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)
Huntington’s Disease: Sx:
Chorea, w/ late parkinsonian sx (bradykinesia, unsteady gait, masking, dysarthria). Early loss of
ENK neurons, late loss of Substance P neurons in striatum. Cognitive deficits of executive function, mood, depression, & irritability.
Huntington’s Disease: Pathogenesis:
IT15 gene (4p16.3). Encodes for huntingtin. CAG expansion of N-‐terminus. The greater the expansion the earlier & more severe the dz. Mutation is thought to be “gain of function” & make huntington’s into a transcription factor. Causes a loss of striatal neurons (ENK, then SP). Essentially leads to a decreased output from STN (hyperkinetic).
Huntington’s Disease: Tx: Symptomatic;
Depression=
Fluoxetine (SSRI) & Carbamazepine (Voltage Na Channel blocker).
Huntington’s Disease: Tx: Symptomatic;
Chorea=
Reserpine & Tetrabenazine (Cause the depletion of DA). Chlorpromazine & Haloperidol (D2
antagonists). D2 antagonists cause an increase in
the indirect pathway (cause parkinson’s).
Endogenous Opiates: Regulate CNS activity of
pain, thermoregulation, appetite, & reward. Derived from pre-‐pro compounds.
POMC -> β-‐endorphin.
POMC producers are
only in CNS (Arcuate nucleus of hypothalamus, Nucleus Tractus Solitarius (NTS)). These areas project to limbic & spinal cord. POMC also made in pituitary (circulating endorphins).
Proenkephalin is made in areas of
pain modulation (PAG, spinal cord, trigeminal spinal nucleus).
Dynorphins are made
diffusely.
Spinothalamic Tract: Peripheral Stimulus is blocked by
NSAIDs (Decrease Prostaglandins).
Spinothalamic Tract: Conduction of afferent peripheral nerve is blocked by
Voltage gated Na channel blockers (-‐caines).
Spinothalamic Tract: Spinal cord transmission is blocked by
opiods, antidepressants, NSAIDs, antiepileptics, α2 agonists, celecoxib (COX2), and α2δ
ligands (gabapentin/pregabalin).
Spinothalamic Tract: Cortical modulation is by
opioids only.
Peripheral Transduction: Mechanical, chemical, or thermal pain signal lead to
activation of their respective receptors. All of these will lead to influx of cation -> Increase EPSP -> Voltage gated Na channel activation -> AP. Free nerve endings can release substance P & CGRP that Increase inflammation. Release of local inflammatory cytokines (bradykinin, histamine, PGE2)= Increase likelihood of AP= Peripheral sensitization
Spinal cord Signal transduction: Primarily transmission
of glutamate, substance P, & CGRP for excitation.
Spinal cord Signal transduction: Inhibitory receptors
that are pre & post synaptic are α2, GABA-‐B, & μ-‐opioid.
Spinal cord Signal transduction: These presynaptic receptors inhibit
Voltage-‐gated Ca channels=decrease synaptic vesicle fusion/release.
Spinal cord Signal transduction: These postsynaptic receptors activate
K channels=K+ leaving the postsynaptic terminal=Hyperpolarization.
Spinal cord Signal transduction: inhibiting Voltage-‐gated Ca channels & activating K channels
Both of these MOAs lead to a decrease in synaptic transmission of pain stimuli.
Central sensitization: Mechanism
Sustained depolarization of the postsynaptic terminal (glutamate -> AMPArs, glutamate -> mGLUrs, & SP -> NK1rs) leads to activation of NMDA receptors. Mg is removed from the NMDA Ca channel -> Sensitization through phosphorylation of PKC, CaKinase, & ERK.
Phosphorylation of gene regulatory proteins that make the neuron more excitable long term= Wind Up.
NMDA receptor Blockers: Surgery
preemptive blockade of NMDA can prevent surgery induced Wind Up.
NMDA receptor Blockers: Drugs
o Ketamine:
o Dextromethorphan:
Ketamine: AEs:
hallucinations, amnesia, HTN (pressor), increase ICP
AKA Angel Dust.
Dextromethorphan: AEs:
dizziness, confusion, fatigue. Used as an anti-‐tussive.
Neuropathic Pain: Define:
Injury to nerve fibers can lead to altered gene expression (changes in Na channel expression in the injured fibers & adjacent fibers).
Neuropathic Pain: Mechanism:
Damaged C-‐fibers can lead to Aβ fiber growth into the area. This changes the sensitivity to nociception & can lead to phantom limb.
Neuropathic Pain: Drug used:
Carbamazepine: Voltage gated Na channel blocker is used to treat TN & neuropathic pain.
APS/AAPM opiate recommendations:
Try other tx first, Assess risk of abuse, Realistic expectation (pain won’t go away completely), Start w/ a short term trial, Weigh individual Risk/Benefit ratio. WHO has a 3 step ladder for cancer pain that is similar.
