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690 Cards in this Set
- Front
- Back
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Opiate
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-Drugs derived from opium
-Natural compounds -Morphine -Codeine -Thebaine |
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Opioid
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-All drugs with morphine-like properties
-Natural or synthetic compounds -Produce analgesia without loss of touch, proprioception, or consciousness |
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Endogenous opioid peptides
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-Naturally occurring ligands for opioid receptors
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Narcotics
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-Associated with opoioids
-Substances with abusive or addictive potential |
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Endogenous Opioid Peptides
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-Act on all 3 opioid receptors
-Work all of the time, even during periods of stress -Peptides synthesized from precursor molecules -Each precursor has characteristic anatomic distribution -Naturally produced in the CNS --released from pituitary and adrenal glands -ACTH and B-endorphin have common precursor --allows for stress-induced analgesia -Enkephalins, Dynorphins, Endorphins -Nociceptin, Endomorphin 1 and 2 (recently discovered) |
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Endogenous Pain Suppressive System
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-Each peptide group has variable affinities for opioid receptors
-No opioid peptide binds exclusively to one opioid receptor -Endorphins inhibit release of NT from nerve terminals carrying nociceptive impulses -Analgesia can be produced from electrical/mechanical stimulation of peripheral areas --acupuncture |
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Phenanthrenes
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-3 ring structure with amine group
--amine group allows metabolism in the liver -Morphine -Codeine -Thebaine Alkaloids of opium |
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Benzylisoquinolones
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-Lack opioid activity
-Papaverine -Noscapine |
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Semi-synthetic opioids
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-Produced by making simple modifications to morphine molecule
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Synthetic Opioids
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-Morphinan series (levorphanol, butorphanol)
-Diphenylpropylamine series (methadone) -Benzomorphan series (pentazocine) -Phenylpiperidine series (meperidine, fentanyl) -Contains phenanthrene nucleus of morphine -Manufactured by synthesis, not chemical modification of morphine |
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Opioid Receptors
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-Mu, Delta, Kappa
-Nociceptin/Orphanin FQ receptor -All are G-protein coupled receptors |
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Mu opioid receptor
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-Most important opioid receptor for analgesia
-Responsible for supraspinal and spinal analgesia -Mu1: analgesia -Mu2: bradycardia, hypoventilation, dependence -Other sub-types have unclear mechanisms -Endomorphins in brain have high affinity and selectivity for Mu receptors |
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Kappa Opioid receptor
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-Provides mild analgesia
--not great for a painful surgery -4 sub-types (K1a, K1b, K2, K3) -Mediates analgesia in the CNS and PNS -Opioid agonist-antagonists act on Kappa receptors -Hard to distinguish Kappa analgesia from Mu analgesia -High intensity pain may be resistant to analgesic effects of Kappa receptors -Less respiratory depression vs. Mu receptors --less chance of respiratory arrest -Dynorphin acts mostly on Kappa receptors -Agonists give inhibition of neurotransmitter release via Ca channels --agonist binds to kappa receptor and decreases pain by inhibiting Ca channels that inhibits NT release |
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Delta Opioid Receptor
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-Poor alangesic activity
-May modify Mu receptor-mediated anti-nociception -Enkephalins act on delta receptors and modulate Mu receptor activity -Involved in vomiting caused by analgesics? |
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N/OFq receptor
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-Nociception receptor
-Inhibits pain facilitating and analgesia facilitating neurons in RVM --Pain OR Analgesia -Effects on pain response depend on pre-existing state of pain in the animal -Can have pro-nociceptive effects -Little to no affinity for conventional opioid ligands -Precursor molecule is located in the dorsal and ventral horns of spinal cord, hippocampus, cortex, and numerous sensory sites -Produces effects related to drug reward, reinforcement, stress responsiveness, feeding behavior, and memory process - |
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Mu1 Receptor Stats
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-Effects: Supraspinal and spinal analgesia, euphoria, miosis, bradycardia, hypothermia, urinary retention
-Low abuse potential -Agonists: Endorphins, Morphine, Synthetic opioids -Antagonists: Naloxone, Naltrexone, Nalmefene |
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Mu2 Receptor Stats
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-Effects: Spinal Analgesia, Depression of ventilation, marked constipation
-Physical dependence -Agonists: endorphins, morphine, synthetic opioids -Antagonists: Naloxone, Naltrexone, Nalmefene |
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Kappa Receptor Stats
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-Effect: Supraspinal and spinal analgesia, dysphoria, sedation, miosis, diuresis
-Low abuse potential -Agonists: Dynorphins -Antagonists: Naloxone, Naltrexone, Nalmefene |
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Delta Receptor Stats
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-Effect: Supraspinal and spinal analgesia, depression of ventillation, minimal constipation, urinary retention
-Physical dependence -Agonists: Enkephalins -Antagonists: Naloxone, Naltrexone, Nalmefene |
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Mechanisms of Action for Opioid Receptors
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-Opioid binds at stereospecific GPCRs
--can be Gi and/or Go -Signal transduction mechanisms produce effect --inhibits inward shift of K (hyperpolarizes cell) --Inhibits adenylyl cyclase, decreases cAMP and inhibits Ca release --Inhibits voltage-gated Ca channels, prevents Ca influx into cell -Presynaptic and postsynaptic inhibition of NTs --ACh, dopamine, NorEpi, Substance P, tachykinins all inhibited -Main effect is to decrease neurotransmission via activation of opioid receptors |
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Pain pathways and Opioids
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-Opioid receptors in periphery in supraspinal and spinal locations
-INhibit peripheral and central afferent nociceptive transmission --Decrease pain transduction --inhibits pathways up to brain AND pathways out of the brain -Inhibits directly ascending transmission from spinal cord dorsal horn -Activates pain control circuits that come down from brain via rostral ventral medulla to spinal cord dorsal horn -Produce via direct action on spinal cord -Produce neurally mediated action in region separate form site of administration -Neuropathic pain responds poorly to opioids --need higher doses -Dosage, species, stimulus intensity, efficacy of opioid, character, and duration change analgesic effects |
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Opioid Agonist Receptor-Ligand Interaction
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-Stimulates Mu, Kappa, and Delta receptors
-Full Mu agonists act on ALL receptors --higher dose will increase effect -Binds to both Mu and Kappa receptors -Increased analgesic effect with increased dose -Morphine, Oxymorphine, fentanyl |
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Partial Opioid Agonists Receptor-Ligand Interaction
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-Binds to Mu receptors, not Kappa receptor
--only binds to Mu part of the receptor, not Kappa -Produces only limited clinical effect -Ex: buprenorphine at Mu receptor -Prevents full agonist from fitting into the binding site, acts as partial agonist and partial antagonist |
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Opioid Agonist-Antagonists
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-Competitive Mu receptor antagonists
-Analgesic effects from binding to Kappa receptor (agonist activity) -Acts kind of like a partial agonist but still activates Kappa receptor -Ex: butorphanol, buprenorphine, nalbuphine |
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Opioid Antagonists
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-High affinity for opioid receptors
-Displace opioid agonists from Mu and Kappa receptors -Just take up space and prevent agonist form binding -Effect is based on concentration -Ex: Naloxone |
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Neurophysiological Effects of Opioids
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-Analgesic Action:
--analgesia, drowsiness, mental cloudiness, euphoria --Pain-free individual may feel unpleasant -Anesthetic action: --Unconsciousness is unpredictable and inconsistent, may need propofol/fentanyl in combo -Different species interact differently --horses, cats, ruminants get excited by Mu full agonists --dogs and primates get sedate with Mu full agonists |
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Specific Neurophysiological Effects of Opioids
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1. Cerebral Metabolic Rate decreases
--neuroexcitation may cause regional increase 2. Cerebral Blood flow: depends on drugs being used, usually no influence or only small increase 3. Intracranial Pressure: generally minimal effect, depends on surgical procedure 4. Pupil Size: usually constriction by excitatory action (miosis) --In cats cause mydriasis 5. Neuroexcitatory phenomena: can cause delirium or grand mal seizures Safe for Neurologic Cases |
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Respiratory Effects of Opioids
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1. Therapeutic Effects:
-Prevents hyperventilation from pain/anxiety --decreases RR and turbulence -Dyspnea -Increases tolerance to endotracheal intubation -Anti-tussive 2. Non-therapeutic Effects (side effects) -Respiratory depression --can be issue in brachycephalic dogs with stenotic ariways -Decreases hypoxic ventilatory drive -Decreases CO2 ventilatory drive, brain does not respond to increase [CO2] -Anti-tussive |
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Respiratory Depression with Opioids
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-Dose-dependent depression
--more drug has a bigger effect -Mediated by Mu2 receptors -Co-administration of other sedatives (benzodiazepines) -Humans are more sensitive -Decreased clearance -reuptake from muscle, fat, lung, etc. |
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Cardiovascular Effects of Opioids
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-Minimal cardiovascular effects, no major effect
-Can reduce sympathetic tone -Can cause hypotension of patient is dependent on high sympathetic tone --increases vagal tone -Bradycardia due to medullary vagal stimulation --Issue for neonates -Histamine release leads to hypotension --morphine and meperidine |
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Neonates and Opioids
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-Cannot increase Stroke Volume
-Increasing Heart Rate is the only way for neonates to maintain cardiac output -With opioids, neonates cannot compensate for decreased HR |
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Endocrine Effects of Opioids
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-Inappropriate ADH response
-Inhibits pituitary-adrenal axis -Endorphin and ACTH are co-secreted during stress -Can give pre-emptively for decreasing stress response |
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Renal/Urologic Effects of Opioids
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-Mu receptor activates anti-diuresis
-Kappa receptor activates diuresis --inhibits ADH -Urinary Retention |
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Opioids and GI motility
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-Decrease GI motility, cause constipation and delayed gastric emptying
-Dogs will defecate initially -Causes ileus and constipation -Horses can colic -Ruminants can end up with rumen tympani with full Mu agonist -Mediated by Mu and Delta receptors -Affects myenteric plexus of the GI tract |
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Opioids and Nausea and Vomiting
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-Stimulate chemoreceptor trigger zone in area postrema of medulla
-Mediated by delta receptors |
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Pharmacokinetics of Opioids
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-IV injection leads to plasma concentrations peaking
-Lung takes up a lot of opioids before it redistributes --uptake by lung can be significant, leads to rapid release -Rapid redistribution phase -If administered to central compartment is eliminated or distributed to peripheral compartments -Highly lipid soluble, high volume of distribution --easily diffuses into membranes --easily goes in and out of membranes, redistributed to fat and muscle -Redistirbution has a high impact on plasma concentration |
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Methods of Administration for Opioids
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-IV
-IM -Subcutaneous -Transdermal (fentanyl patch) -Intra-articular -Inhaled -Oral -Buccal mucosa in cats -Rectal -Neuroaxial -Ocular |
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Neuroaxial Administration
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-Into epidural or subarachnoid space
-Uptake into epidural fat -Systemic distribution or diffusion across the dura into CSF --lipophiic drug goes quickly into systemic vasculature -Diffusion of drug across dura to CSF and opioid receptors -Receptors in substantia gelatinosa of spinal cord -Penetration of dura depends on lipid solubility and MW -Poorly lipid soluble opioids (morphine) have longer duration than lipophilic opioids (Fentanyl) --increased cephalid movement in CSF |
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Neuroaxial Side Effects
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Neuroaxial Side Effects of Opioids
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-Sedation
-CNS excitation due to cephalad migration of opioids to non-opioid receptors in brainstem or basal ganglia --May block GABA mediated inhibition -Viral reactivation: reactivation of herpes 2-5 days after epidural -Neonatal Morbidity due to systemic absorption of opioids --depression of ventilation in the newborn -Vertigo, nystagmus, water retention, paresis, paralysis |
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Opioid Agonists
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-Pure/Full agonists elicit maximal activation of opioid receptors
--Mu or Kappa agonists -Full Mu agonists are superior analgesics -Opioid agonists are drug of choice for moderate to intense pain |
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Morphine
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-Full agonist at all opioid receptors (Mu, Kappa, and Delta)
-Sedation and analgesia --IV or IM onset is 15-30 minutes --Peak effect in 45-90 minutes --Lasts 3-4 hours, epidural can last 12-24 hours -Relatively hydrophilic --delays onset of action -Histamine release can occur after IV administration --never give bolus of morphine IV! Will cause histamine release! -1st pass effect occurs after oral administration --bioavailability is about 25% |
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Morphine Metabolism and Excretion
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-Conjugates with glucuronic acid
--morphine 6-glucoronide is active metabolite --Morphine 3-glucoronide -Major metabolites are eliminated via glomerular filtration -Renal failure may result in accumulation -Liver failure has minimal impact on clearance |
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Oxymorphine
Hydromorphone |
-Synthetic full opioid agonist
-Acts on Mu receptors, full Mu agonist -Sedation and analgesia is comparable to morphine for onset of action and duration -10x potency of morphine, takes smaller dose to get the same effect -Relatively more lipid soluble than morphine -Causes less vomiting than morphine -Does not produce histamine response --can use with mast cell tumors -Mainly used in small animal species at the moment |
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Meperidine
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-Full opioid agonist at Mu and Kappa receptors
--also has other binding at A2 receptors, blocks Na channels -Sedation lasts 1-4 hours --shorter acting than morphine -Same dose as morphine causes similar analgesia and euphoria -much less potent than morphine -Absorbed better than morphine from GI tract --50% bioavailability -Epidural effects may be advantageous due to local anesthetic-like effects |
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Meperidine Metabolism and Excretion
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-90% undergoes demethylation in liver to normeperidine
-Hydrolysis to meperidinic acid -Excretion via renal and urinary system --pH dependent, acidification speeds up elimination --Decreased renal function can lead to accumulation |
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Meperidine Side effects
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-Lots of side-effects
-Negative inotropic effects -Atropine-like effects (tachycardia, mydriasis) -Seizures and Delirium due to accumulation of normeperidine -Histamine release occurs with IV administration -Combination with MAO inhibitor leads to serotonin syndrome |
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Fentanyl
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-Synthetic Full Mu receptor opioid agonist
-Highly lipid soluble, crosses BB faster than morphine --gets into the brain quickly -Redistributes quickly --longer infusion results in longer lasting after 3 hours --will have to re-bolus unless given as CRI --Fentanyl is still in body, not metabolized -75-125x more potent than morphine |
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Fentanyl Indications
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-Most often given as CRI or transdermal patch
-For use in dogs and cats -Also in horses, cows, sheep, goats, pigs -Previously in combination with Droperidol |
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Fentanyl Metabolism and Elimination
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-Highly lipid soluble
-Rapid redistribution to fat and skeletal muscle -1st pass pulmonary uptake --75% of initial drug -Saturation of tissues leads to liver metabolism --Substrate for CYP450 enzymes -Elimination half-life of 2-3 hours after brief infusion or single bolus -Context-sensitive half-life increases with duration -Renal excretion |
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Remifentanil
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-Opioid agonist
-Structurally similar to fentanyl -More rapid onset of action and termination -Metabolized rapidly by plasma esterases to inactive metabolites -has ester bond instead of amide bond -Need to give as CRI -Hepatic or renal dysfunction has little impact on metabolism -Expensive!! |
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Methadone
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-Synthetic Mu agonist, full agonist
-Affinity for NMDA receptors --NMDA agonist, helps with chronic pain -Excellent oral absorption -High potency -No active metabolites -Good for management of chronic pain or withdrawal -Becoming more popular in vet med |
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Tramadol
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-Synthetic analog of Codeine
-Centrally acting analgesic -moderate activity at Mu receptor, weak affinity for Kappa and Delta receptors --weak agonist -5-10x less potent than morphine -Metabolite IS active, cats make metabolite --dogs do not make metabolite -Spinal inhibition of pain by decreasing reuptake of NorEpi and Serotonin -Naloxone only antagonizes 30% of effects -Metabolized by hepatic CYP450 enzyme systems -IV, IM, or PO administration |
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Opiate Agonist-Antagonist
