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NU 600

Exam 6 - Autocoids and Antiemetics

T/F: Autocoids are not biologically active. False-consist of an array of biologically active substances
Where are autocoids synthesized? At the site of action whose specialized function is to initiate the response to tissue injury
What are the 4 key autocoids as r/t to drug therapy? Histamine, bradykinin, serotonin, prostaglandins
What is histamine? Naturally occurring low molecular weight vasoactive amine autocoid
Where and how is histamine synthesized? Synthesized in tissues by decarboxylation of histidine
What is histamine released in response to? Stimulation by mast cells, basophils, and neurons
What mediates the initial response to tissue injury? histamine
What are the origins of the word "autocoid"? "autos"=self, "akos"=remedy
Histamine is stored in an intricate composite with ____________. Heparin
Who rec'd the Nobel Prize in Physiology and Medicine for their work on histamine and curare? Bouvet (1957)
What catalyzes the metabolization of histamine and how is histamine metabolized? Catalyzed by histamine-N-methyl transferase; methylation
After methylation, histamine is further degraded by what enzyme? monoamine oxidase (MAO)
What are the 5 receptor subtypes for histamine? H1, H2, H3, H4, Hic
Histamine induced excitation is mediated by _____ receptors and _______. H1; primary sensory neurons
In what body tissues can H1 receptors be found? Most body tissues, including cardiac smooth muscle, histaminergic nerves of the brain, enterochromaffin-like cells of the antrum
Which histamine receptor plays a central role in hypersensitivity allergic responses? H1
What changes occur with H1 cardiac receptor agonism? Decrease AV nodal conduction, mediate vasoconstriction in coronary vessels, reduced atrial natriuretic peptide
What is the function of atrial natriuretic peptide? Vasodilation
How does H1 agonism affect the airway? Induces bronchospasm
H2 agonism (constricts/dilates) the airway. dilates
How does H2 agonism affect the stomach? What conditions can H2 agonism increase instances of? Stimulates gastric acid secretion; GERD and peptic ulcer disease
(H1/H2) stimulation results in sustained generalized vasodilation of slower onset. H2
What are the cardiac effects of H2 agonism? Positive chronotropic effects, dysrhythmias
Why does H2 agonism in cardiac tissue lead to dysrhythmias? D/t histamine-induced catecholamine release
1st gen H1 antagonists (are/are not) H1 specific. are not
1st gen H1 antagonists elicit what 3 types of responses? Dopaminergic, serotonergic, cholinergic
H1 receptor antagonists (do/do not) cross the BBB. do
What neuro symptoms can H1 antagonists elicit? Somnolence, cognitive dysfx
An overdose of H1 antagonists can lead to what effects? Toxic psychoses w/hallucinations resembling schizophrenic breaks
Name three H1 receptor blockers. - Generic (Trade) - Promethazine (Phenergan), hydroxyzine (Vistaril), demenhydronate (Dramamine), diphenhydramine (Benadryl)
What are H1 receptor blockers effective at treating? PONV (effective antiemetic), motion sickness, pruritis
H2 blockers (do/do not) exhibit antiemetic effect. do not -- used in allergic rhinitis
Which H1 antagonist can be used to treat drug-induced extrpyramidal rxn and Parkinson-like symptoms? Diphenhydramine
(H1/H2) antagonists can be used as an adjunct in anesthesia d/t the production of sedative effects of long duration. H1
What types of drugs are cyclizine and meclizine and what do they treat? 1st gen antihistamines used to treat vomiting associated w/motion sickness and vertigo
Which antihistamine is used to potentiate narcotics? Hydroxyzine (Vistaril) - don't give IV
Which antihistamine is associated with T-wave abnormalities? Hydroxyzine (Vistaril)
2nd gen antihistamines (do/do not) cross the BBB. Do not
Which generation antihistamine has a greater specificity at the H1 receptor: First or second? 2nd gen
True/False: Cardiotoxicity of newer 2nd gen antihistamines does not occur. False--remains if metabolism is inhibited
