Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
103 Cards in this Set
- Front
- Back
|
Agents with morphine-like actions (opiates) are known as _________ and are used for treatment of all types of __________.
|
narcotic analgesics
severe pain |
|
|
What determines the clinical use of a particular opioid?
|
action at the opiate receptor
|
|
|
Where are opioid receptors located in the CNS?
|
Areas involved in pain transmission:
1. Substantia Gelatinosa (doral horn of spinal cord) 2. Periaqueductal Gray 3. Rostral Ventral Medulla 4. Thalamic Nuclei (several) |
|
|
Are opiate receptors located in peripheral tissues?
|
Yes
|
|
|
How does the "structural specificity" of the opioid receptor relate to different opoids?
|
small modifications of the drug molecule cause large changes in drug binding (and in drug effect in vivo)
|
|
|
Which isomeric form of an opioid agent binds with high affinity (and is active as an analgesic)?
|
L (-)
|
|
|
How is binding affinity of opioids related to drug efficacy?
|
good correlation exists between the affinity for binding to the receptors and potency of agonist or antagonist in vivo
|
|
|
What are the agonist ligands that bind to the Mu receptor?
|
Morphine
Synthetic opoids Endorphins |
|
|
The actions of ligands binding to the Mu-1 receptor include:
|
SUPRAspinal analgesia
Euphoria Miosis |
|
|
The actions of ligands binding to the Mu-2 receptor include:
|
SPINAL analgesia
Respiratory depression Physical dependence Constipation |
|
|
What ligand binds to the Kappa receptor?
|
Dynorphins
|
|
|
The results of Dynorphins binding to the Kappa receptor include:
|
Spinal analgesia
SUPRAspinal analgesia Sedation Miosis |
|
|
What ligand binds to the Delta receptor?
|
Enkephalins
|
|
|
The results of Enkephalins binding to the Delta receptor include:
|
Spinal analgesia
Modulation of Mu receptor activity |
|
|
All three receptors are members of the __________ family
|
GPCR
(G-protein-coupled family) |
|
|
What are the three endogenous opiate peptides (opiopeptins) derived from precursor polypeptides?
|
beta-endorphin
dynorphin enkephalin |
|
|
Beta-endorphin is a large peptide split off enzymatically from:
|
POMC
(proopiomelanocortin) |
|
|
Where in the brain is beta-endorphin found?
|
Pituitary & Hypothalamus
3rd and 4th Ventricles |
|
|
When the periaquaductal gray is stimulated during painful episodes, the release of beta-endorphin into the _______ has been demonstrated.
|
CSF
|
|
|
Dynorphins are formed from _____________.
|
Prodynorphin
|
|
|
Where do Dynorphins localize?
|
within nerve endings of CNS pain pathways
|
|
|
Enkephalins are pentapeptide breakdown products of ________________.
|
Proenkephalin
|
|
|
Where are Enkephalins present in the CNS?
|
In areas related to the perception of pain
|
|
|
What is the significance of the localization of Enkephalins in primary afferent nerve endings?
|
these peptides appear to regulate transmitter release thereby inhibiting transmission of pain stimuli
|
|
|
What are some properties of the Opiopeptins?
|
Bind with high affinity to opiate receptor
Opiate receptor binding reversed by narcotic antagonists Cross-tolerance exhibited to narcotic agonist administration Dependence is produced with chronic administration Withdrawal reaction induced by the administration of narcotic antagonist in dependent animals |
|
|
Oral absorption of narcotic agents is usually (good/poor).
|
Poor
*high first pass metabolism & glucuronidation *F of Morphine is only 25% |
|
|
After IM administration of narcotic agents, maximum blood levels are achieved in ________ minutes.
|
15-30
|
|
|
What two narcotic drugs are protected from first pass metabolism and therefore can be administered orally?
|
Oxycodone
Codine |
|
|
Distribution to tissues is based largely on:
|
regional blood flow
|
|
|
CNS levels of narcotic agents are influenced by:
|
BBB
Lipid solubility Protein binding Rapid hepatic conjugation w/ glucuronic acid |
|
|
What is important about the glucuronidation product of Morphine (Morphine-6-glucuronide)?
|
more potent than Morphine
|
|
|
Accumulation of the the N-demethylation product of _______________ can produce seizures.
|
Merperidine
|
|
|
How are the water soluble metabolites and the glucuronide conjugates eliminated?
|
water soluble: renal
glucuronide conjugates: bile |
|
|
What signal transduction processes occur upon opiate binding to the receptor?
