Transcript Neuropharmacology (yes everything)

Robert Kobelja
Rite Review 2016
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
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)
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Antidepressants
Antipsychotic
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SSRI
SNRI
TCA
MAOI
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Mechanism of action.
Specific neurotransmitters involved and not
involved
Unique side effects
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Fluoxetine (Prozac)• Vilazodon (Viibryd)**
Sertraline (Zoloft) • Vortoxetine
(Brintellix)**
Paroxetine (Paxil)
Fluvoxamine
(LuVox)
Citalopram (Celexa)
Escitalopram
(Lexapro)
**5HT1A partial agonist
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Most common first-line agents for:
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Major depression, dysthymia
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Panic disorder, generalized anxiety, social phobia
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Obsessive compulsive disorder (1st line)
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Eating disorders
Mechanism of action:
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Inhibits CNS neuron serotonin reuptake; minimal or
no effect on reuptake of norepinephrine or
dopamine; does not significantly bind to alphaadrenergic, histamine, or cholinergic receptors
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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
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Delerium, hyperthermia, tachycardia,
diaphoresis, clonus, hyperreflexia, tremor
Caused by concombinate use of MAOI and
SSRIs, TCA, SNRI, trazadone,
dextromethorphan, tramadol.
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Venlafaxine (Effexor)
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Desvenlafaxine (Pristiq)
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Duloxetine (Cymbalta)
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Levomilnacipran (Fetzima)
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Trazodone (Desyrel, Oleptro)
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Tricyclic antidepressants (TCA)
Same mechanism,
Usually classified
separately
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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.
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Side effects
Insomnia or somnolence
 Weight loss or weight gain
 Cardiac conduction abnormalities
 HTN
 Duloxetine ALT elevations
 Sexual dysfunction
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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. Anticholinergic moderate properties.
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Side effects
Sedation
 Hypotension
 Priapism
 Sexual dysfunction
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Tertiary Amines
• Amitriptyline (Elavil)
• Clomipramine
(Anafranil)
• Imipramine (Tofranil)
• Doxepin (Sinequan)
Secondary Amines
• Amoxapine (Asendin)
• Desipramine
(Norpramine)
• Nortriptyline
(Pamelor)
• Protriptyline (Vivactil)
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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
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Side effects
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QT prolongation
Sedation
Lethal in high doses suicide
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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.
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Side effects
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No sexual dysfunction or cardiac compications
Insomnia and dry mouth
Lowers seizure threshold
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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)
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Side effects
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Weight gain and sedation
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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
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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
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Side effects
sedation, hypotension, hypertensive crisis,
anticholinergic effects, sexual dysfunction
 Hypertensive crisis with tyramine reaction
 Serotonin syndrome
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5HT
NE
SSRI
XX
SNRI
XX
Trazadone
X
TCA
Buproprion
X
X
x
Mertazepine
X
X
MAOI
X
X
D
H1
XX
Ach
Alpha 1
x
X
x
X
X
X
X
X
x
x
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Main mechanism: D2 receptor blocker through
the mesolimbic pathway
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Other activity:
 D2 receptors in the mesocortical pathways cause
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sedation
Alpha 1 antagonist decrease blood pressure
Anti-cholinergic angonist consitpation and dry mouth
Histamine antagonist weight gain and dowsiness
No serotonin activity
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First generation:
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Higher D2 affinity
 More EPS and more
TD
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Less cholinergic side
effects
Less metabolic
dysregulation
• Second generation:
– Lower D2 affinity
• less EPS and more
TD
– More cholinergic
side effects
– More metabolic
dysregulation
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First generation
High Potency
• Droperidol (Inapsine)
• Fluphenazine
(Prolixin)
• Haloperidol (Haldol)
• Perphenazine
(Trilafon)
• Pimozide (Orap)
• Thiothixene (Navane)
Low Potency
• Chlorpromazine
(Thorazine)
• Loxapine (Loxitane)
• Thioridazine (Mellaril)
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•
•
•
•
•
Second generation:
• Paliperidone
Aripiprazole
(Invega)
(Abilify)
• Quetiapine
Asenapine (Saphris)
(Seroquel)
Iloperidone (Fanapt)
• Risperidone
Lurasidone (Latuda) (Risperdal)
Olanzapine*
• Ziprasidone
(Zyprexa)
(Geodon)
• Clozapine (Clozaril)
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Side effects
Sedation
 Weight gain
 Sexual dysfunction
 Metabolic Dysregulation: DM, elevated LDL,
elevated triglycerides, HDL decreased
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Clozapine
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Side effects:
 Agranulocytosis
 Increased risk of seizures
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Parkinsonism and Antipsychotics
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Worsened by first and second generation
medication
First generation is contraindicated in Lewey body
dementia
 They easily get neuroleptic malignant syndrome.
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Psychosis in Parkinson's can be treated with
clozapine
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Neuroleptic malignant syndrome
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Hyperthermia, tachycardia, HTN, delerium, board
like rigidity
Treat with Bromocriptine: dopamine agonist
 Or Dantrolene: prevents release of calcium from the
sarcoplasmic reticulum.
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Know carbamazepine
Know spectrum of medication
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Most seizure types
