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183 Cards in this Set
- Front
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General pharmacokinetics of anti-epileptics
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Most are orally active
80-100% of [drug] into circulation Most not highly bound to plasma proteins (except for Phenytoin and Valproic acid Plasma clearance is slow and most are considered to be medium to long acting Predominantly distributed into total body water |
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Metabolism of anti-epileptics
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Cleared through hepatic mechanisms
Metabolites (also active) cleared through liver Most older AEDs are inducers of P450 enzymes Few are inhibitors of P450 |
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Partial seizures and Generalized T-C seizures
Drugs |
Phenytoin
Carbamazepine Phenobarbital Primidone Vigabatrin Lamotrigine Felbamate Gabapentin Pregabalin Lacosamide Levetiracetam Tigabine Topiramate Zonisamide |
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Phenytoin
MOA |
Alters Na+, K+, Ca2+ conductance
Prolongs INACTIVE state of Na+ channel Inhibits generation of repetitive APs Decreases Glu release Increases GABA release |
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Phenytoin
Pharmacokinetics |
Given orally (phenytoin sodium)
2 forms: one dissolves slowly and the other rapidly Absorption from GI tract is ~100% and time to peak is 3-12 hours |
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Fosphenytoin
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More soluble form of phenytoin
Parenteral use Rapidly converted to phenytoin |
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Phenytoin
Metabolism |
Induces hepatic microsomal enzymes
Elimination is dose dependent At low blood levels, metabolism follows first order kinetics At increased blood levels, liver capacity to metabolize drug maxes out Half life is ~24 hours |
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Phenytoin
Interactions |
Highly bound by protein
Other highly bound drugs may displace phenytoin leading to increase in free drug Has affinity for thyroid-binding globulin May confound thyroid function tests Should measure TSH levels instead |
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Phenytoin
Toxicity |
Hirsutism
Gingival hyperplasia Diplopia and ataxia (requires dose adjustment) Nystagmus and loss of smooth extraocular pursuit movements (does not require dose adjustment) |
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Phenytoin
Long term toxicity effects |
Coarsening of facial features
Mild peripheral neuropathy Osteomalacia |
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Phenytoin
Clinical uses |
Simple partial seizure
Complex partial seizure Partial w/ 2* generalized T-C |
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Carbamazepine
MOA |
Blocks Na+ channels and inhibits high frequency repetitive firing of neurons
Acts presynaptically to reduce synaptic transmission |
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Carbamazepine
Clinical uses |
Seizures (simple partial, complex partial, partial w/ 2* generalized T-C, T-C)
Bipolar disorder Trigeminal neuralgia |
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Carbamazepine
Pharmacokinetics |
ORAL ONLY (effective in kids and adults)
Peak levels reached at 6-8 hours Large doses are given after meals to slow absorption Induces P450s Half life of ~36 hours |
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Carbamazepine-10,11-epoxide
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Metabolite of carbamazepine
Shows anticonvulsant activity |
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Carbamazepine
Drug interactions |
Increased metabolism of self and other drugs (primidone, phenytoin, ethosuximide, valproic acid, and clonazepam)
Metabolism may be decreased by valproic acid Metabolism may be increased by phenytoin and phenobarbital |
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Carbamazepine
Toxicity |
BLOOD DYSCRASIAS (black boxed); mild but persistent leukopenia requires careful monitoring; fatal cases of aplastic anemia and agranulocytosis
Diplopia, ataxia, and CNS depression |
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Phenobarbital
MOA |
Enhancement of inhibitory neurotransmission
Binds to GABAA receptor and prolongs opening of Cl- channel Diminished effect of excitatory neurotransmission Effect is on presynaptic Glu release May inhibit spread of abnormal firing from seizure foci |
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Phenobarbital
Clinical uses |
Partial w/ 2* generalized T-C
T-C Uncontrollable seizures of all types |
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Primidone
MOA |
Blocks voltage sensitive Na+ channel (like phenytoin)
Potentiates GABA (formation of phenobarbital) |
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Primidone
Metabolism |
Parent drug with 2 active metabolites: phenobarbital and phenylethylmalonamide (PEMA)
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Primidone
Clinical uses |
Seizures in infants and elderly
Seizures (simple partial, partial w/ 2* generalized T-C) T-C |
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Primidone
