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Dr. Wang's CNS Pharmacology

Tetrodoxin puffer fish toxin -- helped us understand action and resting membrane potential by blocking sodium channels
Strychnine Glycine receptor antagonist
Frontal lobe skeletal muscle movement, information coordination, behavioral integration
parietal lobe somatic sensory
occipital lobe vision
temporal lobe hearing
Cerebral cortex integrates sensory/motor activity, controls thought/memory/consciousness
limbic system integrates emotions with motor coordination
Basal ganglia -- part of? function? Part of the limbic system -- forms extrapyrimidal motor system
Hippocampus -- part of? function part of limbic system -- incorporates recent memory
thalamus -- part of? function part of limbic system -- contains nuclei which relay information between sensory and cortical pathways
Hypothalamus -- part of? function? part of limbic system -- integrates autonomic nervous system (temp, water balance, sleep, BP regulation)
Two motor systems Pyramidal and extrapyramidal
Pyramidal motor system located on outer cerebral cortex in motor strip, move limbs voluntarily (conscious effort)
Extrapyramidal motor system Located in deep brain structures (outside pyramidal system), controls tone-posture-other involuntary motor functions (do not require conscious effort. Functions and locations are less well-defined compared to pyramidal system.
Antipsychotics have what effects on the extrapyrimidal system? Toxic - parkinsonian syndrome
Brain stem is composed of? pons and medulla
Brain stem is the center of? life
brain stem function coordinates essential reflexes, swallowing, vomiting, cardiovascular, respiratory
Reticular activating system is part of and does what part of brain stem, regulates sleep, wakefulness, arousal, and eye movement
chemoreceptor trigger zone is part of and does what part of brain stem, responds to drugs via emesis
emesis vomiting
cerebellum function posture, visceral function, learning, memory
spinal cord motorneurons, sensory relay cells, these convey signals between brain and periphery
Hierarchical neuronal system function sensory perception and motor control
Hierarchical neuronal system composition large, myelinated fibers capable of fast conduction
Hierarchical neuronal systems and lesions incapacitates system
lesion damage
Two types of hierarchical neurons Relay/projection and local circuit
relay/projection hierarchical neurons excitatory/glutamate
glutamate excitatory or inhibitory excitatory
local circuit hierarchical neurons inhibitory/GABA or glycine
GABA excitatory or inhibitory inhibitory
Connection ratio for hierarchical systems 1:1
Connection rato for diffuse/nonspecific neuronal systems More than 1:1
Diffuse or nonspecific neuronal systems use what neurotransmitter types monoamine or peptides
monoamines 5-HT, catecholamines
Diffuse or nonspecific neuronal systems axon type fine, unmyelinated, slow, long-lasting conduction
Diffuse or nonspecific neuronal systems convey what sort of information non-topographically specific
Diffuse or nonspecific neuronal systems control sleep/wake cycle, attention, appetite, emotion
Classify neurons by function excitatory, inhibitory
classify neurons by location cortical, subcortical, spinal
classify neurons by neurotransmitter gabanergic, adrenergic, dopanergic, seritonergic
two types of synapse signalling electrical and chemical
two types of ion channel on synapses voltage and ligand gated
two types of receptors on synapses metabotropic and ionotropic
action potential brief fluctuation in membrane potential cuased by rapid opening and closing of voltage-gated ion channels
synapse in greek to fasten together
stimulus to presynaptic neuron causes? influx of calcium that induces NT release, NT binds postsynaptic neuron and causes EPSP or IPSP
EPSP Depolarization
IPSP hyperpolarization
2 neuron cell types axons and dendrites
Place were axons synapse terminal or terminal bouton
Synthesis of NT requires what from where? ATP from mitochondria
recurrent neuronal interaction negative feedback from a neuron to itself
feed-forward neuronal interaction negative feed-forward from a neuron to itself
Axoaxonic neuronal interaction negative input from one neuron to another
dendrodendritic neuronal interaction complicated, not just axon-axon, gives brain sophistication
voltage gated channels -- which ions? Ca, Na, K
Ligand-gated channels (ionotropic receptors) respond to? ligands
membrane-delimited/diffusible second messenger metabotropic ion channels are what? GPCRs
A GABAa receptor is what kind of channel receptor? ligand-gated channel
Excitatory pathways involve ionotropic receptors that allow what ions through to induce depolarization? K+ and Na+
Inhibitory pathways allow what ion through to cause hyperpolarization? Cl-
Criteria for a neurotransmitter Localization, release, and synaptic mimicry
Neurotransmitter -- localization criterion present in the presynaptic terminals of the synapse and in the neurons from which those presynaptic terminals arise
Neurotransmitter -- release criterion released from the presynaptic nerve as a result of presynaptic nerve stimulus. neurotransmitter release is dependent on Ca2+ influx into the presynaptic terminal and corresponding voltage change
Neurotransmitter -- synaptic mimicry criterion Exogenous copies of the molecule thought to be a neurotransmitter induce the same effect when introduced to the synapse
Amino acid neurotransmitters y-aminobutyric acid (GABA), glycine, glutamate
glycine (excite or inhibit) inhibitory
Amine neurotransmitters dopamine, norepinephrine, serotonin, histamine
Which amine neurotransmitters have reuptake transporters? Dopamine, norepi, and serotonin -- NOT histamine!
Peptides Substance P, endogenous opioids (enkephalins, beta endorphin), cholecyctokinin (CCK), vasoactive intestinal peptide (VIP), angiotensin (AT), and neuropeptide Y (NPY)
NO and CO are gases but also? neurotransmitters
where are amino acid neuortransmitters synthesized? in the nerve terminals
GABA, BZDs, flumanzenil, and zolpidem bind to what site on the GABA receptor? allosteric sites
GABAa is a channel for what ion? Cl
muscimol affects what receptor as an agonist or antagonist? GABAa agonist
picrotoxin -- receptor? affect? competitive GABAa antagonist
bicuculline -- receptor? affect? competitive GABAa antagonist
GABAb is what kind of receptor? GPCR
Baclofen -- receptor? affect? GABAb agonist
2-OH-saclofen -- receptor? affect? GABAb antagonist
Baclofen relieves spasticity of? ALS (Lou Gehrig's disease)
Picrotoxin is an alkaloid derived from? plants
glutamate receptors are both? ionotropic and metabotropic
Glutaminergic ionotropic receptors are excitatory or inhibitory? excitatory
three types of glutaminergic ionotropic receptors N-methyl-D-aspartate (NMDA), kainate receptor, and AMPA
NMDA is an agonist of? NMDA excitatory glutaminergic ionotropic receptors
dizocilpine (MK-801) is an antagonist of? NMDA excitatory glutaminergic ionotropic receptors
AMPA is an agonist of? AMPA excitatory glutaminergic ionotropic receptors
CNQX is an antagonist of? AMPA excitatory glutaminergic ionotropic receptors
Glutaminergic metabotropic receptors -- excitatory or inhibitory? Both
Glutaminergic metabotropic receptors -- ionotropic or GPCR? GPCR
glutaminergic metabotropic receptors have 3 groups. Group 1 is where? Groups 2 and 3 are where? Group 1 is post-synaptic, excitatory. Groups 2 and 3 are presynaptic and inhibitory.
