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38 Cards in this Set

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Overview of narcotic analgesics.
These are agents with morphine-like actions (opiates) and are used for treatment of all types of severe pain

Action mediated through binding of agents to “opiate” receptors which are located in various tissues and as such produce multiple actions

Natural and synthetic opiates are used not only in management of pain but also in treatment of
-- cough
-- diarrhea
-- dyspnea due to acute LV failure
-- anesthetic and adjunctive agent

Multiple actions also responsible for the adverse S/E’s
How are narcotics classified?
Based on SOURCE
1. Naturally occurring from the exudate of the seed pod of the opium poppy
-- contains over 20 alkaloids including morphine and codeine
2. Commercial synthesis has resulted in over 20 cmpds w/ varying therapeutic properties

Based on ACTION at the opiate receptor
1. Actions at opiate receptors can be full agonists, partial agonists, agonist-antagonists or full agonists
2. Action at opiate receptor determines clinical use
General characteristics of the “opiate” receptor?
1. radioligand binding and immunohistochem techniques have demonstrated presence of an “opiate” receptor

2. high concentrations of these receptors are located in areas of the CNS known to involve pain signal transmission
-- dorsal horn of spinal cord
-- periaqueductal gray
-- rostral ventral medulla, and several thalamic nuclei

3. also located in peripheral tissues and mediate diverse pharm effects
More specific characteristics of the opiate receptor?
1. Structural specificity
-- small modifications of the drug molecule cause large changes in drug binding (and in drug effect in vivo)

2. Stereospecificity
-- only the L-isomeric form of the agent binds w/ high affinity (and is active as an analgesic)

3. Competition btwn agonists and antagonists
-- drugs of partially similar structure can bind to the receptor and block binding of agonists such as morphine

4. Reversibility
-- bound drug can be displaced from the receptors by an excess of other molecules that possess binding affinity

5. Binding affinity vs. efficacy
-- good correlation exists btwn the affinity for binding to the receptors and potency of agonist or antagonist in vivo
What are the subtypes of the opiate receptor?
Mu (μ)

Kappa (κ)

Delta (δ)

All three receptors are mbrs of the G-protein-coupled family of receptors and show significant a.a. sequence homologies

Actions at each receptor have now been subclassified into Mu1, Mu2, Delta1, Delta2, Kappa1, Kappa2, and Kappa3 subtypes as defined by radioligand binding and pharmacological criteria

Newer agents have been developed w/ selectivity for these subtypes
What are the three families of endogenous opiate peptides or “opiopeptins”?
1. beta-endorphin

2. dynorphins

3. enkephalins
Beta-endorphins?
Large peptide split off enzymatically from proopiomelanocortin

-- located in pituitary and hypothalamus and is concentrated in areas around the 3rd and 4th ventricles

-- during painful episodes, release of this endogenous peptide into the CSF has been demonstrated
Dynorphins?
Formed from prodynorphin

-- share many properties of the enkephalins

-- localized w/in nerve endings of CNS pain pathways
Enkephalins?
Pentapeptides and are breakdown products of proenkephalin

-- present throughout the CNS in areas related to the perception of pain

-- based on localization in primary afferent nerve endings; these peptides appear to regulate transmitter release thereby inhibiting transmission of pain stimuli
Properties of the endogenous opiate peptides?
1. bind w/ high affinity to opiate receptor

2. opiate receptor binding reversed by narcotic antagonists

3. cross-tolerance exhibited to narcotic agonist administration

4. dependence is produced w/ chronic administration

5. withdrawal reaction induced by the admin of narcotic antagonist in dependent animals
What are the narcotic analgesics?
Morphine
Fentanyl
Methadone
Butorphanol
Nalbuphine
Buprenorphine
Codeine
Pharmacokinetics of narcotic analgesics – absorption?
1. depending on the agent, oral absorption is usually poor and variable due to first-pass metabolism and glucuronidation (bioavailability of morphine is only 25%)

2. absorption following IM admin is usually complete w/ max blood levels is 15-30min

