Glossary of pharmacology test 2 2

Start Studying! Add Cards ↓

general anesthesia is the...
reversible loss of consciousness and of awareness of all senstory stimuli
commonly present with general anesthesia
-lack of somatic and autonomic response to pain
-skeletal muscle relaxation
phases of clinical anesthesia
descending CNS depression stage of anesthesia
-not actually a stage
-general depression of the CNS depending on concentration
-small conc- cerebral cortex (thinking)
-middle conc- mid brain and brainstem (loss of consciousness)
-high conc- medulla (cardiovascular and respiration)
-low conc- spinal cord
guedel stage 1
-decreased awareness of pain
-conscious but drowsy
-thinking is blurred
-amnesia begins
guedel stage 2
-transitions to loss of consciousness
-speak incoherently and struggle
-irregular breathing
-reflexes are enhanced
-involuntary urination and defication
-coughing, gagging, vomitting, breath holding, cardiovascular responses (vagal inhibition of heart rate)
-epinephrine causes hypotension and tachycardia
guedel stage 3
surgical anesthesia
-4 planes
-somatic and responses to pain are absent
-regular breathing
-airway and ocular protesctive reflexes are attenuated or absent
-increasing depth, respiration slows and skeletal muscle relaxation increases
guedel stage 4
medullary depression
-slow and shallow and ceasing respiration
-blood pressure drops
-cardiac action ceases
goals of clinical anesthesia
-rapid and pleasant loss of consciousness
-amnesia for entire procedure
-profound analgesia
-msucle relaxation
ancillary drugs- reason for use
to get analgesia and muscle relaxation
ancillary drugs- preoperative meds, goals
-reduce preoperative apprehension (sedative-hypnotic and anxiolytic agents)
-pre-op and intra-op analgesia (opioids)
-reduce common adverse effects of anesthesia (antiemetics, anticholinergics)
-reduce volume and acidity of gastric contents (to decrease chance of vomiting)
ancillary drugs- induction agents, goal
assure a rapid and pleasant induction into surgical anesthesia
ancillary drugs- induction agents, agents
selected opioids
ancillary drugs- muscle relaxants, MOA, side effects
-D Nm block
-ND Nm block
-respiration block
ancillary drugs- intraoperative opioids, use
boost analgesia
inhalational anesthetic agents, state
-gas or votalie liquid
-N2O is only gas
-votalie liquid is vaporized to make a specific concentration of a gas
inhalational anesthetic agents, use
inhalational anesthetic agents, MAC
-meausre of potency and dose
-prevent movement in 50% of pts with a surgical incision
-represented in v/v at one atmosphere
inhalational anesthetic agents, PK
-excreted via the lung unchanged
-minor metabolism and excretion via other routes
-metabolites might be toxic
-blood-gas partition coefficient (high is more soluble)
-lipid solubility is required for potency and penetration of bbb but excessive solubility prolongs recovery time
inhalational anesthetic agents, intraoperation adverse effects: hypotension
-due to decrased cardiac output and/or vasodilation
-not N2O
-can be severe
inhalational anesthetic agents, intraoperation adverse effects: cardiac arrhythmias
-less than hypotension
-not N20
-heart is sensitive to SNS (automaticity)
inhalational anesthetic agents, intraoperation adverse effects: cerebral vasodilation, increased CBF, increased ICP
-increases blood flow, increased blood volume, increased pressure
-not a problem in most people
inhalational anesthetic agents, intraoperation adverse effects: malignant hyperthermia
-some pts need both to have it occur
inhalational anesthetic agents, postoperation adverse effects: N/V
-1/3 of pts with inhaled anesthsia
-immediately post-op
-frequency and strength vaires with drug and surgery
inhalational anesthetic agents, postoperation adverse effects: liver damage
-halothane hepititis
-direct toxic metabolite on liver
-immune response to metabolite in liver
Inhalation anesthetic agents, mechanisms of action
-no obvious SAR
-lipid solubility is correlated with potency- act at hydrophobic domain at neurons
membrane pertubation theories
-anesthetics dissolve in the lipid bilyar changing the volume or fluidity which changes the neuron function
protein binding theory
bind weakly to hydrophobic domains, such as channel proteins, altering neuron function
lipid protein interface theory
anesthesics dissolve in the membrane but effects are at the interfce between the bilayer and the membrane proteins
anesthetic effects on synaptic transmission
-enhanced inhibitory transmission and decreased excitatory transmission
-mainly due to actions on ligand-gated ion channels but voltage gated ion channels may be effected
synaptic effects from anesthetics that are most likely involved are:
-more GABA and glycine inhibition
-inhibition of ACh, 5HT, and glutamate
-opening VG K Channels (hyperpolarize), block ca and Na
amnesia is mediated by effects on the
loss of consciousness is mediated by effects on the
reticular activating systems, the thalamic relay nuclei, and cerebral cortex
inhibition of movement in response to painful stimuli is mediated by effects on the
spinal cord
ether, ntirous oxide, chloroform
-changed surgery and dentistry
-n2o is only one still used
