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147 Cards in this Set
- Front
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why don't we know the moa for neuro drugs?
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black box- we don't know what happens in vivo in the neuro system, so we extrapolate from what we know happens in a closed system
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specific mechanism of action
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specific drug action with an effect on a recognized protein target
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describe the areas where drugs have an effect on synaptic transmission
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NT synth, storage, metabolism, release, receptors, reuptake, degradation
Ionic conductance in teh post-synaptic neuron |
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drug-induced alteration of membrane potential
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leads to excitation or inhibition making it harder or easier to fire
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what is a neurotransmitter?
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substance that is released locally and causes a change in post-synaptic potential
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what is a neuromodulator?
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substnace which acts to modify the response of the synapse to a neurotransmitter
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○ acetycholine
○ amino acids ○ biogenic amines ○ peptides ○ purines ○ nitric acid ○ endocanabinoids |
neurotransmitters
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compare and contrast ionotropic receptors with metabotropic receptors on speed and effected substance
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ionotropic: short and fast effects; ↑ Cl, Na, K or Ca and cause EPSP or IPSP
metabotropic: slow and long-lasting; leads to synth of cAMP, IP3, and DAG which alter intracellular pathways; can also modulate voltage-gated ion channels |
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how are capillaries in the BBB different from the rest of the body?
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§ less permeable
§ tight junctions § fewer pinocytotic sites § surrounded by pericytes and astroglial processes § carrier mediated transport |
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fxn of and disorders affecting cognitive processing
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motor activity, reasoning, forethought
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fxn of and disorders affecting memory
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coordination of many brain structures to recall events
dementia |
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disorders affecting and fxn of emotional processing
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limbic structures and frontal lobe cortex that coordinate the conscious perception of neuronal activity
anxiety, mood disorders, schizophrenia |
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fxn of and disorders affecting sensory processing
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vision, hearing, olfaction, touch, pain
sleep disorders, chronic pain |
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fxn of and disorders affecting motor processing
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control of motion and posture
parkinson's, degenerating and demyelinating dz |
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sx of migraine
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recurrent attacks of steady or throbbing pain that frequently occur at night; often unilateral and associated with anorexia; may or may not have prodromal aura
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pathogenesis of migraine
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underlying disturbance of brain function
disturbance in central pain processing pathways leads to release of serotonin and neuropeptides (CGRP, substance P, neurokinin A); release causes VD in cranial circulation -> pain |
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cluster headache vs. migraine
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related to migraine, but characterized by brief, excruciating, non-throbbing pain occurring in a series or cluster of attacks
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moa of triptans
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5HT1B or D receptor activation leads to vasoconstriction of large cranial blood vessels
↓ inflammation around sensory nerves inhibit trigeminal neuronal discharge |
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moa of ergotamine
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ergotamine binds to all subtypes of 5HT1 and 2 as well as adrenergic and dopaminergic receptors
agonist activity at 5HT1B and D probably responsible for antimigraine fx constriction of dilated arteries causes a ↓ in pain |
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s/e of triptans
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nausea and vomiting
pain and redness at injection site tingling, dizziness, burning sensations tightness and pressure (contraindicated in pts with CAD or angina) |
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contraindicated i npts with CAD or angina
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triptans
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s/e of ergotamines
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nausea and vomiting
muscle weakness and pain numbness and tingling in fingers and toes chest pain, tachycardia, bradycardia allergic reaction ergotamine dependence if given with CYP3A4 inhibitor (macrolides, protease inhibitors) may cause fatal ischemia |
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fatal ischemia occurs if given with macrolides, protease inhibitors (CYP3A4 inhibitors)
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ergotamine
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why use cafergot?
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caffeine increases absorption
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which has worse S/E, triptans or ergotamines?