Glycine receptors -- excitatory or inhibitory? inhibitory
Taurine -- receptor and effect -- why found in Red Bull? glycine receptor agonist -- for its calming effects
Beta-alanine -- receptor and effect glycine receptor agonist
strychnine -- receptor and effect glycine receptor antagonist
function of Ach and Ach receptor systems arousal, sleep-wake cycle, learning, memory
Ach tract 1: Medial septal nuclei innervates? hippocampus
Ach tract 2: basal nucleus meynert (cell body in basal forebrain) innervates? neocortex
Ach tract 3: basal forebrain innervates? which then innervates? cerebral cortex and pontomesencephalotegmental complex, which innervates the thalamus and forebrain
AchE inhibitors are used to treat? Alz
Alz is characterized by a lack of what NT? Ach
DA system is comprised of two brain regions -- they are? substantia nigra (Parkinson's), and the ventra tegmental area (VTA) -- reward center/schizophrenia
NE system is where in brain? locus coeruleus (blue spot)
is the NE system diffuse or specific? diffuse -- 1 neuron can have 250,000 synapses
NE system functions attention, arousal, sleep-wake cycles, learning, memory, anxiety, pain, mood, brain metabolism
5-HT functions control of sleep-wake cycles, different stages of sleep, emotional behavior
5-HT system brain region raphe nuclei in midline of brain stem, and ascending reticular activating system (responsible for arousal and awakening)
Raphe Ridge or seam
Serotonin is derived from tryptophan
5-HT is related to emotional behavior. Drug classes include SSRI -- for anxiety, OCD, and depression
Peptide neurotransmitters work alone or in concert Work with coexisting transmitter, can have 1+ at the same time
peptides are not small molecules synthesized in terminal. they are peptides synthesized from mRNA in the ER. They are synthesized as precursors, transported to the terminals from the perinuclear cytoplasm, and are NOT reuptaken into the terminal
4 types of general/nonspecific CNS depressants General anesthetics, some sedative hypnotics, alcohol, and local anesthetics if accidentally injected (applied systemically)
3 types of general or nonspecific CNS stimulants and their 2 mechanisms Work through disinhibition or direct stimulation. analeptics (strychnine, pentylenetetrazol, picrotoxin), methyxanthines (caffeine), and amphetamines/amphetamine-like drugs
Analeptics disinhibit glycine or gaba receptors
methylxanthines like caffeine inhibit phosphodiesterase (PDE), preventing cAMP degradation
amphetamines and amphetamine like drugs function inhibit reuptake of NE or DA and increase concentration of catecholamines/MOAs in the presynaptic terminal, then induces their release
4 stages of general anesthetics 1- induction 2- excitation (don't raise dose! Body is fighting anesthesia) 3- surgical anesthesia 4- overdose
Steps toward excitation Normal>alertness>hyperexcitation>convulsion>death
Steps toward depression Normal>sedation/hypnosis>anesthesia>coma>death
Characteristics of Selective CNS Drugs Selective distribution, differential actions on different neurons (5-HT vs. Dopaminergic), selectivity through functional neuron state, and interaction with specific sites (presynaptic vs. postsynaptic receptors and autoreceptor feedback)
dopamine hypothesis many antipsychotics block D2 receptors in CNS, drugs that up DA activity aggravate schizophrenic symptoms, increased DA receptors sensitivity is found in schizophrenics, and homovanillic acid (DA breakdown product) urine levels change in treated pts
Apomorphine DA agonist, induces psychosis
levodopa provides DA precursor
amphetamine and DA stimulates DA release
Problems with DA hypothesis -- current antipsychotics treat how many patients? some not all
Problems with DA hypothesis -- phencyclidine is an NMDA receptor antagonist does what when given to healthy pts? Induces much more schizophrenia like symptoms than DA agonists.
Problems with DA hypothesis -- atypical antipsychotics are effective in treating schizophrenia. But they are less potent in what? blocking D2 receptors
Problems with DA hypothesis -- DA blockade occurs in hours with antipsychotics. How long before therapeutic effects seen? weeks
Serotonin hypothesis for schizophrenia -- hallucinogens like LSD and mescaline are? 5-HT agonists
Serotonin hypothesis for schizophrenia -- clozapine and quetiapine are inverse agonists of? 5-HT2A receptors
Serotonin hypothesis for schizophrenia -- 5-HT2A/C receptors regulate? DA and NMDA neurotransmission
Which class of antipsychotics are the oldest first generation? Phenothiazines
Chlorpromazine (Thorazine) -- class? aliphatic phenothiazine first generation antipsychotic
Triflupromazine (Vesprin)-- class? aliphatic phenothiazine first generation antipsychotic
Piperidine antipsychotic potency vs. aliphatic potency and extrapyrimidal/weight gain symptoms Aliphatic antipsychotics are more potent and also have more extrapyrimidal side effects/promote more weight gain
Thioridazine (Mellaril) -- class Piperidine phenothiazine first gen typical antipsychotic
Mesoridazine (Serentil) -- class Piperidine phenothiazine first gen typical antipsychotic
Piperazine phenothiazines -- potency? selectivity and corresponding cytotoxicity? extrapyramidal side effects? when compared to aliphatic phenothiazines: Potent (effective in low dose), selective (not sedative or hypnotic), but have severe extrapyramidal side effects
Fluphenazine (prolixin) -- class piperazine phenothiazine first gen typical antipsychotic
Trifluoperazine (Stelazine) piperazine phenothiazine first gen typical antipsychotic
Perphenazine piperazine phenothiazine first gen typical antipsychotic
Two classes of thioxanthene antipsychotics aliphatic and piperazine
chloprothizene (Taractan) -- class? aliphatic thioxanthene
thiothixene (Navane) -- class? piperazine thioxanthene
Which is more potent -- thioxanthenes or phenothiazines? phenothiazenes are slightly more potent
Butyrophenones -- most famous and only member we discussed Haloperidol
Haloperidol -- class, how often used, relative potency to other first gens, relative autonomic side effects, relative extrapyramidal side effects butyrophenone, most widely used typical, unique structure, more potent, fewer autonomic but more severe extrapyramidal side effects
Action and mechanism of antipsychotics -- antipsychotic effects suppression of conditioned responses, diminution of spontaneous motor activity
Which antipsychotics are most effective for reducing spontaneous motor activity? haloperidol and piperazines
What is thought to cause psychotic events? increased DA activity in mesolimbic/mesocortical areas -- which is also related to psychosis-related abnormal behaviors
Action and mechanism of antipsychotics -- mechanism block DA receptors and thus suppress antipsychotic behaviors
Mesolimbic-mesocortical pathway -- DA system component responsible for? behavioral control, also the major site of anti-psychotic effects
nigrostriatal pathway -- DA system component responsible for? voluntary and involuntary movement coordination
tuberoinfundibular pathway -- DA system component responsible for? neuroendrocrine regulation (mental state goes through here to change endocrine function
medullary-periventricular pathway -- DA system component responsible for? eating behavior
incertohypothalamic pathway -- DA system component responsible for? behavioral regulation (not control -- that's the mesolimbic-mesocortical)
D1 receptor family -- intracellular effects and receptor subtypes Increases cAMP, increases PIP2 hydrolysis, mobilizes Ca2+, activates PKC -- D1 and D5
D2 receptor family -- intracellular effects and receptor subtypes Decreases cAMP, increases K currents, decreases voltage-gated Ca2+ currents -- D2, D3, D4
All DA receptors are what type? GPCR
CNS side effects/toxicity -- extension of main effect (especially caused by aliphatics Depression, sedation, pseudodepression (at high doses)
CNS side effects/toxicity -- decrease of which thresh hold (especially aliphatics)? seizure
CNS side effects/toxicity -- selectively depress what (thioridazine is especially good for this as a clinical effect)? Chemoreceptor trigger zone for emesis -- anti-nausea
CNS side effects/toxicity -- extrapyramidal or neuroleptic symptoms occur especially with and cause them by doing? Occur with butyrophenones and potent piperazines -- blockade of DA receptors in the basal ganglia
CNS side effects/toxicity -- Tardive diskinesia Late-appearing neurological syndrome -- caused by DA receptor supersensitivity in the basal ganglia (from up-regulation of the receptor caused by years of blockade by antipsychotics)
Extrapyramidal symptoms and treatment -- Parkinson's Syndrome Akinesia, resting tremor, rigidity. Antiparkinsonism drugs of the muscarinic type or amantadine.
Extrapyramidal symptoms and treatment -- Akathiisia feelings of distress/discomfort compelling one to constant movement -- may be mistaken for agitation in psychosis but will be made worse by dose increase --treated by dose reduction, antiparkinsonism drugs, or anticholindergic sedatives (diphenhydramine)
Extrapyramidal symptoms and treatment -- Acute dystonia State of abnormal muscle tone, also called torticollis, treated with anticholinergic antiparkinsonian drugs
Extrapyramidal symptoms and treatment -- Catatonia, hyperthermia rare. occurs only in high doses or most potent antipsychotics. seizures in chlorpromazine or clozapine.
Extrapyramidal symptoms and treatment -- neuroleptic malignant syndrome emergency state, rare, occurs with high doze of antipsychotics, 10-20% of pts. die, STOP antipsychotics, give antiparkinsonism drugs, bromocriptine, and muscle relaxants like diazepam or dantrolene
DA neurons do what to GABA neurons? Disinhibit their inhibition
ACH neurons do what to GABA neurons? stimulate their inhibition
Tardive Dyskinesia -- associated with supersensitivity to what that causes a relative low concentration of what Dopamine supersensitivity occurs as a result of upregulation, causing a relatively lower concentration of Ach
Tardive dyskinesia -- more pronounced in? caused by? stereotypical symptoms? treatable? More pronounced in elderly patients. Caused by the immediate withdrawal of antipsychotic agents, characterized by sucking, smacking lips, lateral jaw movement, fly-catching darting of tongue, and coreiform movements of the extremities. Untreatable.
treating tardive dyskinesia withdraw or lower dose of causative agent, switch to newer atypical agent, and eliminate all drugs with known anticholinergic effects (antiparkinsonism drugs, TCAs), add muscle relaxer like diazepam
DA activity in pituitary does what to prolactin release? inhibits it
Lack of DA activity in pituitary does what to prolactin release? stimulates it
Peripheral side effects of antipsychotics -- hyperprolactinemia and amenorrhea Blocks DA, causes prolactin release. causes increased conversion of androgens to estrogen, leading to false-positive pregnancy tests. Infertility. Impotence. Treat with dose reduction or aripiprazole (decreases DA receptor sensitivity).