Opiate Anatagonists: Mechanism
Antagonize μ, δ, and κ. Cause withdrawal Sx, but can also be used to antagonize the AEs of opiates.
Opiate Anatagonists:
o Naloxone:
o Naltrexone:
o Nalmefene:
Naloxone: ADME
30min t1/2. Paraenteral only. Rapid acting for OD reversal.
Naltrexone: ADME/other uses
4 hr t1/2 oral. 5-‐10 days IM. Used for addiction programs. Tightly binds opiate receptors & slowly releases from them. Decrease EtOH craving in alchoholics (Decrease β-‐endorphin release).
Nalmefene:
11hr t1/2. Paraenteral only.
Opiate Receptors:
o μ (OP3):
o δ (OP1):
o κ (OP2):
μ (OP3):
Endorphins: Cortical & spinal analgesia, sedation, decrease respiration, increase GI transit, altered hormone & NT release.
δ (OP1):
Enkephalins: Cortical & spinal analgesia, altered hormone & NT release.
κ (OP2):
Dynorphins: Cortical & spinal analgesia; psychomimetic, decrease GI transit
Opiate Drugs Delivery:
PO preferred for convenience. Morphine & morphones can be suppository. SC/IV from pain pump. Can be lozenges & intranasal too
Opiate Drugs Absorption:
Oral effective drugs have low first pass, others have a high first pass metabolism. Most well absorbed from SC/IM
Opiate Drugs Distribution:
Weak plasma protein binding. Distributes to increase blood flow organs first. Muscle is biggest reservoir. Not adipose because decrease blood flow to adipose. Can go to adipose with prolonged high doses= depot.
Opiate Drugs Desensitization:
Opioid receptors are G-‐PCR. Binding leads to internalization of the receptor. Exogenous opioids don’t let the receptors recycle as efficiently (degraded by endosomes) as endogenous opioids. Recycling facilitated by GRK2 & β-‐arrestin.
Opiate Drugs AEs:
Restlessness/hyperactivity/Convulsions, Respiratory depression, N/V, increase ICP, Orthostatic HypoTN, Constipation, Urinary retention, Pruritis/urticaria, Bradycardia, Miosis. Tolerance to these AEs can occur (because of receptor internalization). AEs that won’t go away are Miosis, Constipation, & Convulsions. Respiratory depression can be worse w/ sleep apnea
Opiate Drugs B/c the constipation (MC AE) won’t go away,
always give a laxative. If the laxative doesn’t work use an opiate antagonist (will also decrease analgesia though).
Opiate Drugs B/c the somnolence can be severe from these drugs,
be careful w/ other centrally acting drugs & rotate opiates if needed (or give a stimulant).
Opiate Drugs N/V typically develop when
drug is given too quickly. Respiratory depression really only occurs w/ OD, give Naloxone to reverse it.
Opiate Drugs Some opiates cause histamine
release (morphine). Others don’t (fentanyl). But, they all can cause itching. Tx with antihistamines.
***Opiate Overdose Triad:
Coma, Respiratory Acidosis, Pinpoint Pupils*** Coma is from decrease cortical stimulation. Respiratory acidosis is from decreased drive to breath even with increase pCO2. Pinpoint pupils from modulation at Edinger-‐Westphal Nucleus.
Opiate Drugs interxn:
Sedatives (increaseCNS/respiratory depression), Antipsychotics (increase sedation & CV effects), MAOIs (contraindicated w/ all opiates b/c hyperpyrexic coma & HTN)
Opiate Drugs FDA Label:
Variability in CYPs can lead to increase AEs from codeine. It crosses into breast milk (respiratory depression in baby). Metabolites are renally eliminated (RF). Worry about Drugs that interact w/ CYP
All Opiates are contraindicated in
renal failure except hydromorphone & fentanyl.
Morphine:
μ>κ. Low oral availability.
Hydromorphone:
μ+. Low oral availability. Ok for renal failure
Oxymorphone:
μ+. Low oral availability.
Methadone:
μ+. High oral availability. Elim t1/2 is 120 hrs. Used to manage opiate withdrawal. Rx requires special state license from physician (given long term). Tx of choice for Pregnant addicts. Can cause decrease libido & increase QT interval arrhythmia.
oMeperidine:
μ+. Medium oral availability. 1 metabolite has big increase to CNS toxicity. Also an anti-‐cholinergic+ SNRI. Lots of bad AEs & relatively low analgesia.
Fentanyl:
μ+. Low oral availability. Transdermal patch/lozenge. Patch makes SC depot. Heat makes the patch drug absorb faster. Suicide. Ok for renal failure
Remifentanil.
μ+. IV only.
Codeine:
μ±. High oral availability. Gets converted to morphine by CYP2D6.
