robert kobelja rite review 2016

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


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


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


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.


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)


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.


Tertiary Amines• More

anticholinergic• More sedation• More hypotension

Secondary Amines• Less

anticholinergic• Less sedation• Less hypotension


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


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


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


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


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

robert kobelja rite review 2016

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