442-MT2

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jgiantess
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129915
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442-MT2
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2012-03-19 02:11:28
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pharmacology
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pharmacology
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  1. cyclobenzaprine
    • skeletal muscle relaxant
    • MoA: decreases activity of locus coeruleus, so decreases activity of descending facilitative influence on motor neuron excitability
    • decreases muscle tone (less flexion and extension)
    • aka "disfacilitation"
    • structurally similar to TCA
    • SE: antimuscarinic: sedation, confusion, dry mouth, dizziness, urinary retention
    • OoA: 1 hr
    • t1/2: 18 hrs
  2. methocarbamol
    • muscle relaxant
    • MoA: unclear...may suppress excitatory interneurons in spinal cord -> decrease amp of polysynaptic reflexes.
    • less excitatory drive to motor neurons -> muscle relaxation
    • said to decrease muscle tension without reducing basal muscle tone to maintain posture.
    • SE: sedation (v. significant), dizziness, blurred vision, dyspepsia, metallic taste
    • OoA: 30 mins
    • t1/2: 1-2 hours
  3. baclofen
    • GABA-mimetic, spasmolytic
    • agonist at GABAb receptors. does not requre presence of GABA for action.
    • reduces muscle spasticity, equally effective but less sedating than BZD
    • OoA: rapid after oral admin
    • t1/2: 3-4hrs
    • can be given intrathecally for refractory spasticity
  4. benzodiazepines (e.g. diazepam) for lower back pain
    • act on GABAa receptors but require GABA to exert action (not bind to same part as GABA)
    • enhances effect of GABA, increases frequency of chloride channel opening
    • OoA: almost immediate. oral 15-30mins.
    • t1/2: 5-50 hours (depends on metabolism and properties of diff agents)
    • SE: sedation, confusion, slurred speech, hypotension, brady, apnea
    • DEPENDENCE, withdrawal if stop. Important to taper dose.
  5. triptans
    • selective agonist for 5-HT1d and 5-HT1b receptors
    • e.g. suma, riza, nara, zoli, almo, ele
    • MoA: 1) bind to presyn 5-HT1d and inhibit release of neuropeptides, 2) direct VC/px of VD of meningeal bv, 3) block afferent input to 2o neurons in trigeminal nucleus caudalis.
    • PK: most effective when given in early stages of migraine (within 2 hours of onset). hepatic metab via MAO-A enzymes
    • dosage routes: PO, SL, intranasal, IV, IM
    • OoA: 15 mins with SC/IV
    • suma F 15%, newer agents F 50-70%, but not 100% so IV is most preferred.
    • SE: well tol'd...ass'd with stroke and CVD?
    • risk of serotonin syndrome if: MAOI in past 2 weeks, Ergot in last 24 hrs.
    • SSRIs and SNRIs not absolute CI...but must tell pt how to monitor for serotonin syndrome.
    • CI: ischemic vascular disease
  6. ergotamine
    • ergot alkaloid, purified
    • agonist, partial agonist, antagonist: 5-HT & alpha-adreno
    • agonist, partial agonist: dopamine receptors
    • MoA: VC of meningeal blood vessels. stronger affinity, up to 24 hours before dissociates from receptors.
    • dosage routes: IM, IV, SC, intranasal
    • SE: may worsen N/V, cause rebound headache, dependence, prolonged vasospasm
    • Administer with antiemetic.
  7. dihydroergotamine
    • ergot alkaloid, semi-synthetic
    • agonist, partial agonist, antagonist: 5-HT & alpha-adreno
    • agonist, partial agonist: dopamine receptors
    • MoA: VC of meningeal blood vessels. Higher affinity to alpha-adrenoreceptors, but lower receptor affinity vs. ergotamine for all other receptrs...mmore rapid hepatic elimination.
    • dosage routes: IM, IV, SC, intranasal
    • OoA: 15-30 mins
    • CI: hypertension, ischemic cardiovascular disease, current use of MAOI or strong CYP3A4 inhibs (azoles, macrolides)
    • SE: may worsen N/V, not cause rebound h/a or dependence.
    • Administer with antiemetic.
  8. metoclopramide (chlorpromazine, prochlorperazine)
    • antiemetic, used as monotherapy or adjunctive therapy in tx migraines
    • block dopamine and alpha-adrenoreceptors
    • - chemoreceptor trigger zone: decrease N/V
    • - trigeminovascular system: vasoconstriction...helpful for migraines?
    • metoclopramide enhances ACh action...accelerates gastric motility, increases lower esophageal sphincter tone.
    • SE: extra-pyramidal (akathisia, tardive dyskinesia, dystonia) if long term, and drowsiness
  9. monoamine oxidase inhibitors
    • irreversible: phenelzine, tranylcypromine
    • reversible: moclobemide
    • - well absorbed from GI, peak levels in 2-3 hrs, metab’d in liver (acetyl), excreted in urine
    • - *precaution: hepatic or renal impairment, pregnancy and lactation
    • - NOT 1st line: resistant depression.
    • - SE: INODES
    • - overdose: sx 12 hours after ingestion: tachy, circulatory collapse, sz, coma
    • - tx of overdose: eliminate toxin via gastric lavage, urine acidification, hemodialysis
    • - DI: TCA, sympathomimetics, SSRI/SNRI, meperidin, tyramine.
  10. TCAs for depression
    • tricyclics: 2o: desi, nortrip (pref NE block). 3o: imip, amitrip, clomip, doxepin, trimip (pref 5-HT block)
    • tetracyclic: maprotiline
    • increasing NE selectivity: ami < imi < nor < maprotiline
    • - well absorbed from GI, highly PB and lipid solub, peak levels in 2-3 hrs, metab’d in liver (acetyl), excreted in urine
    • - *precaution: hepatic or renal impairment, pregnancy and lactation
    • - depression, childhood enuresis (imipramine), OCD (clomipramine), adjunctive analgesics, trigeminal neuralgia
    • - SE: antichol, antihist, antiadrenergic, sexual dysfxn, reduced sz threshold
    • - overdose: lethal. tx: activated charcoa, urine alkalinization to speed elim, life support.