What are two examples of 2nd gen H1 receptor antagonists? Loratidine (Claritin), cetirizine (Zyrtec)
Identify 3 second gen H2 antagonists. Cimetidine, ranitidine, famotidine
What are second gen H2 antagonists used for and how do they achieve this effect? Tx PUD and GERD by blocking histamine effect on parietal cells (secrete HCl) of the stomach
_________ is a potent inflammatory mediator and vasoactive peptide. Bradykinin
What is the most potent endogenous vasodilator released after allergic reactions and tissue damage? Bradykinin
Bradykinin is a product of what biochemical cascade? Kallikrein-kinin system
(Histamine/Bradykinin) modulates the series of events that accompany inflammation (vasodilatation, increased cell permeability, hyperalgesia, pain). Bradykinin
Where is bradykinin stored? CNS
What are circulating kallikreins activated by? plasma proteases
How are pH and temperature involved with bradykinins? Changes in pH and temperature can activate prekallikrein and lead to the conversion of prekallikrein to bradykinin after tissue damage
What does bradykinin stimulate? Release of neuropeptides: substance P and neurokinin
Bradykinin is a potent (algesic/analgesic). algesic
What incites the mediators of the pain cascade and the pain "wind up"? Bradykinin
Bradykinin is (more/less) potent than histamine as a vasodilator. more (10x more)
What substance is thought to play a role in hereditary angioedema, carcinoid syndrome, and septic shock? Bradykinin
What are the two receptors for bradykinin? What type of receptors are they? B1, B2; G-protein coupled receptors
(B1/B2) is the more active bradykinin receptor body, causing ________ and _________. B2; inflammation, bronchoconstriction
Where are serotonin receptors primarily found? Where else are they located? Primarily cerebral and CNS; also GI tract, platelets
What receptor body families do 5-HT receptors belong to? G-protein coupled
What roles are 5-HT receptors integral in? Pain signaling and inflammation
Dopamine, norepi, and serotonin are responsible for what neurologic states? Mood, feelings, motivation
How many different 5-HT subtypes are there? 14
What is the 5-HT(1a) subtype implicated in? Psychiatric d/o, immunomodulation, cerebral ischemia
What is serotonin generated from? Tryptophan
How is serotonin metabolized to its inactive form? Oxidative deamination by MAO
Where is the action of 5-HT terminated? At the synaptic junction and in the outer membrane of platelets
Which 5-HT receptor agonists are effective as migraine therapeutics? Who are they contraindicated in? 5-HT 1b/1d; contraindicated in patients w/CAD
What does the 5-HT2 receptor subtype have a high attraction to? Choroid plexus (site of CSF production)
Identify a 5-HT4 agonist? What have they been used to treat? Why were these removed? Cispride; GERD, IBS, constipation; cardiac problems
Ongoing neuropsychiatric research is ongoing with agonists of which 5-HT subtype? 5-HT4
5-HT3 has a strong relation with the (nicotinic/muscarinic) ACh receptor. nicotinic
Where are 5-HT3 receptors found? Where are the highest levels located? CNS; highest levels in the dorsal vagal complex of the brainstem and parasympathetic terminals of the GIT
What region of the brain is responsible for the vomiting reflex, and what 5-HT receptor subtype is found in this region? Dorsal vagal complex; 5-HT3
What does the dorsal vagal complex (vomiting reflex) consist of? Nucleus tractis solitarius, area postrema, dorsal motor nucleus of the vagus
What does antagonism of 5-HT3 contribute to? Anti-emetic action
What does polymorphism of the 5-HT3 gene play a role in? Psychiatric disorders
Prostaglandins are metabolites of _______> arachidonic acid
What do the metabolites of arachidonic acid play a role in? Inflammation
Arachidonic acid is broken down through which pathway? Cyclooxygenase
Prostaglandins are members of what family of receptors? G-protein coupled
Prostaglandins play a role in what other parts of the body? Systemic vascular resistance, airway resistance, platelet aggregation, increased uterine tone