-used first for absue
-hypotension, arrythmias
-liver toxicity
-increased intracranial pressure
-still used
-less hypotension, hepatitis
-causes transient seizures
-less side effects than enflurane
-no seizures
-number 1 in US
-faster onset because low blood:gas partition
-irritating to airways (inj first)
-same as desflurane but no irritation
-very ideal
-very expensive
Nitrous oxide
-does not help GABA, does block nicotinic, NMDA, and releases endogenous opioids
-low potency
-fast and pleasant onset and recovery
-excellent analgesia at subanesthetic dose (25%) due to release of opioids
-little respiratory depression or CV effects
-low toxiticy as typically used but when abused it oxidizes cobolt in b12 leading to amnemia
-adjuvant anesthetic (carrier gas to give less resp, cv and to help recovery)
-used in dentistry and childbirth
injectable anesthetic agents, route
iv, im (ketamine)
injectable anesthetic agents, barbiturates, agent
injectable anesthetic agents, barbiturates, general characteristics
-derivative of barbituric acid
-cateogorized by duration of action
-ultra short, short intermediate, long
-for inductin or brief surgery for humans
-sometimes TIVA in animal research
injectable anesthetic agents, used for
induction, brief surgery, distressful procedures
injectable anesthetic agents, barbiturates, pk of ultra short
-fast onset (10-30 sec) due to high lipid solubility
-duration is short (5-8 min) due to redistribution to skeletal muscle
-first: brain, heart, kidbey, liver
-second- skeletal muscle, skin
-third- fat
-duration after repeated dose is longer due to metabolism and excretion
injectable anesthetic agents, barbiturates, advantages
-fast onset and recovery
-little post-op NV
-reduction of intracranial and intraocular pressures
-good antiseizure activity
injectable anesthetic agents, barbiturates, disadvantages
-not good for long procedures
-strong resp depression
-dose dependent hypotension
-no analgesia
injectable anesthetic agents, barbiturates, mechanism of anesthetic action
-act at hydrophobic domains
-enhance gaba's inhibition
-can open cl channels
-no effect on glycine or glutamine
injectable anesthetic agents, propofol
-non-barbiturate stucture
-oil at room temp, inject as emulsion (will grow bact at room temp)
-onset and duration is short due to lipid solubility and redistribution
-used for maintenance and induction (TIVA)
injectable anesthetic agents, propofol, advantages
-rast onset and recovery and not a lot of post-op NV
injectable anesthetic agents, propofol, disadvantages
-respiratory depression
-pain at injection
-no analgesia
injectable anesthetic agents, propofol, mechanism of action
-at hydrophobic domain
-enhance gaba inibition
-open cl channels
-no effect on glycine or glutamate
injectable anesthetic agents, ketamine
-iv or im
-fast onset(longer than thiopental) but longer duration (slower redistribution)
-dissociative anesthesia
injectable anesthetic agents, ketamine, dissociative anesthesia
-EKG of awake person
-eyes open
-airway reflexes are normal
-resp rate is higher or normal
-bp and cardiac output is high
-muscle tone increases
-bad dreams, hallucinations, illusions, irrational behavior during recovery (not in kids)
-stong analgesia at subtherapeutic dose and recovery
injectable anesthetic agents, ketamine, use
-minor surgery, diagsnotic procuedures
-not so much for induction
-vet med
injectable anesthetic agents, ketamine, MOA
-no action on reticular formation, acts on cerebral cortex, limbic system, and spinal cord
-inhibits glut by high-affinity binding to PCP site on the NMDA
injectable anesthetic agents, ketamine, abuse
-special K
-more abused now than before
-liquid- oral or evap and snort, smoke
-high psychological dependence but rare phsycial depedence
-less negative effects from using ketamine vs PCP
opioid analgesics
-block pain without blocking anything else or losing consciousness
dried resin from the seed capsule of opium poppy
alkaloids found in opium (morphine, codeine, thebane, papaverine, noscapine) and semisynthetic congeners derived from them (heroin, hydromorphone, hydrocodone)
any agent (natural, semi-synthetic, or synthetic) with morphine-like activity
-any drug producing sleep
-opioid analgesics
-legal term referring to opioid analgesics and a number of non-opioid abused substances such as marijuana and concaine
endogenous opioids (endopioids), where made
-formed in body, mostly in CNS,
endogenous opioids (endopioids), act as
-act as NT and neuromodulators
endogenous opioids (endopioids), mainly what
-mainly peptides but also morphine and codeine also present
endogenous opioids (endopioids), four classes of peptides
-preproenkelphalins become enklephalins (met-enkephalin, leu-enkephalin)
-preproopiomelanocortin (POMC) become endorphins (β-endorphins)
-endomorphins (endomorphin 1 and endomorphin 2)
-preprodynorphin becomes dynorphin (dynorphin A and dynorphinB)
opioid receptors
-μ1, μ2 (mu) for β-endorphins and endomorphins
-δ1, δ2 (delta) for enkephalins
-κ1, κ2, κ3 (kappa) for dynorphins
opioid action at receptors
full agonist (most)
partial agonist
mixed agonist/antagonist
opioid receptors, cellular effector mechanisms
-all G proteins
-open K- hyperpolarization
