agitation
OVERDOSE TX                      * Avoid CNS stimulants (↑ mortality)                                               2) anxiety
                                 * Alkanization of urine = ↑ excretion of acidic barbs                              3) Seizure (life-threatening)


                                                                                                                                                   SCN = ↑ GABA
                             Mel1a = SCN, (Gq)
Melatonins                                                          Tryptophan → Seratonin → Melatonin (Pineal Gland) →                        Hipp, Cortex = ↓ GABA
                             Mel1b = retina, (Gq)
                                                                                                               Drowsiness, Hallucination              Beware in Pregnant, Children
Melatonin                         *circadian rhythms *                    Insomnia, Jet Lag                      EtOH, Caffeine = ↓                      ↑ Depression, ↓ Sex
                                                                                                              Flumazenil, naloxone = (-)                  avoid if on SSRI's

                                                                                                                                                          NO Dependance/Abuse
                                                                                                             ↑ prolactin, ↓ testosterone                Fluvoxamide, ketoconazole
Ramelteon                            ML1, ML2 agonist                Insomnia (sleep latency)                  Anaphylactic Allergies                    (inhibit CYP metabolism)
                                                                                                             Avoid Pregancy (teratogen)                     Rifampin, Fatty meal
                                                                                                                                                          (reduced effectiveness)



                                          Status Epilepticus (kids), Delerium Tremens
Paraldehyde                             Psychiatric Excitement, Abstinence Phenomenon


                                  Insomnia, pre-op sedation                  Cardiac, Renal,….
Chloral Hydrate                       Children (Dental)                      Hepatic Failure….
                                                                               Street Drug….
Meprobamate                                                                   similar to BZ….
                                                                            high dose = Barb….
                                      Anxiety, Sedation
Hydroxyzine
(long-acting)                                                               Anti-Chlinergic…..
                                                                           (anti-DUMBELLS)…..
                                    1st gen anti-histamine.                additive w/ ↓CNS…..
Diphenhydramine                            Insomnia
                                                    Barbiturates + Alcohol                linear = lethal... * Pain unipaired until unconscious
                   coma                            .                                         - more CNS... * small dose = ↑ pain
    UNSAFE     .
 Cardio & Resp .
                   medullary depression                 Benzodiazepines                   plateau = safer.. * less CNS = NOT anesthetic
     Inducers   . anesthesia                       .                                          - allosteric…. … - Not relaxed, still aware
                                                                                              - less CNS…. … - pre-anesthetic = amnesia
                   hypnosis
     SAFE      .
                 sedation, anxiolytics + anti-seizure
Drug Treatment .
   Drug Abuse   . Paradoxic Dis-Inhibition

                               [Dose]



                                                                                                                         Delerium
                                                                                                                         Tremens

                                                                          * cross tolerance b/n all 3                    * life-threatening withdraw
                                                                                                                             1. Hyperactive.
                                                                          * Abuse : BZ < Barb & EtOH.                               * HTN, tremo
                                                                                                                                    * arrythmia
                                                                                                                              2. Psychosis
                                                                                                                                    * visual & tactile
 unconscious
n
                              BZ1 = sleep                                       GABA binding site = ↑ Cl- influx




                                                                                                                               Hyperpol
Benzodiazepines                                                        α
                                                                      Clinical Uses                 Side Effects
                              BZ2 = memory/motor                         - γ                                                              * require 2 GABA to activate
                                                                      Cl        BZ binding site = ↑ GABA binding
                                                                                                             (potentiation)               * Penicillin binds inside channel
Beware :: Children, Liver Failure (CYP metab)                           β           Barb binding site = ↑ K+ efflux                       * Tetanus(-) GABA release
Pregnancy, Sleep Apnea, COPD (Resp Acidosis)

         Midazolam                                             Low Dose: Anxiety                                                          most metabolized by liver
         Oxazepam                                              - Siezure                                                                  .... CYP3A4, CYP2C19
                                                                                                    Arrythmia, ↓CNS, Hypotension,
        Temazepam             * potentiate GABAA-R             - Heart Vasodilate (IV)                                                    .
                                                                                                           mild Respiratory
         Alprazolam           .                                ..... * ↓ BP, HR                                                           .......... ** SAFER **
                                                                                                                  .
         Lorazepam            ↑ frequency Cl opening ......... High Dose: Sleep                                                           NO anesthesia or death
                                                                                                         Motor > Cognition
          Diazepam            = plateau                        - Pre-Anesthetic (amnesia)                                                 toxic if combine w/ EtOH
                                                                                                        CNS affects ↑ as age
               .
      BZ withdrawl:           .                                … * NMJ block at high dose                                                 .
               .                                               OTHER                                              .                       Lipohillic :: oral, cross BBB
1)   rebound insomnia         note: NOT GABA receptor
                                                               - ↓ CO (Diaz, Midolozam)                     Paradoxical
2)   anxiety .                ...... .. but require GABA                                                                                  ... * redistribute (muscle, fat)
3)
.    Tremors                .                                                                           ↑ Anxiety, Paranoia               ... * cross BBB, placenta
                                                               - ↓ GI acid from anxiety
4)   anorexia, .fainting                                       Alcohol/Barb Detox                                                         ... * excreted in breast milk

ANXIETY ::
Oxazepam           <       Lorazepam (IV) < Clonazepam < Alpralozam                      <     Chlordiazepoxide (IV), Diazepam (IV)
                     * extrahepatic conjugation               * panic disorder                     * alcohol withdrawl             * alcohol withdrawl
                          (glurcuronidation)                  * Seizure                                                            * Seizure
                                                                                                                                   * Spasm, Spasticity
                                                                                                                                    FULL BZ AGONIST
Insomnia::                                                                                                                             (-)Ionitropy :: ↑heart BF, ↓CO
 Zaleplon, Zolipedem < Triazolam                   <    Temazepam < Estazolam                  <    Flurazepam
 * not change sleep stage                                                                                                                 IV = acute :: pre-op anesthesia



Zolpidem (Ambien),                                                    sleep disorders
                                      BZ1 receptor
Zaleplon                                                         (sleep onset, not ∆ stages)
                                         agonist                              .
Eszopiclone                     ** not benzodiazepine **            dizzy, drosy, headache



Flunitrazepam                    10x more potent than                   Date-Rape
(Rohypnol)                            diazepam                   * deep sedation, amnesia



                                     BZ-binding site              ↑ anesthesia recovery,               can't reverse ↓ CNS                  Also zolpidem and zaleplon
Flumazenil
                                       antagonist                     BZ overdose                    * avoid in Barb b/c siezure                  (IV), t1/2 = 1 hr
                                   GABA-binding site
Bicuculline
                                      antagonist

				
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