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ergotamines- only used if triptans fail
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reduces frequency and severity of migraine attacks
*preferred |
beta blockers: propranolol and timolol
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prohylactic with similar effectiveness to β blockers
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antiepileptics: valproate and topiramate
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which antidepressants can be used to prevent migraines?
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amitrityline, MOAI's, SSRI's for menstrual migraine
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prevent the vasospasm that can lead to migriane; questionable efficacy
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CCB: verapamil, nimodipine
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decreases the frequency of migraines by decreasing the inflammation
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montelukast
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supplements that show possible effectiveness for the treatment of migraines
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coenzyme Q10, under the theory that mitochondrial defects contribute to migraines
petastites hybridis has sohwn effectiveness in RCT |
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longest duration triptans
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naratriptan (1-3 hours onset, oral)
frovatriptan (2-3 hours onset, oral) |
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shortest duration triptan
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sumatriptan SQ (onset 15 minutes)
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contraindicated in patients known to be at risk for ischemic heart disease, uncontrolled HTN hemiplegic or basilar migraines
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triptans
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absorption, metabolism and excretion of ergotamine
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slowly absorbed with oral administration, rapidly metabolized by liver, or stored in tissue, excreted by biliary excretion
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triptans: important interaction
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with SSRI's: serotonin syndrome
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1st choice, alternative, and prevention of cluster headache
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prophylactic: verapamil DOC, melatonin also effective
1: fast-acting triptan (nasal or SQ or O2 alt: serotonin-type drug cyproheptadine |
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what is the basic defect in MS?
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neurons become demyelinated due to a/i disease
possible viral exposure, genetic predisposition |
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what is the most common symptom in MS? What is most often the presenting symptom?
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common: fatigue and weakness
presenting: visual change |
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moa of IFN in MS
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decreased antigen presentation in the CNS; limited immune attack on myelin
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glatiramer MOA
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resembles myelin component and draws immune cells away by acting as a decoy
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mitoxantrone MOA
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antineoplastic agent that suppresses the immune attack
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natalizumab MOA
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binds to the α4 subunit of the cell surface adhesion molecule of the α4 β1 subunit on lymphocytes and monocytes
blocks cell adhesion and prevents leukocyte migration across the BBB= interrupts the immune attack |
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fingolimod MOA
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inhibits T cell migration out of lymph nodes via an action on sphingosine -1-phosphatase receptor
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which IFN appears to ↓ antigen presentation within the CNS to ↓ the attack on myelin
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IFN beta 1b
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which prep can be given weekly by IM injection?
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avonex
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which MS drug causes flushing, chest pain, shortness of breath within 15 minutes of adminstration?
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glatiramine
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which 2 MS drugs cause musculoskeletal symptoms?
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glatiramer- muscle stiffness and joint pain
natalizumab- arthralgia |
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which MS drug causes flu-like symptoms?
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IFn
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which MS drug has a cumulative effect on cardiac conduction and cannot be used for more than 2-3 years?
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mitoxantrone
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which MS drug causes loss of menstrual cycle?
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mitoxantrone
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which MS drug causes mouth sores?
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mitoxantrone
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which MS drug cuases bladder infection?
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mitoxantrone
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which 2 MS drugs cause Ab formation?
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natalizumab
IFN |
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which MS drug can cause progressive multifocal leukencephalopathy?
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natalizumab
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which drugs are used to treat inflammatory symptoms of MS?
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methylprednisolone
dexamethasone prednisone betamethasone prednisolone |
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which antidepressants are used to treat MS?
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fluoxetine
amitrityptiline imipramine |
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What are clonzepam, diazepam, baclofen, and tizanidine and dantrolene used for in the treatment of MS?
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antispasmodic
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Identify the reason for the use of each of the following in MS:
amatidine meclizine oxybutanin carbamazeine/phenytoin |
amantadine for tremors and fatigue
meclizine for vertigo oxybutanin for urinary incontinence carbamazepine/phenytoin for neuralgia |
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what is the only treatment for ALS? what is its moa?