Which COX isoform exhibits cytoprotective activity? COX1
Which COX isoform is induced at the site of inflammation with rapid increases in its amount during inflammation? COX2
Which COX isoform is constitutive (always occurring), and which is inducible (only with pain)? COX1=constitutive; COX2=inducible
Inhibition of (COX1/COX2) predisposes to CV insult (e.g. MI, stroke, heart failure). COX2
What is the primary site for prostaglandin synthesis? Lungs
The suppression of what COX1 product triggers cardioprotection? Which medication achieves this effect? Thromboxane-A2 (TXA2); ASA
Name two COX2 inhibitors associated with MI and sroke. Vioxx, Celebrex
What condition does thromboxane exacerbate? Bronchoconstrictive dz (asthma)
Pulmonary vasoconstriction may occur as a result of circulating levels of what two products? Prostaglandin, thromboxane
Protamine (stimulates/depresses) TXA production. What effect does this have? stimulates; pulmonary HTN and bronchospasm
What percentage of surgical patients may experience PONV? 30-70%
Identify states of health/dz that predispose a patient to N/V. Infx, pregnancy, vestibular dysfx, CNS issues, peritonitis, hepatobiliary d/o, post-radiation, GI d/o, SE from meds
There is a (strong/weak) memory association with vomiting. strong
Where does the vomiting stimulus originate in the GIT? What provides the strongest stimulus in the gut? Anywhere in the GIT; Distention or stimulation of the duodenum
The vomiting reflex is controlled in what area of the brain ("emetic center")? Reticular formation of the medulla oblongata
What is the strongest stimulator for emesis? Duodenal distention
Identify the antagonist associated with each of the following emetic agonists: 1)Serotonin 2)Histamine 3)ACh 4)DA 5)Neurokinin (Substance P) 6)Endorphins (opioids) 1)Zofran 2)Promethazine 3)Scopolamine 4)Droperidol 5)Aprepitant 6)Narcan
In what two pathways does N2O stimulate the emetic center? Vestibular portion of the 8th nerve and vagus nerve
Sensory input arises from afferent impulses originating from what 5 areas of the body? 1)pharynx 2)GIT 3)mediastinum 4)cerebral cortex 5)sensory organ
The CTZ (is/is not) protected by the BBB. is not
Which area can specifically be targeted by anesthesia providers in the treatment or prevention of PONV? Chemoreceptor trigger zone (CTZ)
What are the different hormones that stimulate the CTZ, leading to pro-emetic scenarios? Serotonin, histamine, ACh, dopamine, substance P (neurokinin)
Serotonin is a widely distributed hormone that evokes complex changes on what body system? Cardiovascular system--vascular beds (serotonin is an endogenous vasoactive autocoid)
Where is serotonin released from? Enterochromaffin cells of the small intestine
How does serotonin initiate the vomiting reflex? Stimulates vagal afferent pathways through 5-HT3 receptor stimulation, which initiates the vomiting reflex in the medulla
Through what pathways does serotonin initiate the vomiting reflex? Vagal afferent
Serotonin is a key neurotransmitter in the transmission of _______ and _______ Emesis, pain
Identify the 4 serotonin antagonists. Ondansetron, dolasetron, granisetron, palonosteron
What are the most common SE of serotonin antagonists? HA, dizziness, constipation or diarrhea
What are the indications for the use of serotonin antagonists in treating nausea? 1) chemo induced 2)post-radiation 3)PONV 4)vomiting w/pregnancy
Which medication is the standard/prototypical selective serotonin receptor antagonist? Ondansetron
What is the onset and T1/2 of Zofran? 15min onset; T1/2 4h
What is the trade name for dolasetron? Anzemet
Which SSRA is a prodrug? Anzemet
What is the product of metabolism of dolasetron and how much more potent is it than the parent drug? What is the T1/2 of dolasetron? Rapidly metabolized to hydro-dolasetron; 100x more potent than dolasetron; T1/2 8h
What are the IV and PO doses of dolasetron (Anzemet) and when are they given? 12.5mg IV prior to end of surgery; 50-100mg PO 2hr pre-op (as effective as Zofran for ppx).