Peripheral side effects of antipsychotics-- poikilothermia condition of not reacting to temperature change in environment -- cold-bloodedness
Peripheral side effects of antipsychotics -- Alpha-adrenergic blockade (especially aliphatic phenothiazines) orthostatic hypotension, faintness, palpitations, nasal stuffiness, impaired ejaculation, longer QT interval
Peripheral side effects of antipsychotics -- Anticholinergic action Reverse SLUDGE
Peripheral side effects of antipsychotics -- hypersensitivity (allergic) reaction skin rashes, obstructive jaundice, blood dyscrasias (blood count off), photosensitivity
Peripheral side effects of antipsychotics -- weight gain Especially piperazine drugs (clozapine, thioridazine, olanzapine)
Pharmacokinetics of antipsychotics -- absorption most are highly lipophilic, protein bound, long duration of action
Pharmacokinetics of antipsychotics -- liver metabolism significant first pass metabolism, oxidation by P450 enzymes and conjugation
Pharmacokinetics of antipsychotics -- elimination metabolites excreted in urine and bile
Mesoridazine metabolite of thioridazine, even more potent
Antipsychotic drug interactions -- combined with CNS depressants anticholinergic effects, potentiate sedatives and analgesics, alcohol, hypnotics, and antihistamines. Overall additive/synergistic effect.
Antipsychotic drug interactions -- dopamine agonists or levodopa antipsychotics inhibit the effects of these drugs, which are used to treat Parkinsonian symptoms
Antipsychotic drug interactions -- with antihypertensive Guanethidine Block effects
Antipsychotic drug interactions -- with digitalis quinidine like cardiac effects of thioridazine and ziprasidone nullify the inotropic effects of digitalis
fluphenazine decanoate antipsychotic used for delusional paranoid state
All older antipsychotics can be used as antinauseas except thioridazine -- it blocks DA receptors centrally AND peripherally
prochlorperazine antiemetic
benzquinamide antiemetic
trimeprazine (Temaril) used for intractable hiccough
antipsychotics can be used to treat pruritus severe itch or rash on skin
haloperidol can be used to treat what disease (proper name)? Huntingdon's
butyrophenone droperidol is used in combination with fentanyl to induce? neuroleptanesthesia -- anesthesia
Clozapine -- typical or atypical? atypical
Clozapine -- most potent for? D4 receptor
Clozapine -- potent anti? anticholinergic
Clozapine -- Blocks what receptors? 5-HT2a and limited blocking of D2 receptor
Clozapine -- Major side effect? Fatal agranulocytosis. 1-2% of pts. have to do regular blood counts.
Clozapine -- seizure in how many pts? 2-5%
Clozapine -- should you use it in old patients with dementia? No. It has potent anticholinergic effects -- alzheimer's is due to an already existent lack of Ach
Clozapine -- does it cause weight gain? yes
Olanzapine (Xyprexa) -- blocks what receptor? 5-HT2a
Olanzapine is the most tolerated what? atypical antipsychotic
Olanzapine -- older pts. with dementia? Do not use. Increases death by stroke rate.
Olanzapine causes? weight gain
Loxapine (Loxitane) is a? Modern antipsychotic (second gen atypical)
Risperidone (Risperdal) is similar to Clozapine, but has more? Clozapine DA antagonism
Risperidone (Risperdal) is similar to Clozapine, but has fewer? Side effects from seritonergic and anticholinergic activity
Paliperidone Metabolite of risperidone -- also active
Quetipine (Seroquel)-- similar to Risperidone how? No anticholinergic effects
Which antipsychotic is the most prescribed as of 2007? Quetipine (Seroquel)
Aripiprazole (Abilify)-- reduces what serious atypical side effect and has a long what reduces weight gain, has a long half-life
Aripiprazole (Abilify) is used for? depression, mania, schizophrenia, bipolar disorder, and the aggression/temper tantrums associated with autism
Antipsychotics have hypotensive effects. What receptor mediates these? Alpha-adrenergic receptors
which 3 antipsychotics are never recommended for fat people? Thioridazine, clozapine, olanzapine
Which antipsychotic is recommended for people with extrapyramidal problems? Risperidone
Which antipsychotics are best for patients with alzheimer's? Quetiapine and Risperidone
Neuropathology of Parkinson's Loss of dopanergic neurons in substantia nigra, intracellular inclusions (Lewy bodies), symptomatic PD
Drug-induced parkinsonism (pseudoparkinsonism) is caused by what drugs? DA receptor antagonists (antipsychotics like haloperidol/thorazine and anti-emetics like metoclopramide and prochlorperazine)
Pseudoparkinsonism is also caused by what toxic agent? MPP+ derived from MPTP by MAO-B
Pathophysiology of parkinsons Loss of neurons in substantia nigra
MTPP looks like what molecule and is converted into what, which kills neurons in the substantia nigra by doing what? Dopamine, MPP+, being taken in by the reuptake transporter and used as if it were dopamine -- this kills the cell
Triad symptoms of Parkinson's Disease Bradykinesia or akinesia (difficulty in initiating movement), resting tremor, skeletal muscular rigidity or hypertonicity
The substantia nigra uses dopaminergic neurons to communicate with? The corpus striatum
What are the ways you can shut down DA neuronal communication in Parkinson's or pseudoparkinson's? You can block DA receptors, destroy dopaminergic neurons, or hurt the quantity of useful dopamine in the brain (release or production)
How does one treat Parkinson's? replace dopamine, decrease cholinergic neurotransmission by withdrawing cholinergic drugs and anticholinesterase drugs
Parkinsons and alzheimers both deal with a delicate balance between dopamine and acetylcholine. Which one is high and low in which condition? Parkinson's: High DA. Low ACH. Alzheimer's: Low DA. High Ach.
We can deal with parkinson's by upping dopamine or decreasing what? Ach
Trihexyphenidyl (Artane) Anticholinergic used to treat parkinson's
Benztropine (Cogentin) Anticholinergic used to treat parkinson's
What characteristic must a drug have if it is to treat Parkinson's or any disease of the CNS? The ability to penetrate the blood-brain barrier
Ach antagonists are used by themselves to treat Parkinson's when it is mild or severe? Mild
If severe parkinson's is present, what drug(s) do we select for treatment? Ach antagonists AND L-Dopa
Side effects of anti-parkinson's Ach antagonists drowsiness, mental slowness, GI side effects, tachycardia, dry mouth, constipation (Anti SLUDGE)
When should you NOT give anti-parkinson's Ach atnagonists? prostate hyperplasia (urinary retention is exacerbated), obstructive GI disease, or close-angle glaucoma (causes retention of aqueous humor) -- open angle glaucoma is OKAY
Too high a dose of levodopa causes dyskinesia
Too low a dose of levodopa causes akinesia
why not give DA -- why do we need a precursor? DA cannot penetrate BBB
Tyrosine-->?-->Dopamine Tyrosine is converted by tyrosine hydroxylase to DOPA which is converted by decarboxylase to dopamine
How well does L-DOPA work for Parkinson's? How long does it work? Do we use it right away? It works very, very well -- but only for 3-4 years. Then its effects are diminished. We do NOT use it for mild idiopathic parkinson's. We save it for later, when the patient really needs help.
Does levodopa stop the progression of parkinson's? No
What is the wearing-off affect of levodopa? At the end of their dose, the therapeutic level may drop so far in a patient that they experience dyskinesia
On-off levodopa effect akinesia and then wham, dyskinesia
Side effects of dopaminergic antiparkinson drugs--GI Disturbances. drugs enhance emetic response -- you get sick to the stomach -- treat with antiemetics but be careful as these can induce parkinsonian attack
Side effects of dopaminergic antiparkinson drugs--Cardiovascular tachycardia. orthostatic hypotension.