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-Varying opioid receptor profiles
-All occupy Mu opioid receptors -Competitive Mu antagonists -Analgesic actions at Kappa receptor agonists -Less respiratory depression -Lower addictive potential, less euphoria -Ceiling analgesic effect |
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Butorphanol
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-Synthetic agonist-antagonist Opioid
-Originally an anti-tussive agent, suppresses coughing for 8 hours -Analgesic effects through Kappa receptors, provides mild analgesia -Antagonist at Mu receptors -Minimal sedation alone, is best in combination -Analgesia for mild to moderate visceral pain -Spares MAC in dogs and cats -In horses is used in combination with A2 agonists -Provides good analgesia for cattle, sheep, goats -Lasts 1-3 hours -Reversal of pure Mu agonist -Metabolizes to inactive metabolite -Excreted in bile and urine |
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Partial Agonist
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-Binds to Mu receptors with high affinity
-Produces limited clinical effects |
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Buprenorphine
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-Semi-synthetic Opioid Partial agonist
-highly lipophilic opioid -Cannot elicit maximal response at Mu receptor -Causes sedation and analgesia --onset of action is delayed 30 min-1 hour after IM injection -Lasts 6-12 hours -Good for mild to moderate pain -Difficult to antagonize the effects of the drug -Antagonist action at Mu and Kappa receptors -Excreted in bile and urine -Oral transmucosal absorption in cats -Transdermal patch is available |
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Opioid Antagonists
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-high affinity for opioid receptors
-Displace opipid agonists from Mu and Kappa receptors -Bind to receptor but do not activate -Causes reversal of all effects, including analgesia -Development of intense pain and activation of SNS |
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Naloxone
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-Opioid Antagonist
-Reverses all opioid agonist effects at all receptors -Can be used to treat: --ventilatory depression post-operatively --ventilatory depression in neonate --overdose --detect physical dependence -Lasts 1 hour, then patient will fall asleep again -Excitement or anxiety may develop -Causes hypertension, tachycardia, pulmonary edema |
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Naltrexone
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-Opioid antagonist
-Clinical effects last twice as long as Naloxone -Advantageous in prevention of renarcotization -Similar side effects as Naloxone --hypertension, tachycardia, pulmonary edema |
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Cats and Opioids
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-Opioids do not always cause Morphine Mania
-can cause opioid mediated hyperthermia -Mydriasis due to overriding sympathetic nervous system response --may make excitation worse -Constipation of not adequately hydrated |
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Horses and Opioids
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-Cause nervousness and excitement
-Locomotor stimulants -Ileus and colic -Used in combination with sedatives/tranquilizers -Butorphanol is most common opioid used -Morphine should not be given until fully sedate -Epidural opioids provide long-lasting analgesia --no CNS excitement |
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Pharmacological effects of Benzodiazepines
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-Anxiolysis
-Sedation -Anticonvulsive effects -Spinal-cord mediated muscle relaxants -Anterograde amnesia |
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Benzodiazepine Uses in Vet med
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-Prevent muscle rigidity associated with ketamine
-Synergistc effect with other drugs --induction of anesthesia with propofol or etomidate --With opioids in neuro-leptic induction --Has inhalant sparing properties -First line of drug treatment in seizure cases |
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Ketamine
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-Causes muscle ridigidy
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Benzodiazepine Mechanism of Action
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-Works on GABA-A receptors only
-Facilitates binding of GABA to GABAa receptor --enhances affinity of receptor for GABA with a ceiling effect --Makes Benzodiazepine safe, and barbituates not safe -At molecular level increases Cl consuctance and hyperpolarizes cell |
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GABAa Recepto
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-Large macromolecule
-Pentameric protein complex --Different expression of subunits in different species in different levels of the body give different affinity and responses -Separate binding sites for endogenous GABA, Benzodiazepines, barnituates, propofol, alcohol, inhaled anesthetics --GABA binds to A and B subunits --Benzodiazepines binds to A and Gamma units -Binding changes conformation and gives GABA a different affinity -Does not mimic GABA, just changes affinity -Gives safety profile |
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GABAa Subunit
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-Several subunits isolated
-A1: responsible for sedataive effects --60% of receptors --in Cerebral cortex, cerebellum, and thalamus -A2/3: responsible for anxiolytic effects --less abundant --Hippocampus and Amygdala -Only known in humans -Accounts for different effects in different species |
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Pharmacodynamic Effects of Benzodiazepines
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-Causes delirium at recovery
-Can have excitatory phase in dogs and cats if used alone --excitatory phase followed by sedation phase when given IV -Different receptor subunits and receptor distribution variation between species gives different effects |
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Benzodiazepines in Vet Med
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-Diazepam: fast onset, long lasting
-Midazolam: fast onset, short duration -Lorazepam: Immediate onset and duration --mostly human drug -Zolazepam: long-lasting --used in conjunction with telazol --ONLY used in vet med |
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Benzodiazepine Receptor Occupancy
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-Binding to receptor is saturable
--has ceiling effect -Lorazepam has greatest receptor affinity, then midazolam, least diazepam -Chronic administration causes decreased receptor binding and function --only important with chronic use or abuse -20% occupancy gives anxiolytic effect -30-50% occupancy gives sedation -more than 60% occupancy gives unconsciousness |
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Benzodiazepine Pharmacokinetics
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-Highly lipophilic
--allows for rapid onset of action and fast redistribution --Also give shorter duration -Midazolam is most lipophilic, then diazepam, then lorazepam -Has large volume of distribution --gives rapid CNS effects -High protein binding to albumin -Clearance rates differ between different benzodiazepines |
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Benzodiazepine Metabolism
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-Hepatic microsomal oxidation
-Glucoronidation --watch for cats and liver function -Awakening comes from redistribution of drug from brain to other less perfused tissues --NOT metabolized, just left the brain |
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CNS effects of Benzo
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-Decreases CMRO2 and Cerebral Blood Flow
--neuroprotective, protects against cerebral hypoxia -Increases seizure threshold of local anesthetics --can tolerate more of lidocaine before seizure -Midazolam does not produce isoelectric EEG --increases ICP when given rapidly IV --give slowly and with other drugs --DO not used Midazolam to treat seizures |
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Respiratory Depression with Benzodiazepines
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-Minimal in animals
-Midazolam causes more respiratory effects than diazepam or lorazepam -Respiratory depression with fast IV dose of midazolam -Additive effects with opioids give respiratory effects -Decreased tidal volume -Flattened CO2 rose response curves |
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Cardiovascular effects Benzo
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-Cardiovscularly stable
-Will have some reduction in BP --Seen more with midazolam than diazepam --Can have synergistic effects with other anesthetic drugs |
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Diazepam
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-Insoluble in water, viscous solution
-pH 6.6-6.9 -5mg/ml --contains 0.4ml propylene glycol (Toxic!), 0.1ml alcohol, and sodium benzoate -Dilution with sterile water or saline -Injection may be painful -Not recommended to give IM --absorption is not predictable and it stings --have other drugs that work better |
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Diazepam Metabolism
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-90% bound to protein
-Metabolized hepatic microsomal oxidation -Has active metabolites! unpreditable --Desmethyl-diazepam --Oxazepam -Decreases hepatic biotransformation -Low extraction ratio drug, takes the liver a long time to get rid of |
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Diazepam in Propylene Glycol Formulation
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-Has been reported to cause hypotension and ventricular arrhythmia
-40% propylene glycol is toxic -Recommended to give slowly IV |
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Diazepam Clinical Pharmacology
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-Less reliable sedation in veterinary medicine
-Can be used in ruminants and swine pretty reliably -Causes arousal in dogs and excitement or aggression in cats -Causes Ataxia and recumbency in horses in very small doses --horse can fall down with a small dose |
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Midazolam
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-More potent than diazepam (2-3x)
--Has 2-3 times affinity for GABA receptor -Water-soluble -Can be used IV or IM |
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Midazolam IM and Benzene Ring
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-Changes to chemical structure at different pH
-IN bottle, pH 3.5 --Benzene ring is open, and very water-soluble --great IM absorption without irritating -At pH greater than 4, benzene ring closes --more lipid soluble than diazepam --gives fast onset and easily crosses BBB |
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Midazolam Metabolism
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-Short duration of action
-Rapidly redistributed from the brain to inactive tissues -Accumulates, but not as much as diazepam -Hydroxylation by hepatic and small intestine -Rapid renal clearance -Metabolite 1-hydroxymidazolam has 20-30% potency |
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Midazolam in Exotic Species
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-Very effective due to IM use and fast onset
-ferrets, rabbits, birds, swine -Can give intranasally in swine -Costs more than diazepam, but almost same price |
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Flumazenil
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-1,4-imidazobenzodiazepine derivative
-Competitive antagonist against GABAa receptor -Reverses benzodiazepines activity -has high affinity for receptors -Cannot overdose, just give to effect -Minimal agonist activity at high doses -Similar structure to midazolam -Weak water solubility, moderate lipid solubility -Rapidly cleared from plasma --short half-life gives potential for re-sedation -Lower protein binding, 36-46% -Metabolized by the liver --5 active metabolites |
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Alpha2 Agonists History
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-Good reputation in large animals
-Have to be more careful in ruminants and cows -Bad reputation in small animals, esp. cats -Used a lot in wildlife capture -Discovered during development of human anti-hypertensive agents --used to lower blood pressure -Xyalzine was first in 1962 -Detomidine in 1908s -Romifidine and medetomidine in 1990s -Dexmedetomidine in 2000s |
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A2 Agonist Imidazoline
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-Clonidine
-Romifidine, Detomidine -Medetomidine -Dexmedetomidine -Mivazerol -Azepexole |
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A2 Agonist Thiazine
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-Xylazine
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Alpha2 Agonists
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-Cause hypertension first, then hypotension due to central mediation
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Alpha2 Agonist Reversal
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-Not FDA approved for humans!
-A2 agonists are VERY potent, can cause massive hypotension -A2 agonists in everyday practice are not super potent --for wildlife are VERY potent, be careful! |
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A1/A2 ratio
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-A1 and A2 receptors
-For every A1 that is activated, there are a given number for A2 that are also activated -A2 agonists preferentially affect A2 receptors but also have A1 effects -Reversibility of drug with higher A2 affinity is higher, easier to reverse -Ratio is only an advantage as far as reversibility is concerned |
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A2 Receptor Subtypes
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-3 subtypes
-Based on susceptibility to activation/inactivation by agonists and antagonists -Confirmed by molecular Biology |
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A2a Receptor
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-Sedation
-Hypnosis -Analgesia -Sympatholysis |
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A2b Receptor
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-Vasoconstriction
-Anti-shivering action -Analgesia |
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A2c receptor
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-learning
-Startle Response |
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A2 receptor Structure
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-Metabotropic receptor
-G-protein coupled receptors -Different results in activation re due to coupling to different G-proteins -Agonist binding site involves 3 contact points --amino acid residues on at least 2 separate transmembrane domains |
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A2 receptor distribution
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-ALL OVER the body
-Each subtype is distributed ubiquitously throughout the body -Want analgesia, but have to deal with all other types of activation and body response -Very important side effects due to distribution of receptors |
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Pre-synaptic A2 receptors
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-In sympathetic nerve endings and noradrenergic neurons of CNS
-Also act in peripheral nerve endings -Inhibit the release nor NorEpi and Epi -Work on negative feedback loops |
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Post-synaptic A2 receptors
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-Located in the CNS and many tissues
-Have been found in platelets, lung, adipose tissue, pancreas, salivary gland, kidney, spleen, vas deferens, ileum, and eye |
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Junctional vs. Extrajunctional A2 receptors
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1. Extrajunctional: Vasculature
--controlled by A2 receptors -Causes dramatic vasoconstriction --heart slows down, is pumping against a larger pressure --If bradycardia is concern, take patient off of A2 agonist 2. Junctional: in synapse |
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Signal Transduction of A2 receptors
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-A2 agonist binds to receptor and causes activation of Ai subunit
--inhibits adenylyl cyclase and decreases accumulation of cAMP dependent protein kinase --Results in decrease in phosphorylation of target regulatory proteins -May not be responsible for clinical effect that is observed -Results in alteration of function of ligand gated ion channels through direct coupling |
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CNS effects of A2 agonists
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-A2a receptors located pre-synaptically on neurons in Locus Coeruleus
-G-protein mediated hyperpolarization -Decreases sympathetic outflow from the brain --decreases HR, decreases BP --NOT the same as post-synaptic effect on blood vessels (will see increased BP and reflex decrease HR) -Causes sedation/hypnosis, analgesia, decreased sympathetic activity |
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Xylazine Dosage
|
-Should not be used in dogs and cats anymore
--have better drugs like medetomidine and dexmedetomidine -1.1 mg/kg -Peak effect within 15 minutes -Lasts 45-60 minutes |
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Medetomidine Dosage IM
|
-30 ug/kg
-Given IM -Onset within 5 minutes -Lasts 1-2 hours |
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Medetomidine Dosage IV
|
-20ug/kg IV
-Onset within 5 minutes -Lasts 90 minutes -Smaller dose has same onset and shorter duration -After 40 ug/kg will not have a change in degree of sedation --will just have longer effects --may have to reverse, ideally do not overdose |
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Horses and Xylazine A2 agonists
|
-1.1mg/kg IV
-Peak within 5 minutes -Heavy sedation for 20-30 minutes -Some sedation for up to 60 minutes -Good for short surgeries, field castrations |
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|
Horses and Romifidine A2 agonist
|
-80-120 ug/kg
-Peak within 10 minutes -Heavy sedation for 1 hour |
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|
Horses and detomidine A2 agonist
|
-20ug/kg
-Peak within 15 minutes -Lasts about 1 hour |
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|
Horses and Medetomidine A2 agonist
|
-Expensive for horses!
-10ug/kg -Peak within 5 minutes -Heavy sedation for 20-30 minutes |
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|
A2 agonist equipotent doses in Horses
|
1.0 mg/kg Xylazine
100 Ug/kg Romifidine 20 ug/kg Detomidine 10 ug/kg Medetomidine 5 ug/kg dexmetdetomidine Duration of sedation for equipotent doses: Xylazine is the shortest, Medetomidine and dexmedetomidine and equal, then detomidine, and romifidine lasts longest |
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A2 agonist Xylazine in Calves
|
-0.3 mg.kg IV
-Onset within 1 minute -Lasts about 420 minutes (7 hours) |
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A2 agonists in Cows
|
-0.01-0.05 mg/kg
-Lower dose compared to dog or horse -Onset within 1 minute -lasts about 1 hour |
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|
Analgesic Effects of A2 agonists
|
-Supraspinal level: activation of descending antinociceptive pathways
--suppresses pain -Spinal level: --Presynaptic and postsynaptic inhibition of nociceptive transmission --dorsal horn of spinal cord --Good for tissues with chronic pain |
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A2 agonist cardiovascular effects
|
-Vasoconstriction
-Decrease in sympathetic tone -As systemic vascular resistance increases, CO decreases --SVR decreases, CO mirrors and increases |
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|
A2 agonist and Vasoconstriction
|
-A2 receptors in the vascular smooth muscle
-Hypertension and reflex bradycardia cause decrease in cardiac output -Initial phase -No Atropine |
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A2 agonist and Decreased Sympathetic Tone
|
-Causes hypotension, direct bradycardia, and decreased CO
-Secondary phase |
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A2 agonist and Increased Vagal Tone
|
-Causes direct bradycardia
-AV blocks |
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Medetomidine in Dogs Cardiovascular effects
|
-Increase in systemic and pulmonary artery pressure
-Decrease in HR by 20-63% -Decrease in CO by 50% --big deal -Increase in systemic and pulmonary vascular resistance -No direct myocardial depressant effects -Decreases in coronary blood flow due to decrease in CO -Can cause arrhythmia (maybe, evidence is shaky) |
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Anticholinergics in Hypertensive Patient
|
-Do not give!
