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NU 600
Exam 6 - Autocoids and Antiemetics
| Question | Answer |
|---|---|
| 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
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