Side effects of dopaminergic antiparkinson drugs--dyskinesia 80% of pts -- due to DA overload
Side effects of dopaminergic antiparkinson drugs--Choreoathetosis involuntary irregular, repetitive, twisting or writhing movements alleviated by dose reduction
Side effects of dopaminergic antiparkinson drugs--behavioral agitation, delirium, hallucination, psychosis. Use ATYPICAL antipsychotics like clozapine! DO NOT USE TYPICALS! These are DA antagonists!
Side effects of dopaminergic antiparkinson drugs--Hormonal tonic inhibition of HPA axis and prolactin by DA. DA blocks prolactin release and DA antagonists induce its release. Massive decrease in milk production.
Drug interactions of dopaminergic antiparkinson drugs -- pyridoxine (vitamin B6) This causes a big increase in dopamine levels and is an amino acid decarboxylase cofactor (boosts last step in dopamine production pathway -- DOPA-->Dopamine)
Drug interactions of dopaminergic antiparkinson drugs -- MAO inhibitor antidepressants MAO-A1 is blocked and this blocks the breakdown of dopamine. It can cause hypertensive crises.
Drug interactions of dopaminergic antiparkinson drugs -- antipsychotics Levodopa is simply prohibited in psychotic patients. No way, no how.
Drug interactions of dopaminergic antiparkinson drugs -- Physostigmine Cholinesterase inhibitor used for glaucoma
AD aldehyde dehydrogenase, converts dopamine into inactive forms
COMT catechol-O-methyltransferase, converts dopamine and L-DOPA to inactive forms
D-beta-H dopamine beta hydroxylase, converts dopamine to norepinephrine
AAD aromatic L-amino acid decarboxylase, converts levodopa to dopamine and uses vitamin B6 as a cofactor
MAO monoamine oxidase, converts dopamine to inactive metabolite
Sinemet L-DOPA+carbidopa
carbidopa peripheral aromatic L-amino acid decarboxylase inhibitor (blocks conversion of L-dopa into dopamine in the periphery and decreases side effects thereby -- also boosts amount that makes it to be effective in CNS) -- reduces necessary levodopa dose by 75%
Bromocriptine (parlodel) D2 agonist
Perglide (permax) D1 and D2 agonist, used to treat fibrosis of valves in the heart
Ropinirole (requip)/Ropinirole XL selective D2 agonist, used for restless leg syndrome
Pramipexole (mirapex) preferred affinity for D2 receptors
Rotigotine Skin patch for early Parkinson's disease
DA receptor agonist other than L-DOPA are better for what phenomenon? on/off phenomenon
DA receptor agonists other than L-DOPA are useful for those who cannot? Tolerate L-Dopa's side effects
DA receptor agonists other than L-DOPA are useful for those who are already experiencing? Toxicities similar to L-Dopa's side effects (GI and cardiovascular)
DA receptor agonists other than L-DOPA are contraindicated in which patients? pts. with history of psychotic illness, recent myocardial infarction, GI ulceration -- this is especially true of the ergot-derived DA agonists
Amantadine (symmetrel) antiviral that potentiates DA activity -- do not use in pts. with renal failure, congestive heart failure, and seizures
Selegiline (eldepryl) irreversible MAO-B inhibitor that decreases L-DOPA's wearing off effect and dyskinesia. It also delays the initiation of L-DOPA therapy for PD treatment -- it buys the patient more time before they have the L-DOPA wearing off effect.
Entacapone (Comtan) short duration COMT inhibitor, blocks DA degradation
Stalveo Has L-DOPA, carbidopa, and entacapone. Entacapone blocks DA degradation, carbidopa blocks peripheral conversion of L-DOPA to dopamine (decreases L-DOPA dose needed), and L-DOPA is a dopamine precursor
Tolcapone (Tasmar) long duration COMT inhibitor, acts at CNS and PNS, 2% hepatotoxicity, which is very high
Surgical antiparkinson procedures Deep brain stimulation, injection of fetal brain tissue
COMT Degrades catacholamines like DA
Neurodegenerative disorders any disorder with progressive and irreversible loss of neurons from specific regions in the brain
Major difference between Parkinson's Disease and Huntingdon's Disease Parkinson's is very sporadic. Huntingdon's is very genetic.
Major similarity between Parkinson's and Huntingdon's Loss of neurons in basal ganglia and corresponding loss in movement control
Alzheimer's Disease Loss of hippocampal and cortical neurons -- impairment of memory and cognitive capacity
ALS (amyotrophic lateral sclerosis) degeneration of spinal, bulbar, and cortical motor neurons. Muscular weakness in the muscles requires to speak, swallow, and make facial expressions
Which nerves are hurt in Parkinsons? Dopaminergic
Which nerves are hurt in Huntingdon's? Gabanergic
Genetic factors associated with Huntingdon's CAG repeats, autosomal dominant
Genetic factors associated with Parkinson's Disease alpha synuclein (synaptic protein), LRRK2 (leucine-rich repeat kinase 2), Parkin (ubiquitine hydroxylase), UCHL1 (ubiquitin carboxy-terminal hydroxylase 1)
Genetic factors associated with Alzheimer's Disease amyloid precursor protein (APP), presnilins (for APP processing), apolipoprotein E (cholesterol and lipid transport)
Genetic factors associated with ALS (amyotrophic lateral sclerosis) mutation of SOD1 -- an enzyme that decreases the number of ROS in a cell. Loss of this enzyme through mutation increases the ROS in a cell.
Environmental factors that can contribute to neurological disorders Infection agents (viral), Toxins (MPTP -- insecticides), injuries (stroke)
Excitotoxicity and neurological disorders glutamate, NMDA receptors, and Ca2+ input can exceed the voltage capacity of a neuron and literally fry it. (can be due to AD or stroke)
Oxidative stress and neurological disorders free radicals can be scavenged by glutathione, SOD, or vitamin E. If something happens to remove these, it is possible that ROS might cause issues
what is augmented in the treatment of alzheimer's cholinergic function in the brain
Tacrine (Cognex) Cholinesterase inhibitor used in the treatment of alzheimer's -- LOTS of side effects and very dose limited
Donepezil (Aricept) AchE inhibitor used in the treatment of alzheimer's
Rivastigmine (Excelon) AchE inhibitor used in the treatment of alzheimer's
Galantamine (Reminyl) AchE inhibitor used in the treatment of alzheimer's
Memantine (Namenda) NMDA antagonise used in the treatment of alzheimer's
Riluzole (Rilutek) Delays ALS -- first ever approved by FDA for this. Inhibits glutamate release, blocks glutamate receptors, relieves spasticity (it's a spasmolytic)
Baclofen (Lioresal) Relieves spasticity in ALS by agonizing the GABAb receptor (operates in CNS)
tizanidie (Zanflex) alpha-2 adrenergic agonist (presynaptic autofeedback) (increases negative feedback mechanism in nerves)-- LOTS of cytotoxicity
Blocker of physiological tremors Beta2 blocker (nonspecific beta blockers like propranolol)
Blocker of essential tremors Beta1 blocker (metoprolol, atenolol, esmolol)
Tics Chronic multiple tics -- Gilles de la Tourette's Syndrome
Tardive dyskinesia drug induced by? DA receptor blocker
Tardive dystonia drug induced by? DA receptor blocker and also anticholinergic drugs
tardive akathisia drug induced by? anticholinergic antiparkinsonian drugs
Restless leg syndrome treated by? pramipexole, ropinirole
Wilson's Disease caused by? Recessively inherited disorder in the metabolism of copper
Wilson's Disease treated by? penicillamine -- chelating agent for copper
Major Depressive Disorders (MDD) Mental state of excessive sadness characterized by persistent low mood or extensive loss of pleasure or interest
Tricyclic antidepressants (TCA) structure three-ring molecular core. similar to phenothiazines. most NE-reuptake inhibitors.
Class 1 of TCAs Tertiary amines -- inhibit NE AND 5-HT reuptake
Class 2 of TCAs Secondary amines -- selective NE reuptake inhibitors
Imipramine (tofranil) Class 1 TCA, inhibits NE and 5-HT reuptake, also has anticholinergic antimuscarinic side effects
Amitriptyline (elavil) class 1 TCA, blocks NE and 5-HT reuptake
Trimipramine (Surmontil) Class 1 TCA, unknown mechanism, does NOT block reuptake!