3. transdermal and epidural admin are quite effective
Pharmacokinetics of narcotic analgesics – distribution?
1. Distrib to tissues is based largely on blood flow

2. CNS levels are influenced by:
-- BBB
-- lipid solubility of opiate
-- protein binding of opiate
-- rapid hepatic conjugation w/ glucuronic acid
Pharmacokinetics of narcotic analgesics – metabolism?
1. rapid hepatic conjugation w/ glucuronic acid to water soluble products

2. morphine-6-glucuronide is an active metabolite

3. esters such as MEPERIDINE are hydrolyzed by esterases

4. accum of the N-demethylation product of MEPERIDINE can produce seizures

5. codeine and oxycodone demonstrate good oral:parenteral potency ratios due to structural protection from conjugation
Pharmacokinetics of narcotic analgesics – elimination?
1. water soluble metabolites eliminated by renal mechanisms

2. glucuronide conjugates are eliminated in bile
Cellular actions of narcotic analgesics?
1. ALL actions are mediated via binding to opiate receptors at pre- or post-synaptic sites in the CNS or peripheral tissues

2. Opiate receptors are coupled to various types of GTP-dependent proteins (Gi/Go)

3. Binding to receptors initiates dissociation of the GDP “regulator” form the G protein, freeing the GTP subunit to activate adenulate cyclase, phospholipase and/or protein kinase leading to alterations in ion channel function

4. Agonist affinity and/or the number of receptors activated regulate the quantitative response to opiate ligands

5. Presynaptic agonist actions decrease voltage-gated Ca++ influx and reduce excitatory neurotransmitter release

6. Postsynaptic agonist effects produce increased K+ conductance via activation of receptor-operated K+ currents leading to hyperpolarization and reduction in signal strength
CNS effects of narcotic analgesics?
1. analgesia
2. sedation
3. mood changes
4. respiratory depression
5. separate central effects
Describe the analgesic CNS effects of narcotics.
1. inhibit nociceptive reflexes at both spinal and supraspinal sites, primarily by interactinv w/ mu and kappa receptors
-- raise threshold for pain perception
-- diminish rxn to pain (even though pain is perceived)

2. continuous dull pain is relieved more effectively than sharp, intermittent pain

3. partial agonists and atonist-antagonist ligands produce lower “maximum” analgesia compared to morphine, due to a “ceiling” effect w/ these agents
Describe the sedative CNS effects of narcotic analgesics.
1. drowsiness and sedation produced by the narcotic analgesics is quite variable based on
-- age
-- debilitation
-- other drugs

2. decreased anxiety may also be a component
Describe the mood changing CNS effects of narcotic analgesics.
1. euphoria or a feeling of being “detached” (pleasant floating sensation)

2. pt response varies from a relaxed, dreamy state to an unpleasant experience (dysphoria) if the agent is given in the absence of pain
Describe the respiratory depressive effect of narcotic analgesics.
1. all produce dose-dependent respiratory depression
-- decreased sensitivity of the respiratory center chemoreceptors to CO2
-- direct effects to decrease respiratory rhythmicity

2. decrease in rate, minute volume, and tidal exchange

3. respiratory depression is variable from patient to patient
Describe the separate central effects of narcotic analgesics.
1. MIOSIS
-- result of increased activity in the parasympth nerve innervating the pupil

2. NAUSEA/VOMITING
-- direct stim of CTZ for emesis, in the area postrema of the medulla
-- all clinically useful mu agonists produce some degree of nausea and vomiting

3. COUGH SUPPRESSION
-- a useful side effect
-- results from direct depression of cough center in medulla

4. TRUNCAL RIGIDITY
-- result of increased tone in large trunk muscles
-- probably due to increased descending motor impulses
Peripheral effects of narcotic analgesics?
Largely through activation of mu receptors

1. minimal effects on CV system in supine patient
-- does produce arteriolar and venous dilation and may produce orthostatic hypotension

2. histamine release
-- can produce cutaneous flushing and loss of body heat
-- although effects vary, bronchoconstriction and hypotension may occur