Hydrocodone:
μ±. Medium oral availability.
Oxycodone:
μ+. Medium oral availability.
Pentazocine:
μ±, κ+. Medium oral availability.
Nalbuphine:
μ-‐, κ+. IV only.
Buprenorphine:
μ±, δ-‐, κ-‐. Low oral bioavailability. Made w/ naloxone so it can’t be crushed & injected. Use for dependence programs. Has a plateau of effect (additional opiates don’t increase euphoria). Very strong binding at receptor. Low risk of OD.
Butorphanol:
μ±, κ+. IV only.
Propoxyphene:
Old opiate that was withdrawn b/c long QT arrhythmias.
Opiate Withdrawal:
Onset depends on drug t1/2. Peak of Sx at 2 days & last 7-‐10 days. Craving/drug-‐seeking behavior first then “skin crawling, diaphoresis, rhinorrhea, anxiety, fear, arthralgia, myalgia.
Opiate Withdrawal: What are not Sx?
** fever/seizure/hallucinations aren’t Sx of opiate withdrawal.
PE of opiate withdrawal pt:
Agitated, diaphoretic, lacrimation, piloerection, pupillary dilation. Slight tachycardia from agitation
Think PP LAD
Opiate Withdrawal: Tx:
Tx: Methadone for inpatient. Clonidine for outpatient.
Withdrawal
DDX:
o EtOH: Delirium tremens, hyperthermia, HTN, tachycardia
o Sympathomimetic intoxication: More severe mydriasis, agitation, tachycardia, & HTN than opiates
o Cholinergic intoxication: SLUDGEBBB
Schedule Drugs: Opiates
Remember that drugs are classified as schedule 2-‐5. Opiates are schedule 2 (as addictive as we can Rx). Addiction is associated w/ increased DA signaling. Opioids disinhibit DA signaling (inhibit GABAergic neurons from blocking DA). Others classes directly excite DA neurons (benzos) or decrease DA reuptake (amphetamines).
Dependence vs. Addiction:
Physical need=dependence,
Psychological need=addiction.
Addiction usually occurs when there are negative consequences in the patients. Dependence requires chronic exposure. Addiction doesn’t.
Addictive features:
Unsanctioned use (doesn’t follow Rx), Crush & inject, buys off the street, drug-‐seeking at the hospital, Hx of addiction, severe withdrawal Sx, Negative social features.
Addiction: Tx for dependence:
Methadone, Naltrexone, Buprenorphine.
Addiction: Toxic Screen:
Urine Ab enzyme assays used for opiates. Different ratios of morphine:codeine can indicate what the pt is taking. Morphene:codeine >2:1 (heroin). <2:1 (codeine). Synthetic opiates are negative. Fluoroquinolones can be false positive.
Opiates for non-‐analgesia:
Cough:
NTS is the cough pattern generator. Codeine may or may not work. Dextromethorphan.
Opiates for non-‐analgesia:
Diarrhea:
Opiates in the enteric nervous system increase GI transit & peristalsis:
Loperamide (OTC-‐doesn’t cross BBB/ no analgesia).
Diphenoxylate (Rx-‐ formulated w/ atropine to decrease abuse).
Non-‐medical/surgical tx of pain:
Spinal manipulation, massage, acupuncture, transcutaneous electric nerve stimulation. Herbal remedies (capsaicin, cod-‐liver oil, devil’s claw, Epsom salts, white willow)(wtf?)
Finally: Surgical Tx of pain:
Ablate the nerve w/ radio frequency or chemical
New FDA limit on Tylenol
in combo is 325mg. Worried about AHF
Ancillary Pain drugs: Non-‐Narcotic:
Gabapentin & Pregabalin:
α2δ subunit of voltage gated Ca channel blocker. Inhibits neuronal hyperexcitability. Normal nerve function unchanged. Doesn’t affect GABA. Renally eliminated. Dizziness and Drowsiness
Ancillary Pain drugs: Non-‐Narcotic:
Lamotrigine & Carbamazepine:
Voltage gated Na channel blocker. Decreased neuron conduction. Dose adjust in hepatic failure. Suicide.
Ancillary Pain drugs: Non-‐Narcotic:
Lamotrigine: AEs:
Lamotrigine AEs: BBW for Steven-‐Johnson’s. Vision problems.
Ancillary Pain drugs: Non-‐Narcotic:
Carbamazepine: AEs:
Carbamazepine AEs: dizzy/drowsy, agranulocytosis
Ancillary Pain drugs: Non-‐Narcotic:
TCAs:
NE and 5-‐HT reuptake inhs are useful for pain (ascending MAO involved in pain). Chronic pain pts also get depressed (2 birds). Don’t affect DA. Hepatic metabolism (CYP2D6). AEs: dizzy/drowsy, HA, fatigue, lethargy, memory impairment.