-Transient decrease in bradycardia -Arrhythmia -2nd degree AV block, tachycardia, pulsus alternans, premature ventricular contractions -Decreased contractility and impairs myocardial oxygenation -Patient actually does worse |
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A2 agonist Respiratory effects in Horses
|
1. Normal horses:
-A2 is muscle relaxant, horses have issues breathing -Increased work of breathing -Increased resistance to breathing 2. Horses with COPD: --changes in respiratory function are not more severe 3. Ponies: -Xylazine decreases pulmonary resistance and increases compliance |
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A2 agonist Respiratory effects in Cows
|
-Xylazine and Medetomidine in Calves
-Will decrease PaO2 from 90mmHg to 42mmHg -After reversal will go back up, but not to normal levels |
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A2 agonist Respiratory effects in Sheep
|
-Damage capillary endothelium and pulmonary macrophages
-Degranulation of pulmonary alveolar macrophages -Can result in sever hemorrhage, pulmonary edema, and hypoxemia -Xylazine, medetomidine induced damage to capillary endothelium and PAM -Even if drug is reversed, damage is still there |
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|
Xylazine
|
-A2 agonist
-IM injection -Peak plasma concentration in 15 minutes -LOW dose in bovines --give 1/10 dose given to horses |
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|
Dexmedetomidine
|
-A2 agonist
-A1/A2 ratio of 1:1620 --MUCH more effect on A2 receptors -Distribution half life of 6 minutes -Terminal elimination half-life is 2 hours -Metabolized by the liver --methyl and glucuronide inactive conjugates -Secreted by kidneys -Large volume of distribtion -Longer elimination half life than xylazine -Sedation lasts 45 min-2 hours |
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A2 agonist reversal
|
-A2 antagonists do the job
-Yohimbine -Tolazoline -Atipamezole for dexmedetomidine due to high A1/A2 ratio --if given IV on its own, can cause hypotension and excitement |
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Phenothiazine and Butyrophenone History
|
-Originally developed as schitzophrenia medication
--Did not really treat patient, just made them incapable --Decreases arousal and motility -Anxiolytic? Or just not showing anxiety? |
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Antipsychotic Agents
|
-Phenothiazines
-Butyrophenones -Thioxanthenes -Benzepines -Dyphenylbutylpiperidines -Indolones |
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Phenothiazines and Butyrophenones
|
-Phenothiazines: Acepromazine
-Butyrophenones: Azaperone -Tranquilizers |
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|
Classification of Antipsychotics
|
-Neuroleptics or "Traditional Antipsychotics"
-Prominent D2 antagonism --works on dopamine receptor -Increased release of prolactin -Increased risk of extrapyramidal side effects -Older agents, 1st generation drugs |
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Neuroleptic Syndrome
|
-Suppression of spontaneous movements and complex behaviors
-Spinal reflexes and unconditioned nociceptive-avoidance behaviors remain intact --can pull hand off of hot stove -Used to describe the effects of chlorpromazine and reserpine in lab animals and psychiatric patients |
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Neuroleptic in Humans
|
-Reduced initiative and interest in the environment
-Reduced manifestation of emotions --emotions still present, just less manifestation -Possible drowsiness and diminished response to external stimuli -Remain easily aroused --can answer questions, retain intact cognition -Also exert neurological effects --bradykinesia, mild rigidity, tremor, subjective restlessness |
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Phenothiazine Structure and Activity
|
-Tricyclic Structure
-2 benzene rings linked by S and N atom -Side chains at positions 2 and 10 -Substitutions at position 2 affect antipsychotic effects -Substitutions at position 10 affect antidopaminergic effects, antimuscarinic effects, antihistaminergic effects, antiadrenergic effects, antiserotoninergic effects |
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Butyrophenone Structure
|
-Hetercyclic Structure
-Derivatives of phenylpiperidine opioid meperidine |
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Dopamine Receptors
|
-G-protein coupled receptors
-D1: excitatory -D2: inhibitory --inhibits adenylate cyclase intracellular formation -5 types total --D1-like: D1, D5 --increase cAMP --Increase PIP2 hydrolysis, leading to Ca mobilization and PKC activation --D2-like: D2, D3, D4 --Decrease cAMP --Increase K currents --Decrease voltage-gated Ca currents |
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Dopamine Receptor Function
|
-Agonist: promotes release of dopamine
--fosters symptoms of schizophrenia --Amphetamine and Cocaine block reuptake of dopamine, keeping it in the synapse for longer, and fostering symptoms of schitzophrenia -Antagonist: Blocks symptoms of schitzophrenia --occupies dopamine site on D2 receptor, prevents dopamine from activating the receptor |
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Chlorpromazine
|
-Dopamine antagonist
|
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Distribution and Characteristics of Dopamine Receptors in CNS
|
-D1: Striatum and Neocortex
-D5: Hippocampus and hypothalamus -D2: Striatum, SNpc, Pituitary -D3: Olfactory tubercle, nucleus accumbens, hypothalamus -D4: Frontal Cortex, medulla, midbrain |
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Dopamine Pre-synaptic Receptors
|
-Autoreceptors
-D2 and D2-like receptors -Coupled to Gi -Decrease phosphorylation of Tyrosine Hydroxylase --decreases dopamine synthesis -Modulation of Ca and K currents leads to decreased dopamine synthesis |
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|
Dopamine Post-synaptic Receptors
|
-D1 and D1-like receptors
--coupled to Gs, activate adenylate cyclase and increase cAMP to activate PKA -D2 and D2-like receptors --coupled to Gi, inhibit adenylate cyclase and decrease cAMP -D1/D2 heterooligomer --coupled to Gq, activates Phospholipase C and causes PI hydrolysis --Leads to intracellular Ca release and downstream signaling --DAG activation allows for activation of protein kinases |
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Antidopaminergic effects of Phenothiazines and Butyrophenones
|
-What you rely on for sedation
-Works on Cerebral cortex, basal ganglia, and limbic system -Cerebral cortex: --prefrontal and deep temporal regions --causes EEG abnormalities and seizures -Basal ganglia: --caudate nucleus, putamen, globus pallidus --extrapyramidal effects -Limbic System: --amygdala, hippocampus, olfactory tubercle, septal nuclei --schitzophrenia |
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|
Phenothiazine and Butyrophenone Mechanism of Action
|
-Hypothalamus and Pituitary:
--prolactin secretion --impaired thermoregulation, can cause hypothermia in anesthetized patients -Brainstem: impaired motor reflexes -Medulla: --CTZ, protection against nausea and emesis |
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|
Non-dopaminergic Effects of Phenothiazine and Butyrophenone
|
-ANS
--antimuscarinic M1 receptors -Antiadrenergic A1 and A2 receptors --Hypotension that is hard to treat -Antihistaminergic H1 receptors -Antiserotoninergic receptors |
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|
Absorption of Acepromazine
|
-Relatively slow absorption after IM administration
--15-30 minutes -Poor bioavailability, 20% --can be variable |
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|
Distribution of Acepromazine
|
-Mostly highly lipophilic, highly membrane or protein bound
--lends to wide distribution -Volume of distribution is 4-6 L/kg in horses -Accumulates in the brain, lungs, and other VRG tissues -Can enter fetal circulation and breast milk |
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|
Metabolism of Acepromazine
|
-Very slow!
-Halflife in dogs is 6-8 hours, horses 2-3 hours -Dose dependent, but overall long half-life -Oxidative metabolism via CYP450 in liver --Followed by glucuronidation, sulfation, and other conjugation -Most metabolites are inactive -Excreted by the kidneys |
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|
Acepromazine
|
-approved for use in many animals
--dogs, cats, cattle, horses, swine, sheep -Has milk withdraw of 48 hours -Meat withdraw of 7 days, long time! |
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|
Indications of Acepromazine in Dogs and Cats
|
-Used as preanesthetic agent
-In conjunction with opioid --provides chemical restraint -Use doses that are lower than label dose --0.01 mg/kg -Used extensively as preanesthetic agent |
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|
Indications of Acepromazine in Horses
|
-Supplement to preanesthetic medication
-Anti-anxiety effects? -Antispasmodit effect to treat colic pain? |
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Indications of Acepromazine in Cows
|
-Anti-anxiety effects
-Not commonly used -Can be alternative to A2 agonists |
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Indications fo Acepromazine in Small Ruminants
|
-Not used, need high doses
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|
Acepromazine in CNS
|
-Sedation
-MAC reduction is needed (30-45%) -Hypothermia -Sedation onset is 15 minutes, peak effect in 30 min -Lasts 3-4 hours -Injectable induction agent is needed -reduces MAC by 30-45% -Can cause hypothermia -No evidence to suggest that acepromazine lowers seizure threshold -Prevents onset of halothane-induced Malignant hyperthermia in pigs |
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|
Acepromazine Complications
|
-Inconsistent calming
-Orthostatic Hypotension -Extrapyramidal side effects --anti-dopaminergic |
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|
Effects of Acepromaznie on Cardiovascular System
|
-Decreases Mean Aeterial Pressure by 20-30%
-decreased stroke volume and CO also reported in dogs and horses -Hypotension is worse with isoflurane compared to halothane -At clinical doses HR may not change significantly, ot may increase a little -At very high doses may see bradycardia and SA block -Prevents arrhythmogenic effects of Epi and halothane |
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|
Effects of Acepromazine on Respiratory System
|
-Minimal effects on pulmonary function
--oxygenation and ventilation stay the same -Respiration rate may decrease in conscious animals |
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|
Effects of Acepromazine on Hematologic System
|
-Decreased hematocrit and PCV by 20-50% in dogs and horses
--RBCs go to the spleen, splenic sequestration -Occurs within 30 min and last for at least 2 hours -Magnitude and duration of effect is dose dependent -Platelet aggregation is also inhibited --minimal hemostatic significance |
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Effects of Acepromazine on GI system
|
-Antiemetic effect when administered 15 minutes before morphine, hydromorphone, or oxymorphone
-Decreases Lower esophageal sphincter tone and leads to increased risk of gastric reflux -Decreased GI motility and delayed gastric emptying in horses |
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Effects of Acepromazine on Urinary system
|
-GFR and Renal blood flow are maintained in dogs on Acepromazine and isoflurane
-Decreased urethral pressure by 20% in cats under halothane anesthesia -Penile protrusion/pariapism in stallions --magnitude and duration of protrusion are dose dependent --Mediated via A-adrenergic antagonism |
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|
Effects of Acepromazine on Integumentary System
|
-Antihistaminergic effects
-not suitable for use in allergic skin testing patients |
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|
Acepromazine in Boxers
|
-No scientific evidence of sensitivity
|
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|
Azaperone
|
-Tranquilizer in swine
-Only used in pigs -Used to reduce aggression when groups of animals are mixed -not really a sedative -May be used as a preanesthetic in pigs to produce sedation --15 minute onset --peak effect in less than 30 minutes --lasts 2-3 hours -Has similar cardiovascular effects as acepromazine --Decreases BP and CO --HR has been reported to decrease also -Penile Prolapse reported |
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|
"Anesthesia"
|
-Greek for "Insensibility"
-Loss of sensation to entire body or any part of the body -Regional anesthesia: insensibility of a large but limited body area -General Anesthesia: drug-induced unconsciousness --controlled but reversible depression of the CNS --patient is not arousable by noxious stimulation |
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|
Elements of the Anesthetic State
|
-Unconsciousness
-Amnesia -Analgesia -Immobility (skeletal muscle relaxation) |
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|
Stages of Anesthesia
|
1. Analgesia
2. Excitement --want to pass through rapidly 3. Surgical Anesthesia --desired stage, where you want to be 4. Medullary paralysis --too deep --animal cannot regulate BP or RR --want to get out of this stage as soon as possible |
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|
Theories of Anesthesia
|
-CNS site of action
-Cellular site of action -Molecular site of action |
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|
CNS sites of action in Anesthesia
|
-Many sites involved
-Cerebral cortex -Reticular Activating System -Thalamus, amygdala, vestibular system -Areas are inhibited, depressed --do not send out impulses |
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|
Cellular Sites of Action
|
-Interference with synaptic mechanisms
-Pre-synaptic release by inhibiting synthesis or release of NT -In synapse by altering NT clearance -On post-synaptic membrane by changing membrane potential or NT receptor binding -Inhibit axonal nerve impulse conduction |
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|
Molecular Sites of Action
|
-Ion channels and neuronal cell membrane proteins
-Can activate lipid bilayer as a while -Lipids at protein/lipid interface -Protein site bounded by lipid -Protein site exposed to aqueous environment |
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|
Lipid Theory of Anesthesia
|
-Hydrophobic Site
-Can cause membrane volume expansion -Membrane fluidisation |
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|
Protein Theory of Anesthesia
|
-Interaction of anesthetics with specific NT receptor proteins
-GABA receptor plays a role --Has sites on receptor for almost every inhibitory drug --Barbiturate site --benzodiazepine site --General anesthetics site |
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|
How GABA receptor works
|
-Spans membrane with 5 subunits
--subunits form pore -GABA binds to site, opens channel, chloride molecules go through -Hyperpolarizes the cell membrane |
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|
Properties of the Ideal Injectable Anesthetic
|
-Minimal cardio-respiratory effects
-Rapid onset -Short duration of action -Smooth emergence afterwards -Water soluble -Long shelf-life -Small volume required for induction of anesthesia -Wide safety margin, hard to mess up -No effect on vital organ functions except CNS -No histamine release elicited -No anaphylactic reactions -No local toxicity |
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|
Benefits of Injectable Agents
|
-Good for induction, start of anesthesia
-Rapid loss of consciousness --inhalants take a long time for induction -Quick control of airway --important for hypoxic or regurgitating animals -No environmental pollution from waste gasses -Some may be administered intramuscularly --easy to give to fractious or wild animals |
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|
Negatives of Injectable Agents
|
-Some have low margin of safety
--have moved away from most really bad ones -Induce some degree of hypotension, respiratory, cardiovascular depression -Some can have long-lasting effects compared to inhalant --have to be metabolized to leave the body -Patient physiology will influence pharmacokinetics and pharmacodynamics of agent -Once it’s in, can’t get it out --have to wait for effects to wear off |
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|
Rapidly Acting Injectable Anesthetics
|
-Barbituates (Thiopental
-Phenols (Propofol) -Imidazoles (Etomidate) -Cyclohexanones (Ketamine, Tiletamine) -Steroids (Alfaxalone) |
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|
Slower Acting Injectable Anesthetics
|
-Not used often anymore
-Chloral hydrolase -Chloralose -Urethan -Potent Opioids -Neuroleptanalgesics |
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|
Barbituates as Injectable drugs
|
-Formed from Urea and Malonic acid
-No longer used here in US |
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|
Oxybarbituates
|
-Oxygen at C2
-Delayed onset of action -Long effect -Hypnotic Action -Barbital, pentobarbital, phenobarnital |
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|
Methylated oxybarbituates
|
-Oxygen at C2
-Rapid onset of action -rapid recovery -Some excitatory effects -Methohexital |
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|
Thiobarbituates
|
-Sulfur at C2
-Rapid acting -Smooth fast recovery -Thiopental -Thiamylal |
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|
Methylated thiobarbituates
|
-Sulfur at C2, Methyl at C1
-Rapid onset of action -Very rapid recovery -High incidence of excitatory effects |
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|
Structure Activity Relationship of Barbituates
|
-Lipid solubility increases action
-2-5 carbon side-chains increase lipid solubility -Sulfur on 2 carbon increases lipid solubility, faster action -Changes that increase lipid solubility decreases duration of action --also decrease latency of onset of action -Accelerate degradation -Increases albumin binding -Increases hypnotic potency |
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|
Mechanism of Action of Barbituates
|
1. Depress transmission in CNS at synapse level
-Presynaptic inhibition of NT release --ACh, glutamate -Inhibits post-synaptic impulse transmission -Targets thalamus and ascending Reticular Activating System |
|
|
Main Mechanism of Action of Barbituates
|
-Alloesteric modulation of GABAa receptor
--increase binding of benzodiazepines and GABA receptors -Enhance action of GABAa receptor --inhibtory on CNS -Allow longer duration of Cl to enter cell -Increase average duration of GABA activated Cl-ion channel opening |
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|
CNS actions of Barbituates
|
-Direct activation of GABAa Cl channel
-Interaction with central Ca and Na channels and glutamate and nicotinic ACh receptors -Depresses autonomic ganglia |
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|
PNS actions of barbituates
|
-Blocks ACh effects at nicotinic synapses
-Inhibits transmembrane Ca fluxes |
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|
Pharmacological effects of Barbituates
|
-Depresses activity in CNS
-Gradual depression of CNS activity -Sedation leads to hypnosis leads to anesthesia -Decrease in EEG activity at anesthetic doses leads to global CNS depression |
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|
Analgesic effects of Barbituates
|
-No effects
-No Anti-nociceptive effect -Need to give something else to give analgesia |
|
|
Non-hypnotic effects of Barbituates on CNS
|
-Decreases Cerebral Blood Flow, ICP, and CMRO2
-Decreases convulsive activity |
|
|
Respiratory effects of Barbituates
|
-Respiratory depression
-Central and peripheral chemoreceptor sensitivity to CO2 is decreased -Plasma concentration needed for respiratory arrest is less than what is needed for cardiac arrest -Treatment for barbituate overdose is ventilatory support |
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|
Cardiovascular effects of Barbituates
|
-Decreases BP
-Decreases CO -Decreases contractility by decreasing intracellular Ca release -May cause ventricular bigeminy --every other beat is a premature ventricular complex -Decreases occur in a dose-dependent manner |
|
|
Adverse effects of barbituates
|
-Affects other organs
-Decrease in renal blood flow -Decreases hematocrit due to splenic sequestration of RBCs --normal finding -Decreases WBC -CYP450 enzymes are induced --speeds up clearance of other drugs used -Cannot go out of the vein! Causes severe phlebitis with perivascular injection --make sure catheter is well-placed --due to basic pH |
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|
Correlation between lipid solubiity and onset of anesthesia
|
-more lipid soluble gives faster acting anesthetic
-Barbital is least lipid soluble, loss of consciousness occurs in 22 minutes -Thiopental is most lipid soluble, gives immediate loss of consciousness after injection |
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|
Pharmacokinetics of Barbituates
|
-As concentration in blood decreases, concentration in other tissues increases
-Brain and viscera is first in distribution -Lean tissues are moderate -Fat has long increase in concentration --poorly perfused |
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|
Contact sensitive half-life of thiopental
|
-As duration of use increases, time it takes for drug levels in the body increase
-Need to pay attention to how much dose over how much time -All about how drug redistributes in the body |
|
|
Pharmacokinetics of Barbituates
|
-Hepatic Metabolism
-Oxidated and converted in glucaronic acid --Conjugated with glucaronic acid -Excreted in bile or in urine --less than 1% of intact drug is excreted in urine -Changed in tissues and excreted |
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|
Greyhounds and Barbituate Pharmacokinetics
|
-May have different CYP450 metabolism
-Have very little fat and extensive muscle --different volume of distirbutiuon -Takes much longer for animal to recover --especially with Thiopental |
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|
Thiopental
|