-closing of VG Ca channels- prevent NT release
-decerased/increases andenylyl cylase- usually inhibitory at receiving cell
receptors involved in opioid effects- analgesia
MU, delta, kappa
receptors involved in opioid effects- lowering respiration
receptors involved in opioid effects- lower G motility
MU, kappa
receptors involved in opioid effects- psychomimetic (LSD-like effect, lose touch with reality)
receptors involved in opioid effects- sedation
mu, kappa
receptors involved in opioid effects- euphoria
receptors involved in opioid effects- miosis
mu, kappa
receptors involved in opioid effects- increased GI, biliary, urinary sphincter tone
receptors involved in opioid effects- antitussive
who know
pharmacological effects of opioids- analgesia
-pain has sensory and psychological/emotional components, opioids affect both
-block of pain sensation is selective- no loss on consciousness and no effet on other sensory modalities
-no celing effect, larger doses can control almost all types and intensities of pain except neuropathic pain (malfunction of pain receptor function of receptor or CNS)
pharmacological effects of opioids- analgesia, MOA
-brain and spinal cord
-opioids augment effects of endgenous anitnociceptive (antipain)systems (LOOK AT PICTURE)
-need a shot (not oral) because need to stimulate periperheral nerve endings
antinociceptive system
-off shoots in spinal cord active opioid cell and they fire on presynaptic cell to inhibit (lower NT)and fire on postsynaptic cell to hyperpolarize in spinal cord
-off shoots on the way to the cerebral cortex activate opioid cell which inhibits GABA cell (take away tonic inhibition) which then allows more 5HT and NE transmission which lowers amount of NT released and hyperpolarizes receiving cell
-PAG- activates LC and NRM
- LC- NE
pharmacological effects of opioids- euphoria/psychological dependence
-high abuse liability: watch for psychological dependence, but no one should be turned down for previous history, pain relief dose does not cause happiness
-mechanism of euphoria is due to opioid activation of the VTA/NA dopamineric pleasure pathway which is not needed for analgesia
pharmacological effects of opioids- sedation (drowsiness, impaired thinking)
-possible to avoid with dose change
-higher dose- sedation, loss of consciousness
-toxic- not drunk late
-protentiated with other sedatives: alcohol, antidepressants
pharmacological effects of opioids- respiratory depression
-decreased rate and depth of respiration
-cause of death in overdose
-no air hunger because opioids block intrinsic drive (give Oxygen with pressure)
-direct depression of brainstem respiration centers and depression of responsiveness
-can be beneficial to decrease hyperpepnia
pharmacological effects of opioids- nausea and vomiting
-due to activation of the cheoreceptor trigger zone (CTZ)
-vestibular contribution (lie down)
pharmacological effects of opioids- antitussive effect
-depresseion of cough reflex by action in the "cough center" in the medulla
-at doses lower than that needed for analgesia
-involves receptors not yet characterized
pharmacological effects of opioids- pupillary constriction (miosis)
-reduces night vision
-reveals users because no tolerance
-due to stimulation of midbrain nucleus, controlling parasympathetic tone to the iris (Edinger-Westphal nucleus)
pharmacological effects of opioids- prurtits
-usually in injection and not oral dose
-release histamine from mast cell
-also vasodilation, flushing, and sweating
-due to spinal mechanisms
pharmacological effects of opioids- GI effects
-decreased gastric acid, biliary, intestinal and pancreatic secretions (constipation due to small volume)
-increased segmental tone and decreased propulsive movements in SI and LI
-for most opioids, both effects are mediated partly locally (enteric plexus nervous system) and partly in the CNS
-good for diarrhea but cause constipation
-no tolerance
pharmacological effects of opioids- biliary spincheter, ureter, bladder effects
-increase tone in biliary spincter (stone or biliary spasm, both cause pain, and opioid cause more tone and more pain, but high enough dose will block pain and allow passing)
-increased tone in ureter and bladder neck cause urinary retention
pharmacological effects of opioids- cardiovascular effects
pharmacological effects of opioids- neuroendocrine effects
-decreased release of Gonadatropin-releasing hormone (GnRH) and corticotropin-releasing hormone (CRH) causing erratic menstruation in women and decreased libido and impotence in men
pharmacological effects of opioids- tolerance
-consequence of prolonged frequent use (10-100 times)
-rate of development and magnitude varies with drug, dose, frequency, and duration
-rate of developement and magnitude vary among effects
-extensive cross tolerance amung mu agonist opioids, but not complete for mu1 to mu2, switch drug when tolerant to analgesia to avoid side effects
-caused by internalization, desensitization, and uncoupling of G protein
pharmacological effects of opioids- physical dependence
-inevitable consequence of prolonged frequent use of most
-rate of development and magnitude vary with drug, dose, frequencey, and duration (morphine is 10-14 days of multiple use/day)
