Pharmacy Neurology Flashcards
P-‐GP: Define
efflux pump that is particularly important in access to the neuropil. If you are using a drug for a CNS effect, check it’s P-‐GP substrate status. Also, don’t combine w/ P-‐GP inhibitors (will increase drug concentration). Vera CAN Quit (Verapamil, Cyclosporin, Amiodarone, Nifedipine, & Quinidine).
P-‐GP can have
polymorphisms (like CYP2D6). Don’t increase the dose. Switch to a non P-‐GP substrate drug.
Brain Tumors: BBB effect
Many chemo drugs are substrates for P-‐GP (problematic). The BBB problematic for
diagnosis MRIs are typically done w/ contrast (gadolinium=Renal failure) to better detect lesions, but gadolinium doesn’t cross BBB until a tumor has affected the tight junctions.
CNS NTs: Excitatory=
Glutamate & Aspartate (Acidic AA’s),
CNS NTs: Inhibitory=
GABA, glycine, β-‐alanine, & taurine.
Ach receptors
(Cholinergic at Nicotinic & Muscarinic Rs).
Adrenergic=
DA, NorEpi, & Epi (D1&2, α1&2, & β1&2).
Serotonin=
(5-‐HT) has 14 types of receptors.
CNS Adrenergic Pathways:
NorEpi found through the brain but highest in Hypothalamus, Amygdala, Dentate gyrus of Hippocampus, & Locus Coeruleus of the Pons.
Adrenergic receptors are metabotropic (intracellular signaling)
α1=Gq,
α2=Gi,
β1/2=Gs.
Adrenergic pathways are important in
sleep & arousal regulation. Hyperactivity may=Anxiety through limbic activation. Β activation in amygdala may reinforce negative memories (PTSD).
Central Cholinergic Pathways:
Found throughout the CNS. Nicotinic Rs are ionotropic (Open Cation channels). Nm (at the NMJ). Nn (at postganglionic autonomic synapse). Alpha4-‐Beta2 construct type receptors. Muscarinics are metabotropic. Odds are Gq & Evens are Gi. M1/3/5=Gq & M2/4=Gi.
Wakefulness: Both Ach and NorEpi paths are
involved in wakefulness. Blocking them can cause drowsiness.
AEs of antipsychotics:
Muscarinic Blockers:
(PNS=Xerostomia, urinary retention, constipation, and increase accommodation) (CNS=Toxic confessional state)
AEs of antipsychotics:
AlphaBlockers:
PNS=Orthostatic HypoTN, impotence, ejaculation failure
AEs of antipsychotics:
Dopamine Blockers:
(CNS=Parkinsonism, dystonias, akathisia, Tardive dyskinesia (Endocrine= Amenorrhea/galactorrhea, infertility, impotence)
AEs of antipsychotics:
Weight gain is likely from
H1 and 5-‐HT2 combined blockade.
Antidepressants: Typically block
reuptake of 5-‐HT, NorEpi, or Dopamine. But, they can also act at other receptors (AEs)
Antidepressants: NorEpi reuptake block
AEs: Anxiety, increase BP, diaphoresis, Tachycardia, tremor
Antidepressants: α1 reuptake block
AEs: Orthostatic HypoTN, reflex tachycardia
Antidepressants: Muscarinic reuptake block
AEs: Opposite of SLUDGEBBB, glaucoma + CNS effects on memory & cognition
Parkinson’s: ACh has effects that
oppose Dope in the basal ganglia through striatal cholinergic interneurons. Blocking these will decrease the striatal GABA outflow to the indirect pathway in the absence of DA (which normally shifts basal ganglia from indirect to direct pathway). Benztropine, Diphenhydramine, Trihexyphenidyl
can be used to accomplish this.
Amygdala: Most important NTs.
Apparently every NT acts here. Important in memory modulation. He said to note α1 and β1 here.
PTSD: Define
Post event physiological and psychological response to traumatic memory
PTSD: Sx: Intrusion:
Re-‐experiencing the event (Nightmares at night & flashbacks in the day). This responds to β-‐Blockers.
PTSD: Sx: Avoidance:
Can’t talk about the experience. Decrease emotional responses & detachment.
PTSD: Sx: Hyperarousal:
Insomnia, irritability, anger, hypervigilance, & easily startled. This responds to α-‐Blockers.
PTSD: Tx:
Paroxetine & Sertraline (SSRIs) FDA labeled tx. Prazosin (α-‐blocker) & Propanolol (β-‐blocker) can be used to target intrusion & Hyperarousal. These are off-‐label but well tolerated (be careful of HypoTN). Used to help re-‐calibrate amygdala response to memory recall.
Parkinson’s Dz: Epidemiology
Affects ~1.5 million in the US. Average age of onset is 55y/o (~10% of cases are pts <40y/o).
Parkinson’s Dz: 4 Cardinal Sx:
Bradykinesia (Slow movement), Rigidity (increase muscle tone/resistance), Resting Tremor (goes away w/ voluntary movement), & Postural Instability (impaired gait is a late sx).