|
GDP is exchanged for GTP
The GTP bound subunit dissociates to activate adenylate cyclase, phospholipase, and/or protein kinase This leads to alteration in ion channel function |
|
|
What are the effects of opiate agonists on ion flux when acting as pre-synaptic agonists & when acting as post-synaptic agonists?
|
Pre-synaptic: decrease voltage-gated Ca2+ influx and reduce excitatory neurotransmitter release
Post-synaptic: increase K+ conductance leading to hyperpolarization and reduction in responsiveness of postsynaptic neuron |
|
|
Where are Morphine's pre-synaptic and post-synaptic analgesic effects taking place?
|
Spinal (substantia gelatinosa)
Supraspinal locations *raise the threshold for pain perception *diminish the reaction to the pain (even though pain is perceived) |
|
|
Are opiates better at relieving continuous dull pain or sharp, intermittent pain?
|
Dull
|
|
|
Do partial agonist and agonist-antagonist ligands produce more or less "maximum" analgesia as compared to Morphine?
|
less, due to a "ceiling" effect with these agents
|
|
|
Other than analgesia, what other effects do the opiates produce?
|
Sedation
Mood changes Miosis Cough suppression--depression of cough center in medulla Respiratory depression Nausea/vomiting Truncal rigidity--increased descending motor impulses |
|
|
What mood changes do opiates produce?
|
Variable
-Euphoria: pleasant floating sens. -Dysphoria: unpleasant (if agent is given in the absence of pain) |
|
|
What are the mechanisms underlying the dose-dependent respiratory depression opiates produce?
**this is how you die from Morphine** |
Decreased sensitivity of the respiratory center chemoreceptors to CO2 (inspiratory drive)
Direct effects on respiratory center to decrease respiratory rhythmic cycle Decrease in rate, minute volume, and tidal exchange *respiratory depression is variable from patient to patient |
|
|
What is the mechanism underlying opiate induced nausea/vomiting?
|
Direct stimulation of the chemoreceptor trigger zone for emesis, in the area postrema of the medulla.
*all clinically useful Mu agonists produce some degree of n/v |
|
|
Morphine is a full agonist at what receptors?
|
Mu
Kappa Delta |
|
|
What drugs are full agonists at the Mu receptor only and no action at the kappa or delta receptors?
|
Fentanyl
Methadone* *additional action as an NMDA antagonist |
|
|
What drugs are partial agonists at the Mu receptor and full agonists at the Kappa receptor?
|
Nalbuphine
Butorphanol |
|
|
What drug is a partial agonist at the Mu receptor and has no effect on the kappa and delta receptors?
|
Buprenorphine
|
|
|
What are the advantages of drugs that are partial agonists at the Mu receptor?
|
Achievement of analgesia with the development of LESS tolerance & dependence than the full agonists
|
|
|
A Heroin addict comes into the emergency room following a car accident where his hip was dislocated and needed analgesia. Morphine was administered but it requires 6 X to produce the same therapeutic affect as a single dose. What is the reason for this?
|
Cross-tolerance
-anything that interacts with the opiate receptor will lead to tolerance (Heroin); anything else given that interacts with this same receptor--tolerance to this compound will be seen as well (Morphine given in E.R.) |
|
|
What is tolerance?
|
With repeated administration, a greater dosage is required to produce the same biological effect
|
|
|
With repeated administration, tolerance to the effects of Morphine & other agonist opiates can develop over a period of ___________.
|
1-3 weeks
|
|
|
Tolerance is gained to all effects except:
|
Miosis
Constipating effects |
|
|
Cross-tolerance to all opiates occurs & includes tolerance to:
|
analgesic, euphoric, sedative, and respiratory depressant affects
|
|
|
What is one mechanism for tolerance?
|
Reduction in the receptor-ion channel coupling in the membrane w/ increased drug use
|
|
|
Inhibition of ____________ can prevent tolerance from developing.
|
Nitric Oxide Synthase
|
|
|
What is the mechanism of dependence?
|
With repeated use of the drug, the receptor coupling mechanism becomes altered in such a way that without the continued presence of agonist at the receptor site, the cellular processes linked to the receptor becomes hyperexcitable, leading to withdrawal syndrome
|
|
|
True/False As tolerance increased dependence decreases
|
False
The development of tolerance parallels the development of dependence |
|
|
Response Set (Bias) & Response Style
|
1. RESPONSE SET (BIAS): The tendency to respond to test items in a particular way, regardless of the nature of the test items. Social desirability and acquiescence are examples of response sets. The FORCED-CHOICE ITEM FORMAT is a method of presenting test items in which an examinee must choose one of two or more equally desirable or undesirable statements.