-based on internalization, desensitization, and G-protein uncoupling
pharmacological effects of opioids- physical dependence----withdrawal syndrome
-provoked by sudden decrease or an opioid receptor anatagonist
-symptoms are opioid-craving and psychological and physical effects which are opposite of opioid effects: insomnia, anxiety, irritability, dysphoria, increased sensitivity to pain, abdominal cramps, NVD, muscle aches, mydriasis, sweating, pilioerectoin, tachycardia, hypertension, fever
-unpleasant but not lethal
-onset and duration differ with half life of agent
-detoxification by substitution and gradual withdrawal (remove physical dependence of a drug with physcial dependence and short duration of action by switching to a long acting drug and decreasing the dose slowly)
pharmacological effects of opioids- toxic overdose
-die, Emergency Room
-due to respiratory depression, miosis (unless hypoxia and dilate), and coma
-pulmonary edema in 50% of cases (initiated by mu receptors but not maintained by mu)
-treatment is a support of vital functins plus an opioid antagonist (watch for withdrawal if they are dependent, buit will reverse opioid activity quickly, won't reverse pulmonary edema)
pharmacokinetic factors of opioids
-well absorbed orally, but bioavailability varies due to first pass
-high lipid soluble opioids are well absorbed through nasal, buccal, and skin (therapeutic and abusive routes, also smoking)
-also im, sc, iv, intrathecal/epidural (CSF/subarachnoid space or fatty tissue to act on spinal cord but no higher CNS effects
-full mu agonist prototype (most used opioid in the world)
-drug of choice for terminal cancer pain because available and cheap and works
-25% F
-morphine-6-glucuronide is an active metabolite on my receptors with a long half life, it accumulates and gives most of the opioid activity in long term use
-can be IV, IM for fast relief
heroin (diacetylmorphine)
-no medical use, sch I
-extensive illicit use, drug of choice because of the high (IV)
-high lipid solubility so crosses bbb quickly
-monoacetylmorphine also has high lipid solubility
-herion metabolized to monoacetylmorphine to morphine
codeine (3-methylmorphine)
-mu agonist
-10% crosses BBB
-low affinity agonist
-most analgesia is due to 10% metabolic conversion to morphine by 2D6
-parent insensitivity will result in no conversion
-watch for more conversion and morphine poisoning
-when used alone, not a potent analgesic
-combined with NSAIDS, APAP and acheive additive analgesia
-high F
-psychological dependence is unlikely abuse can occur with lame punk kids and herion addicts who can't get a fix
-physical dependence is extremely unlikely regardless of dose or duration of use
meperidine (pethidine, demerol)
-mu agonist
-1/10 the potency of morphine and shorter duration of action (2-3 hr)
-less constipation, less miosis, less urinary retention
-metabolite is N-demethylmeperidine (nomeperidine) and is a toxic CNS stimulant with a long half life, not a opioid agonist, accumulates and causes seizures for the short term
-interacts with MAOI so must wait for 2 weeks after dc-ing MAOI to avoid Serotonin syndrome
-is abused by health care professionals
fentanyl (sublimaze)
-mu agonist
-80-100 times morphine potency, but not the most potent
-high lipid solubility
-short duration of action (.5-2 hours)
-versatile, numerous uses: a) analgesia in preop, intraop, and postop; b) opioid anesthetic; c) treatment of chronic pain using transdermal skin partch (to lipid solubility and potency) and breakthrough pain (transmucosal system/ lollipop), abused, sedates kids
-tranquilization of wild animals and used with droperidol (antipsychotic drug with rapid sedation) (dart gun)
methadone (dolophine)
-mu agonist
-good oral bioavailability
-long half life (15-40 hours) and strong tissue binding yields a long effect with repeated doses
-uses: analgesia, detox in opioid dependence, methadone maintenance
diphenoxylate (lomotil)
-mu agonist
-for diarrhea
-few other effects at therapeutic doses
-abuse unlikely due to added atropine so you would get atropine poisoning
-not water soluble, so don't give iv
loperamide (imodium)
-mu agonist
-used for diarrhea
-few other effects
-abuse unlikely because poor oral absorption and not crossing bbb
-not water soluble, don't give iv
propoxyphene HCL (Darvon) and propoxyphene napsylate (Darvon N)
-mu agonist
-potency is less than codiene
-use for moderate pain, no tussis
-psychological dependence can develop but physcial dependence is unlikely
partial mu agonists and mixed k agonist/mu antagonist
-large doses can cause withdrawal symptoms in persons with physical dependency
-low tendency of respiratory depression
-low to moderate chance of psychological dependence
-low risk of physical dependence
buprenorphine (bupronex)
-partial mu agonist
-binds to receptors tightly and dissociates slowly so long duration of action (qod)
-25-50 x morphine potency for analgesia
-low bioavailability so iv or subL
-analgesic and detox and maintenance of herion addicts
pentazocine (talwin)
-strong kappa agonist and weak my antagonist
-analgesia is due to kappa
-f=25% so only slightly more potent than codeine po