    • - DI: MAOIs, barb/cbmz/rifampin induce enzymes, cimetidine/atipsychs inhibit enzymes, clonidine (dec'd anti-htn effects)
  11. SSRIs
    • citalopram, fluoxetine, fluvoxamine, paroxetine, escitalopram, sertraline
    • increasing 5-HT selectivity: clomipramine < fluoxetine < sertraline
    • - selectively inhibit human serotonin transporter (hSERT) and cause increased 5-HTP concentrations at nerve endings.
    • - little/no effect NE/DA
    • - little/no CVS effects
    • - 1st Choice AD because greater tolerability and ease of dosing.
    • - CNS: h/a, sleep disturbance, dizziness, anorexia, tremor, nervousness
    • - GI: N, D, C, dry mouth, GI bleeding
    • - sweating
    • - sexual dysfunction
    • - DI: MAOIs, CYP450 inducers, CYP450 inhibitors.
  12. SNRIs for depression
    • venlafaxine, desvenlafaxine, duloxetine
    • - inhibit reuptake 5-HTP, NE, dose dependent.
    • - low doses: SSRI
    • - med doses: + NE block
    • - high doses: + DA block
    • - Use: depression, neuropathic pain, pain ass`d with fibromyalgia
    • - SE: CNS: sleep disturb, insomnia, drowsiness, dizziness, nervousness
    • - GI: nausea, dry mouth (Ach) at high doses
    • - CVS: htn at high doses
  13. NE and DA reuptake inhibitors
    • bupropion
    • - antidepressant effects thru NE and DA reuptake inhib
    • - blockade of DA uptake > NE uptake
    • - sx of DA deficiency targeted: anhedonia, hypersomnia, cognitive slowing, inattention, craving
    • - good sub for SSRI-induced sexual dysfunction
    • - Use: depression, smoking, ADHD
    • - SE: agitation, anorexia, insomnia, Sz (dose dependent)
    • - CI: current Sz disorder, bulimia or anorexia nervosa (GABA changes inc risk of sz)
    • - DI: MAOIs
  14. 5-HT antagonist/reuptake inhibitor
    • trazodone
    • - potent blocker of post-synaptic serotonin receptors
    • - weak serotonin reuptake blocker
    • - Use: depression, hypnotic in depressed pts
    • - SE: daytime sedation at tx doses
    • - orthostatic hypo, N, h/a, priapism, dry mouth
  15. NE and specific 5-HT antidepressants
    • mirtazapine
    • - drug blocks central presyn alpha-2 adrenergic inhibitory autoreceptors
    • - results in increased central NE and 5-HTP activity
    • - Use: depression
    • - SE: antihist (weight gain, sedation), antiadrenergic (orthostatic hypotension)
    • - DI: MAOIs
  16. chronic antidepressant use:
    • - desensitization of of post-synaptic receptors
    • - block NMDA receptors (reduce glutamate activity), increase synthesis of microtubules (change signal transduction), enhance synth and transport of NT synthesizing enzymes (tyrosine and tryptophan hydroxylase)
    • - normalize muscarinic supersensitivity
    • - reduce proinflammatory cytokines and PGE2 (and normalize/increase central MA release)
    • - reduces cortisol, increases BDNF (transcription factor) to increase neuronal plasticity and recovery (esp increase hippocampal volume)
    • - sensitizes GC receptors on catecholamine and 5-HT cell bodies to normalize NE and 5-HT function (that is reduced by hypercortisolemia)
  17. phenobarbital
    • 1) GABA-A receptor allosteric modulator: enhance GABA-mediated pre-syn & post-syn inhibition
    • 2) block release of glutamate from pre-syn terminals (axo-axonic)
    • - partial & tonic-clonic seizures
    • - long action, t1/2 100 hours
    • - CYP2C and CYP3A enzyme inducer: alters metab of many drugs (e.g. oral contraceptives)
    • - VPA increases phenobarb levels
    • - SE: sedation (w/ tolerance), nystagmus & ataxia (higher doses), hyperactivity in kids, confusion in elderly.
  18. primodone
    • - active metabolite is phenobarb, but primodone also active.
    • - use similar, but used as adjunct
    • - SE: blood dyscrasias more likely
  19. phenytoin (Dilantin)
    • 1) Na+ channel blocker: increase refractory period,decrease ability to generate high f Na+ spikes (stabilizes neuronal membrane, decreases NT release, focal firing, and sz spread.)
    • - partial, tonic-clonic, status epilepticus.
    • - NOT effective in absence or myoclonic: may worsen
    • - saturable metabolism, t1/2 20-60hours
    • - Topiramate enzyme inhib (increase PHT), CBZ, VGB enzyme inducers (reduce PHT), and vice versa.
    • - pregnancy increases metabolism, so dose must be adjusted before and after delivery
    • - SE: nystagmus, ataxia, slurred speech, confusion, tremor, gingival hyperplasia, skin rash/acne, hirsutism, coarsened facial features
  20. carbamazepine (Tegretol) for epilepsy
    • 1) Na+ channel blocker: increase refractory period,decrease ability to generate high f Na+ spikes (stabilizes neuronal membrane, decreases NT release, focal firing, and sz spread.)