Pharmacokinetics |
Primidone is slowly metabolized
Metabolized by oxidation to phenobarbital (accumulates slowly) Metabolized by scission to form PEMA |
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Primidone
Dosing |
Must start doses small and increase over weeks to avoid GI upset and sedation
Dose adjustments must consider steady state of parent drug (rapid) and metabolites (days to weeks) |
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Vigabatrin
MOA |
Irreversible inhibitor of GABA aminotransferase (GABA-T) which is the enzyme responsible for degrading GABA
Inhibition of vesicular GABA transporter Decreased brain glutamine synthetase activity |
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Vigabatrin
SHARE Program |
Only specific physicians and pharmacists can prescribe and distribute
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Vigabatrin
Clinical uses |
Infantile spasms
Refractory complex partial seizures |
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Vigabatrin
Toxicity |
VISION LOSS (black boxed)
Anemia Somnolence Suicidal ideations |
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Lamotrigine
MOA |
Suppresses rapid firing of neurons
Produces a voltage and use dependent inactivation of Na+ channels May also decrease release of Glu |
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Lamotrigine
Clinical uses |
Can be adjunctive or monotherapy (for partial)
Absence and myoclonic seizures in children |
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Lamotrigine
Adverse effects |
LIFE THREATENING DERMATITIS IN 1-2% of PEDIATRIC PTS (black boxed)
Dizziness, HA, diplopia, nausea, somnolence, skin rash |
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Gabapentin and Pregabalin
MOA |
Structurally similar to GABA but do not directly activate GABA receptor
Both block voltage gated Ca2+ channels Modify release of GABA Decrease release of Glu at synapse |
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Gabapentin and Pregabalin
Clinical uses |
Both typically given as adjunct therapy and also treat post herpetic neuralgia
Gabapentin for partial and generalized T-C Pregabalin for partial seizures |
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Gabapentin
Adverse effects |
Somnolence, dizziness, ataxia, HA, tremor
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Pregabalin
Adverse effects |
Schedule 5 for euphoria
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Lacosamide
MOA |
Enhanced slow inactivation of Na+ channel
Blocks actions of neurotrophic factors in axonal and dendritic growth Has no effect on P450s |
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Lacosamide
Clinical uses |
Adjunctive therapy in pts >16
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Lacosamide
Adverse effects |
Dizziness, HA, nausea, diplopia
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Levitiracetam
MOA |
Binds selectively to synaptic vesicle protein SV2A
Protein may modify release of Glu and GABA |
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Levitiracetam
Adverse effects |
Somnolence, asthenia, dizziness, and CNS depression
Avoid EtOH |
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Levitiracetam
Clincal uses |
Partial seizures
Primary generalized T-C Myoclonic seizures in juvenile myoclonic epilepsy |
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Tiagabine
MOA |
Inhibitor of GABA uptake in both neurons and glia
Increases extracellular GABA in forebrain and HC Prolongs activity and increases tonic inhibition |
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Tiagabine
Clinical uses |
Adjunctive therapy of partial seizures
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Tiagabine
Adverse effects |
Nervousness, dizziness, tremor, difficulty concentrating, depression, excessive confusion, somnolence or ataxia
Excessive confusion, somnolence or ataxia may require discontinuation of drug |
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Topiramate
MOA |
Blocks repetitive neuronal firing through blockade of Na+ channels
Potentiates inhibitory effects of GABA May interfere with excitation of Glu neurons |
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Topiramate
Clinical uses |
Monotherapy
Lennox-Gastuat syndrome West's syndrome Absence seizures Migraines |
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Topiramate
Adverse effects |
Occur initially while establishing dose
Somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion Acute myopia and glaucoma may require prompt drug W/D Urolithiasis |
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Zonisamide
MOA |
Inhibition of Na+ and Ca2+ channels
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Zonisamide
Clinical uses |
Partial and generalized T-C
Infantile spasms Certain myoclonias |
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Zonisamide
Adverse effects |
Drowsiness, cognitive impairment, and serious skin rashes
Metabolic acidosis |
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Felbamate
MOA |
Use-dependent block of NMDA receptor
Potentiates GABAA receptor response |
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Felbamate
Clinical uses |
Partial seizures
Lennox-Gastaut syndrome |
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Felbamate
Adverse effects |