2. RESPONSE STYLE: A type of response set in which an examinee tends to select the most socially-desirable response, regardless of the nature of the test item. |
|
|
What disease states should precautions be taken when administering opiates?
|
pulmonary disease--resp. depression
hepatic disease--prolonged drug effects head injury--increased CO2 --> increase cerebral blood flow --> increase ICP' pancreatitis--further increase in biliary tract pressure w/ narcotic analgesics |
|
|
The peripheral effects of morphine and other narcotic analgesics is largely through activation of _____ receptors.
|
Mu
|
|
|
What are the peripheral effects of Morphine & other narcotic agents?
|
Orthostatic hypotension--arteriolar and venous dilation
Histamine release--flushing, itching, bronchoconstriction, hypotension Small/large int. SM tone increased (spasm) & propulsive contractility dec. Constriction of biliary SM & sphincter of Oddi --> Inc. biliary pressure Increased tone in ureter, detrusor muscle, vesicle sphincter --> urinary retention |
|
|
Combined administration of narcotic analgesics & CNS depressants (barbiturates, antianxiety agents, antipsychotics) result in potentiation of the ____________ effects.
|
sedative
*Alcohol and Opiates DO NOT go well together |
|
|
____________ administered to patients taking MAO inhibitors, can produce excitation, convulsions, hyperpyrexia, respiratory depression and hypertension
|
Meperidine
|
|
|
What is the "triad" of symptoms for opiate toxicity?
|
Depressed respiration
Pinpoint pupils (except w/ merperidine) Coma |
|
|
What are the treatment goals for Narcotic toxicity?
|
Establish an airway for respiratory support
Administration of a narcotic antagonist which quantitatively & qualitatively reverses the effects of the narcotic agonist Symptomatically treat CNS depression or excitation |
|
|
Does a full antagonist have affinity at the mu, kappa, and delta opiate receptors? Efficacy?
|
Full affinity
No efficacy (action) |
|
|
What two drugs are antagonists at the opioid receptor?
|
Naloxone
Naltrexone |
|
|
Which antagonist has a half-life of 1-2 hours following IV administration?
|
Naloxone
|
|
|
Naltrexone is (longer/shorter) acting than Naloxone and can be given _________.
|
Longer
Orally |
|
|
___________________ due to partial agonist activity at the mu receptor and long half-life can be used orally to decreased opiate craving in addicts
|
Buprenorphine
|
|
|
What are the clinical uses of full antagonists?
|
i.v. to reverse excessive respiratory and CNS depression due to narcotic analgesic administration (naloxone)
Orally to decrease craving and maintain opiate-free state in opiate-abusing patients (naltrexone, nalmefene) |
|
|
What are some precautions when administering opioid antagonists?
|
Unmasking of analgesia
Increased incidence of post-op n/v Antagonist may have shorter half-life than Morphine and resp. dep. will reoccur Precipitation of withdrawal in physically dependent individuals Mixed agonists/antagonists or partial agonists can induce withdrawal in addicted patients |
|
|
What is local anesthesia?
|
REVERSIBLE depression of both central and peripheral conduction in a circumscribed area of the body
|
|
|
Local anesthetics are classified into two groups, __________ vs __________, according to their structure.
|
Esters ( ex. procaine HCL)
Amides (ex. lidocaine HCL) |
|
|
Esters are hydrolyzed by _________________ to water soluble metabolites which are eliminated by the Kidney. Amides are metabolized largely by the ________ to water-soluble metabolites which are excreted in the urine.
|
Plasma cholinesterase
Liver |
|
|
Local anesthetic agents are weak bases. pKa in the range of ______ and are available as salts as this confers both __________ and _________.
|
8-9
solubility, stability |
|
|
Solutions of local anesthetic agents are in an equilibrium mixture of unionized and ionized forms. The relative proportion of these two forms is governed by their ______ and _____ of the environment into which injected
|
pKa
pH |
|
|
Which form penetrates across the nerve sheath?
|
uncharged (lipophilic) base
|
|
|
pH-dependent re-equilibration occurs in the interior of the nerve sheath to?
|
water soluble (charged) form
|
|
|
__________ form binds to the active site in the nerve membrane
|
water soluble
|
|
|
One way to increase the density of the nerve block is to increase the _____________ of the solution which creates more unionized drug.
|
alkalinity
|
|
|
What are factors that influence the onset and potency (density of the block) of local anesthetics?