Parkinson’s Dz: Pathophys:
Unknown (neurotoxin exposure (MPTP)/free radical damage have been implicated).
Parkinson’s Dz: Genetic components
Have been implicated in early onset Parkinson’s. Autosomal Dominant mutations of α-‐synuclein, LRRK2, Parkin, and UCHL1. Has been associated w/ infxn/encephalitis, stroke, trauma, antipsychotic drugs (These are tx-‐resistant).
Parkinson’s Dz: Hallmark feature
Hallmark feature is loss of dopaminergic neurons of the substantia nigra pars compacta. Sx not evident until 75% loss of DA neurons.
TX of Parkinson’s Disease:
- Replacement of Dopa:
- Stimulate the D2 receptor
- Increase Dopamine Release
- DA metabolism inhibitors:
- Alter DA/ACh Balance:
Replacement of Dopa:
DA cannot cross the BBB. Give the Precursor:
Tyrosin -> Levodopa -> DA -> DOPAC ->HVA.
Parkinson’s Disease: Single most effective tx.
L-‐DOPA (Levodopa): Can ameliorate all sx.
L-‐DOPA (Levodopa): MOA:
Replenishes DA stores in the DA neuron nerve terminals of SNc.
L-‐DOPA (Levodopa): ADME:
Orally available but inhibited by food. [L-‐DOPA] peak at 2 hrs & t1/2 is 3 hrs. L-‐DOPA is converted in periphery & brain to DA by L-‐AAD. 99% of L-DOPA converted in periphery to DA which can’t cross BBB. Given w/ Carbidopa, which blocks peripheral L-‐AAD (not CNS L-‐AAD). This reduces the peripheral AEs & allows decrease dose.
L-‐DOPA (Levodopa): AEs:
L-‐DOPA monotherapy. GI (N/V) & CV (arrhythmias & Orthostatic HypoTN). L-‐DOPA/Carbidopa=Behavioral (give antipsychotics) Dyskinesias (hyperkinetic ones). May increase free radicals & progress the parkinson’s dz
L-‐DOPA (Levodopa): phenomenon:
ON/OFF phenomenon: just quits working sometimes & may start working again. Usually completely exhausted after 3-‐5 years.
L-‐DOPA (Levodopa): Contra-‐
psychotic pts, glaucoma, CV Dz, PUD, melanoma. Drug Interxn w/ Vit B6(increase L-‐DOPA metabolism MAO-‐A Inhs (HTN)
Stimulate the D2 receptor
(Block the Indirect pathway) Dopamine agonists
Dopamine agonists used Parkinson’s Disease:
Dop Bro RAP
Apomorphine (NS)
Bromocriptine (D2/±D1)
Pramipexole (D2, free radical scavenger)
Ropinirole (D2, CYP1A2)
Parkinson’s Disease: Preferred initial therapy.
Dopamine Agonists: Save L-‐DOPA for progressed Dz & reduces ON/OFF in combo tx w/ L-‐DOPA. Don’t need to be converted, no toxic metabolites, no GI absorption issue, crosses BBB.
Drug that increases Dopamine Release
Amantadine: (No Effect on Metabolism!!!!)
Amantadine: MOA
Antiviral that increases DA release.
MOA is unknown.
Amantadine: Elim.
Renal
Amantadine: AEs:
Behavioral/Psychiatric. Psychosis w/ overdose.
Amantadine: Contra
Seizure & CHF.
DA metabolism inhibitors: general MOA:
DA is metabolized into DOPAC by MAO-‐B. DOPAC is converted into HVA by COMT. Block both enzymes!
MAO-‐B Inhs: drugs used for Parkinson’s Disease:
Selegiline & Rasagiline (increase potency so can be used alone. irreversible inhibitor ). Used when pt response to L-‐DOPA decreases. Little effect alone. May also increase release of DA. May be neuroprotective. Metabolized into amphetamine/methamphetamine. Drug Interxn w/ Meperidine, TCAs, & SSRIs.
COMT Inhs: drugs used for Parkinson’s Disease:
Entacapone & Tolcapone: Prolong the action of L-‐DOPA, increase L-‐DOPA bioavailability. Helps reduce ON/OFF. Highly protein bound. Entacapone (Peripheral COMT only & no AEs). Tolcapone (Peripheral & central COMT & Hepatic failure).
Alter DA/ACh Balance: drugs used for Parkinson’s Disease:
ACh opposes DA action in the striatum. Block that shit. Anticholinergics: Benztropine, Diphenhydramine, Trihexyphenidyl.
Anticholinergics:
Benztropine,
Diphenhydramine,
Trihexyphenidyl.
Used before L-‐DOPA. CNS AEs: sedation, confusion, hallucination, & mood change. PNS
AEs: Opposite of SLUDGEBBB.
Contra-‐ BPH, OBD (Organic Brain Syndrome),
glaucoma, avoid use w/ anti-‐H1 & TCAs.
Huntington’s Disease: Define
AD genetic dz (Trinucleotide repeat expansion disorder-‐CAG repeats at N-‐terminus)