APLASTIC ANEMIA AND SEVERE HEPATITIS AT VERY HIGH RATES (black boxed)
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Generalized seizures
Drugs |
Ethosuximide
Phensuximide Methsuximide Valproic Acid Sodium Valproate |
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Ethosuximide
MOA |
Inhibits Ca2+ currents of T-type currents
T-type Ca2+ channels provide pacemaker currents in thalamic neurons Generate the rhythmical cortical discharge of an absence attack |
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Ethosuximide
Clinical uses |
Absence seizures
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Ethosuximide
Adverse effects |
Gastric distress (N/V, pain)
Transient lethargy or fatigue Blood dyscrasias SLE |
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Methsuximide vs. Ethosuximide
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Methsuximide is MORE TOXIC than ethosuximide
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Phensuximide vs. Ethosuximide
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Phensuximide is LESS EFFECTIVE than ethosuximide
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Valproic Acid and Sodium Valproate
MOA |
Blocks high frequency neuronal firing
Blockade of Na+ currents Blockade of NMDA receptor mediated excitation GABA levels increased after valproic acid (enhanced synthesis or inhibited clearance mechanisms) |
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Valproic Acid and Sodium Valproate
Clinical uses |
Used for absence seizures in presence of generalized T-C attacks
Myoclonic seizures Bipolar disorder Migraine prophylaxis |
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Valproic Acid and Sodium Valproate
Pharmacokinetics |
Time course of activity is poorly correlated to blood or tissue levels of drug
Enteric-coated capsule of 1:1 Valproic Acid and Sodium Valproate |
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Valproic Acid and Sodium Valproate
Drug interactions |
Displaces phenytoin from plasma proteins
Inhibits metabolism of phenobarbital, phenytoin, and carbamazepine Decreases clearance of lamotrigine |
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Valproic Acid and Sodium Valproate
Toxicity |
HEPATOTOXICITY; greatest risk for young pts < 2 years or pts taking multiple drugs
PANCREATITIS INCREASED RISK OF SPINA BIFIDA N/V, abdominal pain, heart burn Fine tremor at high [drug] Thrombocytopenia in small population |
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Treatment of hepatotoxicity from Valproic Acid and Sodium Valproate
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Oral of IV L-Carnitine
Can be reversible if caught in time |
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Status Epilepticus
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Recurrent episodes of T-C seizures
Remain unconscious and without normal muscle movement b/w episodes Lack of O2 can lead to brain damage |
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Status Epilepticus
First line Tx |
Requires immediate CV, respiratory, and metabolic management
IV Diazepam or Lorazepam for 30-45 minutes until pt is seizure free |
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Status Epilepticus
Second line Tx |
IV Phenytoin (push or saline; not diluted in glucose)
Need to monitor cardiac rhythm and BP in elderly IV fosphenytoin Phenobarbital (no response to phenytoin) |
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Why do you need to monitor cardiac rhythm and BP in elderly pts taking IV phenytoin for status epilepticus?
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Cardiotoxicity from propylene glycol which is a dissolving agent
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Why is fosphenytoin better than phenytoin in status epilepticus?
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Freely soluble in IV solutions (safer)
More potent than phenytoin |
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Benzodiazepines
MOA |
Increase GABA inhibition but does not work as GABA
Binds to allosteric site on GABAA receptor |
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Diazepam
Clinical uses |
Given IV or rectally; can be given orally for long-term tx
Stops continuous seizure activity |
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Lorazepam
Clinical uses |
Also treats continuous seizure activity
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Clonazepam
Clinical uses |
Long acting
Absence seizures Myoclonic seizures |
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Clonazepam
Adverse effects |
Sedation
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Clorazepate dipotassium
Clinical uses |
Adjunct to tx partial seizures in adults
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Clorazepate dipotassium
Adverse effects |
Drowsiness
Lethargy |
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Acetazolamide
MOA |
Inhibitor of carbonic anhydrase
Possibly causes mild acidosis in brain Possibly causes diminished release of bicarb ions from GABAergic neurons |
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Acetazolamide
Clinical uses |
All seizure types
Tolerance quickly develops |
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Women should use non-hormonal methods of birth control with which drugs?