Valproate
 Lamotrigine
 Topiramate
 Zonisamide
 Levetiracetam
 Felbamate
 Phenobarbital
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• Partial seizures
– Carbamazepine
(Oxcarbazepine)
– Gabapentin
(Pregabalin)
– Perampanel
– Lacosamide
– Tiadabine
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Absence
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Ethosuxamide (only)
Valproic acid (2nd
line)
• Infantile spams
– Vigabatrin
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Absence seizures
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Gabapentin
Tiagabine
vigabatrin
• Myoclonic seizures
– Carbamazepine
– Gabapentin
– Pregabalin
– Tiagabine
– Vigabatrin
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Blockade of voltage-gated sodium channels
Structurally similar to TCAs
Side effects:
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Aplastic anemia
SIADH
Steven’s Johnson Rash:
 Associted with HLA-b1502 allele with 10 fold increase
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Metabolism:
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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.
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Glucuronidation:
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Adding on a glucuronic acid
How lamotrigine is cleared from the body
Induced by Carbamazepine lowers Lamotrigine
levels.
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Topamax
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Blocks voltage-sensitive Na channels, and highvoltage calcium channels; potentiates GABAmediated 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
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Phenytoin
Mechanism: Blockade of voltage-dependent sodium
channels
 Zero order kinetics
 Side effects:
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 Purple glove syndrome from pH
 Use fosphenytoin to avoid this (can also be used IM)
 Gingival hyperplasia, morbiliform rash, hypotension
 Induces Glucuronidation
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Perampanel
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Mechanism: antagonist of the AMPA receptor
Side effects:dizziness somnolence and headache. As
well as hostility and aggression
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Lamotrigine
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Mechanism: Blockade of voltage-dependent slowinactivated sodium channels
 Also can block calcium channels and K channels
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Cleared by Glucuronidation
 Elevated levels of lamotrigine with VPA
 Decreased levels of lamotrigine with Carbamazepine,
Phenytoin, and phenobarbital
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Side effects
 No effect on vitamin D metabolism
 Steven’s Johnson rash
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Valproic acid
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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
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Zonisamide
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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
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Pregabalin
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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
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More used for neuropathic pain through same
mechanism.
No Drug-Drug interactions
Weight gain
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Symptomatic treatment
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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.
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Immune modifying drugs
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Injectable
 Interferon Beta
 Flu like symptoms
 Glatiramer acetate
 Four peptide polymer similar to myelin basic protein
 Injection site reactions with little other side effects
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Immune modifying drugs: oral medications
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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
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Immune modifying drugs: oral medications
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Fingolimod (Gilenya)
 activates sphingosine-1 phosphate-receptor reduces
lymphocyte recirculation in lymph nodes
 Side effects
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PR prolongation
Macular edema
Liver injury AST and ALT
VZV infection
PML
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Immune modifying drugs: oral medications
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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
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Immune modifying drugs: IV medications
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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
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Immune modifying drugs: IV medications
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Alemtuzumab
 Monoclonal antibody to CD 52 causes B and T cell
depletion. Spares hematopoietic cells
 Side effects:
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Thyroid dysfunction (30%)
Thrombocytopenia (bone marrow suppression)
Goodpasture
Malignancy risk
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Parkinson’s Drugs
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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)
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Parkinson’s Drugs
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Dopamine Agonists
 Ropinirole and pramipexole
 Compulsive gambling, hypersexuality
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Tremor predominant
 Treat with trihexyphenidyl
 Anticholinergic
 Avoid in patients over 60 or with cognitive impairment
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Orthostatic hypertension
 Midodrin: converted to an alpha agonist
 Supine hypertension
 Used for patient unresponsive to fludrocortisone
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Tardive dyskenesias
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Treat with amantidine
Caused by long term anti-psychotic use but also
prochlorperazine and metoclopramide
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Tourette’s

First line agents: guanfacine or clonidine
 Alpha 2 receptor agonists
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Haldol more effective but more troublesome side
effects
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Essential tremor
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Propranolol: non specific beta blocker
 Don’t use if the patient has asthma, COPD, or CHF

Primadone: converted to phenobarbital
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Restless legs

First line is ropinirole
 Causes intrauterine growth retardation and digit
malformation

In pregnancy use Carbidopa/Levodopa
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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
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Tramadol
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
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