Clomipramine (anafranil) Class 1 TCA, the most potent of them all, also approved to treat OCD -- Doxepin/Sinequan
Desipramine (norpramin) Class 2 TCA, NE reuptake only (not 5-HT), is a metabolite of imipramine and has less anticholinergic effect
Nortriptyline (aventyl) Class 2 TCA, NE reuptake blocker but less selective so it still may hit 5-HT reuptake and block it too
protriptyline (vivactil) Class 2 TCA, NE reuptake only, not 5-HT
Do TCAs have any effects in a normal person? No. They do not elevate the mood of normal persons.
What do TCAs do in depressed patients? they elevate mood and decrease time in REM sleep
Which have more anticholinergic action? tertiary or secondary amines? tertiary
TCAs have alpha-adrenergic blockade. Which receptor do they block more? Alpha 2 WAY over alpha 1. They have NO affinity for beta receptors.
Mechanism of action TCAs Inhibit the neuronal uptake of biogenic amines in the CNS (NE, 5-HT), however exceptions of this hypothesis do exist (trimipramine)
Pharmacokinetic properties of TCAs High protein binding, high lipophilic, anticholinergic effects, drug absorption (slows GI motility, delays absorption), Fairly well absorbed after oral administration, and significant first pass metabolism in the liver
Side effects of TCAs (anti-Ach M and alpha-adrenergic) GI side effects and posterual hypotension (anti-alpha1-adrenergic)
CNS side effects of TCAs take someone right out of depression into hypomania or mania, restlessness, insomnia, tremors, or potentiation of seizures (antihistaminic effects)
Cardiac toxicity caused by TCAs palpitation, tachycardia, orthostatic hypotension (alpha-1 adrenergic effect)
Weight/sweating side effects of TCAs weight gain, excessive sweating
TCA drug interactions -- plasma proteins and liver metabolism compete with antiepileptics (piperazine phenothiazines in particular), antipsychotics, smoking, and barbiturates
TCA drug interactions -- with antipsychotic drugs Protein binding and additive anticholinergic action (muscarinic)
TCA drug interactions -- with guanethidine inhibits NE release from presynaptic nerver terminal by BEING UPTAKEN with the reuptake transporter! This is the precise mechanism BLOCKED by TCAs!
TCA drug interactions -- with MAO inhibitors Serotonin syndrome when co-treated with SSRIs. causes akathisia-like restlessness
Serotonin Syndrome -- caused by SSRIs given with MAOIs. SSRIs in this situation include TCAs with 5-HT reuptake inhibition.
Serotonin Syndrome -- severity Can be lethal
Serotonin Syndrome -- cause(s) occurs when 2+drugs that affect serotonin levels are taken simultaneously. (MAOIs, SSRIs, meperidine, dextromethorphan)
Serotonin Syndrome -- signs and symptoms agitation, diarrhea, heavy sweating, fever, mental status change, muscle spasm, overactive reflexes, shivering, tremor, ataxia
Serotonin Syndrome -- Treatment BZDs (diazepam, lorazepam), cyproheptadine (inhibits serotonin), withdrawal of MAOIs or SSRIs causing the syndrome, fluids/breathing machine to maintain patient until danger passes
Therapeutic uses for TCAs Less popular due to side effects, but the tertiary amines are still prescribed for endogenous depression
TCAs are used together with lithium to treat what? Bipolar disorder
TCAs can be used for what condition in children or geriatrics? Enuresis -- provides rapid, temporary suppression
NE-selective TCAs can be used to treat what condition? ADHD
TCAs can be used to treat what syndrome? Tourette's
TCAs can be used to treat which severe anxiety disorders? panic-agoraphobia, social phobia, obsessive-compulsive disorder
TCAs can be used to treat what kind of pain? chronic
fluoxetine (prozac)class and serious side effect original SSRI. Can induce suicidal ideation in juveniles/adolescents, norfluoxetine is active metabolite with 240 hour halflife
paroxetine (paxil) class and unique feature (has to do with how many neurotransmitters it blocks) SERT and NET -- serotonin reuptake and also norepi reuptake inhibitor -- research shows it affects BOTH even though it's an SSRI
sertraline (zoloft)class SSRI
SSRI selective serotonin reuptake inhibitor
citalopram (celexa) class SSRI
fluvoxamine (luvox) class SSRI
SSRI pharmacodynamic properties 80% inhibition of 5-HT reuptake transporter -- does NOT affect histamine, acetylcholin, or alpha-adrenergic receptors -- this decreases side effects tremendously
SSRI pharmacokinetics lipophilic, EXTREMELY long half life (10 days for fluoxetine's active metabolite, norfluoxetine), and fluoxetine/paroxetine are potent inhibitors of CYP2D6 and TCA
Side effects of SSRIs GI upset, weight gain, sexual function
SSRI drug interactions -- do NOT use with? MAOIs
Therapeutic uses for SSRIs major depressive disorder, general anxiety disorder, post-traumatic stress disorder, obsessive compulsive disorder, panic disorder, pre-menstrual depressive disorder, and bulimia
SNRI serotonin/norepi reuptake inhibitor
Venlafaxine (Effexor) class SNRI
Duloxetine (Cymbalta) class SNRI
Drug interactions SNRIs MAOI -- causes serotonin syndrome
Therapeutic uses SNRIs panic disorder, social anxiety disorder, pain disorder (duloxetine is really good for diabetic neuropathic pain and fibromyalgic pain), and urinary incontinence (esp. when due to stress)
Trazodone (desyrel) SNRI 5-HT2 antagonist, also a hypnotic
Nefazodone (Serzone) SNRI 5-HT2 antagonist, hepatotoxicity is an issue
Buproprion (wellbutrin) SNRI unicyclic, blocks dopamine/NE reuptake -- unique to this drug only, increases the availability of both neurotransmitters, and is used for smoking cessation
Mirtazapine (remeron) SNRI tetracyclic, presynaptic alpha2 receptor antagonist (DISinhibitor, blocks inhibition effects of the alpha-2 receptor), blocks 5-HT2 and 3 receptors, H1 antagonist
MAOI monoamine oxidase inhibitors
MAOI drug interactions A LOT. In fact, this is the main reason we study them. Normally they aren't even prescribed -- but when they are, they are a BIG deal.
phenelzine (nardil) class non-selective, irreversible MAOI
tranylcypromine (parnate) class non-selective, irreversible MAOI
selegiline (eldepryl) class selective MAO-B inhibitor
selegiline use parkinson's
clorgyline class MAO-A selective inhibitor
Pharmacological actions of MAOIs mood elevation of depressed patients, increased motor activity, increased appetite, excitement, euphoria, suppression of REM sleep
mechanism of action MAOIs inhibit oxidative deamination (degradation) of monoamines (NE, 5-HT)
Tranylcypromine has what type of effects? Amphetamine-like
Pharmacokinetics MAOIs aborbed readily orally, not given parenterally
Pharmacokinetics phenelzine MAOI, cleaved to hydrazine and then acetylated
MAOI CNS side effects excessive CNS stimulation
MAOI cardiovascular side effects orthostatic hypotension (VERY prominent)
MAOI weight side effects weight gain
MAOI sexual side effects anorgasmia -- inability to orgasm
MAOI liver side effects serious hepatotoxicity, especially with hydrazides
Drug interactions MAOIs Enhance CNS depressants by interfering with their metabolism (esp. BZDs), potentiate the effects of indirect sympathomimetics (causes hypertensive crisis)
Food interactions MAOIs Tyramine rich foods augment MAO inhibitors and lead to hypertensive crisis
Tyramine and MAOIs Tyramine is a false neurotransmitter present in many, many foods. It is normally metabolized by MAO. But if MAOIs are blocking MAO, then it floods the nervous system and causes issues.
Therapeutic use of MAOIs secondary use for depression, phobic-anxiety when TCAs and ECT (shock therapy) are inadequate
Uses of Lithium bipolar disorder, esp. manic phase (slow onset), prevention of mania or depression in bipolar disorder, recurrent endogenous depression that is drug resistant, schizoeffective disorder, schizophrenia, antipsychotic/antidepressant resistant patients
Lithium Mechanisms Blocks Na+ channels. Blocks IP3 and DAG production in neurons. Inhibits GSK-3 and NE-sensitive adenylyl cyclase. Decreases NE and DA turnover and increases 5-HT activity and Ach synthesis. Blocks DA receptor supersensitivity.
Pharmacokinetics lithium readily and completely absorbed. eliminated via urine. Na loading enhances Li excretion. Low therapeutic index, requires blood monitoring.
