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151 Cards in this Set
- Front
- Back
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What are excipients?
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fillers or solutions in drugs that aid release or maintain drug bioavailability
can induce side effects |
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What are some problems with sustained release formulations?
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dose dumping and delayed release
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What are depot formulations?
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oily based formulations delivered intramuscularly and slowly leach into system
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What are some areas of the brain NOT protected by the BBB?
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chemoreceptor trigger zone (area postrema - has serotonergic and dopaminergic receptors)
circumventricular organ of hypothalamus - uses CSF for communication |
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What are some instances in which the BBB may be temporarily opened?
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surgery
ethanol osmotic diuretics (mannitol) bacterial toxins |
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Most CNS drugs are biotransformed by which CYP450 enzymes?
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CYP2D6 and CYP3A4
2D6 not usually induced but many genetic polymorphisms 3A4 inducible |
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Can indirect-acting agonsits be receptor subtype specific?
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NO
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What is the mode of drug action for a direct-acting agonist?
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affinity and efficacy at receptor (may be specific subtype of receptor)
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What is the mode of drug action for a indirect-acting agonist?
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NO affinity for receptor, but possesses efficacy at receptor
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What is the mode of drug action for a direct-acting antagonist?
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affinity for receptor but NO efficacy at site (can be receptor subtype specific)
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What is the mode of drug action of a indirect-acting antagonist?
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NO affinity or efficacy at receptor!
block NT action by: blocking NT release depleting NT levels interfering with consequence of NT function |
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What is the mode of drug action of an inverse agonist?
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drug binds to regulatory site to inhibit NT action at its receptor site
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How is the duration of the effect of a drug that acts through an ionotropic receptor determined?
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by its half life
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What are two processes that are classified as excitotoxic?
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-excess NT leading to increased NO production which can than lead to free radical attack (NO+superoxide=peroxynitrite)
-excess NT induce Ca influxes, inc intracellular oncotic pressure and neuronal swelling |
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Which neurotransmitter is generally responsible for excitotoxicity?
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glutamate
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What is denervation hypersensitivity?
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upregulation in receptor number when neurotransmitter availability is reduced
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How do up or down regulation of receptor numbers affect the potency and efficacy of drugs?
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efficacy is NOT affected
upregulation reduces potency of antagonists, increases agonist potency downregulation increase potency of antagonists, decreases agonist potency |
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What is the principle of counter adaptation?
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drug receptors exhibit predicted changes as a result of chronic exposure - chronic agonists decrease and chronic antagonists increase receptor numbers - leading to pharmacodynamic tolerance
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What is the rebound phenomenon?
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an example of the consequences of counter-adaptation
removal of drug causes withdrawal/abstinence behavior which is opposite to original intended use of drug |
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What are 2 organizing principles of tolerance?
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more systems involved with regulation of a function, more rapid the tolerance
closer the drug action is relative to the target function, greater the impact on the tolerance generated - if works directly a more significant tolerance will develop |
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What is disinhibition release?
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the paradoxical state of excitement that follows the administration of a CNS depressant since these drugs tend to first shut down the inhibitory activity
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Where is the bed of dopamine nuclei located?
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ventral portion of mesencephalon
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According to the balance hypothesis HYPERkinetic movements are a result of what?
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increased dopamine relative to acetylcholine (dopamine=dopamove)
treat by reducing DA or increasing ACh |
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According to the balance hypothesis HYPOkinetic movements are a result of what?
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reduced dopamine relative to acetylcholine
treated by increasing dopamine or reducing ACh |
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What is the "gating" function of dopamine?
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facilitates the rate at which gutaminergic cortico-striatal activity flows through striatum on its way to globus pallidus and eventually cortex
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What is the striatal function of dopamine?
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inhibits acetylcholine function in striatum
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What are the cardinal features of parkinson's?
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rigidity, hypokinesia, rest tremor, loss of postural reflexes
associated features: sialorrhea, dysautonomia, depression, bradyphrenia |
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What is MPTP?