-psychotomimetric effects at large doses due to kappa
-talwin Nx (pentazocine and naloxone) is made in response to abuse with solution (talwin and antihistamine triple enamine) to give heroin-like high, with naloxone there is no oral F so IV it blocks talwin
butorphanol (stadol)
-mixed kappa agonist/mu antagonist like pentaxocine
-abused as nasal spray to avoid first pass
opioid antagonists
-pure anatagonists at all receptors
-prevent and reverse all actions of clinically available opioids
-can be used to treat opioid OD and post-op effects
-helps to avoid opioid dependence because it can prevent high (naltrexone)
-naloxone (narcan)
-naltrexone (ReVia)
-nalmefene (revex)
Tramadol (ultra)
-weak mu agonist, inhibit 5HT and NE reuptake (codeine, propoxyphene), helps antinociceptive pathway
-for moderate to severe pain
-low but increasing abuse potential
-no action at opioid receptor
-no high, physcial dependence
-abused for hallucinogenic effect at high enough dose because it binds/blocks to glutamate NMDA receptors at PCP site so you get PCP effects but not as potent as PCP
epilepsy- definition
chronic neurological disoder characterized by recurrent seizures
epilepsy prevalence
causes of symptomatic epilepsy
structural lesions, head trauma, intracranial neoplasms, intracranial infections, developement abnormalities, stroke, vascular malformations
syndrome characteristics
-Lennox-Gastaut Syndrome
-status epilepticus
-age of onset
-reponse to TM
reactant seizure
is a single seizure or a group of seizures and is not epilepsy

-withdrawal from CNS depressants, acute illenss, toxic conditions, diabetic hypoglycemia, fever, certain drugs
a seizure is
-a brif episode of abnormal brain functino and one or more of the following: change in consciousness; sensory, psychic or autonomic disturbances; behavior change; loss of muscle tone; convulsions
-msost have EEG evidence of excessive and hypersynchronous dischange of cerebral cortical neurons
-need excessive glutaminergic excitation, not enough gaba inhibition, or a combo
seizure focus
-small groups of neuron
-abnormal discharge
-high frequency bursting
propagation of a seizure
-recruitment of normal neurons
-local or distant
-gradual or instantaneous
clinical manifestation of a seizure
depends on part of cortex affected and partern of propagation
simple partial seizure
-no consciousness impairment
-focal motor, autonomic, psychic, or sensory symptoms
complex partial seizures
-attacks have confused behavior
-impaired/loss of consciousness
-start as simple partial, psychic or sensory seizures
partial seizures secondarily generalized
-loss of consciousness
-tonic-clonic, tonic, or clonic
-begin as partial seizures
-abrupt and brief loss of consciousness associated with 3 per second spike and wave of EEG
-symmetrical clonic motor activity, varying from eyelid blinking to jerking of entire body
tonic seizures
-contraction of all muscles
-rigid extension of limbs, trunk, neck
-loss of consciousness
clonic seizures
rhythmic clonic contrations of all muscles, mostly arms and legs
-loss of consciousness
-loss of consciousness
-decrease in muscle tone which leads to falling
-brief loss of consciousness
unclassified seizures
-does not fit into any other cateogory
status epilepticus
-any seizure type but if unspecified it is tonic-clonic
-prolonged state of continuous or repeated seizures without regainig seizures
-not related to epilepsy: fever, withdrawal
-over one hours, get excitotoxiticy
release of a lot of glutamate causes a saturation of glutamate disposal so glutamate floats around and stimulate NMDA receptors and allows Ca into the cell which is lethal to neurons. This is CA POISONING
distant propagation
via long axonal tract
maximal electroschock seizure test (mice or rats)
-brief shock to brain through ear or corneal electrodes causes sz to test drugs which block tonic phase to see which drugs would be useful in human tonic-clonic seizures
pentylenetetrazole (metrazole) test (mice)
-inject PTZ
-clonic seizure
-these drugs are good in absence
kindled seizures (rats)
-model of complex partial
-study the biological basis of sezure focus development
-screen for drugs that may be useful in complex partial
-prevent seizure focus development
-implant electrode in one amygdala or hippocampus
-apply each day a 2 sec train of schocks subthreshold
-afterdischarges- seizure focus develops
-repeated daily shocks cause stronger and more widespread seizure activity which propagate to other hemisphere to give complex partial seizure that become spontaneous seizures
therapeutic goal of seizure disorders
total control of seizures with minimal side effects
therapeutic outcomes of seizure disorders
65%- total control
35%- little or no control
primary generalized seizures: 80% total control, 20% little or no control
resistance to AED
- overexpression of drug efflux pump proteins (pGP) (in bbb) and multidrug resistance problems (MDR)
how to avoid side effects of AED
-titrate slowly
-also monitor serum levels
duration of treament of AED
-a lot of people spontaneously recover
-not related to drug
-look for sz-free period of 2-4 years
pregnancy and AED
-more sz during pregnancy