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riluzole: voltage-gated sodium channel blocker which is thought to ↓ glutamate release
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what is ALS?
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progressive degenerative disease of motor neurons
glutamate excitotoxicity is a possible mechanism |
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what is the major complication of riluzole?
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ALT (SGPT) elevation may occur
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why are acetylchoinesterase inhibitors used in the treatment of Alzheimer's?
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the cognitive defects present in alzheimer's are thought to be related to the degeneration of cholinergic neurons in the cortex and hippocampus
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what are the 4 acetylcholinesterase inhibitors used in the tx of alzheimer's?
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donepazil
glanatamine rivastigmine tacrine |
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moa of memantine
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NMDA receptor antagonist; use-dependent blockage of glutaminergic overstimulation of NMDA receptors, which can be toxic to neurons which are important to learning and memory
allows low levels of receptor activation |
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defect in parkinson's disease
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○ progressive motor dysfunction due to tremor, rigidity, bradykinesia, and disturbance of posture
○ signs and sx are due to progressive degeneration of the inhibitory dopaminergic pathway projecting from the substantia nigra to the caudate nucleus |
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pill-rolling tremor
bradykinesia rigidity posture psychological sx |
parkinsons
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L-dopa moa
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○ immediate precursor of dopamine that does cross the blood-brain barrier
○ ↑ amount of dopamine in the undamaged neurons |
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L-dopa fx
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○ rapid reversal of bradykinesia and rigidity
tremors require continued therapy ○ changes in mood patients and more alert and interested in their environment dementia may not reverse |
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factors that limit the fx of l-dopa
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rate gastric emptying
pH of gastric fluids degradation by enzymes dietary protein 95% is metabolized in the periphery |
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dose-dependent effects, and tolerance may develop; GI (nausea and vomiting) and CV (orthostatic hypotension , cardiac arrhythmia)
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early side effects of l-dopa
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severity of side effects correlates with the degree of clinical improvement, duration of therapy, and dose. no tolerance develops
abnormal involuntary movements (dyskinesia) develops and requires a dosage reduction |
late side effects of l-dopa
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l-dopa and pyridoxine
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increased peripheral conversion of dopa to dopamine
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interaction: l-dopa and antipsychotic dopa antagonists
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counteracts effects of l-dopa
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l-dopa and MAOIs
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increased effects of dopa and may lead to hypertensive crisis
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anticholinergic drugs and l-dopa
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slow gastric emptying and decreased absorption
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TCAs and l-dopa
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aggravation of hypotensive sx
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carbidopa MOA
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the enzyme responsible for conversion of dopa to dopamine is l-aromatic amino acid decarboxylase
causes 95% of the l-dopa to be converted in periphery carbidopa inhibits this decarboxylase and allows more to get into the CNS advantages lower dose of dopa nausea and vomiting ↓ cardiac side effects ↓ pyridoxine antagonism prevented |
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selegiline MOA
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inhibits MAO B to ↓ the catabolism of dopa
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side effects: nausea, dizziness, hallucinations, confusion
depression, insomnia if taken late in the day |
rasagiline
selegiline |
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tolcapone MOA
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inhibit COMT to ↑ the duration of ldopa and dopamine
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side effects: diarrhea, bright yellow urine,↑ l-dopa s/e
hepatotoxicity |
tolcapone
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entacapone vs. tolcapone
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entacapone doesn't have hepatotoxicity
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amantidine moa
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acts by ↑ dopamine release from intact dopaminergic neurons
blocks NMDA receptors |
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side effects: effective quickly but for only about 2 months
confusion, delirium, somnolence, hallucinations cycloplegia, constipation, urinary retention |
amantidine
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ropinirole
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D2 agonist that cause direct stimulation of DA receptors rather than relying on DA neurons to convert