Lithium toxicity -- acute acute -- nausea, vomiting, diarrhea, ataxia, convulsion, confusion, coma, hyper-reflexia, cardiac arrhythmias, hypotension, tremor (manage with propranolol or atenolol)
Lithium toxicity -- prolonged Ligand-GPCR uncoupling (receptor activates but nothing happens), hypothyroidism (thyroid enlargement and increased TSH production), polydipsia, polyuria, nephrogenic diabetes insipidus, and edema (Na retention and water follows Na)
Why does TSH cause goiters? Because it stimulates cells OTHER than endocrine thyroid cells to perform. Low thyroid hormone = large levels of TSH = lots of stimulation to thyroid cells = large thyroid = goiter.
Lithium drug interactions diuretics (esp. thiazides) -- increase reabsorption of lithium, and include aspirin and acetaminophen. Lithium antagonizes NE's effect on blood pressure. Old neuroleptics when given with Li have a much higher propensity toward extrapyramidal syndrome.
Carbamazepine (tegretol) use antiepileptic/antiseizure
Valproate (depakene) use first choice for antidepressant
Olanzapine (zyprexa) use Good choice for antidepressant
Lamotrigine (Lamictal) or topiramate (Topamax) use VG-Na channel blocker
Why are BZD's such better choices than older hypnotics? the dose curve drops off below the level that induces anasthesia -- older hypnotics keep on a goin' and hit coma level effects
Alprazolam (xanax) class/use BZD -- depression
Chlordiazepoxide (librium) class/use BZD alcohol withdrawal syndrome
clonazepam (klonopin) class/use BZD convulsion, panic disorder, muscle relaxation
clorazepate (tranxene) class/use BZD convulsion
lorazepam (ativan) class BZD
flurazepam (dalmane) class BZD
oxazepam (serax) class BZD
triazolam (halcion) class/use BZD, rapid onset of action and shorter duration, early morning-insomnia
pharmacological properties BZDs all have same pharmacological profiles, differe in pharmacoKINETICS -- do not EVER cause true anesthesia, rarely ever fatal unless taken with other CNS depressants--HUGE NO NO
Overall pharmacological profile of BZDs sedation. hypnosis. sleep. decreases sleep latency period. increase non-REM sleep. decrease NREM or Stage 4 (deepest) sleep, decrease the duration of REM sleep.
When do BZDs cause muscle relaxation and how do they do it? neuromuscular blockade at extremely high doses
Anterograde amnesia inability to form or recall memories from the duration of a drug's effects -- great for preanaesthesia so the patient can't remember what happened during an unpleasant procedure
Can BZDs be used as anticonvulsants? You bet. Especially clonazepam, lorazepam, and diazepam.
Peripheral effects of BZDs coronary vasodilation (therapeutic doses given via IV)
Which receptors do BZDs bind? GABAa
BZDs bind the allosteric site of the GABAa receptor, and do what? first, they do NOT actually open the Cl channel. Instead, they potentiate GABA binding to the channel and increase the FREQUENCY of binding+opening events
Side effects of BZDs -- other CNS depressants NO. Absolutely NO. BZDs potentiate other CNS depressants, including alcohol.
side effects BZDs -- motor function lightheadedness, lassitude, incoordination, ataxia, and mental slowing
side effects BZDs -- abuse/dependence less problematic than barbiturates or alcohol -- but still present an issue with dependence
side effects BZDs -- chronic use and abrupt withdrawal rebound anxiety. insomnia. agitation. panic. paranoia. myalgia. muscle twitches. convulsions.
drug interactions BZDs ethanol increases absorption rate and associated CNS depression, combined therapy of BZDs and valproate can lead to psychosis
Ultra-short acting BZDs half-life less than 30 minutes. no current agents.
short-acting BZDs half-life less than 6 hours
intermediate acting BZDs half life from 6-24 hours
long acting BZDs half life greater than 24 hours
Clorazepate unique characteristic prodrug, converted to nordiazepam in stomach
Lunesta (eszopiclone), Ambien (zolpidem), and zaleplon all have what in common? short half-lives (no more than 6 hours) and are used to help with insomnia
Oxazepam and lorazepam are similar in what way? neither of them have active metabolites, contributing to their shorter half lives
Buspirone (Buspar) class non BZD selective anxiolytic
Buspirone (Buspar) mechanism agonist 5-HT1a and D2 receptors
Buspirone (Buspar) onset and rebound anxiety/toxic facts Slow onset. no rebound anxiety. minimal abuse issue, less psychomotor impairment
Zolpidem (ambien)/zalpelon (sonata)/eszopiclone (Lunesta)--selectively binds what receptor? BZ1 alpha 1 subtype of GABAa
Zolpidem (ambien)/zalpelon (sonata)/eszopiclone (Lunesta)--antagonized by what? Flumazenil
Flumazenil antagonist of GABAa allosteric binding site for BZDs (antagonizes BZD activity)
Zolpidem (ambien)/zalpelon (sonata)/eszopiclone (Lunesta)-- muscle relaxing/anticonvulsive activity Very low as both a relaxant and anticonvulsive
Zolpidem (ambien)/zalpelon (sonata)/eszopiclone (Lunesta)--speed of onset? Very rapid, low rebound insomnia on sudden discontinuation
Zaleplon (sonata) is especially good for patients who? awake early as it has active metabolites (longer half life/duration of effect)
Zolpidem (ambien)/zalpelon (sonata)/eszopiclone (Lunesta)--tolerance/dependence levels less development for both tolerance and dependence
Zolpidem (ambien)/zalpelon (sonata)/eszopiclone (Lunesta)--which patients need lower dose those with hepatic dysfunction, elderly, patients taking cimetidine (blocks CYP3A4)
Zolpidem (ambien)/zalpelon (sonata)/eszopiclone (Lunesta)--patients which need higher dose patients taking rifampin (increases expression CYP3A4)
Flumazenil (romazicon) purpose competitive BZD receptor antagonist
Flumazenil (romazicon) use reverse CNS depressant effects of BZD overdose
Flumazenil (romazicon) pharmacokinetics rapid action, short half life. repeat administration.
Flumazenil (romazicon) dose form IV only. Less than 25% of drug reaches general circulation if given orally.
Long term use of BZDs is dangerous, especially to the elderly. Why? Because if they are taken off rapidly, they can have problems crop up.
Barbiturates -- general info non-selective, dose dependent CNS depressants, go all the way to the top to coma on the dose chart, narrow margin of safety, high incidence of toxicity, greater problems of abuse/tolerance/physical dependence, limited use for sedative/hypnotic/anxiolytic
What is special about acidic barbiturates? they do not affect the CNS as much
What is special about the alkyl group at C5 in barbiturates? it enhances hypnotic action
What is special about the phenol group at C5 in barbiturates? it is essential for anticonvulsant action
If there is a thio group (S) at C2, what is increased in barbiturates? lipid solubility
What four variables affect the onset and duration of barbiturates lipid solubility (greater = faster onset), tissue redistribution/affinity for plasma proteins, liver degradation level (if degraded here, short half life), or renal excretion (if dumped here, longer half life)
Explain how renal or hepatic degradation/excretion affects the duration of barbiturates Renal excretion = long half life and long duration Hepatic degradation = short half life, short duration
Phenobarbital relative onset, peak affect, duration of action, and half life onset is slow (60 min), peak effect seen in 10-12 hours, duration of action is long, half life is 80 hrs
Amobarbital relative onset, peak affect, duration of action, and half life moderate onset (6-8 hrs), intermediate duration of action, and half life of 25 hours
Pentobarbital relative onset, peak effect, duration of action, and half life onset is rapid (10-15 min), peak effect in 3-4 hours, short duration of action, and half life of 20-50 hours
Secobarbital relative onset, peak effect, duration of action, and half life rapid onset (10-15 min), peak effect in 3-4 hours, short duration of action, half life 25 hours
Thiopental (IV only) relative onset, peak effect, duration of action, half life relative onset is incredibly fast (<1 min), peak effect in 0.25 hours, duration of action is ultra-short, and average half life is 3-8 hrs.
Oxybarbiturates ALL except thiopental
Uses of the barbiturates -- sleep sleep (oxybarbiturates only) -- induces sleep, decreases REM time, prolonged use causes rebound insomnia (REM rebound), restlessness, anxiety, and increased nightmare incidence
uses of the barbiturates -- hyperalgesia stops reaction to painful stimuli
uses of the barbiturates -- anesthesia thiobarbiturates and short acting oxybarbiturates can be used to induce anesthesia
uses of the barbiturates -- anticonvulsants phenobarbital has a selective anticonvulsant action unrelated to its sedative action -- good for tonic-clonic seizures
effects of the barbiturates -- respiratory depresses respiration (dose-related) -- depresses medullary respiratory center
effects of the barbiturates -- cardiovascular dose-dependent -- only has effects at anesthetic doses, not sedative/hypnotic doses -- decreases cardiac output, renal plasma flow, and increases total peripheral resistance
Pharmacological properties of the barbiturates -- GI tract decreases GI muscle tone
Pharmacological properties of the barbiturates -- uterus decrease force/frequency of uterine contraction, depresses fetal respiratory rate
Pharmacological properties of the barbiturates -- liver in acute doses, it competes with other drugs for P450 enzymes and other liver enzymes. In long-term use, it wildly increases their expression.