    • 2) Alleyne: also GABA-a receptor allosteric modulator (inc. membrane hyperpol & sz threshold, dec. focal firing, aggravate spike-wave discharges)
    • - complex partial & tonic-clonic, also for trigeminal neuralgia
    • - may worsen absence & myoclonic
    • - slow and variable absorption, t1/2 10-20 hours
    • - induces enzymes (decrease clobazam, VPA)
    • - SE: drowsiness, ataxia, seizures at high doses, diplopia, transient leukopenia
  21. valproic acid (Depakene)
    • 1) GABA-T blocker / stimulator of glutamic acid decarboxylase to synthesize GABA
    • 2) Na+ channel blocker: blocks high f Na+ spikes
    • 3) T-type Ca2+ channel blocker: decrease oscillation of cortical-projecting thalamic neurons
    • - broad spec: partial, tonic-clonic, absence
    • - inhibits drug metabolizing enzymes, and increases phenobarb levels
    • - SE: GI disturbances, sedation, transient hair loss
    • - toxicity: hepatotoxicity(rare) in kids 2 years old, pancreatitis
  22. ethosuximide (Zarontin)
    • 1) T-type Ca2+ channel blocker
    • - absence seizures
    • - SE: GI disturbances, sedation, dizziness, headache
    • - methsuximide is similar but less effective
  23. benzodiazepines
    • 1) GABA-A receptor allosteric modulator: enhance GABA-mediated pre-syn & post-syn inhibition
    • 2) block release of glutamate from pre-syn terminals (axo-axonic)
    • - DOC for arresting status epilepticus (lorazepam, diazepam)...IV for fast effects.
    • - otherwise, not effective for most seizures...tolerance rapid.
    • - used mainly in adjunctive therapy
  24. gabapentin (Neurontin) for epilepsy
    • 1) Na+ channel blocker (high f)
    • 2) may release GABA from glial cells
    • 3) Alleyne: act as alpha-2-gamma ligands to modulate NT release
    • - appear not to have GABA agonist activity.
    • - adjunctive therapy with partial or tonic-clonic seizures, also useful in chronic pain syndromes
    • - *is not PPB, and not metab'd by liver (not induce/inhibit metab of other drugs)
    • - well-tol'd (sedation, dizziness, fatigue, ataxia)
  25. vigabatrin (Sabril)
    • 1) GABA-T irreversible inhibitor (inc. extrasynaptic GABA & membrane hyperpol, dec. focal firing, aggravate spike-wave discharges.)
    • - (gabapentin-like) adjunctive therapy with partial or tonic-clonic seizures, also useful in chronic pain syndromes
    • - *is not PPB, and is excreted unchanged in urine & not metab'd by liver (not induce/inhibit metab of other drugs)
    • - well-tol'd (sedation, dizziness, fatigue)
    • - retinal degeneration
  26. lamotrigine (Lamictal) for epilepsy
    • 1) Na+ channel blocker
    • 2) Glutamate presynaptic release inhibitor, MoA not understood
    • 3) Alleyne: Ca2+ channel blocker
    • 4) Alleyne: enhancer of HCN (hyperpol-activated cyclic nucleotide-gated channels) activity -> bugger large hyperpol + depol inputs
    • - broad spec: partial, absence, tonic-clonic
    • - DI: PHT, CBZ increase metab while VPA reduce elimination
    • - SE: sedation, dizziness, fatigue, ataxia...severe derm reactions in children
  27. topiramate (Topamax) for epilepsy
    • 1) GABA receptor allosteric modulator: enhance GABA-mediated pre-syn & post-syn inhibition
    • 2) Na+ channel blocker
    • 3) AMPA blocker: decreased postsynaptic excitability of target neuron: block PDS
    • - broad spec: partial, absence, tonic-clonic
    • - SE: sedation, dizziness, fatigue, ataxia
    • - excreted unchanged in urine
  28. tiagabine (Gabatril)
    • 1) GABA neuronal uptake blocker
    • - adjunct for partial, tonic-clonic seizures
    • - metabolized by CYP3A - Drug Interactions!
  29. felbamate (Felbatol...not avail in Canada)
    • 1) Na+ channel blocker
    • 2) Glycine recognition site blocker @ NMDA receptor: prevents enhancement of NMDA actions
    • 3) Alleyne: enhance GABA actions
    • - broad spec: partial, tonic-clonic, absence
    • - excreted unchanged in urine
    • - may produce aplastic anemia and hepatic failure
  30. zonisamide (Zonegran...not avail in Canada) for epilepsy
    • 1) Na+ channel blocker
    • 2) T-type Ca2+ channel blocker
    • 3) Alleyne: brain carbonic anhydrase inhibitor (inc. HCN-med'd currents, dec. NMDA-med'd currents, inc. GABA-med'd inhibition)
    • - adjunctive therapy for partial or tonic-clonic
    • - well absorbed - 85% of oral dose is excreted in urine un-metabolized
    • - PHT, CBZ decrease, LTG increase levels of zonisamide
    • - well-tol'd (sedation, dizziness, fatigue, ataxia)
    • - may produce renal calculi (via inhibition of carbonic anhydrase)
  31. TCAs for neuropathic pain
    • desipramine, nortriptyline, imipramine, doxepin, amitriptyline
    • MoA:
    • - Inhibit NE/5-HT reuptake (monoamines), thereby enhances descending inhibitory NE/5-HT systems
    • - Blocks ACh, HA receptors on nociceptive pathways -> analgesia
    • - Stimulates/potentiates opioid analgesia
    • - Blocks ion channels (Na+) in peripheral nociceptors and afferent transmission to 2nd order spinothalamic neurons
    • - Also blocks NMDA receptors
    • Use:
    • - analgesia faster than AD 6-12wks (analgesic independent of antidepressant activit)
    • - E in decreasing burning pain in hyperalgesia
    • - Dose needs to be titrated
    • - Can work for NP pts with no depression
    • - Ca also help with depression, anxiety, insomnia (co-morbidities)
    • - If >100mg or over 40yo, check EEG first
    • o Risk cardiac toxicity (SCD, MI)
    • SE: Blurred vision, Cognitive changes, Constipation, Dry mouth, **Orthostatic hypotenson (esp Ami), Sedation, Sexual dysfunction, Tachycardia, Urinary Retention
  32. SNRIs for neuropathic pain
    • venlafaxine, duloxetine
    • MoA:
    • - Dual blockage of NE + 5-HT to act on descending inhibitory pain pathways (both needed for mediating analgesia)
    • - Duloxetine: similar binding affinity to NE and 5-HT Rs ==optimal efficacy