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contaminant from synthesis of synthetic opioid which is converted by MAO-B to MPP+ which has affinity for DA re-uptake pumps so it concentrates in the DA terminals and uncouples oxidative phosphorylation at complex I
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What function is associated with most of the genes found with familial parkinson's disease?
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proteosomal function (leading to idea that PD might be due to protein toxicity)
abnormal alpha-synuclein |
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How is the effective duration of levodopa action naturally extended?
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once the drug is converted to dopamine it is recycled by dompamine transporters in the terminals
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What is the end of dose wearing off effect as it applies to levodopa?
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with disease progression there are less DA terminals in existence so there will be less recycling and thus decreased effective duration
BUT does not happen at the frontal cortex terminals so inc drug to compensate for wearing effects leads to psychosis |
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Why should levodopa also be considered a competitive reuptake inhibitor of dopamine?
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enters the dopamine terminal at the DA transporter (DAT)
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Which fibers constitute the pain gate?
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Descending 5HT raphe nuclei fibers
Descending NE locus ceruleus fibers Enkephalinergic heteroreceptors |
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What is used to treat neuropathic pain?
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Does NOT respond to opioids
Analgesic anti-epileptics or TCAs used |
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What are the analgesic neuropeptides?
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Enkephalin (primary)
Endorphin Dynorphin |
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What do enkephalins do?
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Reduce the release of substance P from primary sensory afferent (C fiber) in the periphery
Also has effects in PAG and other brain areas |
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Where do enkephalins come from?
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Made from pro-enkephalin in cell body of enkephalinergic neurons
Comes as met-Enk or Leu-Enk depending on whether methionine or leucine is first amino acid |
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Where do endorphins come from?
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Released from pro-opiomelanocortic (POMC)
Thought to have paracrine like effects |
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What do opioid analgesics mimic?
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Action of endogenous substances - enkephalins
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What are the different receptors in the enkephalin system?
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Mu
Kappa Delta Epsilon |
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How do mu opioid receptors act?
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G-protein coupled mechanism
Close voltage gated Calcium channels and reduce neurotransmitter release (Sub P) Open K+ channels and hyperpolarize neurons |
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What are the subtypes of mu opioid receptors?
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Mu-1 located supraspinally - cause side effects like euphoria and respiratory depression
Mu-2 located in segmental systems |
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Kappa opioid receptors?
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Mediate many of the CNS and spinal cord effects of enkephalin system but analgesic potency normally not as great as mu system agonists
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Delta opioid receptors?
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Primarily in limbic system, also in spinal cord
Though to mediate more of emotional and behavioral effects of the system |
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What is the primary action of the direct-acting opioids like morphine?
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Inhibit release of substance P in substantia gelatinosa AND activate descending pain suppressing pathways from PAG
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What is morphine-6-glucuronide?
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The metabolite morphine is conjugated to
Enterohepatically recirculated and is active Excreted so patients with kidney insufficiency have higher potency and frequent toxicity |
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What is the toxic triad of morphine?
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Coma
Respiratory depression Miosis - can become mydriasis if respiration compromised long enough |
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Which enkephlin antagonists are used to treat toxicity?
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Naloxone - used more often, not orally available
Naltrxone - not used as much, orally available |
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What is the opioid withdrawal syndrome?
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Rebound increase in NE from locus ceruleus producing autonomic dysfunction and anxiety (via amygdala stimulation)
These can be treated by clonidine and other alpha-2 agonist |
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What is the prototypical drug for the partial opioid agonists and mixed opioid agonists/antagonists?
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Pentazocine (patial agonist/antagonist effects at mu receptors)
Like the other mixed agonists exhibits respiratory depression ceiling effect |
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Why do opioids have greater efficacy in the elderly and patients with liver disease?
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Increased bioavailability and longer duration of action due to reduced metabolism resulting from decreased blood flow to liver
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Tramadol?