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Phenytoin
Phenobarbital Carbamazepine Topiramate Oxcarbazepine Felbamate |
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Teratogenicity of phenytoin
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Fetal hydantoin syndrome
Linked to phenobarbital and carbamzepine |
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Teratogenicity of valproic acid
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Spina bifida
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Teratogenicity of topiramate
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Hypospadias in human males (urethral opening on underside of penis)
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Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
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Associated with carbamazepine, oxcarbazepine, phenytoin, lamitrogine, tiagabine
Highest risk in first 2 mos of tx Risk highest in pts of Asian descent (HLA-B*1502 allele) |
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Anti-Epileptics
Withdrawal |
Pt must be seizure free for several years
Can cause increased frequency and severity of seizures BZ and barbs are difficult to discontinue (may take weeks to mos) |
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Brand name vs. generic AED
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Has become evident that generic drugs may not be as therapeutically stable as brand drugs (range for dose of active ingredient)
Increased risk of breakthrough seizures |
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AEDs that block Na+ channel
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Phenytoin
Carbamazepine Primidone Lamotrigine Zonisamide |
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AEDs that block Ca2+ current
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Ethosuximide
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AEDs that affect GABA
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Phenobarbital
Tiagabine BZ Vigabatrin |
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AEDs with multiple mechanisms
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Valproic Acid/Valproate
Topiramate Felbamate |
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AEDs with "other" MOA
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Gabapentin
Pregabalin Leviriteracetam Acetazolamide |
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AEDs that inhibit P450
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Phenobarbital
Phenytoin Primidone Topiramate Valproate |
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AEDs that induce P450
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Carbamazepine
Phenobarbital Phenytoin Primidone |
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AEDs metabolized by P450
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Carbamazepine
Phenobarbital Phenytoin Primidone Tiagabine Valproate Zonisamide |
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Neuroleptics
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Subtype of antipsychotic drugs
Antagonize D2 receptor Higher incidence of extrapyramidal side effects at clinical doses |
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Extrapyramidal side effects
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Tremor
Slurred speech Akathisia Dystonia Anxiety Distress Paranoia Bradyphenia |
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Typical antipsychotics
General MOA |
D2 receptors > 5HT2 receptors
Cause EPS |
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Atypical antipsychotics
General MOA |
5HT2 receptors > D2 receptors
No EPS |
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Positive sx of schizo
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Delusions
Hallucinations Grandiosity Bellicosity Thought disorders Bizarre and/or agitated behavior |
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Negative sx of schizo
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Flat affect
Emotional W/D Social W/D |
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Mesocortical pathway
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Tegmentum to PFC
Inhibited by schizo Site of negative sx 5HT blockers increase release of DA to alleviate negative sx |
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Mesolimbic pathway
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Tegmentum to nucleus accumbens
Site of positive sx Disinhibited by schizo D2 receptor blockers inhibit DA release and alleviate positive sx |
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Nigrostriatal pathway
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SNpc to corpus striatum
Site of adverse effects (parkinsonism) Inhibited DA release results in loss of inhibition of excitatory ACh neurons in corpus striatum |
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D1 like receptors
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D1 and D5
Increase cAMP by Gs GPCR activation of adenylyl cyclase D1 located in putamen, nucleus accumbens, and olfactory tubercle D5 located in HC and HT |
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D2 like receptors
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D2, D3, D4
Decrease cAMP by Gi GPCR of inhibition of adenylyl cyclase which inhibits Ca2+ channels and opens up K+ channels D2 found on pre and post-synaptic neurons in caudate, putamen, nucleus accumbens, and olfactory tubercle D3 located in frontal cortex, medulla and midbrain |
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D2 receptor occupancy
Typical vs. Atypical |
Typical antipsychotics require 60% occupancy of striatal D2 receptors and produce EPS at 80%
Atypical antipsychotics require 30-50% receptor occupancy of D2 receptors due to there concurrent high occupancy of 5HT2A receptors |
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Typical antipsychotics
Phenothiazines |
Chlorpromazine
Fluphenazine |
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Typical antipsychotics
Thioxanthenes |
Thiothixene
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Typical antipsychotics
Butyrophenones |
Haloperidol
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Atypical antipsychotics
Members |
Molindone