What are the SE of dolasetron (Anzemet)? HA, dizziness, increased appetite
What is the trade name for granisetron? Kytril
Which has more receptor specificity: granisetron (Kytril) or ondansetron (Zofran)? Granisetron (Kytril)
What is Kytril commonly used in? Anti-emetic in chemotherapy
What is the IV dose of granisetron (Kytril) and when is it given? What is the T1/2? 1mg or 20-40mcg/kg IV immediately prior to induction; T1/2 9h but coverage for up to 24h
What are the SE of granisetron (Kytril). What limits its usage? HA, diarrhea, sedation; cost
What is the newest SSRA? Polonasetron (Aloxi)
Polonasetron (Aloxi) is used as a (prophylactic/rescue) antiemetic. Prophylactic
What is the IV dose of polonasetron (Aloxi) and when is it used? 0.25mg IV, given prior to chemotherapy
What are common SE w/polonasetrong? HA, constipation, diarrhea, dizziness, less common: bradycardia, hypotension, tachycardia
Which SSRA is not recommended for PONV? Polonasetron (Aloxi)
What has been determined among all SSRAs in regards to safety/efficacy? No difference exists among the SSRAs
Corticosteroids are used to enhance the efficacy of what other class of antiemetics? SSRAs
True/False: The mechanism of action of corticosteroids in treating PONV is well defined. False
What is the IV dose of decadron (corticosteroid) given for nausea and when is it given? 4-10mg IV around induction
Identify two phenothiazines. In what other application are phenothiazines used, other than as anti-emetics? Compazine, phenergan; used as antipsychotics
In what scenarios are phenothiazines used as antiemetics? Chemo- + radiation therapy; PONV; Tx of allergic blood transfusion reactions
What is the mechanism of phenothiazines? Inhibition of central DA, muscarinic, and H1 histamine receptors
What are the SE to phenothiazines? CNS depression, somnolence, hypotension, possible EPS -- *think compazine*
What mechanism allows phenothiazines to treat anaphylaxis? Blocking of H1 histamine receptors
Compazine and/or phenergan should not be given (IM/PO/IV/SQ). SQ
True/False: Compazine/Phenergan is non-caustic and can be delivered IV without complications. False=Compazine/Phenergan are venous irritants and should be liberally diluted
Butyrophenones are classified as _________. antipsychotics
Which receptors do butyrophenones inhibit to combat N/V? Inhibit central DA receptors
Identify a butyrophenone used in the treatment of N/V. What is its dose and when is it given? Droperidol; 0.625-1.25mg x1 prior to induction
In what scenarios is droperidol used? Chemo/Radiation therapy, PONV
What are the SE to droperidol? Prolonged QT interval
Which antiemetic has a Black Box warning? Droperidol
Patients receiving droperidol at doses of greater than ______mg over ______h have died. 50; 24
What should be done prior to giving droperidol? 12-lead ekg
What two ekg changes have been reported with droperidol? QT prolongation and torsades
What are the QT measurements for men and women that would serve as a contraindication for droperidol? 440ms=men, 450ms=women
When should an ekg be done with administration of droperidol? Prior to administration and 3h post
What is the usual dose of droperidol and when is it given? 0.625mg preop
Besides droperidol, what other butyrophenone is used as an antiemetic? What receptors does it block? Haldol; blocks D1 and D2 receptors
True/False: The doses for haldol as an antipsychotics are the same as those when used to treat N/V. False=Antiemetic doses are much lower
The mechanism of action of cannibinoids (is/is not) fully known. is not
Describe the pharmacokinetics of cannabinoids. 1)Readily absorbed orally 2)Extensive 1st pass metabolism 3)Limited systemic BA d/t excretion of metabolites
Through what routes are the metabolites of cannabinoids excreted? Biliary
Identify a cannabinoid used in the treatment of N/V. Dronabinol
What are the SE of dronabinol? Euphora or dysphoria, sedation, hallucinations
What can abrupt withdrawal of cannabinoids lead to? Withdrawal syndrome (restless, insomnia, irritability)
What are the autonomic (sympathetic) effects of cannabinoids? Tachycardia, palpiations, conjunctival injection, orthostatic hypotension
What is the indication for cannabinoids (dronabinol)? Chemo-induced N/V
What are two types of agents that increase GI motility? Cholinergic agents and prokinetic agents
True/False: Cholinergic agents are useful in the treatment of motility disorders. False
True/False: Prokinetic agents are useful in the treatment of motility disorders. True
What is the method of action of cholinergic agents? Stimulate cholinergic receptors which enhance contractions in an uncoordinated manner, producing limited propulsive activity
What is the method of action of prokinetic agents? Enhances coordinated GIT propulsive motility by acting at receptor sites on motor neurons and increasing the release of ACh.
Which agent is more effective at producing coordinated propulsive GIT motility: cholinergics or prokinetics? Prokinetics
Identify a prokinetic GIT motility agent. Reglan
Identify a cholinergic GIT motlity agent. Bethanechol
Which receptors does bethanechol work as an agonist on? Muscarinic
What does bethanechol resist? Enzymatic hydrolysis
Bethanechol is a/an (direct/indirect) cholinergic agent. direct
Identify an indirect cholinergic agent and what is its classification? Neostigmine; anticholinesterase inhibitor
What has neostigmine been used to treat? Paralytic ileus
What is the pathology behind decreased motility of the GIT? Results from suppression of ACh release from myenteric motor neurons mediated by stimulation of D2 DA receptors.
