robert kobelja rite review 2016
DESCRIPTION
Objectives Go over major category of drugs along with mechanism of action, side effects and primary indication that have appeared on the RITE Will leave out pathophysiology given too much material Will highlight repeat questions (very few)TRANSCRIPT
NEUROPHARMACOLOGY
Robert KobeljaRite Review 2016
Objectives Go over major category of drugs along
with mechanism of action, side effects and primary indication that have appeared on the RITE
Will leave out pathophysiology given too much material
Will highlight repeat questions (very few)
Psychiatry Antidepressants Antipsychotic
Antidepressants SSRI SNRI TCA MAOI
What to know? Mechanism of action. Specific neurotransmitters involved and
not involved Unique side effects
Serotonin selective reuptake inhibitors (SSRI)
Fluoxetine (Prozac) Sertraline (Zoloft) Paroxetine (Paxil) Fluvoxamine
(LuVox) Citalopram
(Celexa) Escitalopram
(Lexapro)
• Vilazodon (Viibryd)**
• Vortoxetine (Brintellix)**
**5HT1A partial agonist
Serotonin selective reuptake inhibitors (SSRI)
Most common first-line agents for: Major depression, dysthymia Panic disorder, generalized anxiety, social
phobia Obsessive compulsive disorder (1st line) Eating disorders
Mechanism of action: Inhibits CNS neuron serotonin reuptake; minimal
or no effect on reuptake of norepinephrine or dopamine; does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors
Serotonin selective reuptake inhibitors (SSRI)
Side effects tend to be mild, but may include: Dizziness, hypotension Nausea, diarrhea Serotonin syndrome – especially in the first
few days of treatment Weight gain Sexual dysfunction (esp. decreased
libido and inhibit oragasm) All QTC interaction, Citalopram highest
QTC risk
Serotonin syndrome Delerium, hyperthermia, tachycardia,
diaphoresis, clonus, hyperreflexia, tremor Caused by concombinate use of MAOI
and SSRIs, TCA, SNRI, trazadone, dextromethorphan, tramadol.
Serotonin/Norepinephrine Reuptake Inhibitor (SNRI)
Venlafaxine (Effexor) Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Levomilnacipran (Fetzima) Trazodone (Desyrel, Oleptro) Tricyclic antidepressants (TCA)
Same mechanism,Usually classifiedseparately
Serotonin/Norepinephrine Reuptake Inhibitor (SNRI)
Mechanism of Action: neuronal serotonin and norepinephrine reuptake and a weak inhibitor of dopamine reuptake. No significant activity for H1-histaminergic, or alpha2-adrenergic receptors. Do not possess MAO-inhibitory activity. But mild anti-cholinergic activity.
Serotonin/Norepinephrine Reuptake Inhibitor (SNRI)
Side effects Insomnia or somnolence Weight loss or weight gain Cardiac conduction abnormalities HTN Duloxetine ALT elevations Sexual dysfunction
Trazadone Used for sleep and agitation Mechanism: Inhibits reuptake of
serotonin, causes adrenoreceptor subsensitivity, and induces significant changes in 5-HT presynaptic receptor adrenoreceptors. Trazodone also significantly blocks histamine (H1) and alpha1-adrenergic receptors. Anti-cholinergic moderate properties.
Side effects Side effects
Sedation Hypotension Priapism Sexual dysfunction
Tricyclic Antidepressants (TCAs)
Tertiary Amines• Amitriptyline (Elavil)• Clomipramine
(Anafranil)• Imipramine (Tofranil) • Doxepin (Sinequan)
Secondary Amines• Amoxapine
(Asendin)• Desipramine
(Norpramine)• Nortriptyline
(Pamelor)• Protriptyline
(Vivactil)
Tricyclic Antidepressants (TCAs)
Headache, depression, anxiety, pain Mechanism of action: increase the
synaptic concentration of serotonin and norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane. Also blocks H1 and anticholinergic properties higher in tertiary amines.