Loxapine Risperidone Olanzapine Pimozide Clozapine Quetiapine Ziprasidone Aripiprazole Asenapine |
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Antipsychotics
Absorption |
Most are readily absorbed
Undergo significant first pass metabolism |
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Antipsychotics
Distribution |
Most are lipid soluble
Have large Vd (get sequestered) Longer duration of action than estimated by half life due to prolonged occupancy at D2 receptors |
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Antipsychotics
Metabolism |
Most undergo oxidation or demethylation rxns (P450)
CYP2D6, CYP3A4, CYP1A2 Drug-drug interactions should be considered when given with other psychotropic drugs or inhibitors of P450 (eg. ketoconazole) |
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Antipsychotics
Excretion |
Can be prolonged
Metabolites of chlorpromazine can be excreted in urine weeks after last dose was administered Long acting injectable formulations may block D2 receptors 3-6 mos after last injection |
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Antipsychotics
Psychological effects |
Sleep aids when given to NON-psychotic pts at low doses
Sleepiness, restlessness, impaired performance on psychomotor and psychometric tests |
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Quetiapine
Clinical uses |
Promotes sleep onset and maintenance (not an approved indication)
Psychotic pts exhibit improved scores on psychomotor and psychometric tests when treated |
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Antipsychotics
EEG effects |
Shifts pattern of EEG frequencies, slowing them and increasing synchrony
Hypersynchrony (slowing) is focal or unilateral which can lead to wrong diagnostic interpretation Some antipsychotics lower seizure threshold and induce EEG patterns typical of seizure disorders Can still be used in epileptic pts if dose is titrated carefully |
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Antipsychotics
Endocrine effects |
Older antipsychotics and risperidone can elevate prolactin levels
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Phenothiazines
CV effects |
Postural HoTN and tachycardia
MAP, peripheral resistance and SV are decreased and HR increased |
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Thioridazine
CV effects |
Prolongation of QT interval
Abnormal ST segments and T waves No greater risk of Torsades de Pointes compared with other typical antipsychotics Reversed up D/C |
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Haloperidol
CV effects |
Increased risk of Torsades de Pointes
Does NOT increase QT interval |
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Atypicals
CV effects |
Increased QT interval
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Psychiatric indications for antipsychotics
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Schizo
Drug-induced psychosis Psychosis involved with manic phase of bipolar Schizoaffective disorders (antipsychotics + AD, Li+ or Valproate) Tourette's Alzheimer's |
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Non-psychiatric indications for antipsychotics
Anti-emetics |
Prochlorperazine, Benzquinamide
Due to DA receptor blockade Centrally: chemoreceptor trigger zone in medulla Peripherally: receptors in stomach |
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Non-psychiatric indications for antipsychotics
H1 receptor blocking activity |
Pruritus
Pre-op sedatives (Promethazine) Neuroleptanesthesia (Droperidol + fentanyl) |
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Drug choice b/w typical and atypical
Efficacy and Sx |
In 70% of pts with schizo, both work equally well for treating POSITIVE sx
Atypicals have benefit for NEGATIVE sx and cognition, diminished risk of tardive dyskinesia, other EPS, lesser increases in prolactin |
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Drug choice b/w typical and atypical
Drug formulations and cost |
Typical drugs can be IM formulations for both acute and chronic tx
Typical drugs are cheaper and used more frequently despite EPS |
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Drug choice b/w typical and atypical
Adverse effects |
Weight gain and increased lipid profile (atypicals more than typicals)
Clozapine and olanzepine biggest changes Can cause DM |
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Antipsychotic selection
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Best guide is pts past response
Clozapine indicated to reduce risk of suicide in schizo High potency typicals preferred over lower potency (Haloperidol >>chlorpromazine and thioridiazine) |
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Risperidone
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Minimal side effects and lower risk of tardive dyskinesia leads to its increased use
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Antipsychotics
Dosage |
Range of effective doses among drugs is broad
Therapeutic margins are broad When in right dosage, antipsychotics can be effective in a broad group of pts May take several drug trials to find best tx |
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Clozapine
Clinical uses |
Used when several drugs have been tried and failed in tx
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Clozapine
Adverse effects |
Biggest change in weight gain and increased lipid profile
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Antipsychotics
Dosage and Maintenance therapy |
Given in divided doses titrating to effective dose (until appropriate dose is defined)
Once daily doses given at night Small minority of schizo pts recover from acute episodes and dosing can be PRN |
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Antipsychotics
Drug combinations |
Can confound eval of drugs used
Can be combined with tricyclic AD or SSRIs to treat concomitant depression Can also be combined with Li+ or Valproate |
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Antipsychotics
Adverse effects Behavioral |
Older, typical agents
Pseudodepression Toxic-confused states |
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Antipsychotics
Adverse effects ANS |
Urinary retention, constipation, dry mouth (antimuscarinic effects)
Postural HoTN or impaired ejaculation |
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Antipsychotics that cause postural HoTN or impaired ejaculation?
