Exam 2 Flashcards
1
Q
drugs applied locally (right at the site of action) to block transmission of nerve impulses, intent is to produce a loss of sensation in a limited area, actions are reversible (temporary) and recovery of sensation is complete
A
local anesthetics
2
Q
these drugs bind to and inhibit the function of voltage gated Na+ channels in periphery primary afferent nociceptors which prevents information transmission, block the pore in the receptor and stabilize the refractory conformation for fewer action potentials (decreased frequency) and lower peaks (decreased max), preferentially inhibit high frequency nociceptors then inhibit motor neurons (nociceptors occur most)
A
local anesthetics MOA
3
Q
these drugs are weak bases due to the presence of amine groups and can exist in ionized or unionized form, at physiological pH most of the drug will be ionized, agent has to go through lipid bilayer (only non-charged drugs can do this so lipophilicity is important for these drugs), these drugs are only bound to channels in ionized charged form (has a higher affinity), to get to site needs to be uncharged but to bind needs to be charged
A
local anesthetics
4
Q
higher protein binding of LAs means _________ (shorter/longer) duration of action
A
longer, drug will “hang out” in the affected area longer
5
Q
does a smaller or greater partition coefficient (PC) mean increased lipophilicity for LAs?
A
greater
6
Q
does a smaller or greater number for potency indicate higher potency?
A
smaller
7
Q
increased PC means increased lipophilicity which means ________ (greater/less) potency
A
greater, more of the drug can get into the neuron because more lipophilic
8
Q
- rate of onset of these drugs depends on rate of diffusion (diffusion through tissues to get to neuron) which depends on ability to penetrate tissue (lipophilicity), rate of onset depends on lipophilicity
- so as the proportion of unionized form increases rate of onset increases (increased pH - sometimes due to bicarbonate - means more unionized molecule so faster rate of onset)
- these drugs are amines (weak bases) so diffusion is favored by alkaline conditions (acidic conditions slow down rate of onset which can happen in infected tissues)
A
LAs
9
Q
- loss of effect is due to diffusion (leaving site of action through things like blood flow) away from the site of action and distribution away from site of action by the blood, increased protein binding in this case means longer duration of action
- may be given along with epi or phenylephrine (restricting blood flow so blood flow doesn’t take drug away from site of action)
- tend to either vasodilate or have no effect on blood vessels (except cocaine and prilocaine)
- high PC are highly tissue bound so longer duration of action
A
LA duration of action
10
Q
this type of LA is hydrolyzed by plasma esterases, metabolized in the BLOOD not the liver
A
esters
11
Q
this type of LA is metabolized by liver enzymes, rare to see allergies
A
amides
12
Q
- high doses of these more likely to be systemically absorbed
- CNS effects (tremor, nervousness, seizures followed by coma and respiratory depression)
- CV effects (decreased excitability and force of contraction, vasodilation)
A
LA systemic toxicity
13
Q
- infiltration anesthesia (intradermal and SC injections)
- IV regional anesthesia (rarely used because of toxicity risk, used with tourniquet occluded limb)
- peripheral nerve blockade (single or multiple nerves, injected near nerve bundle)
- central neural blockade (epidural or spinal - intrathecal)
- topical anesthesia (lotion or cream)
A
LA uses
14
Q
this LA can’t be unionized, very water insoluble, least likely to be carried away by blood in open wounds/sores, no aliphatic amine group
A
benzocaine
15
Q
lidocaine and prilocaine, melting point lower than 2 agents alone, applied to skin and covered with a dressing, produces anesthesia in 30-60 minutes and then lasts about 1-2 hours