-Most commonly used barbiturate
-Used for induction and short procedures -Can get tissue necrosis if it goes out of the vein (perivascular injection) -Biotransformaiton in liver, slow metabolism -Waking up from anesthesia is NOT slow --recovery is due to redistribution, not metabolism --context sensitive half-life |
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|
When to NOT use Thiopental
|
-Patients with cardiovascular dysfunction
--Cardiac failure and low contractility --Hypovolemia --Tachyarrhythmias -Patients with metabolic acidosis -Greyhounds -Cachectic patients -Total Invravenous Anesthesia --drug can build up over time with continued use |
|
|
Phenols
|
-Propofol
-Sedative-hypnotic drug -Unrelated to barbituates -Alkylated phenol, 1% in oil-in-water emulsion -Has short half-life, discard within 6 hours --due to soybean, glycerol, and egg phosphatide solution --No preservatives, lots of possibility for microbial growth in medium |
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|
Propophol Mechanism of Action
|
-Allosteric binding to GABAa receptor
-Synergism with benzodiazepines |
|
|
Propophol Pharmacologic Effects
|
-Gradual depression of CNS activity
--sedation leads to hypnosis leads to anesthesia -General anesthesia within 1 minute --rapid! -Rapid recovery of action without residual CNS depression --Ideal situation! -Can maintain with repeated IV boluses or CRI, do not need inhalant -Can use IV for long-term sedation, low risk of drug accumulation --rapidly metabolized -Non-hypnotic CNS effects --decrease CBF, ICP, and Oxidation -Antiemetic effects, can be very helpful |
|
|
Principle Pharmacologic Effects of Propophol
|
-Intravenous long-term sedation
-Low risk for drug accumulation -Non-hypnotic CNS effects -Decreases cerebral blood flow, ICP, and CMRO2 -Antiemetic effects |
|
|
Respiratory Effects of Propophol
|
-Central Respiratory Depression
-Bronchodilation (usually helpful) -Inhibition of laryngeal reflexes --good for intubation |
|
|
Cardiovascular Effects of Propophol
|
-Causes hypotension
-Vasodilation --decreases sympathetic vasomotor tone centrally --Peripherally has negative inotropic effect and direct vasodilation -Can have effect on contractility, negative inotropy -Usually no change in HR |
|
|
Adverse effects of Propophol
|
-Excitatory effects sometimes (transient)
--10% of dogs and cats -Limb paddling, nystagmus, muscle twitching -not that common and not that big of a deal |
|
|
Pharmacokinetics of Propophol
|
-2-3 compartment open model
-Starts in blood, goes to brain, then muscle and other tissues -Rapidly reaches peak CNS concentrations -Rapidly redistributed, halflife is 7 minutes -Elimination is slower, takes a while to metabolize -Highly protein-bound (97-99% bound to albumin and Hb) -Can cross placenta in pregnant animals but will be removed from fetal circulation very quickly -Significant 1st pass uptake into lungs (28-61%) -Extrahepatic metabolism in kidneys and lungs |
|
|
Extrahepatic metabolism of Propophol
|
-Extrahepatic metabolism in kidneys also
-Significant 1st pass into the lungs --28-61% --big dose goes into lungs! -Also metabolized in the liver via CYP450 and glucuronide conjugation |
|
|
Propophol concentration
|
-Does not really concentrate at all
-Metabolism is fast |
|
|
Cats and Propophol Metabolism
|
-No glucuronide system
-Slower elimination -Repeated dosing can cause prolonged recovery -Reduced conjugation capacity can lead to oxidative injury in RBCs --Heinz body formation --mostly occurs with repeated uses |
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|
When to NOT use Propophol
(or use with caution) |
-Cardiovascular dysfunction
--cardiac failure --decreases contractility and vasodilation --Hypovolemia --Hypotension -Patients with Sepsis or systemic infections --great medium for bacteria due to suspension -Cats with Anemia --heinz body formation |
|
|
Etomidate
|
-Imidazole
-Class of sedative-hypnotic drugs chemically unrelated to other anesthetics -VERY Short-acting -very safe, high therapeutic window -Great in high-risk patients --cardiovascular or respiratory unstable patients -Mostly used off-label in small animal anesthesia |
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|
Chemistry of Etomidate
|
-Carboxylated imidazole derivative
-Racemic mixture, R and S isoforms --R is active isoform -Dissolved in 35% propylene glycol --can cause irritation and kidney issues |
|
|
Etomidate Mechanism of Action
|
-Acts through GABAa receptor, allosteric modulation
--has own binding site -Depression of ascending Reticular Activating System -Synergism with Benzodiazepine and GABA binding to GABA receptor |
|
|
Etomidate Phamacologic effects
|
-Ultra-rapid onset of CNS depression
--less than 20 seconds -No analgesic effects -Non hypnotic CNS effects: --decreases EEG activity --Vasoconstricts cerebral vasculature and decreases CBF, direct cerebral vasoconstriction --Decreases ICP and CMRO2 |
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|
Adverse effects of Etomidate
|
-Minimal respiratory and cardiovascular side effects
-Excitation on induction --vomiting --Need to have a very sedate patient before giving -Inhibits adrenal steroid output, suppresses steroid formation -Hemolysis due to high osmolality of solution --pulls blood into RBCs and bursts cells --Can dilute to reduce effects -Can be painful with IV injection if it goes outside of the vein |
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|
Etomidine Pharmacokinetics
|
-2-3 compartment open model
-Rapidly reaches peak CNS concentrations -Immediate and extensive redistirbtion -Lots of uptake into peripheral tissues -Moderately protein-bound (76%) -Will go into placenta but incomplete transfer --safe for pregnant animals --fast decline once in fetal plasma |
|
|
Etomidine Metabolism
|
-Extensive heptic metabolism via CYP450 system
-Extra-hepatic metabolism in plasma esterases -Renal excretion of metabolites |
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Uses for Etomidine in Clinical Practice
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-Great for patients with hemodynamic issues
--cardiac failure --hypovolemic shock --sepsis/endotoxemia -Patients with cerebral disease and increased ICP --seizures |
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Cautions for Etomidine Use
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-Adrenal insufficiency, Addison’s disease
-Patients with Sepsis |
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Cyclohexanones
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-Dissociative anesthetics
-Ketamine, Tiletamine -Produces anesthesia-like state --Dissociative Anesthesia -Intense analgesia, light sleep, amnesia, catalepsy (rigid muscles) --do not want to use by itself -Provides analgesia |
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Chemistry of Ketamine
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-Cyclohezylamine
-Highly lipid soluble, more than thiopental -Racemic Mixture --S isoform is 3-4x more potent than R isoform --S isoform is 2x as long active -Dysphoria is major issue, more with R isoform |
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Molecular Mechanism of Action of Ketamine
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-Blocks NMDA receptors an sub-anesthetic doses
--NMDA receptor antagonist --"Use dependent block" --"Closed" channel block -Decrease in central glutamatergic activity leads to analgesia and anesthesia |
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NMDA receptor Mg block
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-Mg blocks ion channel
-Activation removes Mg and allows ions to move through channel -Use-dependent block, has to be activated first -Ketamine blocks channel |
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Ketamine CNS action
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-Inhibits nicotinic ACh receptors
-Interacts with central opioid receptors --Mu, delta, and Kappa opioid receptors --Monoaminergic receptors --Muscarinic ACh receptors |
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Ketamine Other Mechanisms of Action
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-Blocks NorEpi reuptake
-Blocks voltage-sensitive Ca channels -Blocks peripheral nerve conduction |
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Ketamine Pharmacologic effects
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-Works on thalamic/neocortical area
-Dissociative because it dissociates area of brain from the spinal cord --not depressing --makes impulses disconnected, more “unaware” -Selective suppression of thalamo-neocortical projection system -Provides analgesia at sub-anesthetic doses |
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Dissociative Anesthesia Features
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-Loss of consciousness despite neuronal activity outside neo-cortex
-Catalepsy, catatonia -Maintains protective reflexes --airway reflexes maintained -Skeletal Muscle Movements still possible --need to use with muscle relaxant |
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CNS effects of Ketamine
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-increases EEG activity
--Common in dogs and non-domestic cats -Increases cerebral blood flow, cerebral vasodilation --increases ICP and CMRO2 -May see emergence delirium or dysphoria with recovery --violent recovery |
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Respiratory Effects of Ketamine
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-Mild, transient decrease in RR and Tidal volume
-Apneustic, shallow, irregular breathing pattern --holds breath at peak of inspiration -Bronchodilation, useful in asthmatics |
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Cardiovascular effects of Ketamine
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-Ketamine Stimulates sympathetic nervous system and causes effects on heart
-indirect stimulation -increased HR, CO, and BP --Good for vasodilatory patients -Inhibits neuronal NorEpi reuptake -Pro-arrhythmogenic effects -Direct negative inotropic and vasodilatory action -Do not want to give to an animal in heart failure! Will get negative inotropic effects |
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Ketamine Adverse Effects
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-increases salivation
-Increases muscular rigidity -Decreases nerve conduction to muscles |
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Pharmacokinetics of Ketamine
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-2-compartment open model
-Rapidly reaches peak CNS concentrations -Rapidly redistributed due to lipid solubility -Slower elimination phase, longer metabolism --effects last longer than other drugs |
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Ketamine Metabolism
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-very dependent on hepatic metabolism
-In cats is metabolized by the kidney also --not in dogs --cats do not metabolize to inactive compounds -Metabolized to norketamine --20-30% residual activity -Hydroxylated to hydroxynorketamine (inactive metabolite) -Glucuronide conjugation -Renal elimination of metabolites |
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Norketamine
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-Active metabolite of Ketamine
-Ketamine is transformed into Norketamine -Norketamine levels increase continually as time goes on --get a big build-up |
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Ketamine Administration
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-Not used as a CRI at anesthetic levels, use as CRI in balanced anesthesia
-Can give IM or IV -Common to give to difficult animals -Dogs, pigs, horses are more susceptible to excitatory effects -Co-administed with tranquilizers and/or central muscle relaxants |
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Ketamine and Muscle relaxant
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-Give together
-Co-administed Ketamine with tranquilizers or central muscle relaxants --guaifensesin, benzodiazepines -Use as CRI |
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When to use Ketamine with Caution
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-Animal is in cardiac failure and does not have sympathetic reserve
-Decompensated shock, causes hypotension -Animals with tachyarrhythmias -Pheochromocytoma (adrenal medullary neoplasia) -Hyperthyroidism -CNS excitatory signs |
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Tiletamine
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- Telazol
-Analog of ketamine (similar chemistry and pharmacology) -Dissociative anesthetic -Longer lasting than ketamine in cats and horses -May cause severe catalepsy and convulsions -Violent recoveries in many species if not combined with tranquilizers -Commercially available ONLY in combination with zolazepam (Telazol) |
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Potent Opioids
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-Fentanyl, sufentanil, alfentanil, remifentanil
-Can be used in high dose in really debilitated animals to get a procedure done -Will not give all anesthesia stages --will give very sedate animal -No adverse cardiovascular effects -Short plasma half-life, fast redistribution and metabolism -Slow onset, not an anesthetic -Combine with muscle relaxant, otherwise will get CNS excitement --will be reactive to light and noise still -Usually combined with benzodiazepines |
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Alfaxalone
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-Neurosteroid, progesterone-related steroid
-CNS depressant -Hypnotic effects -Modulates GABAa receptor -Minimal cardiovascular effects -Provides muscle relaxation -Can give IM (water soluble) -Smooth recovery -Recently approved by FDA in US |
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Serotonin
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-5-hydrocytryptamine (5-HT)
-Causes vasoconstrictor activity in serum after clotting -Gut stimulating factor --present in invertebrates and invertebrates --Indole alkylamine -Widespread distribution with multiple functions -Hard to generalize, does so many different things -Role as NT and role in psychopharmacology |
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Indole Alkylamine
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-Serotonin Gut Stimulating Factor
-Enteramine |
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Serotonin Distribution
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-Widely distributed
-In plants, animals, tissues, -Present in venoms, stings -90% is present in enterochromaffin cells in GI tract --Kulchitsky cells -Concentrated in platelets in blood --platelets are active carrier, not synthesized in platelets -Acts as CNS NT -In mast cells of rodents and cattle, not humans -Present in diet but rapidly metabolized --active serotonin is synthesized in the body |
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Kulchitsky Cells
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-IN gut
-Where most serotonin in the body hangs out -Enterochromaffin cells of GI tract |
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Serotonin in Diet
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-Present but rapidly broken down
-Active serotonin is synthesized in the body NOT taken from diet |
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Serotonin synthesis and Inactivation
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-Tryptophan precursor
--tryptophan-5-hydroxylase forms 5-hydroxytryptophan -Broken down by MAO-a and excreted in urine -Most common breakdown product is 5-HIAA -Serotonin is also precursor of the pathway to make melatonin in pineal body --via separate pathway |
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Tryptophan-5- hydroxylase
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-Forms 5-hydroxytryptophan from tryptophan
-Rate-limiting step in Serotonin synthesis |
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Melatonin
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-Hormone
-Serotonin is precursor for melatonin -Important for circadian rhythms, biological clock, sleep regulation -Also acts as antioxidant |
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Storage and release of Serotonin
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-Serotonin is Stored in secretory vesicles
--complex with ATP allows vesicles to manage acid/base control -Exocytosis results in release --"release reaction" of platelets |
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Serotonin Metabolism
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-Metabolized by MAO (deamination)
--then oxidized or reduced and excreted in urine -High affinity uptake in nerve terminals and platelets |
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Serotonin Receptor Diversity
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-Many subtypes
--25 receptor subtypes in 7 major classes -Mostly GPCR -5-HT3 receptor is an ion channel (only ion gated channel) -Identified based on affinities for 5-HT, Selective angatonists, distribution, and species-specificity -Most receptors have been cloned |
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5-HT3 Receptor
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-Ion-gated channel for serotonin
-Only ion gated serotonin receptor -Monovalent cation channel -Mediates fast depolarization responses |
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CNS functions of Serotonin
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-Involved in making melatonin in pineal body, percursor of melatonin
-Important NT in raphe nuclei of brain --Pain perception, Sleep, Autonomic functions (temperature, BP), Mood, sexuality, food intake, emesis --low levels are associated with mood disorders -Action is somewhat species-dependent |
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Serotonin Actions in CNS
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-Acts as NT
-Perception of Pain -Sleep -Autonomic function, regulates temp and BP -Mood -Sexuality -Food intake -Emesis |
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Emesis and Serotonin
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-Bad food ingested, enterochromaffin cells release Serotonin
-Platelets take up and release more serotonin -high serotonin levels act on 5-HT3 receptors and cause vomiting |
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Neuroendocrine Effects of Serotonin
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-Precursor for melatonin produced in pineal body
-Hypothalamic-hypophyseal secretion control -Endocrine gland co-storage and release with polypeptide hormones --thyroid --pancreas --Serotonin is released along with other hormones |
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Serotonin in GI system
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-Peripheral nervous system, enteric nervous system
-Stored and released from Kulchitsky cells -Contributes to enteric nevous system to control gastric secretion and motility -Stimulates GI smooth muscle contraction --facilitates tone, peristalsis, motility --motility enhancing effect on 5-HT2 receptors, 5-HT2 agonists -Basal release is augmented by mechanical stimulation, hypertonicity, acidity, NorEpi, and vagal tone -Overproduction of serotonin in carcinoid tumor can lead to severe diarrhea |
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Serotonin in Cardiovascular System
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-Promotes vascular smooth muscle contraction
-Acts on 5-HT2 receptor --causes vasoconstriction of vascular smooth muscle -No contraction in skeletal or heart muscle --causes vasodilation of skeletal and heart muscle |
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Serotonin in Platelets
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-Regulation of vascular tone
--Serotonin antagonists cause Anti-hypertensive action -Bleeding time, clotting time, capillary resistance are not by serotonin depletion |
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How to alter Serotonin Levels
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1. Target synthesis
2. Prolong activity by preventing breakdown 3. Change receptor activity |
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Behavior-modifying Activity of serotonin
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-MAO inhibitors within presynaptic terminal prevent serotonin degradation
--prolong serotonin -Tricyclic antidepressants act in synaptic cleft, reduce re-uptake -Selective Serotonin Reuptake Inhibitors in synaptic cleft |
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Tryptophan and Serotonin
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-Precursor to serotonin
-Tryptophan can cross BBB and get into brain, Serotonin cannot -Serotonin is made in the brain by conversion of tryptophan -Need enough tryptophan to get into brain to make serotonin -Useful with PKU because tryptophan amine concentration can outbalance phenylalanine concentration |
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Chloramphetamine
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-Blocks serotonin synthesis
-Will decrease serotonin levels in the brain |
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Serotonin re-uptake inhibitors
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-Increase serotonin activity by prolonging the time serotonin is in the synaptic cleft
--leads to higher concentration of serotonin in synaptic cleft -Tricyclic antidepressants -SSRIs -Ecstasy prevents uptake and induces high serotonin secretion --post-synaptic overload/flooding effect |
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MAO inhibitors
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-Prevent monoamine NT breakdown in synaptic terminal
-Increase serotonin availability |
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Tricyclic Antidepressants
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-Block uptake of serotonin at pre-synaptic terminal