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Chlorpromazine
Mesoridazine |
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Antipsychotics adverse effects
Neurological |
Typical parkinson's
Akathisia Acute dystonic rxns Seizures |
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Antipsychotics that cause seizures?
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Chlorpromazine
Clozapine (de novo seizures) |
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Tx of typical parkinson's in psychotic pts
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Antimuscarinic antiparkinsonism drugs
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Tx of akathisia in psychotic pts
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Sedative antihistamine with anticholinergic properties (diphenhydramine)
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Tx of acute dystonic rxns in psychotic pts
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Sedative antihistamine with anticholinergic properties (diphenhydramine)
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Tardive dyskinesia
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Relative cholinergic deficiency as a result of super sensitized DA receptors in caudate-putamen
Early recognition is important CANNOT be reversed in late stages |
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Causes of tardive dyskinesia
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Typicals
Possibly risperidone |
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Tx of tardive dyskinesia
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Pts should be switched to quetiapine or clozapine
D/C or reduce current tx and switch to newer antipsychotic Remove all drugs with anticholinergic properties (antiparkinsonism drugs and tricyclic AD) Tx with diazepam to enhance GABA activity |
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Antipsychotics adverse effects
Metabolic and endocrine |
Weight gain (clozapine or olanzepine)
Monitor carbs for hyperglycemia Women - amenorrhea, galactorrhea, false + preg tests, decreased libido Men - decreased libido, gynecomastia |
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Clozapine
Adverse effects |
AGRANULOCYTOSIS
Develops rapidly (b/w weeks 6-18 of tx) Need weekly blood count for first 6 mos Reversible upon D/C |
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Chlorpromazine
Ocular adverse effects |
Deposits in cornea and lens
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Thioridazine
Ocular adverse effects |
Deposits in retina
Resembles retinitis pigmentosa |
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Antipsychotics adverse effects
Ocular |
Associated with browning of vision
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Antipsychotics adverse effects
Cardiac |
Postural HoTN
QT prolongation |
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Neuroleptic Malignant Syndrome
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Results from rapid blockade of post synaptic DA receptors
Life threatening Pts extremely sensitive to EPS |
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Neuroleptic Malignant Syndrome
Sx |
Initial sx are muscle rigidity
Fever due to impaired sweating Autonomic instability with altered BP and pulse |
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Neuroleptic Malignant Syndrome
Tx |
Antiparkinson drugs
Muscle relaxants (diazepam) Dantrolene |
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Antipsychotics
Drug interactions |
Mostly pharmacodynamic
Additive effects with other drugs Sedation, anticholinergic effects |
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Antipsychotics
Pregnancy |
Very small teratogenic risk
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Antipsychotics
Overdose |
Rarely fatal except for mesoridazine and thioridazine
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Overdose cause of mesoridazine and thioridazine
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Ventricular tachyarrhythmias
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What is the advantage of SSRIs over other classes of ADs?
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Less autonomic toxicity effects
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What is the importance of the metabolite of fluoxetine?
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It increases the half life of fluoxetine so you need to decrease dose to not have toxicity
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What causes serotonin syndrome?
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Use of SSRI and MAOI
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What are the sx of serotonin syndrome?