A
eutectic mixture of local anesthetics (EMLA)
16
Q
- CNS disease characterized by recurrent seizures (chronic seizures that are periodic and unpredictable)
- abnormal (excessive) neuronal activity - either experiencing too much excitatory or not enough inhibitory activity leading to excessive excitatory activity in neuronal circuit in brain, disordered, synchronous, rhythmic
- may or may not involve convulsions (uncontrolled limb movements)
- excessive discharge/excitatory activity may be localized or spread into both hemispheres
- seizures usually self limiting since relies on ATP which can run out
A
epilepsy
17
Q
type of seizure that involves both hemispheres of the brain
A
generalized
18
Q
type of generalized seizure that has max involvement of both hemispheres, starts with rigid phase (tonic) followed by jerking of limbs (clonic), ends with postictal state (“after the seizure”, patient goes to sleep for 15-30 minutes, no memory of seizure)
A
tonic-clonic, grand mal seizure
19
Q
type of generalized seizure, mainly in childhood, abrupt interruption in consciousness, patient just stares straight ahead, blank stare, sometimes lip smacking or rapid blinking, can be very brief (15-20 seconds) but can happen multiple times a day
A
absence, petit mal seizure
20
Q
type of generalized seizure, brief (about 1 second), rapid jerking of the arms, occurs quickly and can be mistaken for nervousness or clumsiness
A
myoclonic seizure
21
Q
type of generalized seizure, sudden loss of muscle tone, patient appears to pass out, may require wearing of a helmet
A
atonic seizure
22
Q
type of seizure that is localized
A
focal
23
Q
type of focal seizure, confined to one area of the brain that serves a basic function, consciousness is preserved, symptoms depend on location, can spread ipsilaterally (same side)
A
focal without altered mental awareness seizure
24
Q
type of focal seizure, seizure involves brain region that serves a complex function (hippocampus, frontal lobe), consciousness is impaired, preceded by an aura
A
focal with altered mental awareness seizure
25
type of seizure that starts focal but spreads to other hemisphere (now generalized)
focal with secondary generalization seizure
26
- initiation of an increase in electrical activity at the cellular level, network of neurons that increase electrical activity in an abnormal way
- synchronization of electrical activity of surrounding neurons
- spread of electrical activity to adjacent regions
three steps of a focal seizure
27
- failure of this can lead to seizures
- glutamate neuron excites GABA neuron which inhibits the neurons connected to the GABA neuron, *so excitation can cause inhibition which is a safety mechanism to prevent seizures*
surround inhibition
28
- seizure means hyperpolarization of thalamocortical neuron
- these neurons have type T calcium channels, open once hyperpolarization occurs, Ca2+ goes in and depolarizes neuron for action potential, cycle goes back to thalamus
- drug target: block the T type calcium channels
- voltage gated channel that opens by hyperpolarization --> this causes depolarization through Ca2+ influx --> stimulates thalamocortical --> pyramidal neuron --> GABAergic in thalamus --> hyperpolarization --> repeat
thalamocortical-cortical symphony
29
- prolong inactive conformation of voltage-gated Na+ channels (decrease excitatory)
- increase GABA activity (increase inhibitory)
- block T type Ca2+ channels (decrease absence seizures)
- enhance K+ channels (increase K+ influx)
- inhibit glutamate activity (decrease excitatory)
mechanisms of action of anticonvulsants
30
ligand gated ion channel opened by glutamate, antagonist of NMDA receptor (anticonvulsant)
felbamate
31
prevents calcium entry so no excitation (anticonvulsant)
gabapentin
32
bind to and block voltage gated Na+ channel, stabilize the refractory period (anticonvulsants)
phenytoin, carbamazepine, lamotrigine