Pharmacological properties of the barbiturates -- tolerance Induces metabolic and pharmacodynamic tolerance
Pharmacological properties of the barbiturates -- dependence induces psychological and physical dependence
Mechanism of action of the barbiturates Increases the DURATION (not frequency!) of channel opening events on the GABA-gated chloride channels. In high concentrations, it is a GABA mimetic and opens the channel itself. It also inhibits excitatory AMPA receptors.
Adverse effects of the barbiturates CNS depression -- after effects, drowsiness, vertigo, nausea, vomiting, diarrhea, mood distortion, impairment of judgment and fine motor skills -- if used repeatedly, overexcitement, can induce allergic reactions and erthyematous dermatitis
Drug interactions of the barbiturates CNS depressants like alcohol and antihistamines, they inhibit the metabolism of other drugs in the acute phase -- in the long term, they induce liver enzyme production and literally cause other drugs to vanish (vitamins D and K, endogenous steroids)
Drug interactions of the barbiturates -- plasma protein binding Bind EXTREMELY well to plasma proteins, competing with other drugs for the spot.
Contraindications of the barbiturates -- acute intermittent porphyria barbituates induce porphyrin biosynthesis
Contraindications of the barbiturates -- pulmonary insufficiency This may occur in patients that already have respiratory insufficiency
Contraindications of the barbiturates -- cardiovascular diseases can cause fetal cardiovascular collapse by rapid IV injection
Barbiturate poisoning -- signs/treatment Can be deliberate OR accidental -- occurs if taken with other CNS depressants. Signs: difficult to diagnose, especially if subject is comatose. Treatment: general support and gastric lavage if in first 24 hours of taking
Uses of Barbiturates -- sedative hypnotics available, but declined use. Replaced with safer BZDs
Uses of Barbiturates -- anesthetics short acting or ultra short acting barbiturates only -- GREAT for preanesthetic use over volatile anesthetics because volatiles increase cranial pressure. In pts. with already increased cranial pressure this can be harmful.
Uses of Barbiturates -- anticonvulsants popular for children
Uses of Barbiturates -- hypbilirrubinemia and kernicterus hepatic glucuronyl transferase and bilirubin-binding protein (helps prevent resulting brain damage
Other hypnotic sedatives -- chloral hydrate (noctec) -- effects on sleep, hangover as compared to BZDs or barbiturates short acting sedative hypnotic, no affect on REM sleep, less hangover than BZDs or barbiturates
other hypnotic sedatives -- chloral hydrate (noctec) -- metabolism, toxicity, tolerance/dependence, withdrawal rapidly reduced to trichlorethanol (active metabolite) in liver, low toxicity unless given with other CNS depressants, acute intoxication resembles that of barbiturates, habitual use leads to dependence/tolerance/addiction, withdrawal=delerium/seizure
Other hypnotic sedatives -- chloral hydrate (noctec) -- contraindications hepatic, renal, and cardiac disease, gastritis
Other hypnotic agents -- include EToH and what other anti-allergy class? Histamines (diphenhydramine, hydroxyzine)
Other hypnotic agents not really mentioned in class except for by name Glutethimide (doriden), methyprylon (noludar), meprobamate (miltown)
Characteristics of epilepsy periodic and abnormal discharge of brain tissue, second most common neural disorder after stroke, 40 forms, etiology is unclear but may include infection, tumor, head injury, therapy is symptomatic to stop seizure, but no cure exists
Partial seizure Only neurons in the cerebral cortex fire.
Generalized seizure Neurons in both the cerebral cortex and thalamus fire (the thalamus is a subcortical region)
Glioma tumor of the glial cells in the brain -- known to cause epilepsy
Seizure transient alteration of behavior due to disordered synchronous and rhythmic firing of a specific population of brain neurons
Epilepsy disorder of brain function characterized by periodic and unpredictable occurrence of seizures
Nonepileptic seizure has a known trigger (electrical current, chemical convulsants)
epileptic seizure no trigger, no electrical or chemical convulsant stimulus
tonic Muscle tone is tight
atonic muscle tone is slack
Secondarily generalized partial seizures starts as partial seizure, goes to general after some time
tonic-clonic grand-mal seizure
absence seizure petit-mal seizure
Status epilepticus repeated epileptic seizures that last for so long and/or occur so close together that there is no break between them and no recovery time
Mechanisms of antiepileptics -- blocking neuronal firing Block NA channels (phenytoin, carbamazepine, valproate) -- block calcium channels (blocks low-threshhold t-type current) (ethosuximide, valproate, diazepam, barbiturates)
Mechanisms of antiepileptics -- enhancing neuron inhibition Activating GABAa receptor (increases Cl influx to the cell -- BZDs and barbiturates), inhibition of GABA transaminase (blocks the breakdown of GABA), and inhibition of GABA transporter GAT-1 to reduce uptake of GABA
Mechanisms of antiepileptics -- blocking excitatory pathways Block the NMDA receptor (valproate)
Phenytoin (dilantin) -- pharmacology inhibits generation of repeat action potentials. lowers Na, K, and Ca conductance. Decreases glutamate release. Boosts GABA release.
Phenytoin (dilantin) -- clinical value antiepileptic without general CNS depression -- reduces seizure but does NOT lower seizure threshhold
Phenytoin (dilantin) -- class antiepileptic
Phenytoin (dilantin) -- metabolism weak organic acid with good GI absorption, WAY bound to plasma proteins after oral/IV administration, metabolized by CYP450
Phenytoin (dilantin) -- dose-dependent metabolism Eventually all degradative enzymes get full up -- at this point, degradation of the drug stops and an increased dose will REALLY boost you into cytotoxicity
Phenytoin (dilantin) -- CNS side effects at low dose ataxia. vertigo. diplopia. nystagmus.
Phenytoin (dilantin) -- CNS side effects at high dose excitation followed by dysarthria (speech disorder, weakness of speech muscles), lethargy, and finally coma
Phenytoin (dilantin) -- side effects -- Gingival hyperplasia overgrowth of the gingival tissues
Phenytoin (dilantin) -- side effects -- GI disturbances, cardiac arrhythmias what it says, bro
Phenytoin (dilantin) -- side effects -- hirsutism occurs with chronic use. lots of hair growth in odd places.
Phenytoin (dilantin) -- side effects -- osteomalacia abnormal vitamin D and calcium metabolism (softening of bone with pain/weakness)
Phenytoin (dilantin) -- side effects -- hypersensitivity skin rash, fever, and lymphoadenopathy (enlargement of lymph nodes)
Phenytoin (dilantin) -- drug interactions protein binding drug (90%) and metabolism. Isonaizid and cimetidine inhibit phenytoin metabolism, and phenobarbiturate induces the CYP450 that increases phenytoin metabolism.
Phenytoin (dilantin) -- use as an anticonvulsant effective against partial and generalized grand mal seizures -- alternative choice for status epilepticus but not first pick
Phenobarbital -- oldest of what class? anti-epileptic
Phenobarbital -- side effects -- sedation calming effects, induction of sleep, highly lipid soluble
Phenobarbital -- side effects -- neurological and behavioral effects development of tolerance and psychological+physical dependence
Phenobarbital -- side effects -- hepatic effects toxicity
Phenobarbital -- side effects -- hypersensitivity/hematological allergic reactions
Phenobarbital -- side effects -- bones osteomalacia
Phenobarbital -- anticonvulsant use generalized tonic-clonic (grand mal), myoclonic, but NOT petit mal (there is one agent in particular we use for this problem)
Phenobarbital -- first choice for what patients? neonates, infants, and children for febrile seizures
Phenobarbital -- not recommended in? pregnant women -- depresses respiration
Phenobarbital -- used in what condition as an alternative treatment? status epilepticus
Primidone -- chemistry deoxybarbituate analog, metabolized to phenobarbital and phenylethylmalonamine (PEMA)
Primidone -- mechanism of action similar to phenytoin, independent of conversion of phenobarbital and PEMA
Primidone -- toxicity systemic/CNS toxicity limit its use, side effects include sedation, vertigo, nausea, vomiting, ataxia, diplopia, nystagmus, hepatic and hematological toxicity
Primidone -- dose form Oral only. Does not bind to plasma protein more than 30%. Short half life. Increase dose gradually.