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Efficacy at mu receptors but lower affinity
Re-uptake inhibitory properties at NE and 5HT terminals potentiating pure opioid actions but also interacting with other drugs like SSRIs and MAOIs |
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What is diacetylmorphine?
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Heroin
Hydrolyzed to monoacetylmorphine, both DAM and MAM cross BBB more rapidly than morphine - more lipid soluble |
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What is methylmorphine?
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Codeine
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How does codeine compare to morphine?
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More potent antitussive - in every other aspect inferior
Except better absorption of codeine so greater oral efficacy |
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What might be responsible for the antitussive effects of codeine?
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Its affinity for Glu receptors
Glu also likely released from C-fibers |
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What are the pharmacokinetics of codeine?
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It is a prodrug, converted by CYP2D6 to morphine
Also glucuronidated to codeine-6-glucuronidide Majority renally excreted |
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Meperidine?
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Metabolized to normeperidine which has excitatory effects (tremor, muscle twitches, hyperactive reflex, convulsions)
Also has mild 5HT reuptake inhibition which can produces serotonin syndrome when in combo with MAOI |
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Meperidine compared with morphine?
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Less potent than morphine
Less effect on pupils Not good antitussive Constipation, urinary retention, biliary pressure rise less common with meperidine |
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Fetanyl?
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Full opioid agonist derivative of meperidine with much more potency than morphine
Produces neurolept-analgesia when in combo with droperidol |
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Diphenoxylate?
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Of meperidine class, NOT analgesic
Used for diarrhea management Formulated with atropine as lomotil to prevent abuse |
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Loperamide?
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Derivative of haloperidol, resembles meperidine, NOT analgesic
Does not cross BBB due to p-glycoprotein Anti-diarrhea agent |
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Methadone?
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Full opioid agonist
Equi-effective by oral route Longer duration of action - less intense withdrawal syndrome Methadone treatment program - get heroin addicts switched to this |
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Dextromethorphan?
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Non-narcotic centrally acting antitussive - elevates threshold for coughing
Same effect as codeine but without analgesic, euphoric or respiratory depressant OTC as robitussin DM |
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Propoxyphene (Darvon)?
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Full opioid agonist
Used in combo with aspirin, phenacetin, and caffeine or acetaminophen Dependence liability very low |
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Pentazocine?
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Mixed opioid agonist
Weak mu antagonist so can cause withdrawal in opiate addicts Kappa agonist action produces analgesia Respiratory ceiling effect |
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Naloxone?
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Full competitive opioid antagonist
No tolerance, no dependence NOT orally active - extensive first pass effect Short half-life |
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Naltrexone?
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Full competitive opioid antagonist
Long half-life Orally active |
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What is the most important reward center in the brain?
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Nucleus accumbens - connections to frontal cortex mean that even thinking about something causes activation of circuits which inc DA and elicits particular pattern of behavior
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What concepts lead to drug-seeking behavior?
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Incentive salience and reverse tolerance
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What effect do psychostimulants have on the brain?
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Increase DA via re-uptake pump
Affect NE and at higher doses 5HT |
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What are the 3 different mechanisms of action of amphetamines?
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Structures similar to DA and NE so...
Substrate for pre-synaptic uptake sites causing Ca independent release of neurotransmitter Competitive re-uptake inhibitors MAOI at higher concentrations |
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What is the mechanism of action of cocaine?
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Non-competitive re-uptake inhibitor because binds to allosteric regulatory site thus reducing affinity for DA, NE and to lesser extent 5HT
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How is the ceiling toxicity of the amphetamines a consequence of its mechanism of action?
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As concentrations increase the drugs begin to induce the Ca independent release of themselves instead of the neurotransmitter
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How do amphetamines cause death?
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By hyperthermia and metabolic acidosis
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How do the amphetamines compare to cocaine?
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Amphetamines have longer half lives, mostly excreted unchanged
Cocaine has shorter half life because mainly biotransformed in blood by pseudo-cholinesterase |
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What happens when cocaine is mixed with ethanol?