33
inhibits the cycle of hyperpolarization/depolarization (anticonvulsant)
clonazepam (benzo)
34
block T type calcium channel, absence seizure treatment
ethosuximide, valproic acid
35
inhibits GABA transferase, decrease GABA metabolism, increase GABA concentration, increase inhibitory tone, decrease seizures
vigabatrin, valproic acid
36
blocks and inhibits reuptake of GABA so increase GABA concentration, increase inhibitory activity, decrease seizures
tiagabine
37
seizure is repeated so prolonged that it appears to be one continuous seizure, brain is in state of persistent seizure, lasting longer than 30 minutes OR recurrent seizures without regaining consciousness for 30+ minutes, use of diazepam or lorazepam IV, loading dose to prevent reoccurance (phenytoin, phenobarbital, carbamazepine loading dose)
status epilepticus
38
- enzyme induction: increased expression of gene of enzyme so more enzymes present, increased activity 2-4 weeks AFTER continuous dosing because takes time for genes to make more enzymes, increased activity AFTER drug discontinuation, enzymes have already been made, takes time to clear enzymes from the body
- enzyme inhibition: drug binds to and inhibits enzyme, decreased activity whenever drug is present, presence of inhibition follows the drug's kinetics (take drug away means no more inhibition)
metabolism of anticonvulsants
39
phenytoin, phenobarbital, carbamazepine increase metabolism of vitamin D (induce the enzyme responsible for metabolizing vitamin D), valproic acid increases bone resorption (bones less dense, more brittle), recommend daily supplement of calcium and vitamin D, regular weight bearing exercise, avoid smoking and excess alcohol, regular bone density testing
anticonvulsants and bone density
40
link between anticonvulsants and birth defects, do not discontinue drug abruptly, use lowest dose and fewest drugs (monotherapy), valproic acid and phenytoin are most teratogenic (Category D), carbamazepine/phenobarbital/clonazepam also Cat D, all others Cat C
anticonvulsants and pregnancy
41
________ (increased/decreased) failure of oral contraceptives with anticonvulsants
increased, induce metabolism of CYP3A4 which metabolizes estrogen and progesterone in OCs
42
neurodegenerative disease (degeneration or death of cells in the brain, progressive disease), major symptoms are movement disorders (resting tremor/pill rolling tremor, cogwheel rigidity, bradykinesia - slowing of movement, paucity of movement, postural disturbances - stooped over posture, shuffling gait, absence of facial expressions - interferes with social interaction, dementia - especially in later stages - loss of cognitive ability, learning, memory), one side of the brain degenerates faster than the other
Parkinson's disease
43
primary neuropathology of Parkinson's disease is death in the neurons of the ___________
substantia nigra (midbrain structure, "black substance", see symptoms when 75-90% of substantia nigra is gone
44
loss of dopamine --> increased ACh --> increased GABA receptors --> inhibition
*imbalance of dopamine and ACh*
decrease in dopamine due to dying cells leads to excitation of striatum leading to inhibition of remaining substantia nigra
tremor circuit - drugs that act here are for tremors
45
- dopamine stimulates the motor system through direct and indirect mechanisms, gives precise control
- in this disease: cerebral cortex hypoactive, substantia nigra hypoactive, stimulatory D1 is hypoactive, inhibitory D2 is hyperactive
Parkinson's disease
46
- idiopathic: in vast majority of cases the cause is unknown
- small minority of cases have a genetic component, tend to have earlier onset
- drug induced Parkinsonism
- toxin induced (MPTP)
etiology of Parkinson's disease
47
what enzyme converts DOPA to dopamine?
aromatic L-amino acid decarboxylase (AADC)
48
what enzyme metabolizes dopamine?
COMT
49
what enzyme metabolizes dopamine and NE?