Primidone -- interaction with other antiepileptics phenobarbital and lamotrigine
Primidone -- grand mal Used as primary therapy for grand mal if they do not respond to phenytoin or phenobarbital
Carbamazepine (tegretol) -- structure tricyclic, so it is both antidepressive and anticholinergic (anti SLUDGE)) -- tertiary structure is similar to phenytoin
Carbamazepine (tegretol) -- mechanism similar to phenytoin, decreases synaptic transmission presynaptically
Carbamazepine (tegretol) -- pharmacokinetics complex. bioavailability after oral administration is not predictable. binds to plasma protein. almost completely metabolized. induces cyp450 (microsomal enzymes)
Carbamazepine (tegretol) -- side effects -- lower dose diplopia, ataxia, GI upsets
Carbamazepine (tegretol) -- side effects -- higher dose drowsiness, dizziness, blood dyscrasia (aplastic anemia, granulocytosis -- allergic reaction), erythematous skin rash (allergic), stevens johnson syndrome
stevens johnson syndrome Massive allergic reaction, lethal without treatment, caused by carbamazepine, characterized by blotches all over skin
Carbamazepine (tegretol) -- clinical use monotherapy for grand mal and partial seizures, primary drug for trigeminal neuralgia, and bipolar depression after lithium therapy fails
Ethosuximide (zarontin) -- mechanism decreases Ca currents
Ethosuximide (zarontin) -- increases? seizure threshold
Ethosuximide (zarontin) -- metabolism liver metabolized, renally excreted, eliminated more rapidly in children than adults, no protein binding, valproate inhibits metabolism
Ethosuximide (zarontin) -- toxicity -- dose related GI disturbance. drowsiness. headache. hiccough.
Ethosuximide (zarontin) -- toxicity -- not dose relates hematological effects, allergic effects (Stevens-Johnson Syndrome)
Ethosuximide (zarontin) -- anticonvulsant use monotherapy drug of choice for absence seizures (petit mal) -- VERY effective, VERY safe -- also used with carbamazepine or phenytoin for mixed seizures
Valproic Acid (Depakene) or VALPROATE -- mechanism blocks high-frequency repetitive firing of neurons, including decreasing Ca current, blocking NMDA receptor excitation, GABAnergic GAT-1 inhibition and GAD facilitation, inhibits GABA transaminase at high concentrations
GAD converts glutamate to GABA
GAT-1 degrades GABA
Valproic Acid (Depakene) or VALPROATE -- distribution Extensively bound to plasma protein. eliminated by hepatic metabolism
Valproic Acid (Depakene) or VALPROATE -- drug interactions displaces phenytoin, inhibits metabolism of phenytoin/carbamazapin/phenobarbital, decreases lamotrigine clearance
Valproic Acid (Depakene) or VALPROATE -- dose related side effects nausea, vomiting, GI distress, weigh gain, alopecia, hyperammonemia, tremor -- but do not often see dose related problems as only tiny doses of drug are needed for therapeutic effect
Valproic Acid (Depakene) or VALPROATE -- idiosyncratic side effects hepatotoxicity, thrombocytopenia, spina bifida (Developmental disorder in fetus)
Valproic Acid (Depakene) or VALPROATE -- anticonvulsant uses very effective for absence seizures, generalized absence, tonic-clonic (grand mal), myoclonic, monotherapy for mixed seizure, used for bipolar depression after Lithium fails, and for migraine prophylaxis
Benzodiazepenes and seizures -- side effects sedative effect. tolerance.
Benzodiazepenes and seizures -- clonazepam (klonopin) -- uses petit mal, myclonic in children. one of most potent anti-seizure medications known. long-acting.
Benzodiazepenes and seizures -- clonazepam (klonopin) -- side effects sedation. dependence.
Benzodiazepenes and seizures -- diazepam (valium) -- uses status epilepticus. short duration only. also good for serial seizures and prophylaxis of febrile seizures. prolonged oral use of drug is not recommended
Benzodiazepenes and seizures -- lorazepam (ativan) -- uses status epilepticus. more effective and longer duration than diazepam.
Benzodiazepenes and seizures -- clorazepate (tranxene) -- uses acute alcohol withdrawal syndrome, adjunctive therapy for complex partial seizures -- prodrug, has to be hydrolyzed in stomach to nordiazepam before it can be used
Other antiepileptics -- acetazolamine -- class? uses? diuretic and carbonic anhydrase inhibitor. all types of seizures. limited monotherapy use (rapid tolerance), but good adjunct therapy use
Other antiepileptics -- gabapentin (neurontin) -- analog of? mechanism? analog of gaba but does not stimulate GABA receptors. promotes release, reuptake, and metabbolism of endogenous GABA
Other antiepileptics -- gabapenting (neurontin) -- use? metabolism? used as adjunct therapy for polytherapy of partial seizures and generalized tonic-clonic (grand mal) seizures. No hepatic enzyme metabolism, excreted unchanged into urine.
Other antiepileptics -- lamotrigine (lamictal) -- mechanism? use? blocks votalge dependent Na channels and decreases glutamate release. used as adjunct therapy for polytherapy of partial seizures in people over 2 years old and for bipolar disorder, as well as life-threatening dermatitis (Stevens-Johnson syndrome)
Other antiepileptics -- vigabatrin (gamma-vinyl-GABA) -- mechanism? uses? side effects? irreversible GABA aminotransferase (GABA-T) inhibitor. used for partial seizures and infantile spasms. common side effects: drowsiness, dizziness, weight gain. less common: agitation, confusion, psychosis, irreversible visual field defect.
Other antiepileptics -- tiagabine (gabitril) -- mechanism? use? pharmacokinetics? inhibits GABA transporter (GABA reuptake) in both neurons and glia. used as adjunct therapy for polytherapy of partial seizures in ADULTS. rapidly absorbed after oral administration, extensively bound to proteins, metabolized by CYP450 in liver.
Other antiepileptics -- topiramate (topamax) -- mechanism? pharmacokinetics? blocks voltage dependent Na channels, potentiates inhibitory effect of GABA, inhibits excitatory effects of kainate on AMPA receptors. minimal plasma protein binding.
Other antiepileptics -- topiramate (topamax) -- use? used as adjunct for polytherapy of partial/primary generalized tonic clonic (grand mal) seizures, migraine treatment -- TERATOGENIC in animals
Other antiepileptics -- zonisamide (zonegran) -- mechanism? use? sufonamine derivative, inhibits voltage gated Na channels and T-type CA currents, similar to phenytoin/carbamazepine.
Other antiepileptics -- zonisamide (zonegran) -- metabolism? Used as adjunct polytherapy of partial seizures in adults. well absorbed orally, long half-life, bound to plasma protein, metabolized by CYP3A4 and metabolites excreted in urine
What drugs do we use to treat simple partial seizures? carbamazepine, phenytoin, valproate
What drugs do we use to treat complex partial seizures? carbamazepine, phenytoin, valproate
What drugs do we use to treat partial seizures with secondarily generalized seizures? carbamazepine, phenobarbital, phenytoin, primidone, valproate
What drugs used to treat generalized absence seizures? (petit mal) ethosuximide. valproate. clonazepam.
What drugs used to treat myoclonic seizures? valproate. clonazepam.
What drugs used to treat tonic-clonic seizures? (grand mal) carbamazepine, phenobarbital, phenytoin, primidone, valproate
Managing epilepsy: mono or polytherapy? monotherapy is best bet if possible. reduced risk toxicity. select agent based on type of seizure.
Managing epilepsy: understand what about drug? pharmacokinetics
Managing epilepsy: do we need to monitor plasma levels of drugs? yes. therapeutic window is low and toxicity is common. monitoring plasma levels is extremely useful.
Concerns with anti-seizure drugs: teratogenicity not confirmed, but we see fetal hydantoin syndrome (mental defect with facial structure change) with phenytoin and spina bifida by valproate in 1-2% of babies
Concerns with anti-seizure drugs: withdrawal long term meds. condition of withdrawal -- 3-4 years without even 1 seizure, gradual discontinuance -- issues with BZDs and barbituates in terms of dependence
Concerns with anti-seizure drugs: overdose respiratory depression. Give supportive treatment, but do NOT GIVE STIMULANTS. this may induce a massive onslaught of seizures.
Created by: jaishenan