-pregnancy can lower AED conc by lowering absorption, more binding, increasing Vd, increasing metabolism
-AED decrease efficacy of oral contraceptives
drugs for partial seizure
AED for primary generalized tonic clonic
cbz, phenytoin, vpa
AED for absence
AED for status epilepticus
lorazepam iv or diazepam iv followed by phenytoin ic of pb iv if needed
general mechanisms of AED
1- prevent the development of seizure foci or cause foci to go to a non-pathological state (no drugs do this)
2- decrease the excitability in the seizure focus to prevent or reduce abnormal discharge
specific mechanisms of AED: modulation of neuronal membrane voltage-dependent ion channels involved in action potential propagation or burst generation
-block NA channels- frequency dependent blockade of impulse generation and conductance by stabalizing inactive state of channel, only matters in fast neuron
-open K channels to cause hyperpolarization and inhibiting firing
-block T-type CA channels- decrease burst firing in thalamocortical neurons (absence)
specific mechanisms of AED: enhance GABA inhibition
-Gaba facilitation (drug binds and helps gaba bind)
-increase gaba synthesis/release (increase GAD-glu acid decarboxylase, decrease Gaba-T- gaba tranaminase, SSA- succininc semi-aldehyde)
-decrease gaba metabolism
-decrease gaba reuptake
specific mechanisms of AED: attenuation of glutamate-mediated excitation
-decrease glu synthesis/release
-glu receptor block with antagonist
-cerebellar effects- inention tremor, nystagmus, atacxic gait, dilopia, hyperreflxia
-SE unique to each agent
AED drug interactions
-induce or inhibit CYP450
-change binding
-PD interactions, in CNS
-and specific interactions
first generation
second generation
AED second generation SE
-less SE
-not more effective, but better compliance causes better effectivity
-developed with mechanisms in mind (GABA)
phenytoin moa
Na channel block
carbamazepine moa
Na channel block
VPA moa
-increase GABA by more synthesis and/or less breakdown
-t-type Ca block
Pb Moa
-increase gaba inhibition by acting on gaba A receptors
-more inhibition by action on cl channel
-less glu excitation by action on non-NMDA receptors
inhibit thalamic pacemaker by block of T type Ca channels
increase gaba inhibition by action at gaba a receptor
felbamate (felbatrol)
decrease glu excitation of NMDA by occupying glycine binding site
increase gaba level by increasing gaba synthesis or increasing non-vesicular release of gaba
vigabatrin (Sabil)
increase GABA levels by blocking Gaba-T
Tiagabine (gabatril)
decreae GABA uptake
AED to treat neuropathic pain
cbz, gabapentin, lamotrigine
AED to treat migraine
valproate, gabapentin
AED are also used to treat
acute mania
mood stabalizer
dementia: definition
-decline in memory and intellectual anility that causes impaired functioning in daily living
dementia: symptoms
-impaired memory
-impaired use of language
-loss of ingrained morot routines
-impaired ability for abstract thought
-impaired abilty to make and carry through plans
-major personality changes
-disregard for accepted standards of social conduct
dementia: etiology
-caused by 60 disorders
-80-90% is caused by alzheimers or cerebrovascular disorders (vascular dementia)
-also from brain trauma, brain tumor, infections, exogenous toxins, metabolic disorders, neurodegenerative disorders, anoxia
dementia: epidemiology
-age dependent
-unusual in people <65
-is not 3% unti l75 years old but then rapidly increases
-20% of persons between 75 and 84 have dementia, 50% over 85. -10% of persons 65 and over have dementia
Alzheimers Disease: basics
-beings subtly and insidiously and follows a gradual deteriorating course resulting in an incapacity for self care
-decreases life expentancy
-4.2 years for men, 5.7 years for women to live post-diagnosis
-death is due to prolonged immobility (pneumonia or pulmonary embolism, infection, accident, or aspiration
-women are more susceptible
-2% are autosomal dominant, but mostly sporadic
Alzheimers Disease: lesions on the brain
-microscopic lesions
-neuritic plaques and neurofibrillary tangles
-a loss of neurons (10%)
-areas affected are neocortex, hippocampus, entorhinal cortex, amygdala, basal forebrain nucleus of meynert and are needed for memory, higher intellectual functioning, emotional control
Alzheimers Disease: cholinergic hypothesis
-cholinergic projection system degeneration in basal forebrain nuclei and projecting into the hippocampus, cerebral cortex, and amaygdala
-presynaptic cholinergic cells dies, a few receiving die too, but not a lot
-damage accounts to most of the memory, cognitive, and emotional problems
-also NE, 5HT, glutamate, GABA, DA, somatostatin, substance P, neuro-peptide Y
Alzheimers Disease: amyloid beta protein and hyperphosphorylated tau
-neurotic plaques are dead or dying neurons in insoluble deposits of amyloid beta proteins
-tau stabilizes the internal microtubular system of neurons
-hyperphos. tau dissociates from microtubules caused the disorganization of the microtubular network and death of the cell
-hyp. tau can form without beta amyloid but beta amyloid initiates the formation of hyper. tau
vascular dementia
-due to ischemic brain lesions, hemorrhagic brain lesions, ischemic-hypoxix brain lesions