MAO
50
- amino acid precursor to dopamine, AADC converts this to dopamine, carried across BBB by a transporter and carried in DA neurons by another transporter, depends on some of the neurons to still be functional (eventually becomes less effective because not enough functional neurons in substantia nigra)
- acute side effects: N/V, hypotension, arrhythmias (all DA-mediated and are peripheral)
- chronic side effects: abnormal involuntary movement (dyskinesia), nightmares, hallucinations (all central in origin)
L-DOPA
51
first 1-2 years of L-DOPA treatment, pt has smooth day long control of symptoms, at 2-5 years we see peak dose dyskinesia - symptoms return at low point of plasma concentration but before it is time for next dose, *this happens because therapeutic plasma concentration narrows as more and more neurons die*
on-off phenomenon
52
- only 1-5% of L-DOPA reaches the brain
- decarboxylation in periphery leads to side effects and "wasting" of the L-DOPA
- this drug is an AADC inhibitor that works in the periphery that can't cross the BBB, converts L-DOPA to dopamine in the brain
- less side effects, smaller dose, more drug going to the brain
carbidopa
53
dopamine agonist, SQ injection, originally used for emergency
apomorphine (APOKYN)
54
pramipexole, ropinirole, rotigotine (transdermal patch), advantages include long duration of action for less on/off phenomenon, may be used in early course of disease to delay L-DOPA treatment, classic side effects include N/V, hallucinations, hypotension, somnolence (sleepiness), arranging things in compulsive manner, compulsive behaviors like gambling
dopamine agonists
55
COMT inhibitor, acts in the periphery and CNS, given every 2-3 days, hepatotoxic and requires monitoring of liver function
tolcapone
56
COMT inhibitor that only works in the periphery, given with each L-DOPA dose
entacapone
57
COMT inhibitor that only works in the periphery, given with each L-DOPA dose, approved April 2020
opicapone
58
inhibition of MAO-B, purpose is to decrease DA metabolism and decrease free radical formation, therapeutic doses do not cause HTN crisis, loses selectivity at high doses, may interact with meperidine, TCAs, SSRIs, tyramine
selegiline, rasagiline
59
used originally to treat influenza, blocks NMDA glutamate receptors, stimulates the release of DA and inhibits DA reuptake, used in mild cases or as L-DOPA adjunct, loses efficacy over a few months
amantadine
60
used as adjuncts in Parkinson's to address the DA/ACh imbalance in striatum, most effective at reducing tremor but not as effective at reducing rigidity or bradykinesia
anticholinergics - benztropine, trihexyphenidyl
61
- important psychological functions are "split" apart (thought, emotion, motivation, NOT split personality disorder)
- doesn't have a defined consistent neuropathology or a definite genetic cause (neuropathology and psychological disturbances vary between and within patients)
- type of psychosis (disruption and distortion of thought and perception)
- chronic condition - never really goes away, might require pharm treatment lifelong
- occurs in 1% of population uniformly across cultures
- onset is in late teens early twenties
schizophrenia
62
things that a person with schizophrenia has that a healthy person does not
- hallucinations (like hearing voices, generally not nice voices)
- delusions (strong beliefs not based in reality, delusion of paranoia or delusion of grandeur)
- illogical, disconnected, incoherent speech
positive symptoms
63
things that a person with schizophrenia doesn't have that a healthy person does
- not talking very much
- flat or emotions that don't match a situation (inappropriate affect)
- loss of motivation or initiative
- social withdrawal
- anhedonia (loss of pleasure)
- lack of personal hygiene
negative symptoms
64
symptom of schizophrenia, impaired working memory, executive function deficits (lack of activity in prefrontal lobe)
cognitive deficits
65
this (especially positive symptoms) is due to excessive dopamine activity in the brain, amphetamine and cocaine worsen positive symptoms, all antipsychotics block D2 receptors (one exception), some of the negative symptoms and cognitive defects seem to be due to decreased dopamine function in the prefrontal cortex
schizophrenia neurochemical basis dopamine hypothesis
66
phencyclidine (PCP) is a psychotomimetic (mimics psychosis), produces both positive and negative symptoms, mechanism is blockade of glutamate receptors - suggests that glutamate receptors are dysfunctional in schizophrenia
schizophrenia neurochemical basis glutamate hypothesis
67
which generation antipsychotics block D2 and 5HT2A receptors (just as efficacious as older ones for positive symptoms but more efficacious for negative and cognitive symptoms)?
second generation
68
which is associated with positive symptoms of schizophrenia - mesolimbic or mesocortical?