3. increase in muscle tone of small and large intestine smooth muscle
-- spasm
-- propulsive contractility is decreased

4. constriction of biliary smooth muscle in the sphincter of Oddi in biliary tract
-- leads to increased biliary tract pressure
-- biliary colic

5. opiate-induced increase in tone in the ureter, detruser muscle of urinary bladder and vesicle sphincter
-- can produce urinary retention
Tolerance of narcotic analgesics?
1. w/ repeated admin, tolerance can develop over period of 1-3wks

2. tolerance is gained to all effects EXCEPT miotic and constipating effects

3. cross-tolerance to all opiates occurs and includes tolerance to analgesic, euphoric, sedative, and respiratory depressant effects

4. less tolerance is gained to partial agonist/antagonist drugs

5. at least one mech for tolerance is reduction in the receptor-ion channel coupling in the mbrn w/ increased use
Dependence of narcotic analgesics?
1. physical dependence parallels development of tolerance

2. w/o continued presence of agonist at receptor site, cellular processes linked to the receptor become hyperexcitable, leading to characteristic w/d or abstinence syndrome

3. w/d can be precipitated in a dependent individual by administering a narcotic antagonist
Interactions/precautions in disease states or injury for narcotic analgesics?
1. presence of pulmonary disease or hepatic dysfxn are major considerations (resp depression and prolonged drug effects)

2. contraindication for narcotic analgesics in head injury w/o assisted ventilation
-- ↑ CO2  ↑ cerebral blood flow  ↑ ICP

3. pts w/ pancreatitis may experience a further increase in biliary tract pressure w/ narcotic analgesics (spasm of biliary smooth muscle)
Interactions/precautions for drugs and narcotic analgesics?
1. combined admin of narcotics and CNS depressants result in potentiation of sedative effects
-- barbiturates
-- antianxiety agents
-- antipsychotics

2. Meperidine admin to pts taking MAO inhibitors can produce
-- excitation
-- convulsions
-- hyperpyrexia
-- respiratory depression
-- hypotension
BJE**
Narcotic analgesic toxicity?
TRIAD of symptoms
1. depressed respiration
2. pinpoint pupils (except meperidine)
3. coma
Treatment of narcotic analgesic toxicity?
1. establish airway for ventilatory support

2. Judicious admin of narcotic antagonist
What are the different narcotic antagonist types?
1. full antagonist

2. agonist-antagonist (partial agonist)
Describe a full antagonist.
Binds to mu, kappa, and delta opiate receptors (affinity), but has no action or effect on the receptor (efficacy)
What are the full antagonists?
Naloxone

Naltrexone
Naloxone?
Antagonizes the action of narcotic analgesic agonists

Half-life of 1-2hrs following IV admin
Naltrexone?
Longer acting than naloxone and can be given orally
Describe an agonist-antagonist?
Binds to mu, kappa, or delta receptors w/ either full, partial agonist or antagonist activity
Which drugs are agonist-antagonists?
BUPRENORPHINE
-- fxns as partial agonist in absence of morphine, and may, based on dose, antagonize wuantitatively the effects of the full agonist morphine

-- due to partial agonist activity at mu receptor and long half-life, can be used orally to decrease opiate craving in addicts
Uses of full antagonists?
1. IV to reverse excessive respiratory and CNS depression due to narcotic analgesic admin
-- naloxone

2. Orally to decrease craving and maintain opiate-free state in opiate-abusing pts
-- naltrexone
Precautions when using antagonists?
1. Reversal of beneficial effects of the agonist when attempting to reverse the deleterious effects
-- “unmasking” of analgesia
-- increased incidence of postop nausea and vomiting

2. Antagonist may have shorter half-life compared to morphine and respiratory depression will reoccur

3. Precipitation of w/d in physically dependent individuals

4. Mixed agonists/antagonists or partial agonists in presence of full agonist can reduce analgesia

5. Mixed agonists/ antagonist or partial agonists can induce w/d in addicted pts