    • - Venlafaxine: also binds Na+ channels: don’t know if that helps
    • Use:
    • - Duloxetine: start at 30mg/d, increase to 60mg in 2 weeks = tx dose already. (max 120mg/day)
    • - Venlafaxine: 150-225mg/d, need renal dose adjustment, longer to titrate
    • - Minimize SE with slow titration
    • SE:
    • - Duloxetine: N, A, D, C, insomnia, dry mouth, sleepiness, headache, fatigue, urinary retention, sweating, BP
    • - Venlafaxine: dose-dependent inc. BP + HR, agitation, tremor, N (37%) at start, sweating, headache, sleep disturbances, withdrawal effects
  33. Gabapentin for neuropathic pain
    • - After nerve injury, Ca v α2δ-1 upreg in spinal dorsal horn and DRG in NP -> modulates excitability (increase NT glutamate, sub P, calcitonin release during pain, also changes synaptic neuroplasticity in dorsal horn)
    • MoA:
    • - Structural analogs of GABA (but no effect on GABA receptors)
    • - Bind to α2δ subunit of VGCC (N-type Ca2+ channel), reduces NP
    • - Block N-type Ca2+ channel @ VGCC : decrease Ca2+ influx into presynaptic afferent terminals of superficial laminae of dorsal horn -> decrease neurotransmission, decrease hypersensitivity
    • Use:
    • - Most commonly used for NP
    • - For peripheral (PHN, PDN, TGN)
    • - For central (stroke, spinal cord injury) (esp useful for stabbing/shooting pain)
    • - Binds α2δ-1 subunit of VGCC: decreases NT (Glu, NE, Sub P) release to postsynaptic terminals in dorsal horn
    • - NP dose 900-3600mg/d (div tid-qid)
    • SE:
    • - Takes long time to titrate because of SE: e.g. dizziness, edema…
  34. Pregabalin for neuropathic pain
    • - After nerve injury, Ca v α2δ-1 upreg in spinal dorsal horn and DRG in NP -> modulates excitability (increase NT glutamate, sub P, calcitonin release during pain, also changes synaptic neuroplasticity in dorsal horn)
    • MoA:
    • - Structural analogs of GABA (but no effect on GABA receptors)
    • - Bind to α2δ subunit of VGCC (N-type Ca2+ channel), reduces NP
    • - Block N-type Ca2+ channel @ VGCC : decrease Ca2+ influx into presynaptic afferent terminals of superficial laminae of dorsal horn -> decrease neurotransmission, decrease hypersensitivity
    • Use:
    • - For PHN, PDN (also anxiety, depression, and useful in migraine, fibromyalgia)
    • - 6x more potent than GPN
    • - Binds α2δ-1subunit of VGCC: decrease NT (Glu, NE, 5-HT, DA, Sub P) release to postsynaptic terminals in dorsal horn
    • - NP dose 600mg/d (div bid-tid)
  35. Ziconotide for neuropathic pain
    • non-opioid, non-NSAID analgesic
    • MoA:
    • - block N-type VGCC reversibly
    • - prevents release of excitatory NT (Glu, Calcitonin, Substance P) in CNS
    • - promotes NE med'd descending adrenergicinhibitory pathways of pain
    • - augments inhibition by opioids (synergistic)
    • Use:
    • - only approved in US
    • - intrathecal admin only
    • SE:
    • - Sedation, dizziness, N/V, somnolence, H/A, confusion, memory impairment, slurred speech, nytagmus, double/blurry vision, urinary retention, hypotention, increase creatine kinase, gait abnormality
  36. Carbamazepine, Oxcarbazepine for neuropathic pain
    • MoA: Block VGSC (Na+) high-f firing, by decreasing ability of Na+ channels to recover from inactivation
    • Use:
    • - CBZ: trigeminal neuralgia b/c of SE limit
    • - NP dose up to200-800mg/d (div bid)
    • - OXC: being explored for use in NP now
  37. Topiramate for neuropathic pain
    • MoA:
    • - block VGSC (Na+)
    • - activates K+ current: hyperpolarizing, inhibitory
    • - enhances postsynaptic GABA-A Receptor currents
    • - limits activation of AMPA-kainate glutamate receptors
    • Use: considered 3rd line after TCA, PGB, GPN, opioids have been tried
  38. Zonisamide for neuropathic pain
    • MoA:
    • - block T-type Ca2+ currents
    • = block VGSC (Na+) ...neuronal stabilization
    • Use: proposed for migraine, PDN, TGN, PHN, phantom limb pain, post stroke central pain
  39. Lamotrigine for neuropathic pain
    • MoA:
    • - blocks VGSC (Na+) - blocks sustained repetitive firing of neurons and delays recovery
    • - acts on Na+ channels to inhibit glutamate synaptic release
    • Use: beneficial in NP from stroke, chemotherapy...3rd line
  40. Levetiracetam for neuropathic pain
    • - Binds SV2A (synaptic vesicle protein), which interacts with synaptotagmin ==antihyperalgesic/antiexcitatory
    • - Also blocks VGCC (Ca2+) --> inhibit Glu release, Glu synth and regulation.
  41. Lacosamide for neuropathic pain
    • - Enhances slow inactiv. of VGSC (Na+) via shift curve to more hyperpolarized potential (less quick firing)
    • - Allows more membrane potentials to enter slow inactivation state, prolong repolarization & there are limited # of neurons avail for repol --> decrease spread of conduction
    • - Also interacts with collapsing-response mediator protein-2: modulate Glu, impact sprouting and neuroplasticity
    • - Studied in NP
  42. Opioids for neuropathic pain
    • MoA:
    • - Interact with μδκ opioid receptors, activate G-proteins
    • - G-proteins bind to N-type VGCC (Ca2+), inhibits Ca2+ currents and open Ca-dependent inwardly-rectifying K+ channels --> hyperpolarization and decrease neuronal excitability --> decreased ability of DRG sensory neurons to propagate pain signals
    • - decrease intracellular cAMP, decrease release of nociceptive NT e.g. substance P
    • Use:
    • - Ineffective by themselves, usually give GPN/TCA first, then add opioid
    • - Synergistic with ziconitide; may help reduce opioid tolerance, side effects
    • - Effect of Morphine on spinothalamic tract neuron excitability in normal vs NP states
    • o Normal rats: morphine decrease pain signal by 75%
    • o Diabetic rats: desensitized μ receptors (decreased # presynaptic opioid Rs), impaired activation of normal descending inhibitory systems…so morphine action was significantly attenuated.