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Produces conjugate coca-ethylene with mixed stimulant/depressant properties
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What happens when cocaine is present at high concentrations?
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Becomes CNS depressant - complicates the toxic profile when mixed with opioids
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How do the anorexients differ from the amphetamines?
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Virtually no DA action and more NE and 5HT action
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What are the anorexient drugs?
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Phenteramine
Fenfluramine Phenylpropanolamine Phendimetrazine Benzphetamine |
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What are the psychostimulants legally used to treat?
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Narcolepsy
Pain ADHD |
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Which drug is most commonly used to treat ADHD?
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Methylphenidate - has fewer side effects than amphetamine, drug holiday used to reduce tolerance
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What is adderall?
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ADHD drug combo of amphetamine and dextroamphetamine (dexedrine)
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How does caffeine lead to heightened awareness?
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Antagonizes the effects of adenosine on cholinergic terminals of pedunculo-pontine pathway
Performance enhanced only in the face of fatigue |
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Does caffeine have dopaminomimetic properties in the nucleus accumbens?
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Yes but not very potent
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What action does caffeine have at higher concentrations?
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Phosphodiesterase inhibitor leading to increased cAMP and thus decreased ADH and diuresis
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How does nicotine lead to dependence and euphoric effects?
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Increases DA through its action as an MAO inhibitor
The DA properties provide mild stimulant actions that improve concentration like other DA agonists |
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What are the effects of nicotine?
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As a direct-acting nicotinic agonist causes increased muscle tone from NMJ receptors, PANS and SANS effects with net effect of increased BP and pulse rate
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What is bupropion?
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A mild DA agonist
When combo'ed with nicotine patch or gum provides successful reformation of smokers |
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What is the effect of ethanol on GABA receptors?
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Enhances the activity of GABA-A receptors in unknown way
Hence the synergism between alcohol and sedative-hypnotics |
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What leads to ethanol's disinhibition release?
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Alters the fluidity of membranes (especially the inhibitory fibers)
Net effect of a CNS depressant But also a delta opioid agonist which contributes to euphoria Acutely increases DA and NE providing initial alerting effects, SANS activation and dependence liability Reduces ACh release in reticular formation and other areas because interferes with N-type Ca function |
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What is Wernicke-Korsakoff syndrome?
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Associated with alcoholism consists of: emotional aspects, memory loss, cognitive impairment, ataxia and paralysis of external eye muscles, poor diet causing thiamine deficiency and peripheral neuropathy
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What contributes to liver dysfunction in the alcoholic?
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Since ethanol metabolism requires NAD this gets depleted leading to glutamate, lactate, and malonate accumulation in the liver
Leads to dysfunction & fatty, cirrhotic liver less capable of handling sugars - causes more problems for CNS |
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What effect does ethanol have on the GI tract?
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Reduced absorption of water soluble vitamins
Increased HCl secretion & other juices leading to gastritis and pancreatitis Loss of folate leads to mild anemia |
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Why are cardiovascular problems common with ethanol abuse?
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Effect of ethanol on cardiac muscle causes direct cardiomyopathy
Effects on NE, depression of cardio-regulatory centers in medulla, peripheral neuropathy |
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What are the general CNS depressant effects of ethanol?
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Reduced ADH release and diuresis
Body temperature is decreased (with peripheral vasodilatation leads to rapid heat loss) |
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What does fetal alcohol syndrome consist of?
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Reduced body weight
Mental retardation Altered facial features Joint abnormalities Congenital heart defects |
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What is the significance of the fact that alcohol dehydrogenase is rapidly saturated and zero order kinetics achieved?
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Not how much you drink but the rate at which you drink which determines how drunk you will get
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Is alcohol dehydrogenase an inducible enzyme?
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NO, but P450 system does play role in its metabolized and those enzymes are inducible so tolerance possible
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What is disulfiram?