-not cerebral atherosclerosis (rare)
-progressive loss of brain tissue resulting from many small to medium sized cerebral infarctions occuring over years
-resembles alzheimer's disease
-loss of cognitive function is stepwise as each stroke kills more tissue
-memory is less affected
mized dementia
alzheimers and vascular dementia- is multiplicitive
enhancing cholinergic transmission in alzheimers: ACh precursors
-choline- models show no enhanced release of ACh because choline uptake is saturated
-lecithin- natural product metabolized to choline
enhancing cholinergic transmission in alzheimers: musc autoreceptor antagonist
-M2 and M4 inhibit ACh released so block them to release more ACh
-need good affinity for M2 and M4 without blocking M1 an M3
-need specificity
-resonable but no current trials
enhancing cholinergic transmission in alzheimers: nicotinic autoreceptors agonists
-Nicotine gives (+) feedback and releases ACh from presynaptic cell
-also will excite post-synaptic cell
-nicotine is correlated alzheimers but higher CV risk
-need nicotonic agonist that crosses bbb without negative effects
enhancing cholinergic transmission in alzheimers: postsynaptic receptor agonists (musc and nic)
-stimulate M1, M3, Nic which enhances cholinergic activation (not M2 and M4)
-several M1 agonists tried, trials now
-nicotine helps at both pre and post cells
enhancing cholinergic transmission in alzheimers: AChE inhibitiors: MOA
-increases ACh in the synapse
-dual inhibition is not better than just AChE inhibition
-want specificity in CNS
-disease modification: lowers deposition of B-amyloid or lowers toxic response to b-amyloid
enhancing cholinergic transmission in alzheimers: AChE inhibitiors: adverse effects
-NVD, GI cramping, anorexia, weight loss
-worse during induction
-peripheral side effects
enhancing cholinergic transmission in alzheimers: AChE inhibitiors: efficacy
-30-50% of patients with MILD to MODERATE AD get modest but useful increase in cognition, activities of Daily Living, and decrease of neuropsychiatric symptoms
-widely used early on because well tolerated
enhancing cholinergic transmission in alzheimers: AChE inhibitiors: symptomatic effect vs disease modification
-symp. effect has 30-50% improvement for 6mo-1 year, slope is due to decrease in symptom relief, not a change of rate of disease
enhancing cholinergic transmission in alzheimers: AChE inhibitiors: tetrahydroaminoacridine (tacrine)
-first generation drug
-a lot of PNS SE
-liver damage occurs so monitor
enhancing cholinergic transmission in alzheimers: AChE inhibitiors: donepezil (aracept)
-no liver damage
-less SE
enhancing cholinergic transmission in alzheimers: AChE inhibitiors: rivastigmine (exelon)
-no liver damage
-less SE
enhancing cholinergic transmission in alzheimers: AChE inhibitiors: galantamine (reminyl)
-no liver damage
-less SE
-enhances cholinergic activation of pre and post nicotinic receptors to increase effect but this causes no change in therapeutic effect
Glutamate NMDA receptor antagonists in alzheimers: memantine (namenda)
-slow down excitotoxicity in alzheimers to slow disease and heal hurt cells
-uncompetitive NMDA receptor antagonist (channel blocker is frequency dependent)
-possible reduction in excitotixicity but little effect at normal activity level
-SE: none important, can use with AChE inhib
-efficacy: no shown effect with AChE inhib
-no NMDA antagonist SE because of lower affinity
-moderate to severe alzheimer's slows the rate of decline but effect is modest
anti-amyloid and anti-tau approaches in alzheimers
don't exist
B-amyloid creation
-APP with alpha secretase and gamma secretase yield p3 in alpha pathway
-app with b-secretase and gamma secretase give b-amyloid
-monomers aggregate to form soluble dimers and oligomers and then insoluble fibrils that deposit on neurons
-dimers and above are toxic
inhibit b-amyloid formation to prevent alzheimers: increase a-secretase
inhibit b-amyloid formation to prevent alzheimers:decrease b and/or g-secretase activity
-easy to make b-sec inhibitor but have toxic SE
-no SE with g-sec inhibitor but hard to make those which cross bbb
enhance b-amyloid destruction and/or removal from CNS: active immunization against b-amyloid
-active immunication
-6% have inflammatory encephalitis
-use portions of b-amyloid to avoid encephalitis
-systemic dose of b-amyloid gives antibodies causing an efflux from CNS
enhance b-amyloid destruction and/or removal from CNS: passive immunizatino against b-amyloid
-raise antibodies in mice and give to humans
-mice are genetically modified to give human antiboies
-theory- give less encephalitis
Prevent aggregation of beta-amyloid monomers into dimers, oligomers, fibrils
-agents which bind to monomers or oligomers
-tramiprosate (alzhemed) to be approved in 1/07, prevents aggregation
prevent abnormal tau formation
-stop kinases
-activate phosphorylases
-stop b-amyloid stops tau because it is a response to toxic b-amyloid
Misc approaches to treating Alzheimers: Trophic factors (neurontrophins)
-chemicals secreted by neurons or glia cells which assist in neuronal growth and
-“rescue” cholinergic neurons from death after axon section or other trauma.