-Inhibit reuptake by transporter protein on presynaptic cell -Also partially inhibits NorEpi reuptake by blocking amine pump -Amitryptiline HCl --treats behavioral conditions, separation anxiety, spraying, self-mutilation --Tx for pruritus |
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Amitryptiline HCl
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-Tri-cyclic anti-depressant, serotonin uptake inhibitor
-Treatment for behavioral conditions --separation anxiety, spraying, self-mutilation, excessive grooming -Adjunctive treatment for pruritus -Treatment for neuropathic pain |
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Clomipramine HCl
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-Tri-cyclic serotonin uptake inhibitor
-Anti-depressant -Used for treatment of obsessive-compulsive disorders --urine marking, mounting, inter-male aggression |
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Imipramine HCl
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-Tricyclic Serotonin uptake inhibitor
-Treats anxiety disorders in animals -Separation anxiety -Urinary incontinence -Ejaculatory dysfunction -Cataplexy (narcolepsy attacks) |
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Specific Serotonin Reuptake Inhibitors
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-more selective for serotonin
-Little to no effect on other NT (Dopamine, NorEpi) -Good response for reversing depression -Fluoxetine HCl -Paroxetine HCl -Sertraline |
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Fluoxetine HCl
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-SSRI
-Treatment for anxiety disorders in dogs -Can change blood levels of other medications due to CYP450 inhibition --esp. diphenhydramine and propanolol -Treats aggression, Obsessive compulsive disorders, destruction, excessive barking -treatment for inappropriate elimination and pruritus |
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MAO inhibitors
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-Prevent monoamine NT breakdown within the synaptic terminal
-Not very specific to serotonin, will break down NorEpi also -MAO-a -MAO-b |
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MAO-a
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-Mostly serotonin and NorEpi degradation
-Selectively inhibited by Clorgyline --irreversible inhibition -Moclobemide is similar to SSRI --reversible inhibition |
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MAO-b
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-Mostly dopamine degradation
-Selective inhibition of dopamine -Inhibitors can slow down degradation of neurons with age |
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Serotonin Receptor Agonists
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-Cisapride: Stimulates 5-HT4 receptors, GI disorders
-Sumatriptan -Buspirone: 5-HT1a, alleviates anxiety and behavior disorders -Ergot Alkaloid Derivatives: helpful for migraine headaches |
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Cisapride
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-5-HT4 antagonist
-Was used in treatment for GI reflux and GI stasis -Since found to be toxic |
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"Triptans"
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-Sumatriptan
-5-HT1D and 5-HT1B agonists -Expensive |
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Buspirone
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-5-HT1A agonist
-Anxiolytic -Treatment for behavior disorders related to fear or phobias |
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Ergot Alkaloid Derivatives
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-Serotonin receptor agonists
-Partial agonists and antagonists at numberous 5-HT receptor sub-types -Effective treatment for acute migraines |
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Phenoxybenzamine
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-A-adrenergic blocker and 5-HT2 antagonist
-Treats functional urethral obstructions --Decreases sympathetic-mediated urethral tone -Short-term treatment for hypertension -Can treat laminitis in the developmental phase |
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Cyproheptadine
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-H1 agonist
-5-HT2 antagonist -Anti-histamine -Treats skin allergies and pruritus -Acts as appetite stimulant -Reduces cortisol overproduction in equine cushing's disease --overproduction of ACTH release due to pituitary tumor |
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Ketanserin
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-Serotonin Receptor blocker 5-HT1 and 5-HT2
-Blocks platelet aggregation promoted by 5-HT -Anti-hypertensive (experimental) -Unclear mechanism of action |
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Dolasetron Mesylate
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-Serotonin receptor antagonist, 5-HT3 antagonist
-Anti-emetic drug -Blocks 5-HT3 receptors |
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Ondansetron
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-Blocks 5-HT3 receptors, serotonin receptor antagonist
-Anti-emetic, |
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Psilocybin
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-5-HT1a and 5-HT2 agonist
-Compound stimulates receptors -Alters consciousness |
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Serotonin Syndrome
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-Serotonin poisoning caused by combination of drugs that have additive or synergistic effects on serotonin levels
-Contraindicated Combination of antidepressants and opiates -CNS stimulants in combination with something else -Treatment: Benxodiazepines --stimulate GABA activity in brain, counteract hyperstimulation of serotonin system |
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Autacoids
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-“Local Hormones”
-Biologically active amines -Present in many tissues throughout the body -Histamine, Serotonin, endogenous peptides, prostaglandins, leukotrienes, cytokines -Complex physiologic and pathologic effects through multiple receptor types -Can be released together locally |
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Biosynthesis of Histamine
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-Histidine is converted into Histamine via histamine decarboxylase
-2 breakdown pathways --histamine to N-methylhistamine via N-methyltransferase --histamine to Imidazoleacetic acid via Diamine oxiase/histaminase -Broken down pretty quickly -Has robust biological actions, do not want it to linger -Orally ingested histamine is quickly metabolized and eliminated |
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Clinical Importance of Autacoids
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-Broad and undesirable effects
-No clinical application for histamine or serotonin -Imbalances in synthesis or release cause pathological conditions --inflammation, allergies, hypersensitivity, ischemia-reperfusion injury, cardiovascular hypertension -Compounds selectively activate/atagonize receptor sub-types that are clinically useful |
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Histamine
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-2-(4-imidazolyl)ethylamine
-Hydrophilic vasoactive amine -Naturally present in plants and animals -In mast cells and stomach mucosa --concentrations vary --species and tissue specific -4 different GPCR receptors |
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Histamine Major Physiological roles
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1. Immune response and inflammation
2. Regulates gastric acid formation 3. NT or neuromodulator |
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Histamine Metabolism and Elimination
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-2 breakdown pathways
-All excretion is renal |
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Histamine Receptor Subtypes
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-H1, H2, H3, H4
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H1 Histamine Receptors
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-G-protein coupling to Gq
-Increases IP3, DAG --increases Ca and cAMP in the cell -On smooth muscle cells and endothelial cells -in CNS -2-methyl-histamine is agonist -Pyrilamine is antagonist |
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H2 Histamine Receptor
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-G-protein coupled receptor via Gs
--increases cAMP in the cell -On gastric parietal cells, cardiac muscle, mast cells, and in CNS -Agonist is Dimaprit, impromidine, and anthamine -Antagonist is Ranitidine, cimetidine |
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H3 Histamine Receptor
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-GPCR, activates Gi
-Decreases cAMP levels in cell -In CNS, presynaptic terminals, in myenteric plexus of enteric NS -important for arousal in the brain -Agonist is R-a-methyl-histamine, imetite, and immepip -Antagonist is Thioperamine, clobenpropit, iodophenpropit |
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H4 Histamine Receptor
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-GPCR, acts via Gi
--increases Ca and decreases cAMP in cells -On Eosinophils, neutrophils, and CD4-T cells -Agonist is Clobenproprit, imetit, clozapine -Antagonist is Thioperamide |
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Histamine Release
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-Synthesized in cells and packaged into granules
-Stored in specialized vesicles/granules --mast cells --basophil granulocytes --enterochromaffin-like cells in stomach muscosa -Rapid release of granules into the interstitium, stimulated by tissue injury or trauma, physical agents, chemical compounds, or immunological factors |
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Mechanisms of Histamine Release
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-Tissue injury or trauma
-Physical agents: heat, cold, x-rays -Chemical Compounds: morphine, tubocurarine --displace histamine in granules causing release -Immunological response: Fc epsilon RI high-affinity receptor for IgE --respont to tissue damage or immune actions |
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Histamine Triple response
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-Released from mast cells
-Causes vasodilation, allows increased blood flow and increased infiltration 1. Small red dot: local reaction, local dilation of blood vessels --immediate site of injection 2. Large red flare surrounding original red spot 3. Wheal around red spot --Edema due to increase of vascular permeability --separation of endothelial cells Response can be inhibited by prior administration fo H1 antagonists (anti-histamines) |
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Local effects of Histamine Release
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-Dilation of capillary venules (H1 receptor)
-Activates endothelium, increases blood vessel permeability --also increases permeability for WBCs -Chemotactic attraction of inflammatory cells --neutrophils, basophils, eosinophils, monocytes, lymphocytes -Irritates nerve endings |
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Roles of mast Cells in Disease
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1. Allergic diseases: asthma, eczema, allergic rhinitis or conjunctivitis
--Histamine causes more problems than initial insult 2. Anaphylaxis: Strong systemic activation as reaction to allergens --body-wide degranulation of mast cells --causes mass vasodilation and shock --Other factors also involved 3. Immunity: Recruitment of inflammatory cells to skin or joints --integral part of innate immunity |
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Disorders of Mast Cells
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-Mastocytosis: rare over-proliferation of mast cells
--can be cutaneous or systemic -Mastocytoma: Mast cell tumor, often seen in dogs and cats |
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General Histamine Effects
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-Powerful effects on smooth muscle and cardiac muscle
-Effect on nerve cells -Endothelial cells -Stomach secretory cells, promotes acid secretion -Sensitivity to histamine varies species to species -Guinea pigs, dogs, cats, humans have high response to histamine -Mouse and rats have low response to histamine |
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Histamine Effects in Nervous System
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-Stimulation of sensory nerve endings to cause pain and itching
--nettle and insect stings --H1 mediated response -Modulation of respiratory neurons --breathing, sleep, wakefulness --H1 and H3 mediated response -Presynaptic H3 receptors modulate transmitter release --Agonists reduce release of ACh, amines, peptides in brain and peripheral nerves |
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Histamine Effects on Cardiovascular System
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-Decreases systolic and diastolic blood pressure
--due to dilation of arterioles and NO release -Increased HR, tachycardia --stimulates heart and reflex tachycardia -Increased contractility in myocardium escept for atrial muscle -Flushing, sense of warmpth in peripheral tissues due to extra blood flow -Can cause headaches due to vasodilation -Local sites of increased blood flow, Urticaria (Hives) -Some cardiovascular effects are involved in anaphylaxis, other effects are more important |
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Time response of histamine on Cardiovascular System
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1. Drop in cardiac output and blood pressure
2. Breif compensatory tachycardia, then consistently increased HR 3. Increase in peripheral resistance 4. Can cause death within hours --50% lethality after 4-6 hours |
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Effect of histamine on the bronchiolar Smooth Muscle
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-Causes bronchoconstriction via H1 receptors
--can cause death in guinea pigs -Asthma pateints are much more sensitive to histamine, 100-1000x more sensitive -Causes bronchodilation in rabbits and some other species --H2 receptor effects predominate over H1 receptors |
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Histamine effects on GI tract smooth muscle
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-Contraction of smooth intestinal muscle
-Mediated by H1 receptors |
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Histamine effects on Uterine Smooth Muscle
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-Some species are sensitive
-Can have histamine-induced contractions --may lead to abortion |
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Secretory effects of Histamine
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-Powerful stimulant of gastric acid secretion
-increases production of pepsin and intrinsic factor -H2 receptor activated action on gastric parietal cells --increases cAMP, Ca -Stimulates intestinal secretion -H3 agonists can inhibit gastric acid secretion --stimulated by food or pentagastrin |
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Role of Histamine in Gastric Acid Secretion
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-Parietal cells secrete HCl into lumen
-Histamine acts of H2 receptors on parietal cells --increases in cAMP and Ca are blocked by H2 antihistamine drugs, NOT blocked by H1 antihistamine drugs -Parietal cells also respond to Ach, Gastrin, and SSK |
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Histamine Toxicity
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-Bacteria can over-produce histamine
--spoiled fish or meat can have increased bacteria -Symptoms: --flushing, hypotension, Tachycardia, headache, hives, wheals, urticaria, bronchoconstriction, GI upset -Animals with asthma are hyper-sensitive to histamine, should not be given histamine ever -Patients susceptible to GI bleeding are also susceptible |
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Histamine Antagonists
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1. Physiological Antagonists
2. Release Inhibitors 3. Receptor Antagonists (antihistamines) 4. Histidine decarboxylase inhibitors (in the works) |
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Physical antagonists of Histamine
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-Ideally works through a different mechanism to have opposing effect
-Ex: Epi in anaphylaxis --Causes smooth muscle action opposite of histamine -Different receptor -Clinically has life-saving action in acute analhylacis and rapid bronchodilation -H1 receptor antagonists are only suitable prophylactically, need to use epi for acute cases |
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Release Inhibitors of Histamine
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-Reduce immunologically triggered mast cell degranulation
-Reduce histamine release -Cromoglicate, nedocromil for asthma treatment -Beta-2 adrenergic receptor agonists also reduce histamine release |
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Histamine Receptor Antagonists
Anti-histamines |
-Directly block histamine receptors
-Mostly H1 receptor antagonists --little to no effects on H2 and H3 receptors -Side effects intensity varies with compound |
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Common side effects of Antihistamines
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-Sedation, drowsiness
-Dryness of mucous membranes --mouth, nose, throat -Skin allergies with topical treatment -GI motility is affected -Effects on muscarinic, cholinoreceptors, serotonin, or local anaesthesia receptors -Intensity varies with compound |
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Categories of H1 receptor Antagonists
1st generation |
-Ethanolamines: Diphenhydramine (Benadryl)
-Ethylaminediamines: Pyrilamine (Histall, H) -Piperazine derivatives: Hydroxyzine (Ifosfamide, Ifex) -Alkylamines: Chlorpheniramine Maleate --alone or in combination with analgesics or antibiotics --less sedating than other 1st generation agents Strong sedative side-effects, anticholinergic |
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Categories of H1 receptor Antagonsts
2nd Generation |
-Less lipid-soluble, less entry into CNS (or no entry)
-Less sensitive action -Ethylenediamine: Tripelennamine (TBZ, Fenistil) -Chlorpheniramine, Serotonin/Epi re-uptake inhibitors --mild anti-depressants -Loratadine (Claritin) -Cetirizine (Zyrtec) -Fexofenadine (Allegra), Terfenadine (Seldane) |
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Uses for H1 receptor antagonists
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-Prevents bronchoconstriction
--NOT a bronchodilator! Use epi as acute bronchodilator! -H1 receptor antagonists do NOT block gastric secretion --only H2 receptor antagonists -Treatment of allergic reactions -Motion sickness and vestibular disturbances -Do not block gastric secretion --H2 receptors, need H2 antagonists |
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H1 receptor Antagonist Side effects
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-Anticholinergic side effects
-Hyperthyroidism -Cardiovascular Disease -Use with caution in patients with angle closure glaucoma, prostatic hypertrophy, pyloroduodenal or bladder neck obstructions, hyperthyroidism, cardiovascular disease, or hypertension |
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Diphenhydramine Uses
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-H1 receptor antagonist, Benadryl
-Bug bite allergies -Bee stings -Dermatitis in dogs -Reverse sneeze syndrome -Agitation associated with pruritus allergies -Transient behavior management (car travel) -Prevention of motion sickness, antiemetic -Aseptic laminitis -Adjunctive therapy of anaphylaxis in cattle and horses |
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H2 receptor Antagonist Uses
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-Cimetidine, nizatidine, ranitidine
-Treatment for duodenal ulcers or stress-induced gastric ulcers -Upremic gastritis, stress-related erosive gastritis and esophagitis -Duodenal gastric reflux --promotes gastric emptying and GI motility -Reduces gastric acid secretion and helps with gastric acid reflux -Prevents secretion from endocrine adenomas |
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H2 receptor Antagonist Side effects
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-Toxicity is rare
-Can cause issues with older patients or patients with hepatic or renal insufficiency |
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Ranitidine
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-Reduces gastric acid production
-Can be used to treat ulcers, esophagitis, chronic gastritis, gastrinoma, hyperhistaminemia due to mast cell tumors, hypergastrinemia due to chronic renal failure -Pathologic hypersecretory conditions can be reduced -Ranitidine is more effective than cimetidine |
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Local Anesthetic Molecule
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-Weakly basic in nature
-Water-soluble salts -low pH, 4.4-6.4 -Usually already diluted -Lipophilic benzene ring and hydrophilic quaternary amine -Can have an ester or amide linkage --Esters have been moved away from, amides are mainly used --longer chain leads to increased potency and toxicity |
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Local Anesthetics Tertiary Form
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-Uncharged, free base
-Poorly soluble in water -Crosses lipid barriers |
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Important details of Local Anesthetic Molecules
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-Potency, Onset, and Duration are most important
-Potentcy is related to lipid solubility -Onset time is related to degree of ionization --closer the pKa of the anesthetic is to the tissue pH, more rapid onset --important clinical application -increased protein binding prolongs duration of anesthetic in body |