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nausea, dizziness, somnolence, HA, hallucination, impulse control issues
side effects: syncope or hypotension sudden onset of sleep with no warning |
pramiprexole causes all
ropinirole (everything but sleep) |
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why add anticholinergic drugs to a PD pt's regimen
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adjunct that will block the unopposed cholinergic effects in the basal ganglia of PD patients
↓ tremor, but little effect on rigidity and bradykinesia |
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rapid reversal of bradykinesia and rigidity; reversal of tremor with continued therapy
reversal of changes in mood: pts are more alert and interested, but not reversal in dementia |
levodopa
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always given in combination with levodopa to allow reduction in dose, ↓ side effects
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carbidopa
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adjunct to l-dopa in pts with stable PD and in pts with end of dose wearing off with normal l-dopa/carbidopa therapy
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tolcapone
entacapone |
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initial therapy w/o l-dopa, or adjunctive with l-dopa; has a lower incidence of response fluctuation and less dyskinesia
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ropinirole
pramiprexole |
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ergot compound that is a useful as adjunct to allow decreased l-dopa
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bromocryptine
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effective in controlling dyskinesias occurring with l-dopa late in progression; very effective, but only works for about 6-8 weeks
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amantidine
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↓ tremor but little effect on rigidicty and bradykinesia; generally little peripheral fx, but may ↓ ANS sx
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trihexyphenidyl
benztropine |
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↓ symptoms, neuroprotective fx, must be taken at a low dose to maintain specificity
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rasagiline
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end of dose phenomenon
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end of dose- symptoms get worse as medicine wears off
dependent on blood dopa levels |
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on/off phenomenon
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on-off- late s/e of levodopa, patients will go suddenly from being able to have purposeful movements (on) to not being able to (off)
related to reaching a "barrier" sometimes not dependent on blood dopa levels |
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drugs that slow the progression of PD
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rasagiline
pramiprexole |
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simple partial seizure: clinical and EEG
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localized EEG spikes
consciousness preserved various manifestations of motor or sensory disturbances related to specific cortical areas |
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complex partial seizure: clinical and EEG
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focal EEG spikes from temporal lobe
disturbed consciousness confused behavior, automatisms, sensory and emotional disturbances |
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partial seizure, 2* generalized: clinical and EEG
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spread of epileptic activity to affect both hemispheres
loss of consciousness motor pattern similar to generalized seizures |
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non-convulsive absent-type: clinical and EEG
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generalized 3 per second spike and wave EEG activity
brief, abrupt loss of consciousness with or without clonic motor activity |
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tonic clonic
(can be tonic or clonic): clinical and EEG |
generalized high voltage EEG spikes
major convulsion typified by tonic contraction, clonic jerking and a prolonged post-seizure (postictal) depression of CNS loss of consciousness |
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three commonly known general mechanisms of antiepileptic drug action
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limit sustained repetitive firing of neuorns by slowing rate of recovery in Na+ channels
enhancing GABA-mediated synaptic inhibition limit activation of Ca++ channels |
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treatment of status epilepticus
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supportive: electrolytes, arrhythmia, shock, airway
drugs: IV diazepam or lorazepam, followed by slow infusion of phenytoin or phenobarbitol |
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phenytoin MOA
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produces numerous effects but major action is to reduce rate of Na+ recovery from inactivation, slowing firing
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S/E profile: with rapid infusion: CV collapse or CNS depression
acute: ataxia, nystagmus, drowsiness, diplopia chronic: beh Δ, gingival hyperplasia |
phenytoin
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phenobarbitol MOA
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potentiates GABA inhibitory transmission to ↓ glutamate excitation
elevation ofseizure threshold limit seizure spread |
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S/E profile: acute intermittent porphyria
sedation, ataxia, megaloblastic anemia, confusion |
phenobarbitol
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primidone is similar to which drug, except for what?