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Inhibitor of aldehyde dehydrogenase
Also a DA-beta-hydroxylase inhibitor which contributes to hypotension |
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What is chloral hydrate?
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Another substrate for alcohol dehydrogenase
Its metabolite is trichloroethanol, a sedative-hypnotic Due to the involvement of NADH the biotransformation of ethanol drives catabolism of chloral hydrate Mickey Finn is conjunction of ethanol and chloral hydrate - together cause rapid sedation |
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What is fomepizole?
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Direct acting alcohol dehydrogenase inhibitor used to treat methanol or ethylene glycol toxicity
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What is may be present during an ethanol withdrawal syndrome?
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Delirium tremors
Convulsions are often status epilepticus or rebound seizures with Diazepam as preferred agent for treatment |
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What are PCPs main actions?
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Sigma receptor agonist (aka indirect acting NMDA antagonist)
Inhibits DA transporter (but it is not a substrate) |
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What are the consequences of PCPs action as a sigma receptor agonist?
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Inhibits ion flux through NMDA channels - blocks Glu
Leads to DA release via heteroreceptor action Unpredictable effects on other NT levels - ACH, NE, 5HT |
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What is the effect of PCPs action on the DA transporter?
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Inhibits the transporter contributing to euphorogenic effects and tendency for dependence but this is not profound
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Does PCP develop tolerance?
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Very little
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What is pathognomonic for PCP toxicity?
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Cyclic coma from ion trapping in stomach
Treatment with Diazepam |
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What does the toxic profile of PCP include?
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Belligerence, cognitive impairment, agitation, laryngeal & pharyngeal hyperactivity (barking), variable pupil size with blank stare
Unpredictable effects Hiccoughing and sustained vomiting lead into seizure and then cyclic coma |
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What is amandamide?
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Endogenous ligand for cannabinoid receptors in CNS
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What are the mechanisms by which THC exerts is effects?
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At the cannabinoid receptors in the CNS (CB-1 and CB-2)
Inhibits choline re-uptake so indirect acting cholinergic antagonist Also very lipid soluble and dissolves readily in membranes disrupting fluidity |
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What are the medical uses for marijuana?
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Bronchodilator
Appetite stimulant Immuno-suppressor Analgesic Anti-emetic Reduces intra-ocular pressure |
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What are the tri-phasic effects of THC on biogenic amines?
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Initial phase - reduced DA and increased 5HT
Sustained phase - increased DA with reduced 5HT Depressive phase - normal DA and 5HT |
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What is the mechanism of action of THC?
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Choline re-uptake inhibitor leading to ACh depletion via indirect antagonist action
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What is likely responsible for the difficulty in memory consolidation and depressive effects associated with THC?
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ACh depletion
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The biphasic psychic effects of THC are characterized by what?
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Euphoria/stimulant phase: time sense and sensory info distorted, impaired concentration, suppressed appetite
Sedation/depressive phase: lethargy and lack of motivation, REM latency increased and REM suppression occurs (rebound does not occur), appetite is increased |
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Is THC a hallucinogen?
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NO; but at high doses delirium and sensory distortions can occur, hallucinations very rare though
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Is THC a P-450 inducer?
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No but the tars and resins are
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Does tolerance develop to THC effects?
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Yes, to most effects minus the eye reddening
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What are the major classes of hallucinogens?
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LSD
Phenylalkylamines (mescaline) Indoleamines (psilocybin) |
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What are the characteristic signs and symptoms of hallucinogens?
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Somatic signs
Perceptual signs Psychic symptoms |
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The actions on which receptor is likely to lead to hallucinations?
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5HT1D autoreceptor - reduction of raphe firing leads to disinhibition release of limbic input in cortex and disinhibition of activity in occipital cortex
5HT2 receptors in thalamus and cortex may also play role |
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What is HPPD?
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Hallucinogen persisting perceptual disorder - LSD flashback phenomenon
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Why is it nearly impossible to become dependent on hallucinogens?