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Local Anesthetic Site of Action
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-Work by blocking Inotropic Na channels
--Na channels are all over the body, how body propagates AP in nerves -Overdose of local anesthetic will block how nervous system functions --can cause major issues! |
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Local Anesthetic Site of Action Modern Theory
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-traverse membrane, get protonated, protonated form blocks Na channel from the inside
-Local anesthetic acts like a cork, does not let Na through the channel -Binding impedes propagation of action potentials -Cause conduction blockade |
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Na Channel Mechanism of Action
Channel States |
-Na channel is either "Open" or "Closed"
-If closed, can be resting or inactivated -States depend on membrane potential -Ion conducting state is "open" --open for less than 1 millisecond -Non-conducting/resting/inactivated exists for several milliseconds |
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Na Channel "Open" State
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-Channel is open, ions can flow through
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Na Channel "Inactivated/Resting/Non-conducting" state
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-Cannot readily re-open form inactivated states
-Have to recover, or re-prime after hyperpolarization membrane potentials to become available -Channels bind drug when they are depolarized and inactivated -Channels release drug when they regain hyperpolarization and reach rested state |
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Vasomoter tone
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-Keeps body functioning
-Baseline sympathetic tone on organs in the body -Tone always changes but is always present -Maintains pressure -Fibers are always transmitting --easy to catch in a state where drugs will have an effect --always active, always have the chance to affect them |
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Repetitive depolarization of Na channels
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-High affinity with repetitive depolarization
-"Use-dependent block" or "phasic block" -More intense block -Affects fibers that are most active --stronger block in areas that are painful -Excitable tissues show aberrant late Na currents responsible for neuropathic pain, dysrhythmias, epilepsy |
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Lidocaine as anti-arrhythmic drug
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-Blocks foci in heart that are repetitively firing
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Vasomotor tone and phasic block
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-Reason why current local anesthetics have cardiovascular toxicity
-Lidocaine has vascular -Bupivacaine is more cardiovascular -Affect vasomotor fibers and change impulse transmission through sympathetic trunk -Blocks a sector of spinal cord that controls transmission of impulses to a certain splanchnic area --area will collect more venous blood --removes blood from circulation -Impedes venous return to the heart --decreases CO, hypotension, cardiovascular instability -Young animals can tolerate, older/sick animals cannot |
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Lidocaine vs Bupivacane with Cardiac Dysrhythmias
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-Cardiac coltage gated channels are 100-1000x more sensitive to lidocaine than neural channels
-No systemic neuronal interruption with antiarrhythmic effects -High activity of cardiac channels promotes high-affinity slow-inactivated sate and actions of local anesthetics on them |
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Local Anesthetics Effects besides Na Channels
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-Serotonergic and cholinergic receptors also contribute to epidural and spinal anesthesia and behavioral changes
-Anesthesia/sedation -Drowsiness and euphoria --inhibitory actions on excitatory synapses --inhibitory actions on inhibitory neurons -Cocaine and procaine can antagonize behavioral actions of nicotine -Cocaine and other local anesthetics can induce seizures --inhibit anti-nociceptive effects of nicotine --inhibit nicotine-induced motor impairment |
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Factors affecting Local Anesthetic Pharmacokinetics
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-Proximity of injection to nerve
-Anesthetic flow around neural tissue --flow of blood and lymphatics take local anesthetic away from intended site, decreases concentration -Diffusion across barriers into tissue --depends on pH, pKa, concentration, and lipid solubility -Binding of local anesthetic to non-neural sites -Absorption into vascular and lymphatic systems |
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Local Anesthetic Absorption
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-Even locally, will end up being absorbed and will end up acting systemically
-Systemic system serves as depot for drug -Different tissues have more or less absorption --muscle and intercostal speces have most sytemic absorption |
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Lidocaine in the Lung
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-Pharmacokinetics are altered by the lung
-Lung absorbs anesthetic and drops the plasma levels of the drugs -Helpful to decrease systemic absorption -Venous blood goes to lung, leads up uptake by the lung |
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Lidocaine Elimination
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-Metabolized in liver via aromatic hydroxylation, N-dealkylation, and amide hydrolysis
-high extraction ratio: more than 70% of drug is cleared from plasma in one circulation through the liver |
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Extraction Ratio
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-Amount of drug that is removed from plasma circulation by the liver
-Liver metabolism depends on blood flow more than enzymes -Liver function does not really affect metabolism of local anesthetics -Drugs with high-extraction ratio depend on blood flow, are not affected by liver function --generally safer -Drugs with low extraction ratio depends on cytochromes and enzymes, are affected by liver function |
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Local Anesthetic Toxicity
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-Depends on rate of absorption and metabolism
-Toxicity is additive --multiple drugs can have additive effect, need to be careful -Allergic reactions, mostly with ester local anesthetics -Neurotoxicity -Methemoglobinemia -CNS toxicity --can lead to unconsciousness, seizures, and coma --only an issue with certain local anesthetics |
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Cardiovascular Toxicity of Local Anesthetics
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-Associated with local anesthetic potency
-Acidosis, hypoxia, pregnancy, K, addition of epinephrine -Dose related, decreases cardiac contractility -Can constrict or dilate vasculature |
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Hypercarbia and local anesthetics
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-Animals under anesthesia do not breathe well
-With respiratory distress comes respiratory acidosis -Toxicity of drug is higher -Want to keep animal away from an acidic state |
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Bupivicaine IV
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-NEVER USE IV!
-Can kill a healthy young animal with 1 dose -Related to potency |
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Bupivicaine use
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-4x more potent nerve block
--lasts much longer, 4-6 hours -70x more potent cardiovascular toxicity -Delays conduction |
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Toxicity of Local Anesthetics in Awake Dogs
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-Determined by a study on awake dogs that increased dosages and looked at resulting signs
-When dog is anesthetized, can give more local anesthetic because anesthetic agents work as muscle relaxant and decrease muscle tremors -Lidocaine has less toxicity that bupivicaine |
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Toxicity of Local Anesthetics in Anesthetized Dogs
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-Toxic dose is MUCH higher in anesthetized dogs
-In awake dogs, CNS effects will be more dramatic before cardiovascular effects are seen |
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Local Anesthetic Toxic effects
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-CNS effects in awake animals
-Cardiovascular effects in anesthetized animals -Different doses used for awake vs. anesthetized animals |
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Local Anesthetic Toxicity in Cats
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-Need to be very careful in cats
-Small V1 compartment -Toxic effects are very dependent on plasma levels -Have different metabolism and different compartments leading to different distribution --different pharmacokinetics -Will often see side-effects if not careful -Usually only give lidocaine to treat arrhythmias, and even then cats do not respond very well |
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Cardiovascular Toxicity of Local Anesthetics
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-Lidocaine is used IV very often
-As doses increase, difference in mean arterial blood pressure is not that evident -Therapeutic/clinical doses of lidocaine are cardiovascular sparing -At lower doses, CO actually increases -Safe drug to use in cardiovascularly unstable patients as long as you stay away from toxic doses |
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Treatment of Local Anesthetic Toxicity
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-Use lipid emulsions
-Lipid acts as a sink, local anesthetic is trapped in the lipid -Very effective, especially with cardiac arrest |
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Esters vs. Amides
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-Esters have more allergic reactions
-Amides have more CNS and cardiovascular toxicity at high doses -Esters are hydrolyzed by plasma cholinesterase --produces allergic metabolite -Amides are degraded in the liver |
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Lidocaine
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-Very old drug, 2nd local anesthetic amide to be synthesized
-Short onset and long duration -Hypoallergenic -Main local anesthetic used -Only downfall is short duration, only reason you would use something else -has vasodilatory effects |
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Special Effects of Lidocaine
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-Analgesia and MAC sparing-effects
--Can decrease concentration of inhalant anesthetics used at the same time -Cardiovascular sparing -Anti-arrhythmic effects --similar to procainamide -Useful in neuropathic pain -Anti-endotoxic -Prokinetic, can be beneficial for GI system --used pre-surgical or post-surgical in colic situations |
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Lidocaine as anti-endotoxic
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-Beneficial for re-perfusion injury
-Na enters cells, but with no ATP to pump Na out will switch and pump Ca out --causes necrosis -Giving lidocaine blocks Na channel and decreases amount of Na that goes into cell -Will not have a lot of Ca flux |
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Functions of the GI tract
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-Continual supply of water, elecrtolytes, and nutrients
-Highly regulated movement -Most drugs are absorbed in the small intestine, NOT stomach --need to be stable to get through the stomach |
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Stomach Anatomy
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-Fundus
--cardia --esophagus -Corpus/Body --rugae increase surface area -Antrum --pyloric antrum --pylorus |
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Storage of the Stomach
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-Muscle plasticity
--stretches to accommodate load -Vagal reflex inhibits muscle activity during filling -Competitive eaters control vagal reflex |
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Mixing action of the Stomach
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-Regulated by vagal nerve
-Slow constrictor waves in the body of the stomach -Peristaltic constrictor waves in the antrum -Regulation of waves by vagal nerve activity |
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Emptying of Stomach
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-Coordinated action
-Pyloric pump and musculature in the antrum -Solids must be less than 2mm to leave the stomach and enter duodenum -Pyloric sphincter -Regulated by food in the stomach, gastrin, enterogastric reflexes, and hormonal feedback |
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Cell Types in the Stomach
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-Superficial epithelial cells produce mucin and HCO3
-Mucous neck cells produce mucin and pepsinogens -Stem cells/regenerative cells -Parietal cells produce HCl and intrinsic factor -Chief Cell produces pepsin -Endocrine cells |
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Intrinsic Factors
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-glycoprotein that allows for vitamin B12 absorption in ileum
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Gastric Acid Functions
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-Protein digestion
--pepsin preferentially cleaves proteins at carboxylic groups of aromatic AAs -Iron absorption -Inactivation of bacteria, viruses, and parasites |
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Pepsin production
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-Pepsinogen is cleaved at low pH (les than 3.5)
-unfolds, clips part of self, and becomes active -Activated pepsin can covert pepsinogen into active pepsin -Increasing concentration of pepsin will increase pH, and pepsinogen will no longer be activated -Pepsin preferentially cleaves at carboxylic groups |
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Regulation of Stomach Acid Secretion
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-H/K ATPase proton pump is key factor
-Puts H into intestinal lumen -brings K into cell cytoplasm -H comes from H2O |
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Transmitter Systems involved in Regulation of Stomach Acid
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-Gastrin: acts on CCKb receptor, increases acid secretion
-Histamine: Acts on H2 receptor, increases acid secretion -ACh: acts on muscarinic M3 receptors, increases acid secretion -Prostaglandin: acts on EP2 receptors, decreases acid secretion -Somatostatin: acts on SST receptors, decreases acid secretion |
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Gastrin and Stomach Acid Secretion
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-Peptide
-Made in G-cells in antrum of stomach -Acts on CCKb receptor to increase acid secretion --GPCR to activate IP3 and Ca release -Activates H/K ATPase pump to increase secretion -Direct stimulation via ACh and CCkb receptors -Indirect stimulation as well |
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Histamine and Stomach Acid Secretion
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-Released from enter-chromaffin cells
-Binds to histamine receptors (H2 receptor) --activates Gs protein to up-regulate cAMP --leads to increased action of PKA, stimulates H/K proton pump -Increases acid secretion |
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ACh and Stomach Acid Secretion
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-NT released from vagal nerve
-Binds to muscarinic M3 receptor -Increases acid secretion |
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Prostaglandin and Stomach Acid Secretion
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-Acts on Gi protein, inhibitory
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Somatostatin and Stomach Acid Secretion
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-Acts on Gi protein, inhibitory
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Direct stimulation for Gastric Acid Secretion
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-Vagal nerve
--releases ACh directly onto parietal cells -Gastrin binds to CCK receptor on parietal cells |
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Indirect Stimulation for Gastric Acid Secretion
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-Vagal neve releasing ACh onto enterochromaffin-like cells
--releases histamine -Gastrin binds to CCK receptor on ECL cell |
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Cephalic Phase of Gastric Acid Secretion
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-Automated conditioned reflexes
-Comes from the brain -based on smell, taste, chewing, swallowing -Also hypoglycemia acts as a trigger -Acid is released before food is even in stomach |
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Gastric Phase of Gastric Acid Secretion
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-Distention sends signal up to brain
-Brain send signal back to increase acid secretion -Once food is present, AA and peptides activate |
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Gastric Ulcers
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-Go through mucosa into submucosa
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Helicobacter pylori
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-Gram- bacillus bacteria, colonizes antral mucosa of the stomach
-Can cause gastric ulcers --60% of gastric ulcers --90% of duodenal ulcers -Antral inflammation may decrease somatostatin release from antral D-cells --Decreased somatostatin results in increased gastrin release, increases acid production |
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Treatment of gastric Ulcers
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-Amoxicillin
-Clarithromycin -Proton pump inhibitor One week therapy in adults |
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NSAIDs and gastric ulcers
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-NSAIDs are non-selective COX-1 and COX-2 inhibitors
-Prevent formation of PGE and Arachadonic acid -PGE play pivotal role in maintaining gastric mucosal integrity -Blocking prostaglandin synthesis can lead to gastric ulcers |
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PGE and Gastric Mucosal integrity
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-Pivotal role in maintaining gastric mucosal integrity
-Inhibit gastric acid secretion -Stimulate HCO3- secretion -Stimulate mucous secretion -INcrease mucosal blood flow -Modify local inflammatory response caused by acid |
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Rofecoxib
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-Vioxx
-Selective COX-2 inhibitor -Withdrawn in 2004 due to increased risk for heart attack and stroke |
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COX-1
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-Mediates synthesis of PGEs responsible for protection of the stomach lining
-Do not want to inhibit |
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COX-2
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-mediates the synthesis of PGEs responsible for pain and inflammation
-Want to inhibit -COX-2 specific inhibition may minimize gastric ulcers |
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Deracoxib
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-Deramaxx
-Selective COX-2 inhibitor -Pain and inflammation after operations -Used long-term for pain and inflammation associated with osteoarthritis -Large doses can cause COX-1 inhibition and gastric issues |
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Gastric Mucosal Defense Systems
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1. Mucosal cell renewal
2. Prostaglandins 3. Mucosal Blood Flow 4. Mucus Secretion 5. HCO3- secretion |
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Normal gastric Epithelium
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-Mucus acts as a barrier to H and pepsins
-traps alkaline solution -Acid generally tends to stay in the lumen -Keeps mucosa buffered and safe from pepsin digestion |
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Damaged mucosal barrier
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-Mast cell degranulation and release of histamine is bad news
--inflammatory response |
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Therapy for Gastric Erosion and gastric Ulcer
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1. Dietary management
2. Antacids 3. Chemical diffusion barriers 4. ACh receptor antagonists 5. Histamine receptor antagonists 6. Gastrin receptor antagonists 7. H, K, ATPase agonists 8. Prostaglandins |
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Dietary Management and Gastric Ulcers
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-Provide adequate nutrition
-Maintain continuous neutralization of gastric acid with food -Minimize acid secretions -Reduce mechanical, thermal, and chemical irritation to the gastric mucosa |
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Antacids and gastric Ulcers
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-Neutralize acid in the gastric lumen
-Rapid onset and short duration --starts in 30 min, lasts 2-3 hours -Mainly reduce pain associated with acid secretion --prevents HCl from reaching nerves and illicit pain -Binds HCl in lumen, neutralize |
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Sodium Bicarbonate Antacid