Tricyclic Antidepressants (TCAs)
Tertiary Amines• More
anticholinergic• More sedation• More hypotension
Secondary Amines• Less
anticholinergic• Less sedation• Less hypotension
Tricyclic Antidepressants (TCAs)
Side effects QT prolongation Sedation Lethal in high doses suicide
Bupropion (Wellbutrin) Depression (not anxiety or OCD) Mechanism of action: unknown and
poorly understood. But with weak inhibitor activity of the neuronal uptake of norepinephrine and dopamine, and does not inhibit monoamine oxidase or the reuptake of serotonin.
Bupropion Side effects
No sexual dysfunction or cardiac compications
Insomnia and dry mouth Lowers seizure threshold
Mertazapine (Remeron) Indication: Depression, anxiety, panic
disorder Mechanism: Blocks presynaptic alpha2
receptors, causing disinhibition of norepinephrine release. It is also a potent antagonist of 5-HT2 and 5-HT3 serotonin receptors and mild H1 histamine receptors and a moderate peripheral alpha1-adrenergic and muscarinic antagonist. (has TCA like structure)
Mertazapine (Remeron) Side effects
Weight gain and sedation
Monoamine Oxidase Inhibitors (MAOI)
MAO-A: peripherally located (bowel and liver), centrally located
MAO-B: centrally located and located in platelets
Tranylcypromine A>B Phenelzine A=B Selegiline B>A but at 20 mg daily
selectivity disappears
Monoamine Oxidase Inhibitors (MAOI)
Used for major depression, panic disorder (especially with agoraphobia), generalized anxiety, and social phobia. Also for parkinson’s disease (lower dose)
Mechanism: Blocks metabolism of norepinephrine, serotonin, dopamine, and tyramine
Monoamine Oxidase Inhibitors (MAOI)
Side effects sedation, hypotension, hypertensive crisis,
anticholinergic effects, sexual dysfunction Hypertensive crisis with tyramine reaction Serotonin syndrome
Neurotransmitters5HT NE D H1 Ach Alpha 1
SSRI XXSNRI XX XX xTrazadone X X XTCABuproprion
X Xx x
X X
Mertazepine
X X X x x
MAOI X X X
Antipsychotics for the RITE Main mechanism: D2 receptor blocker
through the mesolimbic pathway Other activity:
D2 receptors in the mesocortical pathways cause sedation
Alpha 1 antagonist decrease blood pressure Anti-cholinergic angonist consitpation and dry
mouth Histamine antagonist weight gain and dowsiness No serotonin activity
Antipsychotics for the RITE First generation:
Higher D2 affinity More EPS and more
TD Less cholinergic
side effects Less metabolic
dysregulation
• Second generation:– Lower D2 affinity • less EPS and more
TD–More cholinergic
side effects–More metabolic
dysregulation
Antipsychotics for the RITE First generation
High Potency• Droperidol (Inapsine)• Fluphenazine
(Prolixin)• Haloperidol (Haldol)• Perphenazine
(Trilafon)• Pimozide (Orap)• Thiothixene (Navane)
Low Potency• Chlorpromazine
(Thorazine) • Loxapine (Loxitane)• Thioridazine
(Mellaril)
Antipsychotics for the RITE Second generation:• Aripiprazole (Abilify)• Asenapine (Saphris)• Iloperidone (Fanapt)• Lurasidone (Latuda)• Olanzapine* (Zyprexa)
• Paliperidone (Invega)
• Quetiapine (Seroquel)
• Risperidone (Risperdal)
• Ziprasidone (Geodon)
• Clozapine (Clozaril)
Antipsychotics for the RITE Side effects
Sedation Weight gain Sexual dysfunction Metabolic Dysregulation: DM, elevated LDL,
elevated triglycerides, HDL decreased
Antipsychotics for the RITE Clozapine
Side effects: Agranulocytosis Increased risk of seizures
Antipsychotics for the RITE Parkinsonism and Antipsychotics
Worsened by first and second generation medication
First generation is contraindicated in Lewey body dementia They easily get neuroleptic malignant syndrome.