    • - Also, pathological nerve damage --> “induction” of cholecystokinin (CCK)
    • o CCK antagonizes morphine effects in spinal cord…CCK antagonists found to allow greater analgesia of morphine in lab experiments
  43. Ketamine
    • MoA:
    • - Block NMDA receptor (high affinity, long-term inhib of neuronal hyperexcit.)
    • - Block VGCC (Ca) and depress VGSC (Na), attenuate hyperalgesia
    • - Alter cholinergic neurotransmission
    • - Block reuptake of NE and 5-HT
    • Use:
    • - Not used often (4th or 5th line) due to side effects
    • - Reserved for severe, hard to treat NP
    • - CRPS (complex regional pain syndrome)
    • - Postamputation pain
    • SE:
    • - Non-selective, therefore high % SE
    • - Hallucinations,dizziness, lightheadedness, nausea
  44. Lidocaine Patch/Cream/Gel
    • MoA:
    • - Block use-dependent Na channels (in tissues with high f firing APs)
    • - Reduce ectopic discharges from peripheral afferent fibres w/o numbness of treated skin
    • Use:
    • - If patch: mechanical barrier - decrease allodynia
    • - Confined location/lesion (PHN)
    • - 5% up to 3x applied qd over painful site (12 h on, 12 h off)
    • - 4 patches (1-24h) likely safe
    • Cautions:
    • - DI not likely
    • - Mostly local SE: application-site rash
  45. Capsaicin (topical 8% patch)
    • MoA:
    • - Agonist @ TRPV1 receptor on nociceptor ending.
    • - Normally, TRPV1 stim = integrated response to pH and T
    • - When activated, Na+ & Ca2+ enter cell
    • - Cause excitation (heat, burn, sting itch)
    • - @ 8%: Ca2+ also released from ER and other internal stores
    • - Ca2+ overwhelm local mechs that sequester Ca2+ --> osmotic swelling
    • - Lead to mitochondrial dysfxn
    • - Cells can’t maintain plasma membrane integrity
    • - Overstimulated nerve cells (with too many TRPV1 receptors) are killed
    • - = localized defunctionalization
    • Use:
    • - 8% patch x30-60mins
    • - Pain relief x12wks in HIV-AN and PHN
    • - Works on cutaneous nerves already damaged: already burning and numbness, capsaicin just removes burning.
    • SE: local burning, stinging, erythema…initially may be so painful that opioids are required
  46. Botulism Toxin
    • - Suppresses nociceptor sensitization
    • - Block release of excitatory NTs (CGRP, Sub P, Glu) from afferent nerve terminals
    • - Block P2X (ATP receptor) in sensory nvs
    • - Block TRPV-1 translocation in peripheral nociceptive nerve terms
    • Use: in patiets with muscle contraptures
  47. chlordiazepoxide (Librium)
    • very old BZD, rarely used
    • main use in alcohol withdrawal
  48. diazepam (Valium)
    commonly used, often prescribed to stop episodes of epilepsy, muscle relaxant, alcohol withdrawal, pre-op
  49. oxazepam (Serax)
    sleep, anxiety, alcohol withdrawal
  50. lorazepam (Ativan)
    • short-acting
    • pre-op and for anxiety
  51. flurazepam (Dalmane)
    rarely used: accumulates with use causing "hangover effect"
  52. triazolam (Halcion)
    • high rate of misuse and tolerance
    • withdrawal and rebound effects common
  53. clonazepam (Rivotril)
    anxiety, panic attacks, social phobias
  54. alprazolam (Lectopam)
    • anxiety and panic attacks
    • severe withdrawal can occur
  55. temazepam (Restoril)
    commonly used for sleep
  56. benzodiazepines (for hypnosis/anti-anxiety)
    • MoA:
    • - act allosterically to GABA-A receptors, enhance GABA-mediated presyn and postsyn inhibition by increasing Cl- ion influx --> hyperpolarization
    • - increase frequency of GABA-mediated Cl- channel openings...lowers [GABA] required toopen Cl- channels
    • - increase amplitude of IPSP, lengthen decay phase proportionally (slope not change)
    • - need GABA to function.
    • Sleep - Acute Effects:
    • - dec. sleep onset latency (to stage 2), inc. NREM stage 3 & 4 in first half of period, delayed onset of first REM period and dec. total REM sleep time, more stage 2 and less stag 3/4 in 2nd half of period, reduced phasic muscular twitches during REM, fewer awakenings.
    • Sleep - Chronic Effects:
    • - tolerance to REM effects (and some tolerance to NREM effects)...REM deficit remains een after tolerance develops.
    • - upon discontinuation:
    • 1) REM rebound: increase in nightmares and fear
    • 2) Rebound insomnia: prolonged sleep onset latency
    • Anxiolytic MoA: linked to activation of BZD receptors...
    • Precautions:
    • - hx substance abuse, sleep apnea, CNS depression (synergistic with alcohol), poor cognitive state, renal dysfunction (chlordiazepoxide need dose decrease), hepatic dysfunction (diazepam need dose decrease), elderly, MG
    • - avoid in pregnancy: oral cleft 1st tri, floppy infant syndrome/neonatal withdrawal 3rd tri
    • - avoid in lactation: excreted in breast milk
    • SE: drowsiness, dizziness, CNS depresson, ataxia, psychomotor impairment, disorientation and confusion, anterograde amnesia, dependence and tolerance (withdrawal: insomnia, N/V, twitching, paresthesias, irritability and anxiety, tinnitus, delirium, seizures...can be life-threatening; rebound effects e.g. anxiety or insomnia), aggression and excitement (paradoxical), depression, cardiovascular side effects (hypotension).