mesolimbic
69
which is associated with negative and cognitive symptoms of schizophrenia - mesolimbic or mesocortical?
mesocortical
70
aliphatic phenothiazine and piperidine phenothiazines are high or low potency typical antipsychotics?
low
71
piperazine phenothiazines, thioxanthines, butyrophenones are high or low potency typical antipsychotics?
high
72
- all are D2 antagonists - competitively block dopamine D2 receptors
- when adjusted for potency all are equally efficacious for treating schizophrenia, not much difference in efficacy, choice depends on side effect profiles and patient factors
- main therapeutic effect is to relieve hallucinations, delusions, and disordered thought (positive symptoms)
typical antipsychotics
73
typical antipsychotics can make negative symptoms ______ (better/worse) because they decrease the dopamine binding to D2 and low dopamine binding means _______ (more/less) negative symptoms
worse, more
74
- extrapyramidal motor symptoms - acute dystonia (bizzare contractions of face, trunk, limbs, can be misidentified as a seizure, seen primarily with high potency drugs, dopamine/ACh imbalance), akinesia, Parkinsonism, pseudo-Parkinsonism, (drug induced), akathisia (restlessness, need to move around, beta blocker can help with this)
- thermoregulatory effects - don't regulate body temp as effectively
- endocrine changes (prolactin) - if block D2 receptors prolactin will increase because at baseline prolactin is inhibited by dopamine, symptoms of gynecomastia, galactorrhea, infertility
side effects of typical antipsychotics
75
involuntary repetitive movements of face tongue and lips, thought to be caused by DA receptor supersensitivity due to long term use, most cases preceded by drug induced Parkinsonism, abrupt removal of antipsychotic makes it worse, increased dose only temporarily delays this, anticholinergics make this worse
tardive dyskinesia, typical antipsychotics
76
low potency group more sedating than high potency, can be an advantage in aggressive or violent pts, sedative effects subside in 1-2 weeks because some tolerance builds up
sedation, typical antipsychotics
77
anti-SLUDGE effects most common in low potency group of typical antipsychotics because of antagonism of what receptors?
muscarinic
78
decrease BP, orthostatic hypotension, most common in low potency typical antipsychotics, what receptor?
alpha blockade
79
typical antipsychotics with affinity for blocking muscarinic receptors have ______ (more/less) of a tendency to cause Parkinsonism
less
80
these can be used to treat tardive dyskinesia, normally the enzyme that these drugs inhibit takes dopamine out of cytoplasm and stores it in vesicles, these inhibitors block the storage of dopamine
VMAT2 inhibitors - tetrabenazine, valbenazine
81
distinguished from typicals by side effect profile and efficacy, much lower incidence of EPS and tardive dyskinesia, effective at treating negative symptoms
atypical antipsychotics
82
- activity of mesolimbic pathway stimulated by serotonin, glutamate, DA release --> treatment option is blocking 5HT2A to inhibit everything to decrease positive symptoms
- 5HT2A excites glutamate which excites GABA which inhibits DA release --> treatment option to prevent serotonin from binding to 2A to inhibit glutamate inhibit GABA and increase dopamine in motor striatum --> help resolve negative symptoms
treatment options for second generation antipsychotics
83
- block 5HT2A receptors in addition to D2
- benefits of 5HT2A appear to include decreased EPS, TD, and treating negative symptoms
- these drugs have greater 5HT2A to D2 ratio compared to other antipsychotics
atypical antipsychotics
84
atypical antipsychotic with D4 blocking activity in addition to D2 and 5HT2A, fewer EPS, few cases of TD, no effect on prolactin secretion, strong antimuscarinic action but hypersalivation, weight gain, increased blood sugar, QTc prolongation, dose related seizure risk, agranulocytosis (loss of white blood cells, weekly blood tests, watch for flu like symptoms - NOT DOSE DEPENDENT
clozapine
85