What are the two ways that prokinetic agents enhance GIT and treat N/V? 1)Antagonize inhibitory effects of DA on myenteric motor neurons 2)Relieve N/V by antagonism of DA receptors in CTZ
Identify two prokinetic agents. Metoclopramide, domperidone
Identify two benzamides used in the treatment of N/V. Metoclopramide, trimethobenzamide
What is the antiemetic mechanism of action of benzamides? Central blockade of DA receptors
The SE of benzamides are mainly _________. Extrapyramidal
What are the SE of benzamides? (Mainly EPS)==>Restlessness, dystonias, Parkinsonian sx
How does reglan influence specific areas of the GIT? (3) 1)Enhances coordinated GIT propulsive motility of the upper digestive tract 2)Increases LES tone 3)Stimulates antral and small intestinal contractions
Reglan (does/does not) have significant effects on motility in the colon. does not
What are the 3 mechanisms of action of Reglan in the GIT regarding receptor agonism/antagonism? 1)DA receptor antagonism 2)5-HT4 receptor agonism 3)Vagal and central 5-HT3 receptor antagonism
What is the MOA of Reglan as an antiemetic? Antagonize DA receptors in the CTZ
Which antiemetic should not be given to dystonic and dysphoric patients? Reglan
What are 6 therapeutic uses for Reglan? 1)N/V 2/t GI dysmotility 2)GERD (symptomatic relief) 3)Gastroparesis 4)GIT radiography 5)Post-op ileus 6)Persistent hiccups
What two types of medications can be used in the prevention/treatment of motion sickness or vertigo? H1 receptor antagonists and anticholinergics
What is Meniere's disease and what is used to treat it? Inner ear d/o that causes vertigo, tinnitus, and hearing loss. Treated with either anticholinergic (scopolamine) or H1 receptor antagonists (dimenhydrinate).
What are three different 5-HT3 antagonists? Ondansetron, dolasetron, granisetron
5-HT3 antagonists (do/do not) increase gastric pH and reduce incidences of aspiration pneumonitis. Do not
What promise do H4 antagonists (anti-histamines) show in medicine? Treatment of inflammatory conditions involving mast cells and eosinophils.
What are three different therapeutic applications for H4 antagonists? Allergic conditions, asthma, rheumatoid arthritis.
The vestibular apparatus is rich in what types of receptors? Muscarinic cholinergic type I (M1)
Name two different anticholinergic tertiary amines. Scopolamine, atropine
Which medication is the only anticholinergic that is suitable for PONV? Scopolamine
What is the onset of scopolamine when administered as a transdermal patch? 2h
How much scopolamine is absorbed over 72h? 1gm
In what conditions is scopolamine contraindicated? Closed angle glaucoma, GI or urinary obstruction, metabolic dysfx
When should scopolamine be administered in order to limit exposure of the newborn to medication? 1h before c-section
True/False: TDS patches are MRI compatible. False
What is the elimination half-time of scopolamine? 5h
Identify the only neurokinin 1 receptor antagonist that is FDA approved. Aprepitant (Emend)
What is the MOA of Emend? Blocks substance P, which is a regulatory peptide in the GIT and CNS thought to be involved w/vomiting reflex
What is the T1/2 of Emend? Up to 12h
How much and when should high-risk patients take aprepitant (Emend) in treating N/V? 40mg PO within 3hrs prior to induction
What limits widespread use of aprepitant (Emend)? Cost
When benefit does propofol serve after extubation? May be useful adjunct for PONV
How does ephedrine serve to alleviate PONV? Alleviates PONV when it is 2/t postural changes or hypotention.
What are the doses of ephedrine that are usually given? 5-10mg q5-10min
How long ago was acupuncture and acupressure documented in Chinese medicine? 2500yrs
What is the MOA of acupuncture/acpressure in treating N/V? Stimulation of the *P6* accupoint decreases PONV by blocking abnormal energy flow to relieve s/s of illness.
Where is the P6 accupoint located? Between the palmaris longus and flexicarpi radialus of the wrist
What are approaches to anesthesia that can be used to decrease the incidence of anesthesia? Regional, TIVA, higher FiO2, hydration, no N20, minimize opioids, minimize neostigmine
What are possible causes for PONV? Pain, hypotension, hypoxemia, hypoglycemia, increased ICP, GIB
What are the most common reasons for adults and children to have protracted stays in the PACU or unexpected hospitalization? N/V
Created by: philip.truong