Psychosis in Parkinson's can be treated with clozapine
Antipsychotics for the RITE Neuroleptic malignant syndrome
Hyperthermia, tachycardia, HTN, delerium, board like rigidity
Treat with Bromocriptine: dopamine agonist Or Dantrolene: prevents release of calcium from
the sarcoplasmic reticulum.
Epilepsy Know carbamazepine Know spectrum of medication
Epilepsy – Treatment Spectrum Most seizure types
Valproate Lamotrigine Topiramate Zonisamide Levetiracetam Felbamate Phenobarbital
• Partial seizures– Carbamazepine
(Oxcarbazepine)
– Gabapentin (Pregabalin)
– Perampanel– Lacosamide– Tiadabine
Epilepsy – Treatment Spectrum Absence
Ethosuxamide (only)
Valproic acid (2nd line)
• Infantile spams– Vigabatrin
Epilepsy – What makes things worse?
Absence seizures Gabapentin Tiagabine vigabatrin
• Myoclonic seizures– Carbamazepine– Gabapentin– Pregabalin– Tiagabine– Vigabatrin
Carbamazepine Blockade of voltage-gated sodium
channels Structurally similar to TCAs Side effects:
Aplastic anemia SIADH Steven’s Johnson Rash:
Associted with HLA-b1502 allele with 10 fold increase
Carbamazepine Metabolism:
Inhibits metabolism of phenytoin, cimetidine, diltiazem, erythromycin, verapamil, fluoxetine, and isoniazid.
Induces metabolism of itself, oral contraceptives, sodium valproate, ethosuximide, corticosteroids, anticoagulants, antipsychotics, cyclosporine, and methylphenidate
Levels raised by isoniazid, erythromycin, cimetidine, verapamil, propoxyphene
Levels lowered by phenobarbital, phenytoin, and primidone.
Metabolism Cont. Glucuronidation:
Adding on a glucuronic acid How lamotrigine is cleared from the body Induced by Carbamazepine lowers
Lamotrigine levels.
Epilepsy Topamax
Blocks voltage-sensitive Na channels, and high-voltage calcium channels; potentiates GABA-mediated inhibition at the GABA-A-R; reduces excitatory actions of glutamate via the AMPA receptor
Side effects: inhibits carbonic anhydrase causes a metabolic acidosis Parasthesias, weight loss, Cognitive
impairment Kidney Stones: calcium phosphate
Epilepsy Phenytoin
Mechanism: Blockade of voltage-dependent sodium channels
Zero order kinetics Side effects:
Purple glove syndrome from pH Use fosphenytoin to avoid this (can also be used
IM) Gingival hyperplasia, morbiliform rash,
hypotension Induces Glucuronidation
Epilepsy Perampanel
Mechanism: antagonist of the AMPA receptor Side effects:dizziness somnolence and
headache. As well as hostility and aggression
Epilepsy Lamotrigine
Mechanism: Blockade of voltage-dependent slow-inactivated sodium channels Also can block calcium channels and K channels
Cleared by Glucuronidation Elevated levels of lamotrigine with VPA Decreased levels of lamotrigine with
Carbamazepine, Phenytoin, and phenobarbital
Side effects No effect on vitamin D metabolism Steven’s Johnson rash
Epilepsy Valproic acid
Mechanism: not well defined Side effects:
Liver injury (increased risk in POLG mutation) Hyperammonemia (independent of liver injury) Birth defects
mainly spina bifida only rarely anencephaly (NTD), cardiac, craniofacial,
skeletal and limb defects and a possible set of dysmorphic features, the "valproate syndrome" with decreased intrauterine growth
Weight gain, hair loss, tremor
Epilepsy Zonisamide
blockade of sodium channels, blockade of T-type calcium channels, potentiation of GABAergic transmission, and inhibition of carbonic anhydrase
Side effects Kidney stones Allergies to sulpha Levels lowered by Carbamazepine, phenytoin
and barbituates
Epilepsy Pregabalin
Mechanism: Modulates neurotransmitter release by binding to the a2-d subunit of voltage-gated calcium channels GABA analogue but no activity on GABA or
benzodiazepine receptors More used for neuropathic pain through same
mechanism. No Drug-Drug interactions Weight gain
Multiple Sclerosis Symptomatic treatment
Dalfampridine (Ampyra) Potassium channel blocker improves nerve
conduction on demyelinated axons Used for motor weakness, gait trouble and
fatigue in MS Side effects
Cleared by the kidneys and contrainicated in GFR <50
Causes seizures at higher doses.