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Hyperthermia, muscle rigidity, myoclonus, and rapid changes in mental status and vital signs
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What is the dosing regimen of fluoxetine?
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Due to the active metabolite, pt is given 20 mg for several weeks and then pt response is determined
Higher doses not needed Elderly can use one pill every other day |
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What tolerability advantage dose bupropion have?
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No sexual dysfunction compared to SSRIs
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What safety advantage dose bupropion have?
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Few drug-drug interactions
Treats comorbid conditions (nicotine dependence, ADHD) Improves attention and concentration |
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What is the typical dosing regimen for tricyclic ADs?
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Start low and increase 25 mg every 2-3 days
Inpatient starts at 100 mg Outpatient starts at 10-75 mg |
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What are the 5 D's of AD Tx?
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Diagnosis (is pt perhaps bipolar, psychotic, etc?)
Drug (even if diagnosis is adequate, can another AD improve condition) Dose and Duration (pushed to limit) Different tx (ECT can be very effective and is useful when pt does not respond to drug therapy) |
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What three NTs are affected by tricyclic ADs?
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ACh - blurred vision, dry mouth, epigastric distress, constipation, tachycardia, urinary retention
Histamine - sedation, drowsiness Alpha adrenergic - postural HoTN |
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What are two ways to avoid tricyclic AD OD?
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Prescription less than 1.25 g or 50 dose units of 25 mg
No refills Entrust drug to relative |
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What are three adjunctive therapies to ADs?
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Li+
Thyroid hormone Atypical antipsychotics |
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What is the amine hypothesis?
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If you have enough 5HT or NE in cleft, there will be no depression
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What is the chief flaw of the amine hypothesis?
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Pharmacological effects are more rapid than clinical effects
AD has to be given for weeks or mos to have clinical effects |
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What is the NMDA theory?
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Glu is most abundant NT in brain
Activity at NMDA receptor is associated with depression Therefore ANTAGONISTS are suggested to be ADs |
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What is a pro and con of NMDA theory?
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Pro - Given importance of Glu in brain, potential is great; many AD tx affects NMDA receptors long term; pre-clinical data is positive
Con - there is almost no clinical evidence that NMDA antagonists are effective ADs |
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What is the CRF theory?
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Corticotropin releasing factor stimulates release of ACTH
Important in control of adrenal function and in response to stress CRF receptors show long term changes associated with AD tx CRF is neuroanatomically situated in correct places |
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What is a pron and con of CRF theory?
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Pro - dexamethasone suppression test has long been test of depression and is a measure of HPA axis; CRF is associated with fine control of GI system; CRF antagonists are associated with reduced depression according to small clinical trials
Cons - no extensive clinical trials |
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What metabolic steps in arachidonic acid cycle are inhibited by Li+?
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IP3 and DAG are altered
IP3 and DAG are second messengers for alpha adrenergic and muscarinic receptors as well as for neuropeptides Li+ blocks conversion of IP2 to IP and IP to inositol which depletes PIP2 PIP2 is needed to make phospholipase C Phospholipase C is needed to make IP3 and DAG |
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What is the dosing regimen of Li+ for manic episodes?
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Start on Li+ and antipsychotics
Remove antipsychotic after manic phase if deemed necessary Then consider if you want to keep them on maintenance therapy/prophylactic therapy of Li+ |
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What is the monitoring regimen of Li+ therapy?
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CBC, UA, blood tests, EKG (older pts as baseline measures due to sinus node effect)
5 days after beginning, read steady state Li+ levels Every 5 days until desired level has been achieved and then can increase intervals of monitoring |
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What is the maintenance therapy cautions of Li+?
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If pt has only had one cycle or is unreliable, stop Li+ after one course with gradual D/C
If cycles are worsening or more frequent or greater than once a year, then maintain them on Li+ after remission with approval of pt |
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How is Li+ metabolized and excreted?
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Metabolism - distributed in body water as small inorganice ion and is NOT metabolized
Excretion - excreted by kidneys; reduce dose if creatinine clearance is impaired |
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How should carbamazepine be used in adjunct with Li+ for mania?
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Indicated for seizures, mania, and compulsive aggression
May use it alone for maina or in refractory pts with Li+ as a mood stabilizer Begin with 200 mg bid and increase as needed |