    • Signs of overdose: drowsiness, lethargy, impaired coordination and confusion, ataxia, ypotonia & hyporeflexia, hypotension, resp depression, seizures, coma, cardiac arrest.
    • Tx of overdose: supportive, charcoal, flumazenil (BZD antagonist, CI if BZD chronic or taking TCA)
    • PK: well-absorbed, highly PPB but no interactions, CYP enzyme metabolized, oxidation impared in hepatic dysfunction and elderly (avoid chlordiazepoxide, diazepam, flurazepam), others metab'd by conjugation (pref'd in elderly...LOT)
    • DIs: CNS depressants, grapefruit juice, CYP3A4 inducers/inhibitors, CYP2C19 inducers/inhibitors
  57. Zopiclone, Zolpidem, Zaleplon
    • MoA:
    • - bind to GABA-A receptors close to BZD site, enhance GABA-mediated inhibition by increasng Cl- ion influx, resulting in hyperpolarization.
    • - increase frequency of GABA-mediated Cl- channel openings
    • - increase amplitude of GABA-mediated IPSPs and lengthen decay phase proportionally.
    • - more selective for GABA-A receptors with alpha-1 subunit, most important for sedation.
    • Effect on sleep: decrease sleep latency, minimal changes in sleep architecture otherwise...but high doses may suppress REM sleep.
    • SE: bitter taste, CNS(somnolence, dizziness, confusion, anterograde amnesia, behavioural changes, nightmares, depression, coordination problems, "sleep-driving"), elderly at higher risk of SE, lower dose for hepatic/renal dysfunction, caution with CYP3A4 inhibitors and inducers, tolerance and dependence.
    • Overdose similar to BZD, withdrawal similar to BZD (has rebound insomnia: anxiety, agitation, delirium, seizures)
    • DI: increase CNS depression with other CNS depressants, CYP3A4.
  58. barbiturates (for hypnosis/anti-anxiety...but no longer used as sedatives b/c of SE and toxicity)
    • MoA:
    • - increase duration of GABA-mediated Cl- channel open times presynaptically and postsynaptically.
    • - increase amplitude of IPSP, lengthen decay phase 4-5x normal (slope decreased) because Cl- channels kept open for longer
    • - at high doses, do not need GABA to function...can activate Cl- channels directly --> basis of toxicity and lethality (massive inhibition ad CNS depression, shut down vasomotor centre...heart stops beating, coma, death.)
    • - can also reduce glutamate-induced depol by blocking AMPA receptors.
    • - narrow TI and low degree of selectivity.
    • Effect on sleep: dose-dependent. dec. sleep onset latency, dec. awakenings, inc. total sleep time, decrease slow wave sleep (stage 3 and 4 NREM), decrease REM duration. Tolerance of effects on sleep can develop within a few days...
    • CI: pts with porphyria (barbs increase levels of porphyrins), severe resp depression, pulm insufficiency.
    • Caution in pts with impaired hepatic, hx of drug abuse, elderly.
    • SE: generalized CNS Depression, decreased respiratory drive (higher doses depress neurogenic, hypoxic, chemoreceptor drive), low doses dec. BP and HR, high doses inhibit cardiovascular reflexes, chronic use induces CYP enzymes to increase metabolism of several drugs and substances, residual CNS depression, paradoxical excitement.
    • Overdose: suicide attempts, drug automatism (due to anterograde amnesia). Drowsiness/confusion -> ataxia/hyporeflexia -> hypotension, arrhythmias, pulmonary edema -> shock, coma, death.
    • Tx overdose: respiratory/hemodynamic support, activated charcoal.
    • Tolerance and physical dependence...abuse and euphorogenic effects. Withdrawal - insomnia, nightmares,sweating, irritablity, tremor, anorexia, weight loss, delirium, seizures, death.
    • DI: barbs are hepatic enzyme inducers...increase CNS depression with other CNS depressants (ESP alcohol).
  59. Chloral hydrate
    • MoA: metab'd to trichloroethanol in liver, exact MoA not clear. Act like barbiturates.
    • Use: rare, for paradoxical reactions to BZDs and in peds
    • Sleep: similar to barbs
    • SE: irritate mucosa membranes, cause GI upset **MUST EAT BEFORE TAKING, dizziness, ataxia, nightmares, confusion, vertigo, "hangover effect", paradoxical effect, minimal effect on respiration and blood pressure.
    • Tox: accumulate. Acute overdose similar to barbs, death due to cardiac arrhythmias.
    • Chronic overdose GI irritation/perforation, skin rash, hypotension, renal and cardiac toxicity.
    • Tx overdose: resp and hemodynamic support, activated charcoal, beta blocker.
    • Tolerance: develop after 2weeks. Abuse potential high, similar to alcohol.
    • Delirium tremens: severe withdrawal if abrupt d/c after prolonged use (autonomic instability, confusion, nightmares, agitation, visual disturbances, significant mortality rate)
  60. Tricyclic Antidepressants
    • MoA: antichol, antiadrenergic, antihistaminergic...sedation.
    • But risk of other side effects (dry mouth, cardiac) also significant.
    • Cause drowsiness, reduce latency to sleep onset.
  61. Buspirone
    • MoA: useful anxiolytic, not cause sedation. Not ass'd with dependence or withdrawal.
    • MoA: unclear. partial agonist at 5-HT1A receptors in raphe nuclei, amygdala, hippocampus.(mood and anxiety)
    • Activation of post-synaptic 5-HT1A R -> hyperpolarizaton and inhibition.
    • Also affinity to DA2 receptors.
    • Onset: 2 weeks...not for acute anxiety attacks.
    • SE: light-headedness, dizziness, nervousness, H/A, insomnia, restlessness, GI...more common at beginning.
    • If switching from BZD to buspirone, need to taper BZD + have wash-out period to differentiate btwn BZD withdrawal and buspirone failure.