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-Alka-Seltzer
-Water soluble -Can be absorbed systemically --leads to alkalosis and potentially kidney stones -Rapid generation of CO2, can lead to gastric distention and discomfort |
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Calcium Carbonate Antacids
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-Tums
-Can neutralize 2 molecules of HCl -Increases Ca load in the urine --can lead to development of kidney stones --issue with renal patients -Antacids with Ca can cause constipation |
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Magnesium Hydroxide
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-Milk of Magnesia
-Magnesium containing antacids -Cause diarrhea, acts as laxative -up to 20% of Mg can be absorbed systemically --can cause hypermagnesia in renal patients -Mg can accumulate in patients with renal disease, causes hypermagnesia -Ion imbalances leads to cardiac problems and CNS depression |
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Acid Rebound
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-If stomach pH is increased (above pH4) stomach is stimulated to secrete acid to maintain low pH
--compensatory HCl secretion by stomach -Aluminum salts do not raise gastric pH, do not stimulate compensatory HCl secretion -Mg salts raise gastric pH, can stimulate compensatory HCl secretion -If stop taking Mg salt antacids, can cause acid rebound --compensatory HCl secretion |
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Aluminum Hydroxide Antacid
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-Maalox
-Aluminum-containing antacid -Constipation is a side-effect -Al can form insoluble Al-Phosphate complexes --Can lead to hypophosphatemia with chronic use |
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Magaldrate Antacid
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-Riopan
-Antacid contains mix of Al and Mg -Constipation and laxative effects are off-set |
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Chemical Diffusion Barriers
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-Coat irritated area of the stomach, forms physical barrier against stomach acid
-Mixture of sucrose octasulfate and AlOH -Sucrose octsulfate polymerizes and forms a paste --binds to damaged gastric epithelial cells -Binds and activates bile salts and pepsin -Stimulates prostaglandin synthesis -Increases mucosal blood blow by increasing vasodilatory NO production --increased NO leads to vasodilation |
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Bismuth Subsalicylate
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-Pepto-bismol
--cleaved to bismuth and salicylate in intestine -Bismuth coats ulcerated mucosal surfaces, absorbs toxins, and has mild antibacterial action -Salicylate has anti-inflammatory action -Do not use in cats due to salicylate and inefficient hepatic metabolism in cats --leads to toxicosis |
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Montmorillonite
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-Diarsanyl
-Contains montmorillonite, smectite clay -Combines with mucus to form protective layer on intestinal mucosa to help reduce irritation and fluid loss -High capacity to abosorb toxins, bacteria, viruses, enzymes, free radicals --more absorbent than kaolinite -Given as paste containing dextrose and glycerol |
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ACh receptor Antagonists and Stomach Acids
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-Pirenzepine
-M1-selective antagonist, decreases antimuscarinic-mediated side effects -Exact location of M1 receptors are not know, but work -M3 receptors on parietal cells |
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Anti-Histamines and Stomach Acids
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-Histamine Receptor Antagonists
-H2 antagonist |
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H1 location and action
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-Smooth muscle and endothelium
-In CNS -Promotes vasodilation, bronchoconstriction -Smooth muscle activation -CNS activation |
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H2 location and action
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-Parietal cells
-Regulates histamine-mediated gastric acid secretion |
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H3 location and action
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-Inhibitory autoreceptor
-Regulates histamine release |
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Cimetidine
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-Cimetidine (Tagamet)
-Prototypical H2-selective antagonist -Suppresses gastric acid secretion without H1 side-effects --no drowsiness -Inhibits many CYP450 enzymes -Numerous drug interactions can occur due to CYP inhibition --Coumadin, benzodiazepines, oral contraceptives -Decreases hepatic blood flow -Can decrease clearance of flow-limited drugs --propranolol, lidocaine |
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Ranitidine
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-Zantac
-2nd generation H2-selective antagonist -H2-selective antagonist -Much less CYP450 inhibition than cimetidine -Longer lasting -10x more activity |
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Famotidine
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-Pepcid
-3rd generation H2-selective antagonist -Poor bioavailability, 37% -30x more potent than cemitidine, more potent than ranitidine -No CYP450 inhibition -Pro-motility effects on the stomach |
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Pepsid Complete
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-Famotidine, CaCO3 antacid, and MgOH antacid
-Take effect immediately due to CaCO3 and MgOH, famotidine has long-lasting effect -Ca antacids have constipation effect and Mg antacids have laxative effects |
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Nizatidine
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-4th generation H2-selective
-No CYP450 inhibition -Excreted unchanged in the urine -Has pro-motility effects on stomach |
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Gastrin Receptor Antagonists
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-Experimental CPDs
-High affinity selective antagonists to CCK receptor -Effective in animal models -Inhibits gastrin-stimulated gastric acid secretion -Decreased ethanol-induced damage to gastric mucosa -Adjunct therapy? |
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Proton Pump Inhibtors
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-Omeprazole (Prilosec)
-Lansoprazole (Prevacid) -Esomeprazole (Nexium) -Rabeprazole (Aciphex) |
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Omeprazole
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-Prilosec
-Weak base, unstable at low pH --needs to be coated to survive stomach -Absorbed in alkaline pH of duodenum, low pH -Once inside low pH environment of parietal cell, becomes protonated -Protonated form covalently and irreversibly binds to and inhibits proton pump -One dose lasts 2-3 days due to concentration of drug and irreversible inhibition of the pump -Decreases pump numbers, decreases total acid produced |
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Prolonged use of Omeprazole
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-Prolonged decrease in gastric acid production
-Will increase stomach pH (more alkaline) -Allows GI bacterial growth --risk of pneumonia in certain patients -Sustained HCl reduction can lead to increased gastric levels --hypergastrinemia --need to co-administed CCKb antagonist? -Has caused parietal cell hyperplasia in animals |
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Prostaglandins and Gastric Ulcers
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-Pivotal role in maintain gastric mucosal integrity
-Inhibits gastric acid secretion -Stimulates HCO secretion -Stimulates mucus secretion -Increases mucosal blood flow -Modified local inflammatory response caused by acid |
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Misoprostol
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-Cytotec
-Binds to prostaglandin receptor on parietal cells -Decreases intracellular cAMP levels, leads to decrease in proton pump activity -Increases mucous production in gastric ulcers -CO-administered with NSAID to prevent ulceration -Off label uses: --labor induction, smooth muscle contraction --abortion --erectile dysfunction |
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Renin-Angiotensin System Function
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-Major role in cardiovascular and body fluid homeostasis
-Boosts blood pressure when blood volume has been challenged -Contributes to central hypertension -Works through actions of circulating angiotensin II --angiotensin II acts on target organs -targeted pharmacologically to treat hypertension |
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Renin Angiotensin System Discovery
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-Extract of the kidney
-Realized that it was an enzyme, not a substance of the kidney itself -Angiotensin was found to trigger aldosterone |
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Angiotensin Synthesis
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1. Angiotensinogen precursor in blood (biologically inactive)
-Renin cleaves angiotensinogen into angiotensin I -Angiotensin I is also biologically inactive -Rate limiting step in synthesis 2. Angiotensin I is converted into Angiotensin II by Angiotensin Converting Enzyme (ACE) -provides active peptide 3. Angiotensin III is also formed and may have a small effect |
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Antiogensin I
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-Biologically inactive
-Formed from Angiotensinogen by renin --renin is enzyme the cleaves -Formation is rate-limiting step in formation of Angiotensin II -Needs to be cleaved by ACE to become Angiotensin II |
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Renin
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-In Kidney
-Plasma concentration is rate limiting factor in Angiotensin II formation --converts angiotensinogen into angiotensin I -Secretion is controlled by reduced renal perfusion pressure, reduction of Na concentration in DCT, or sympathetic activation of b-adrenergic receptors |
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Renin Secretion
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-Determines activity of Renin-Angiotensin-Aldosterone system
--Other components are always present, but not activated until Renin is released 1. Reduced renal perfusion is sensed by intrarenal stretch receptor --juxtaglomerular apparatus 2. Reduced Na concentration in DCT triggers renin release 3. Sympathetic activation of b-adrenergic receptors stimualtes renin release --Epi, NorEpi Redundant system to ensure that when BP drops, body secretes renin |
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Juxtaglomerular Cells
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-Produce renin, secrete renin
-In afferent arterioles of renal glomerulus -Act as intra-renal pressure sensor --have stretch sensors, monitor how much pressure is on arteriole -Low pressure results in secretion of renin --increases systemic blood pressure |
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Angiotensinogen
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-Abundant protein in plasma in healthy people
-Cleaved from N-terminus by renin to form angiotensin I -Made by the liver, also found elsewhere -Biologically inert, needs renin to be converted to become active |
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Angiotensin Converting Enzyme
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-Always present
-Really a more non-specific enzyme, can also cleave other peptides -Cuts 2 AA from carboxy end of a peptide -Found in lumen of endothelial cells, including lung --highest concentration is in lung -Prefers substrates that do not have proline as dominant AA at carobxy terminus --will not cleave angiotensin II due to presence of proline --Does not cleave active peptide |
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Angiotensin II
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-Most active form
-Most potent vasoconstrictor in the body! -Most of information for specific activity is in C-terminal --last 7 AA are really important -Agonist activity depends on phenylalanine in 8 position on carboxy terminus -Substitution at position 1 and 8 creates a compound that is less susceptible to degradation by peptidases |
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Angiotensin III
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-Potent in some systems, important for aldosterone release
-Not useful for boosting blood pressure |
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Angiotensin II metabolism
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-Non-specific enzymatic breakdown
--Enzymes are very common, and angiotensin II does not last for long in the blood --15-60 seconds -Mostly destroyed by single pass through pulmonary vascular bed -Rapid removal by "angiotensinases" from circulation --aminopeptidases --endopeptidases |
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Steps in Activation of RAA system
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1. Stimulus that causes reduced blood pressure
-decreases perfusion of juxtaglomerular apparatus 2. Renin released by JG apparatus 3. Angiotensin II formation --most potent vasoconstrictor in the body --Vasoconstriction leads to increased BP --Aldosterone secretion from adrenal cortex prevents Na release Process increases blood volume (Na retention) and blood pressure (vasoconstriction) to increase renal perfusion |
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Aldosterone
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-Steroid hormone
-Made in adrenal cortex zona glomerulosa -Regulates blood Na and K balance --allows reabsorption of Na and excretion of K -Synthesis is stimulated by increased angiotensin II, ACTH, or K levels relative to Na -Can affect acid excretion in kidney, can be stimulated by acidosis -Can also be stimulated by atrial stretch receptors |
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Mechanism of Aldosterone Secretion
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1. Low blood pressure causes stretch receptors to stimulate adrenal gland to release aldosterone
2. Aldosterone increases Na resorption from urine, sweat, and gut -causes increased osmolarity of extracellular fluid 3. Water is retained and blood pressure goes back to normal |
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Renin-Angiotensin System in Adrenal Cortex
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-Stimulates synthesis and release of aldosterone from zona glomerulosa cells
-Augmented by hyponatremia and hyperkalemia -Allows for Na conservation |
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Renin-Angiotensin System in Kidneys
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-Antidiuresis and antinatriuresis
-Promotes Na reabsorption by kidney -Reduces glomerular filtration rate --slows filtering of fluids, might lose fluids |
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Renin-Angiotensin System in Cardiovascular System
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-Very potent vasoconstrictor
-Direct vasoconstriction action on vascular smooth muscles --augmented by Sympathetic nervous system -Increases cardiac contractility with little change in HR -Major role in pathogenesis of hypertension, even when plasma renin activity is not elevated --involved in pathological hypertension |
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Renin-Angiotensin System in Peripheral Autonomous Nervous System
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-Activates sympathetic nervous system via central effects in the brain
-Sympathetic post-ganglionic neurons are releaseing NorEpi -target organs increase sensitivity to NorEpi, results in more response -Adrenal medulla is activated and released catecholamines into the blood |
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Renin-Angiotensin system in the Central Nervous System
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-Circulating angiotensin II will increase sympathetic nervous system drive
-Angiotensin II can get access to brain areas that do not have BBB or weak BBB --activates receptors in these areas -Central pressor response activates sympathetic nervous system -Acts on endocrine system to release ADH and ACTH --ADH conserves H2O in kidney --activates cortisol response, boosts sympathetic activity and responsiveness -Changes behavior to increase thirst and appetite for Na |
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Renin-Angiotensin System in Cell Growth
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-Increases mitosis in vascular and cardiac cells
-May contribute to cardiovascular hypertrophy |
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Angiotensin Receptor
AT1 |
-Mediates most known functions of angiotensin
--Most cardiovascular effects -GPCR -Found on vascular smooth muscle -Activates phospholipase C and liberates IP3 and intracellular Ca --causes smooth muscle contraction -Activation leads to vasoconstriction -Blocking will prevent vasoconstriction |
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Angiotensin Receptor
AT2 |
-Similar affinity for angiotensin as AT1
-GPCR -Present in high density in fetal tissues --contributes to normal growth and development early in life -Found in some brain areas -Functions via serine and tyrosine phosphatases -Up-regulated in pathological conditions --heart failure, myocardial infarction -Ideally do not want to block AT2, has protective effects |
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Inhibition of Renin-Angiotensin System
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-Lots of steps in production, many ways to block action of system
1. Block renin secretion 2. Inhibit renin enzymatic activity 3. Block Convert angiotensin I to angiotensin II 4. Block angiotensin II receptors |
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Block Renin secretion
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-block sympathetic nerves
-Reduces angiotensin II levels |
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Inhibition of renin enzymatic activity
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-mostly experimental drugs
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Block conversion of angiotensin I to angiotensin II
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-ACE inhibitors
-Very convenient way to prevent effects of angiotensin II |
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ACE inhibitors
|
-Decrease systemic vascular resistance without increasing HR
-Promote natriuresis, excretion of Na (and H2O) -Effective treatment of hypertension --decrease mortality and morbidity in heart failure and left ventricular dysfunction -Delays diabetic nephropathy |
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Adverse Side effects of ACE inhibitors
|
-ACE is not specific to Angiotensin I, also converts other peptides
-Change breakdown of other peptides -Inhibits degradation of bradykinin --common side effect is coughing |
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Captopril
|
-ACE inhibitor
-Highly specific blocker of angiotensin I to angiotensin II -Very effective in treatment of hypertension -Most useful in combination with diuretic -Useful for congestive heart failure --reduces pre-load and afterload --improves CO and decreases congestion |
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Enalapril
|
-ACE inhibitor
-Prodrug ethyl ester that is hydrolyzed in the body -More potent than captopril -Lasts longer in the body --only need 1 dose per day |
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Angiotensin Receptor Antagonists
Peptide Congeners |
-Saralasin
-Antagonists with substitutions at positions 1 and 8 of angiotensin II -Bind to receptors but do not stimulate receptors -Anti-hypertensive effect -Only effective if administered IV |
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Angiotensin Receptor Antagonists
Non-peptide antagonists |
-Losartan, Valsartan
-Anti-hypertensive drugs with lower side-effects than ACE inhibitors --do not influence bradykinin system -Interact with AT1 receptor, not AT2 receptor --do not remove beneficial effects of angiotensin II |
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Kinins
|
-Potent vasodilator proteins
-Formed by cleavage of protein substrates (kininogens) -Kallikreins break down precursors into active forms -Lots of similarities to Renin-Angiotensin system |
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Kallikreins
|
-Glycoproteins
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Kininogens
|
-Precursors of kinins and substrates of kallikreins
-Present in plasma, lymph, interstitial fluid -High molecular weight form: 15-25% --in blood stream -Low Molecular weight form: act in tissues, can cross capillary walls |
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Kinins in Mammals
|
1. Bradykinin
2. Iysylbradykinin 3. Methoionyllyslbradykinin |
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Bradykinin
|
-Slows down HR
-Local inflammatory effects -Reduces BP -Very short half-life in blood -Designed to have local effects, not global effects |
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Kininase
|
-Breaks down bradykinin into an inert peptide
-Kininase=ACE! -inhibition results in Bradykinin increase, slower HR |
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Purpose of Inflammation
|
-Bring fluid, proteins, and cells from blood into damaged tissues
-Tissue response to damage -Facilitate healing process, repair damage |
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Cardinal signs of Inflammation
|
1. Heat: localized increased vasodilation