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similar to phenopbarbitol but less potent, except it has higher incidence of drowsiness, dizziness, megaloblastic anemia
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carbamazepine MOA
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slows recovery of voltage-sensitive Na+ channels
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s/e profile: diplopia, blurred vision, drowsiness, dizziness, nausea, vomiting, ataxia, liver toxicity, weight gain, blood dyscrasias, aplastic anemia, agranulocytosis, skin reactions, SJS
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carbamzepine
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oxycarbazepine is less likely to cause
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liver and hematologic toxicity
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ethosuximide MOA
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increases the refractory period by ↓ conductance in Ca++ channels
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s/e profile: nausea, vomiting, drowsiness
parkinsonism, blood dyscrasias, urticaria, SJS |
ethosuximide
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valproic acid MOA
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blocks recovery in Na channels, hyperpolarizes via K channels, and GABA fx
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s/e profile: low tox
GI most common, some sedation and ataxia pancreatitis in children weight gain low risk of hepatotox ↑ risk of spina bifida |
valproic acid
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benzodiazepine MOA
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suppression of seizure spread in cortex, thalamus, and limbic structures
may facilitate GABA inhibition |
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S/E profile:CV and resp depression
paradoxical aggression beh status epilepticus with withdrawal |
benzodiazepines
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moa of benzodiazepines
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suppression of seizure spread in cortex, thalamus, and limbic structures
may facilitate GABA inhibition |
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S/E profile: high incidence of aplastic anemia and liver failure
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felbamate
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felbamate MOA
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sodium channel blockade
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S/E profile: vision loss in 30%
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vigabatrin
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vigabatrin MOA
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inhibition of GABA degradation
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rufinamide MOA
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unk, probably sodium channels
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• Explain the basis of the pharmacokinetic interactions between any combination of valproic acid, phenobarbital and phenytoin.
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all broken down by the same liver enzymes, carried in plasma by plasma proteins
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why do we use serum drug levels in the treatment of epilepsy
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narrow therapeutic index
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what is the goal in antiepileptic therapy?
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complete prevention of seizures without CNS impairment
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when do you use multiple drugs in anti-epileptic therapy
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only when there are multiple types of seizures, or when a single drug fails to provide adequate control at near toxic levels
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what do you do when changing anti-epileptic drugs?
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○ gradually decrease dosage of old drug while increasing dosage of new drug and monitor seizure activity as well as side effects
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phenytoin and OCP
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○ phenytoin may decrease the effectiveness of OCP
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phenytoin in pregnancy
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fetal hydantoin syndrome
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phenobarbitol in pregnancy
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potentially teratogenic
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valproate in pregnancy
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spina bifida
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gabapentin and pregabalin in seizure treatment
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adjunct and acts as a subunit of voltage-gated Ca channels to decrease release of excitatory NT
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lamotrigene
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slows recovery of Na channels to inhibit glutamate, adjunct
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topiramate
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blocks sodium channels and AMPA/kainate receptors, adjunct
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tigabine
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inhibits GABA reuptake, adjunct
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zonisamide
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primarily blocks sodium channels, adjunct
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levitracetem
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binds to synaptic vsicle protein to alter release of gaba and glutamate, adjunct
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lacosamide
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slow inactivation of sodium channels, adjunct
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primary generalized tonic-clonic seizure treatment
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DOC: valproate, carbamazepine, phenytoin
alt: lamotrigine, primidone, phenobarbitol |
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partial seizure, including 2* generalized, treatment
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DOC: carbamazepine, phenytoin, valproate
alt: primidone, phenobarbitol, lamotrigene (adjunct), gabapentin (adjunct) |
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absent seizure treatmetn
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DOC: ethoxusimide, valproate
alt:clonazepam, lamotripine |
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atypical absent, myoclonic, or atonic seizure treatmetn
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doc: valproate
alt: clonazepam, felbamate |
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• Recognize the antiepileptic drugs which are least likely to be involved in drug interactions.
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○ Gabapentin, pregabalin, levertiracetam
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