Multiple Sclerosis Immune modifying drugs
Injectable Interferon Beta
Flu like symptoms Glatiramer acetate
Four peptide polymer similar to myelin basic protein Injection site reactions with little other side effects
Multiple Sclerosis Immune modifying drugs: oral
medications Dimethyl fumerate (Tecfidera)
Unclear mechanism but thought to be from activation on nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway
Side effects: flushing, diarrhea, PML with persistent lymphopenia
Multiple Sclerosis Immune modifying drugs: oral
medications Fingolimod (Gilenya)
activates sphingosine-1 phosphate-receptor reduces lymphocyte recirculation in lymph nodes
Side effects PR prolongation Macular edema Liver injury AST and ALT VZV infection PML
Multiple Sclerosis Immune modifying drugs: oral
medications Teriflunomide (Abagio)
inhibits dihydroorotate dehydrogenase in mitochondria needed for pyrimidine synthesis reducing B and T cell count. But spars slow dividing cells through exogenous supplies of pyrimidine.
Side effects: diarrhea, hair thinning, liver injury with ALT increase
Multiple Sclerosis Immune modifying drugs: IV medications
Superior to orals and injections Natalizulmab
monoclonal antibody against the alpha-4 subunit of integrin molecules
Side effects Increased risk of PML Risk increased to 1/1000 after 2 years with PCR
negative Risk increased to 11/1000 if seropositive after 2
years
Multiple Sclerosis Immune modifying drugs: IV medications
Alemtuzumab Monoclonal antibody to CD 52 causes B and T
cell depletion. Spares hematopoietic cells Side effects:
Thyroid dysfunction (30%) Thrombocytopenia (bone marrow suppression) Goodpasture Malignancy risk
Movement Disorders Parkinson’s Drugs
COMT inhibitors – prevent conversion of levodopa to 3-0 methyldopa Tolcapone
Small risk of liver failure Entacopone Common side effects
Nausea, diarrhea Urine discoloration (orange)
Movement Disorders Parkinson’s Drugs
Dopamine Agonists Ropinirole and pramipexole
Compulsive gambling, hypersexuality Tremor predominant
Treat with trihexyphenidyl Anticholinergic Avoid in patients over 60 or with cognitive impairment
Orthostatic hypertension Midodrin: converted to an alpha agonist
Supine hypertension Used for patient unresponsive to fludrocortisone
Movement Disorders Tardive dyskenesias
Treat with amantidine Caused by long term anti-psychotic use but
also prochlorperazine and metoclopramide
Movement Disorders Tourette’s
First line agents: guanfacine or clonidine Alpha 2 receptor agonists
Haldol more effective but more troublesome side effects
Movement Disorders Essential tremor
Propranolol: non specific beta blocker Don’t use if the patient has asthma, COPD, or
CHF Primadone: converted to phenobarbital
Movement Disorders Restless legs
First line is ropinirole Causes intrauterine growth retardation and digit
malformation In pregnancy use Carbidopa/Levodopa
Headaches and Pain Triptans
Blood vessel constriction due to seratonin receptor agonists 5HT1B and 5HT1D fast onset peak at 2 hours
sumatriptan, zolmitriptan, rizatriptan, almotriptan, and eletriptan
Slow onset naratriptan and frovatriptan use for headaches that recur within 24 hours
Headaches and Pain Tramadol
Mechanism: binds to Mu receptors but inhibits serotonin and norepinephrine reuptake
Two enantomers: both affect Mu receptors. Tramadol inhibits serotonin reuptake And the metabolite O-desmethyl-tramadol
inhibits norepinephrine reuptake