|
Dosage & volume of injectate or applied amount
Site of injection or application (pH, blood flow, etc.) Local anesthetic formulation (pH adjustment) Physicochemical and pharmacological properties of the agent |
|
|
A patient has an ulcer. The core of the ulcer is acidic. Will the application of a local anesthetic produce more block or less block than if the ulcer was not present?
|
Less block b/c more of the anesthetic will be ionized
|
|
|
How does blood flow significantly affect the duration of action of both ester and amide local anesthetic agents?
|
Increased blood flow leads to greater diffusion of the drug away from the injection site
Reducing local blood flow increases the duration of the block |
|
|
What is a strategy to increase the duration of action of a local anesthetic compound?
|
inject epinephrine which will vasoconstrict and decrease local blood flow and thus diffusion of the compound away from the injection site
|
|
|
What can affect the metabolism of amide local anesthetics by the Liver?
|
hepatic blood flow
liver disease--can decrease metabolism & therefore sustain blood levels & increase toxicity competition by other drugs for cytochrome P450 isozymes can occur and delay elimination |
|
|
What is the MOA of local anesthetics?
|
bind to, and block vg Na+ channels thereby blocking Na+ conductance and the ability of nerve fibers to initiate and conduct action potentials
|
|
|
Local anesthetics specifically bind to what part of the vg Na+ channel?
|
S6 trans-membrane helical domain
|
|
|
Local anesthetics selectively bind to Na+ channels in the ________________ state to prevent change to rested-closed (and hence activated-open)
|
Inactivated-closed
|
|
|
What is the sequence of events for blockade of nerve conduction by local anesthetics?
|
Binding to receptor site in the voltage-gated Na+ channel
Blockade of Na+ channel & decreased Na+ conductance Depression of rate of electrical depolarization Failure to achieve threshold potential Failure to propagate action potential resulting in conduction blockade |
|
|
What are the electrical changes in the nerve following local anesthetic binding?
|
Increased in the threshold for electrical excitability
Decreased rate of rise of the depolarization phase of the AP Lengthened refractory period with fewer impulses conducted RMP is not significantly affected Electrical changes are progressive w/ the increasing number of Na+ channels blocked due to the absorption of the local anesthetic |
|
|
What determines the susceptibility of different nerve fibers to local anesthetic blockade?
|
size and myelination
|
|
|
____________ fibers being the smallest and least myelinated are blocked first indicating pain sensation is reduced before motor function is blocked.
|
a-delta, b, c
*in a heavier block, you may progress to blockade of motor fibers (a-alpha) |
|
|
Those nerves firing at a (higher/lower) frequency are most sensitive to local anesthetics.
|
Higher
|
|
|
What is the order of blockade by local anesthetics of different nerve fibers?
|
1 - B - vasoconstriction
2 - A-delta/C - pain/temp 3 - A-gamma - proprioception 4 - A-beta - touch/pressure 5 - A-alpha - motor |
|
|
Toxic effects of local anesthetics are related to binding to neuronal _________.
|
vg Na+ channels
|
|
|
The level of toxicity is directly related to:
|
The blood levels of the local anesthetic
*greater the lipid solubility, longer the duration of action & greater potential for tox. *certain routes of administration produce a greater potential for tox. *dec. blood flow at inj. site reduces abs. into systemic circ. *plasma proteins serve as a "sink" to which local anes. bind decreasing free drug & toxicity *tox. not limited to neuronal vg-Na+ channels |
|
|
What are the two effects of administration of epinephrine when administering a local anesthetic?
|
1. increased the duration of drug action
2. decreases the blood level and potential for toxicity |
|
|
What are CNS signs of local anesthetic toxicity?
|
Initial stimulation--reflected by apprehension, salivation and tremor
Convulsions may occur CNS mediated hypertension & tachycardia followed by hypotension |
|
|
What are Cardiovascular signs of local anesthetic toxicity?
|
Cardiac vg-Na+ channels are blocked leading to alterations in pacemaker activity & conduction blockade
High dosages--cardiovascular collapse may occur due to the combined effects on Cardiac and CNS vg Na+ channels |
|
|
What is the treatment of local anesthetic toxicity?
|
Symptomatic: restore normal ventilation & circulation
Benzodiazepines: used to treat seizures |
|
|
How does neurotoxicity occur with the administration of local anesthetics?
|
occurs w/ placement into epidural or subarachnoid space (direct contact w/ spinal nerves)
|
|
|
What are signs of neurotoxicity caused by a local anesthetic?
|
transient numbness, radicular irritation of lumbosacral nerve or myotomal weakness have been reported
|
|
|
Allergic reactions can occur with the _______ type of local anesthetics.
|
ester (procaine)
*bronchospasm, anaphylaxis have been reported |