Such agents might slow down or stop the loss of cholinergic cells in Alzheimer’s disease
-cannot cross
the BBB, so must be given by injection into the brain ventricles. Not very practical
-nerve growth factor (NGF)
-brain derived neurotrophic factor (DBNF)
-More work needed. Current interest is in manipulating CNS levels of these factors or their
effects by using small molecules (which can cross BBB) to increase production,
decrease breakdown or directly stimulate “receptors”.
Misc approaches to treating Alzheimers: antioxidants (vit E)
-shown to prevent for high risk pts and treat AD but results are conflicting
-scavenge for free radicals
-is prescribed because no SE if you don't need it
-should get 200-800 IU/day
Misc approaches to treating Alzheimers: deprenyl
-inhibitor of MAO-B. It has been suggested that it may act as an antioxidant and may
reduce free radial damage to neurons
-6 RCTs showed positive effects of deprenyl
as a treatment for Alzheimer’s disease. However, there are serious questions about the
interpretation of some of the data
-no data as preventative
-not a lot of SE
-mild AD
Misc approaches to treating Alzheimers: ginko biloba
-herb available without and Rx
-long history of folk
use to increase memory and mental alertness in both normals and those with dementia-like
-EGb 761.
-clinical trials in prevent and treat
-chochrane shows effective like AChE inhibitor but support is lacking
-unknown MOA, may be antioxidant
Misc approaches to treating Alzheimers: NSAID
NSAIDS are not of value in persons who already have Alzheimer’s disease. NSAIDS
are probably protective against AD but, considering the danger of GI hemorrhage associated with
most NSAIDS, they can’t be recommended as standard preventative therapy at the present
Misc approaches to treating Alzheimers: prednisone
-no data on prevention
-recent well controlled prospective study in patients with AD
using a low dose of prednisone for one year found no effect on symptoms or the rate of
cognitive decline. However, the dose used may well have been subtherapeutic. On the other hand, AD patients can’t tolerate larger doses. So glucocorticoids not a likely future treatment.
Misc approaches to treating Alzheimers: estrogens
-suggest about a 50% decrease in AD risk in women who have had
extensive exposure to estrogens via ERT or birth control pills. In addition, a large prospective study
reported in 2002 showed a protective effect of long term ERT.
-preventative, but estrogen has bad SE
- studies show no effect on symptoms or rate of decline
-neuroprotective and anti-inflammatory
Misc approaches to treating Alzheimers: statins
-prevent atherosclerosis
-studies show 84% reduction in risk for disease
-need more data before stating that it is a prevention
-treatment- studies are occuring
-the production of beta amyloid in the
brain is positively correlated with the cholesterol content of brain neuron cell membranes. High
cholesterol seems to inhibit alpha secretase and activate beta and gamma secretases but not all anticholersterol drugs show this
misc approaches to treating AD: ergoloid mesylates
-4 synthetic ergot alkaloids.
-Therapeutic effectiveness in AD is highly questionable.
-not a cerebral vasodilator
treatment of vascular dementia
-hydergine- questional efficacy
-AntiChE and memantine are used with efficacy as seen in AD
-prevent stroke and icerebrovascular arterosclerosis
conventional, phenothiazines, low potency
conventional, butyrophenones, high potency
atypical, low potency
atypical, high potency
antipsychotic activity of conventional APs
-improvement in positive symptoms, minimal improvement in negative and cognitive symptoms
-variable onset time: 2-3 weeks until improvement and new evidence says within 24 hours
-no tolerance to therapeutic effect (no decrease in efficacy on (+) symptoms)
MOA of conventional APs
-blockade of postsynaptic D2 receptors in the mesolimbic dopaminergic pathway (need to block 65% of D2, but dose blocks 70-90%
-VTA to mesolimbic to limbic
-delayed onset is due to gradual development of a cessation of firing of mesolimbic dopamine neurons due to the persistent depolarization (depolarization block)
blockade of D2 in mesocortical
-increases negative symptoms
-VTA (ventral tegmental area) to mesocortical to prefrontal cortex
blockade of D2 in nigrostriatal
-SN (substantia nigra) to nigrostriatal to neostraitum
-motor side effects
blockade of D2 in hypothalamus
-via tuberoinfundibular pathway
-endocrine side effects

Add Cards

You must Login or Register to add cards