    • DI: serotonergic drugs (serotonin syndrome), MAOIs (hypertensive crisis), CYP3A4 interactions (inducers rifampin, inhibitors grapefruit juice, macs, azoles, CCBs)
  62. Methotrexate
    • MoA:
    • - Inhibit of aminoimidazolecarboxamide (AICAR) transformylase
    • (10-formyl THF + AICAR -x-> THF + FAICAR)
    • Accum AICAR: increase adenosine release @ sites of inflammation, increase inhibition of inflammation (adenosine A2 receptors) =action in autoimmune disease.
    • - affects polymorphonuclear chemotaxis
    • - Also inhibit dihydrofolate reductase , and thymidylate synthetase (angiogenesis and affects lymphocyte/mac function)
    • - Anti-inflam: inhibits cytokine production, purine biosynthesis; stimulates adenosine release.
    • - Decreased rate of appearance of new RA erosions
    • - Improves survival (only drug CVD)
    • - 2-3 weeks onset (use NSAIDs to bridge)
    • PK:
    • A: F ~70%
    • D: 35-50% PB
    • M: hydroxylated to less active
    • Parent cpd+ metabolite
    • metab’d further into
    • polyglutamated derivs
    • intracellularly.
    • E: renal: 70-80% unchanged
    • Bile: 30%
    • T1/2: 6-9 hours  24 hours
    • (intracellular t1/2 much longer, so can dose less frequently)
    • SE:
    • HEENT: stomatitis, (+/- pain)
    • Pulm: hypersensitivity lung, fibrosis, pneumonitis
    • GI: Diarrhea, N/V, hepatotoxicity (LE), cirrhosis
    • Heme: thromobocytopeia
    • Teratogenic: CI in pregs
    • MTX is folic acid antag: can induce folic acid deficiency…
    • Supplement (controversial):Folic acid 5mg daily OR Leucovorin once weekly (24 hours after MTX)
  63. Hydroxychloroquine
    • MoA:
    • - Amtimalarial
    • - MOA unknown
    • - No effect on radiographic progression
    • PK:
    • A: “good and rapid”
    • D: “wide” PB 50%, extensively tissue-bound in melanin-containing tissues (retinas)
    • M: deaminated in liver
    • E: t1/2 up to 45 days (long)
    • SE:
    • CNS: dizz, H/A, insomnia, dreams
    • HEENT: decrease accommodation, bullseye retna,benign corneal deposits, burred vision, pre-retinopathy (Get ophthalmologist exam /yr)
    • GI: N/V, D (decreased with food)
    • Heme: hemolysis in G6PD def
    • DERM: rash, alopecia, skin pigmentation
    • May be used in pregnancy (if not already get complete absence of symptoms in pregnancy)
  64. Sulfasalazine
    • MoA:
    • - MOA unknown
    • - Sulfapyridine = antirheumatic props
    • - decrease IgA and IgM rheumatoid factor prod.
    • - Inhibit in vitro B cellproliferation
    • - Decrease radiographic progression
    • - Reduce sn/sx of RA
    • PK: Prodrug cleaved by bacteria in colon to sulfapyridine & 5-ASA
    • SE:
    • HEENT: stomatitis
    • GI: N/V/D, anorexia, increase LE
    • Heme: leucopenia
    • Oligospermia
    • Derm: alopecia, rash, urticaria, serum sickness-like reactions, skin/urine turn yellow-orange
    • Hypersensitivity to sulfa
    • Ok for pregnancy
  65. Gold
    • MoA:
    • - MOA: don’t have to know…reduce phagocytosis by macs, reduce proliferative response of lymphocytes, reduce IgA IgM RF production..etc
    • - Actually unknown.
    • - Given IM
    • - Slow onset of action
    • PK:
    • Give10mg IM x1, then 25mg IM in 2nd week, then 50mg IM weekly -> response/1g
    • If response, decrease to 50mg q2wks x 3mos, then q3wks x 3mos, then maintenance monthly dose (indefinitely).
    • Tx failure: no response after total 1g administered.
    • Onset: 4-6 mo or after 1g
    • SE: Often lead to D/C
    • HEENT: stomatitis
    • GI: mucositis
    • GU: proteinuria -> gold-ind’d membranous glomerulonephropathy -> nephritic syndrome; microscopic hematuria
    • HEME: immune thrombocytopenia, granulocytopenia, aplastic anemia
    • DERM: rash (pruritic erythematous -> severe exfoliative dermatitis); chrysiasis
    • Inj rxns: nitritoid reaction (flush, dizz, faint)
    • Monitoring:
    • If mild mucocutaneous eruption, d/c tx.
    • If eruption better, restart at 10-15mg/wk, increase to 50mg/wk.
    • Chrysiasis- skin bluish gray forever.
    • Not safe in pregs
  66. Leflunomide
    • MoA:
    • - Indirectly inhibits protein synthesis
    • - Competitive inhibitor of pyrimidine synth (enzyme DHODH)   lymphocyte prolif + modulation of inflammation
    • - Arrests activated lymphocytes in G1
    • - Slows radiographic progression of joint damage
    • - Prevents new joint erosions in 80% of patients over 2 year period
    • - Similar efficacy to MTX
    • PK:
    • D:extensive PB
    • E: urine, bile, t1/2 14-16 d
    • Onset of action: 4-8 weeks
    • SE:
    • GI: reversible increase LE >3x ULN (esp w/ MTX)
    • Diarrhea, GI upset
    • DERM: alopecia
    • Teratogenic - Adequate birth control (x2)
    • If want to get pregs:
    • - cholestyramine 8gtid x11d
    • - 2x leflunomide levels drawn 14 days apart
    • - Sr[] <0.02mg/L prior to conception
  67. Cyclosporine
    • MoA:
    • - Immunosuppressive agent, calcineurin antagonist
    • - Inhibits T cell fxn by inhibiting transcription of IL-2 (big contributor to RA)
    • SE: Infection, Renal insufficiency, Hirsuitism
  68. Etanercept(Enebrel)
    • Soluble TNFR (recomb fusion protein)
    • -structure: human p75 extracellular TNF receptor + human IgGI
    • -mimics p75, takes up TNF in circulatin and inactivates them
    • -onset: 1-4 weeks (v fast)
    • -25mg SC twice weekly
    • PK:
    • A: 58% abs SC
    • D: 0.11 L/kg
    • M: neg
    • E: renal – negligible
    • Cl 0.02ml/min/kg
    • T1/2: 4 days (IV 70 hrs, SC 92 hrs)
    • Target: TNF/Lymphotoxin-alpha (both cytokines)
    • SE:
    • CNS: demyelinating syndromes (Do not give for pts with MS)
    • Infections: increase Upper RTI, serious/opportunistic infections i.e. TB
    • Heme: pancytopenia, neutropenia, blood dyscrasias
    • Others: injection site rxns 37% (mild)
    • 1% pts develop anti-etanercept Ab but non-neutralizing.