structurally and pharmacologically very similar to clozapine but without the agranulocytosis, increased body weight, diabetes (don't use in patients who already have diabetes), increased cholesterol, EPS effects at high end of dose range
olanzapine
86
just as efficacious on positive symptoms as other atypicals but not as efficacious on negative symptoms, increased body weight, cataracts, metabolite is an antidepressant so this is sometimes used as an antidepressant
quetiapine
87
atypical antipsychotic contraindicated in patients with history of prolonged QT interval, MI, arrhythmias, can cause QT prolongation, ventricular arrhythmias, sudden death (pts with cardiovascular history - contraindicated), no effect on body weight or blood glucose
ziprasidone
88
most typical of the atypical antipsychotics (most dopaminergic of the atypicals), low to moderate doses no EPS, moderate to high doses can produce EPS, minimal anticholinergic effects, orthostatic hypotension especially on first dose, insomnia, agitation, anxiety, less weight gain than clozapine
risperidone
89
partial agonist for D2 and D3 receptors (partial agonists give less than 100% effect compared to full agonists which have 100% effect), not too much not too little dopamine activity, may decrease DA activity where it is too high (mesolimbic) and increase where too low (mesocortical), minor side effects include headache, agitation, insomnia, anxiety
aripiprazole
90
approved for schizophrenia and as a depression adjunctive, D2 and D3 partial agonist, 5HT2A antagonist, most common side effects are weight gain and akathisia (restlessness)
brexpiprazole
91
approved for schizophrenia and bipolar disorder, D2 and D3 partial agonist, selective for D3, most common side effects are akathisia (restlessness), insomnia, weight gain
cariprazine
92
approved for treatment of psychosis in Parkinson's disease, *not a D2 antagonist*, 5HT2A/C inverse agonist (when drug binds it brings basal activity down)
pimavanserin
93
determined mainly by risk of adverse effects, typicals and atypicals have about equal efficacy for positive symptoms, atypicals more efficacious for negative and cognitive symptoms, typicals are limited by EPS and endocrine side effects, atypicals limited by metabolic effects like weight gain/diabetes, first line therapy is any atypical OTHER than clozapine
choice of antipsychotic
94
all have an ionizable amine that when positively charged forms an ionic bond with part of the D2 receptor, amine is essential for activity, all are lipophilic drugs so they can cross into BBB and distribute extensively into CNS, extensively metabolized by CYP450 (mainly 2D6, 3A4, 1A2)
antipsychotics med chem intro
95
all are first generation antipsychotics, side chain chemistry at position 10 impacts binding affinity AND selectivity at receptors in CNS/PNS, electron withdrawing group at position 2 is essential for producing antipsychotic activity (due to asymmetry which helps position these drugs in receptor binding site in an orientation that favors binding, helps move side chain in cis conformation which is preferred, this happens through van der Waal interactions)
phenothiazines
96
an additional N on piperazine phenothiazine antipsychotics makes the drugs ______ (more/less) potent
more
97
what type of phenothiazines (aliphatic or piperazine) have a greater affinity for D2 (more EPS) but less affinity for M1, alpha 1, H1?
piperazine
98
what type of phenothiazines (aliphatic or piperazine) have a greater affinity for H1, alpha 1, M1 (more sedation, orthostatic hypotension, antimuscarinic effects)?
aliphatic
99
this type of antipsychotic has a 4 carbon chain as well as a phenyl ring with an alpha ketone group, an example is haloperidol, causes less sedation than most phenothiazines
butyrophenone
100
these are second generation antipsychotics that block lots of receptors beyond DA receptors, have an azepine ring plus two aromatic rings
diarylazepines
101
second generation antipsychotics, have a higher ratio of affinity for 5HT2A receptors relative to D2 receptors, cause less weight gain and blood glucose changes compared to other second generations
benzisoxazole and benzisothiazole
102
2 pips and a rip med chem group, partial agonists
phenylpiperazines