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Rapid tolerance (tachyphylaxis) and cross tolerance develops very rapidly
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How does ecstasy work?
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Predominantly effects 5HT system by stimulating its release and inhibiting its re-uptake
Similar but less potent effects on DA system |
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Can ecstasy cause serotonin syndrome all by itself?
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Yes because indirect 5HT agonist
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What long-term effect does ecstasy have on the 5HT system?
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Pruning effect leading to 5HT hypofunction - likely responsible for the depression seen after its use
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Is ecstasy a substituted amphetamine?
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Yes
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Is GHB a substituted amphetamine?
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NO
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What are overdoses of GHB associated with?
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Small overdoses cause temporary unarousable unconsciousness
Large overdoses can be life-threatening, assoc. with clonus |
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What is the mechanism of action of GHB?
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Unknown - taken recreationally as depressant
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Where is GHB naturally found?
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Human cells
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How do delusions differ from hallucinations?
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Delusions are misperceptions while hallucinations is an image that is not there
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What are the most common forms of acetylcholinesterases in the brain?
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G1 and G4 (available nootropics are G1 and G4 preferring)
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What is butyrylcholinesterase (aka pseudocholinesterase)?
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Widely distributed in blood, likely serves to detoxify ingested esters
In brain predominantly located in glial cells |
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With AD progression what happens to acetylchoinesterase?
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This enzyme is lost - partly to cell loss but also because binds to and can be isolated from senile plaques
Thus pseudocholinesterase might become more important as disease progresses |
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What are the mechanisms of inhibition of ACh catabolism via inhibition of AChE?
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Tacrine-like drugs bind reversibly to choline site reducing affinity for ACh
Other site is anionic site Physostigmine-like drugs AChE substrates but biotransformed slowly (organophosphorus compounds similar but more permanent bond) |
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What are the nootropic agents?
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Tacrine
Donepezil Rivastigmine Galantamine |
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Tacrine?
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Nootropic agent with short duration of action
Reversible inhibitor at choline site Significant first pass effect Requires monitoring for reversible liver injury |
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Donepezil?
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Nootropic agent
Non-competitive reversible inhibitor of AChE Long half life Most eliminated renally |
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Rivastigmine?
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Nootropic agent
Pseudo-irreversible competitive inhibitor of AChE at active site (like physiostigmine) |
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Galantamine?
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Nootropic agent
Reversible, low potency Also acts as non-competitive nicotinic agonist - can activate post-synaptic receptors in brain which has some efficacy against AD |
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How do volatile inhalants lead to euphoric effects?
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Probably because they uncouple oxidative phosphorylation leading to hypoxia and disinhibition release
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Do volatile inhalants carry and dependence liability?
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NO
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What are side effects of anabolic steroid use in boys and men?
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Reduced sperm count
Shrinking of testicles Impotence Difficult/painful urination Baldness Irreversible gynecomastia |
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What are side effects of anabolic steroid use in girls and women?
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More masculine characteristics:
Decreased body fat and breast size Deepening of voice Excessive growth of body hair Loss of scalp hair Clitoral enlargement |
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In adolescents of both sexes what are side effects of anabolic steroid use?
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Premature termination of growth spurt - so will always be shorter than they could have been
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In males and females of all ages what are side effects of anabolic steroid use?
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Potentially fatal liver cysts and liver cancer
Blood clotting Cholesterol changes HTN - thus all in combo promote MI, stroke, acne Some think it also leads to aggression |
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Upon stopping anabolic steroids what do some abusers experience?
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Depressed mood
Fatigue Restlessness Loss of appetite Insomnia Reduced sex drive Headache Muscle, joint pain Desire to take more! |
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In the US what are some anabolic steroids that can be purchased legally?
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DHEA - dehydroepiandrosterone
Androstenedione (aka Andro) |
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Methanol toxicity is a result of what?
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Formaldehyde formation - blindness
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