    • Can activate latent TB…just treat concomitantly with INH?
  69. Infliximab(Remicade)
    • TNF MAb (chimeric): high affinity/spec.
    • -stucture: mouse TNF binding site + human IgGI
    • -binds TNF from macs in joints and circ, +inactivates them(px int’n with receptors on surface of inflamm cells)
    • -onset: days to weeks
    • -3-10mg/kg IV w/ MTX q4-8wks T1/2: 8-10 days
    • Target: TNF
    • SE:
    • Infusion related:
    • - “cytokine release syndrome” (fever, chills,h/a)…usually with first infusion and decreases w/ time
    • Anti-infliximab Ab (10-30%) (MUST be used with MTX (blocks Ab that sucks up infliximab)
    • Anti-DS DNA Ab
    • Systemic lupus erythematosus (SLE)
    • Sepsis and disseminated TB and other opportunistic infections
    • Slow infusion rate.
  70. Adalimumab (Humira)
    • TNF MAb (recombinant)
    • -structure: human TNF binding site + human IgGI
    • 40mg SC qoweek T1/2: 10-20 days
    • Target: TNF
  71. Anakinra
    • IL-1 blocker : human recombinant
    • - IL-1 is immune and pro-inflammatory cytokine, autoinduction regulates own expression; mediates disease activity and progression of joint destruction, correlates with plasma/synovial fluid levels of IL-1.
    • - IL-1ra is endogenous R antag.
    • - Blocks IL-1 from binding to IL-1R by binding with same affinity.
    • - Onset: 2-4 weeks Rapid onset of action…but not work well.
    • SE:
    • Injection site reactions (66%): mild erythema, itching, discomfort that reslves over 1-2 mo
    • Infection: increased risk of serious ifxn (shutting down immune system...DO NOT use 2 biologics at same time. Combo increase risk of death from infection)
    • Heme: neutropenia.
    • Comboanakinra/etanercept: 3% severe neutr
    • Neutralizing Abs rare: do not appear to correlate with clinical response or adverse events.
  72. Abatacept
    • - Selective T-cell co-stimulation modulator; recombinant human fusion protein:
    • - EC human CTLA4 (cytotoxic T-lymphocyte-associated antigen-4) + Fc domain of human IgG1.
    • - Normally, T-cell activation needs binding of CD28 and TCR to an APC; but CTLA-4 can displac binding of CD28 to CD80/86, therefore Tcell activation inhibition.
    • - Abatacept acts like the CLTA4.
    • - Onset: within 2-12 weeks. T1/2: 14.7 days
    • Admin: silicone-free syr; IV 30min infusion once, then at week 2, 4, and every 4 weeks thereafter.
    • Blocks not just TNF-alpha (macs), aso blocks IL-6 and MMPs from fibroblasts, and autoantibodies (RF) from b-cells…but response rate === other biologics (50-60%)
  73. Rituximab
    • - B-cell depletion
    • - B-cells important in RA, and CD20 Ag is expressed on B-cells -> target!
    • - Synthetic CD20 monoclonal Ab, selectively depletes CD20+ B cells
    • - Chimeric murine/human MAb: mouse variable region (CD20 binding site) + human IgG1 constant region.
    • - Onset: 2 months
    • - Target: binds to CD20 antigen T1/2: 19.7 days
    • Admin: 1000mg IV days 1-15 (50mg/h up to 400mg/h)
    • Can go without dosng for up to 1.5 years! (mostppl need reinfuson after 6mo -1yr)
    • Other drugs: risk of lymphoma…but rituximab can be used to treat lymphoma!
    • *Depletes B cells w/o compromising immune
    • Lethal brain condition…not much experience. Black box warning.
    • Binds CD20 on pre to mature B cells (hematopoietic stem cells, pro-B cells, plasma cells, and other normal tissuesdo not have CD20 antigen)
  74. Tocilizumab
    • - Anti-IL-6 receptor antibody
    • - IL-6 activates T-cells, B cells, induction of RF, differentiation of monocytes to macs, activation of osteoclasts…etc
    • - 95% human, 5% mice, monoclonal recombinant humanized anti-IL-6 receptor Ab (murine binding site for IL-6 , human IgG1)
    • - Binds directly to IL-6 receptor and prevents Il-6 from binding/activating
    • - Onset: assessed at 12 weeks T1/2: 10 days
    • Admin: 4-8mg/kg IV q4 wks
  75. Tofacitinib
    • - NOT a biological: just small molec
    • - Designed based on congenital JAC3 deficiency -> immunodef. By blocking JAK, block inflamm cascade (many in pathogenesis of RA: IL-6,7.10…)
    • - Efficacy===biologics
    • - Orally active immunosuppressant
    • - Inhibits janus activated kinase 3 (JAK3) Once daily dosing 20mg effective for tx RA. Anemia, diarrhea, increase nasopharyngitis infxns
    • Interacts with fluconazole (increaseAUC and Cmax of tofacitinib)
    • Safe for combo w/ MTX

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