2. Redness 3. Swelling 4. Pain 5. Loss of Function |
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Acute Inflammation
|
-Initial response to tissue injury
-Release of autacoids |
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Chronic Inflammation
|
-Long-term inflammation
-No resolution of the underlying injurious process -Deposition of fibrous tissue |
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Mediators of Acute Inflammation
|
1. Histamine: vasodilation, increased vascular permeabiluty
2. Serotonin: increased vascular permeability --may or may not cause vasodilation 3. Bradykinin: vasodilation, increased vascular permeability, Pain 4. Prostaglandins: Vasodilation, vascular permeability, chemotaxis, pain 5. Leukotrienes: vascular permeability, chemotaxis |
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Prostaglandins and leukotrienes
|
-Major contributors to pain involved with inflammation
-Reducing prostaglandins and leukotrienes will reduce pain -Both are products of arachadonic acid, derived from fatty acids in lipid membranes |
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Mediators of Chronic Inflammation
|
1. Interleukins 1,2,3
2. GM-CSF 3. TNF-a 4. Interferons 5. PDGF3 (platelet-derived growth factor) |
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PDGF3
|
-Stimulates fibroboastic migration into area of inflammation
-Causes fibrous material to be deposited in an area -leads to fibrosis |
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Outline of Inflammatory Response
|
1. Cell damage causes:
--amplification of arachadonic acid cascade and production of leukotrienes and prostaglandins --Activation of inflammatory cells --Production of Oxygen derived Free radicals from neutrophil membrane, interact with fatty acids |
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Activation of Inflammatory cells in response to Tissue Damage
|
-Release of kinins, neuropeptides, histamines, and complement components
--stimulate some cells to produce arachadonic acids, leukotrienes, prostaglandins -Releases autosomal lysosomes |
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Oxygen derived Free Radicals
|
-Released during tissue damage from neutrophil membrane
-Activate immune cells in area -Interact with fatty acids and initiate arachadonic acid cascade |
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Arachidonic Acid Cascade
|
-Synthesis of Arachadonic acid from membrane phospholipids
--rate limiting step -Once arachadonic acids are formed, cell quickly makes leukotrienes and prostaglandins -Synthesis of eicosanoids (Prostaglandins and leukotrioenes) from arachadonic acid |
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Arachadonic Acid Cascade Steps
|
1. Tissue damage and disturbance of cell membranes
2. Phospholipase 2 activated, cleaves fatty acid chains from phospholipids in membrane --produce arachadonic acid 3. Arachadonic acid is converted into prostaglandin or leukotriene depending on cell type --specific type depends on cell --Lipoxygenase enzyme forms leukotrienes --cyclooxygenase enzyme forms prostaglandins 4. Eicosanoids mediate bulk of the inflammatory response |
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Cyclo-oxygenase
|
-Converts arachadonic acid into prostaglandins, thromboxane, and prostacyclin
-Target of many anti-inflammatory drugs |
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Lipoxygenase
|
-Enzyme that converts arachadonic acid into leukotrienes
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Leukotrienes
|
-Important role in airway inflammation and asthma
-Cause bronchoconstriction in airways -Potent chemotactic factor for macrophages, eosinophils, neutrophils -Potent vasoconstrictors -Secreted during asthma attacks and anaphylaxis -Stimulate T-cell expansion |
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Eicosanoids
|
-Prostaglandins, leukotrienes, thromboxanes
-Product of arachadonic acid metabolism -Have very short half-life -Bind membrane receptors on target cells -Induce changes in intracellular Ca levels -Stimulate inflammation response -MANY prostaglandin receptors |
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Factors governing which eicosanoids are produced
|
-Species
-Cell type -Phenotype of cell -Manner in which cell is activated |
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Prostaglandin Receptors
|
-LOTS of different receptors
-Some are inhibitory, some are contractile, some are relaxants -Could be inhibited, but inhibiting the receptors are not as effective as targeting something up-stream |
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Prostaglandin other functions
|
-Have homeostatic functions, are not only involved in inflammation
-Role in vascular smooth muscle contraction -Role in platelet formation and aggreagation -Role in thermoregulation -Gastric protection, stimulate bicarbonate production |
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Prostaglandin Types
|
-PGD, PGE, PGF
--responsible for edema and local swelling --regulate renal vasculature -PGE1 and PGE2: vasodilation --induce fever when present in cerebral ventricles |
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Inflammation-associated fever
|
-Infection leads to production of bacterial endotoxins
-Macrophages release IL-1 (pyrogen) -Has effect in hypothalamus to produce PGE -PGE elevate temperature set point, results in a fever -Fever is caused by PGE |
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Prostacyclin
PGI2 |
-Synthesized by vascular endothelial cells
-Inhibits platelet aggregation --allows fluid accumulation in region of tissue damage -Inhibits smooth muscle contraction, vasodilation |
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Thromboxane
TXA2 |
-Synthesized by platelets and macrophages
-Promotes platelet aggregation --antagonist for prostacyclin -Causes smooth muscle contraction, vasoconstriction |
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Pain associated with Inflammation
|
-Pain due to swelling and nociceptors becoming sensitized by prostaglandins and other inflammatory mediators
-INhibiting prostaglandin biosynthesis will dampen pain sensation |
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Strokes and NSAIDS
|
-NSAID disturbs the balance between prostacyclin and thormboxane
-Favors more inhibitory prostacyclin synthesis and results in strokes |
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Phospholipase A2
|
-Stimulated by cellular damage
-Cleaves some of fatty acid chain from cell membranes --converts to arachadonic acid -Inhibited by corticosteroids |
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5-lipoxygenase
|
-Present in lung, platelets, white cells
--neutrophils, mast cells, monocytes, macrophages, others -Converts arachadonic acid to leukotriene A4 -Following enzymatic steps produce bioactive leukotrienes |
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PGH Synthase
Cyco-oxygenase |
-Converts arachadonic acid to PGH2 in 2 steps
-Cyclooxygenase converts arachadonic acid into PGG2 -Peroxidase converts PGG2 into PGH2 -Biochemically adds 2 O2 molecules to arachadonic acid --peroxidase removes oxygen free radical |
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Cyclo-oxygenases
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-PGH synthase-1 (COX-1)
-PGH Synthase-2 (COX-2) |
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COX-1 (PGH Synthase-1)
|
-Widely distributed "housekeeping" enzyme
-Constitutively expressed in platelets -present in most tissues -Has role in inflammation, larger role in homeostasis and gastric cytoprotection --Stimulates bicarbonate and mucous secretions in gastric mucosa -Exists as a dimer -Closely associated with membranes |
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COX-2 (PGH Synthase-2)
|
-Inducible in inflammatory and immune cells
-Induced 10-20x by growth factors and cytokines --IL-1 and TNF-a, activate NF-kB transcriotion factor -Want to inhibit during inflammatory reaction |
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NF-kB
|
-Transcription factor that is activated during inflammation
-Expression is elevated in many disease states -Enhanced in cancerous cells --plays some role in promoting cancer propagation -Stimulates production of many cytokines and COX-2 |
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NSAIDS
|
-Function by inhibiting Cyclo-oxygenase
-Prevent synthesis of prostagpandins and throboxanes -DO NOT inhibit synthesis of leukotrienes |
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Anti-inflammatory drugs
|
-Dampen inflammation pathways
-Do not eliminate cause of inflammation --underlying injury or autoimmune condition -Palliative effect -Have side effects |
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Pharmacological Targets of Arachadonic Acid Cascade
|
-Anything in the pathway could be inhibited
-Main inhibition occurs at Phospholipase A2 and cyclooxygenase stages -Phispholipase A2 -Cyclo-oxygenase -Lipoxygenase -Prostaglandin synthesis -Autacoid receptors |
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Glucocorticoids as Anti-inflammatories
|
-Steroid hormone derived from cholesterol
-Affect gene expression -Inhibit Phospholipase A2 --early step -Inhibit COX-2 induction --disrupt NF-kB function -Potent anti-inflammatory activity -Many side effects --interfere with adrenal function |
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Adrenal Glands
|
-Provide animal with capacity to adjust to environmental and metabolic stresses
-Produce glucocorticoids |
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Hormones of the adrenal cortex
|
-Glucocorticoids
--cortisol --corticosterone -Mineralocorticoids --aldosterone -Androgens and estrogens |
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Glucocorticoid Function
|
-Regulates blood sugar levels
-Regulates protein, fat, carbohydrate metabolism --regulates starvation stress -Suppresses inflammatory response -Regulated by ACTH from pituitary gland |
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Mineralocorticoids
|
-Aldosterone
-Increases Na reabsorption from glomerular filtrate in kidney -Increases K excretion -Increases fluid volume -Restores electrolyte balance -Raises blood pressure |
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Hypothalamus-Pituitary-Adrenal Axis
|
-Natural glucocorticoids in the blood negatively feed back in hypothalamus and anterior pituitary
--inhibit release of corticotropin-releasing factor from the hypothalamus -No ACTH stimulation for release in the pituitary -Shut down synthesis of ACTH and glucocorticoids -Stimulated by neural mechanisms physical or psychological stress, and diurnal fluctuations -Arenal cortex starts to atrophy if not stimulated by ACTH --causes addisonian crisis |
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Hydrocortisone
|
-Cortisol
-Predominates in man, dog, horse, pig -80-95% protein bound in the blood --corticoid binding globin produced in liver --patients with liver issues are more sensitive to glucocorticoid drugs -20% is free or loosely bound to albumin -Short plasma half-life, 60-90 minutes -Synthesized from cholesterol - |
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Corticosterone
|
-Cortisone
-Predominates in rodents -less protein bound that cortisol, shorter half-life |
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Corticoid Binding Globin
|
-produced in the liver
-Binds cortisol in the blood --80% of cortisol is bound -Synthesis increases during pregnancy -When saturated, free cortisol levels rise rapidly -Patients with liver issues are more sensitive to glucocorticoid drugs |
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Cortisol Metabolism
|
-1% excreted unchanged in the liver
-20% converted to cortisone in the kidney and other tissues -Inactivated and metabolized in the liver --conjugated with glucuronic acid -Excreted in the urine |
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Glucocorticoid Mechanism of Action
|
-Bound to globin in blood, not biologically active
-Free form enters target cells -Binds to intracellular receptor --glucocorticoid receptor -Receptor dimerizes and translocates into the nucleus --binds specific DNA sequences --Glucocorticoid response elements -Affects gene transcription --can activate or repress gene expression |
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Induced Glucocorticoid Genes
|
-Lipocortin1/Annexin 1
--inhibitor of Phospholipase A2, negative feedback -MAP kinase phosphatase -IkB, NF-kB inhibitor |
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Repressed Glucocorticoid Genes
|
-POMC/ACTH
-IL-1 -IL-2 |
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Metabolic Effects of Glucocorticoids
|
-Maintain adequate glucose supply to the brain
-Stimulate gluconeogenesis during gasting -Increases glucose production from proteins --proteolysis of muscle, bone, skin, lymphoid etc. -Increase liver glycogen deposition -Increased glucose stimulates insulin secretion -Decreases cellular uptake of glucose -INhibits glucose uptake by peripheral fat cells -Increased fat deposition around the abdomen |
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Anti-Inflammatory effects of Glucocorticoids
|
-Block all known pathways of eicosinoid synthesis
-Indirectly inhibit phospholipase A2 synthesis --may interfere with phospholipid binding -Stimulate synthesis of lipocortin I/Annexin I --directly inhibits Phospholipase A2 -Inhibits NF-kB dependednt COX-2 induction |
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Mechanisms by which Glucocorticoids dampen inflammation
|
1. INhibit COX-2 expression
--interferes with NF-kB 2. Stimulates lipocortin/annexin expression --inhibits phospholipase A2 3. Inhibits phospholipase A2 by inducing MAP kinase phosphatase I expression |
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Lipocortin 1
|
-Annexin 1
-Production is stimulated by.... -Lipocortin 1 binds to ... and keeps in inactive -May share therapeutic activities of glucocorticoids with fewer side effects --not practical for therapeutic uses |
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Anti-inflammatory effects of Glucocorticoids
Peripheral Leukocytes |
-Suppresses immune system
-Decreases number of neutrophils at site of inflammation --decreased migration from vessels --endothelial cell adhesion molecules -Increases overall number of neutrophils in blood --influx into blood from bone marrow -Decreases lymphocytes, eosinophils, basophils, and monocytes --movement of cells from vascular compartment to lymphoid tissue |
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Anti-inflammatory effects of Glucocorticoids
|
-Inhibit ability of lymphocytes to respond to antigens
-Inhibit histamine release -Reduce cytokine function -Inhibit macrophage phagocytosis -Decrease vascular permeability --inhibits autacoid release --inhibits induction of an endothelial enzyme that increases NO |
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Therapeutic uses of ACTH
|
-Not practical as an Anti-inflammatory drug
--to many side-effects --stimulates production of androgens and mineralocorticoids -Can be used to diagnose adrenal insufficiency (Addison's disease) |
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|
Addison's Disease
|
-Chronic Adrenal insufficiency
-Inability to maintain glucose levels during fasting -Hyperpigmentation, weakness, fatigue, weight loss, electrolyte imbalance -Minor trauma or infection may produce acute adrenal insufficiency and lead to shock or death -Treat with glucocorticoids and mineralocorticoid |
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Cushing's Disease
|
-Adrenalcortical hyperfunction
-Usually caused by pituitary adenoma that produces excess ACTH -Leads to excessive glucocorticoid production --hyperglycemia, hypertenions, diabetes -Will have face and trunk obesity -Muscle wasting, thinning of skin -Poor wound healing -Osteoporosis -Tx: drug therapies or removal or tumor --follow with hormone replacement therapy |
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Cortisol/Hydrocortisone
|
-glucocorticoid
-Standard for steroid anti-inflammatory drugs -Has many side-effects |
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Metabolic effects of Glucocorticoids
|
-Suppress ACTH release
--leads to atrophy of the adrenal cortex -Cause weight gain via hyperglycemia and increased insulin requirements -Electrolyte imbalances --increased Na and increased body volume |
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Other effects of Glucocorticoids
|
-Weakness
-Increased gastric acid and pepsin secretion -increased number of platelets and RBCs -Effects on fetal development --higher abortion rates in cattle |
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Immunosuppression and glucocorticoids
|
-Slow wound repair
-Large doses can suppress antibody production -Impaired hypersensitivity reactions -Infections may persist |
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|
Fluid and electrolyte disturbances with glucocorticoids
|
-Mineralocorticoid effect
|
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Glucocorticoids and glaucoma
|
-Increased intraocular pressure leads to cataracts and glaucoma
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|
Synthetic Glucocorticoids
|
-Actions are similar to cortisol
--bind same receptor -Can be short, intermediate, or long-acting -Oral, topical, IV, and IM forms |
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Cortisol an Mineralocorticoid activity
|
-It has it
-Can make chemical modifications to cortisol to engineer out mineralocorticoid activity -Change glucocorticoid to mineralocorticoid ratio --add a double bond --forms prednisolone --less water retention with prednisolone than with cortisol and increases half-life |
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Categories of Action for Synthetic Glucocorticoids
|
-Short acting: 1-24 hours
-Intermediate acting: 24-48 hours -Long acting: more than 48 hours -Ultra long acting: several weeks -Addition of fluoride increases time of elimination, increases halflife |
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Modifications to Ester groups in Glucocorticoids
|
-In general, less soluble esters increase glucocorticoid half-life
-Drug is not active until esterase cleaves groups |
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Solubility of groups on synthetic glucocorticoids
|
1. Water Soluble
--phosphate --succinate esters of a drug 2. Poorly water soluble --acetate, diacetate 3. Non-water soluble drugs --Acetonide, diproprionate |
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Hydrocotisone
|
-Low anti-inflammatory activity
-Has some mineralocorticoid activity --retains water -Oral, injectable, and topical forms available |
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Prednisone
|
-More anti-inflammatory activity that cortisol
-Less mineralocorticoid activity |
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|
Prednisolone
|
-Short-acting
-Double bond between carbons 1 and 2 --gives less mineralocorticoid activity, 70% less -More anti-inflammaotry activity than cortisone, 4x -Water soluble -Orally administered --also topical or injectable |
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Methylprednisolone
|
-Methylated derivative of prednisolone
-short-acting -4-5x anti-inflammatory activity of cortisol -Very little mineralocorticoid activity -Oral, topical, and injectable forms exist |
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|
Triamcinolone
|
-Intermediate-acting synthetic glucocorticoid
-Very similar to dexamethasone, has substitution instead of methyl group -Oral and topical forms --oral is 5x activity --topical is 5-100x activity, acetonide increases surface activity -Very little mineralocorticoid activity -Similar to dexamethasone |
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|
Dexamethasone
|
-Long-acting, fairly slow onset of action (6 hours)
-Lower doses needed -30x anti-inflammatory activity of cortisol -Very little mineralocorticoid activity -oral, topical, and injectable forms |
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|
Most common Side Efects of Short-term Glucocorticoid Therapy
|
-Increased susceptibility to infection
-Increased urination and thirst (PU/PD) -Increased appetite -Behavioral mood changes -Diarrhea -Development of pancreatitis -gastric ulceration -Dogs get hepatomegaly -Long-term leads to suppression of HPA axis and cushing's syndrome |
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|
Hyperadrenocorticism Symptoms
|
-Looks like Cushing’s disease
-Suppression of the immune system: --decreased lymphocyte proliferation --increased incidence of infections in skin, urinary tract, and respiratory tract -Poor wound healing -Tendon, ligament, joint abnormalities -Dull/dry hair coat or hair loss -Dry, thin skin that bruises easily -Decreased muscle mass and tone --weak abdominal muscles give pendulous abdomen --Muscle pain, stiff gait, rigid limbs |
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|
Glucocorticoid Therapy
|
-Short-term therapy is faster acting
-Good for acute inflammation -Sooner patient is treated with glucocorticoids, the less inflammation-associated damage there is -Taper off the drug --if withdrawn abruptly adrenal gland may not recover -Prolonged adrenal suppression may cause irreversible damage |
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Glucocorticoid Alternate Day Therapy
|
-For long-term therapy
-Short half-life and water soluble --drug should be gone from system by day 2 -Ensures less suppression of the adrenal gland endogenous cortisol and ACTH |
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|
Glucocorticoid Repositol Therapy
|
-Good for cats, not good for dogs
--Cats are less sensitive to side effects -Methylprednisolone acetate, triamcinolone acetonide -Long-lasting (weeks to months) -Give when oral medication is impossible |
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Topical Therapy of Glucocorticoids
|
-Ointments, creams, lotions, etc.
-readily absorbed through the skin -May suppress HPA axis |
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NSAIDs
|
-Competitively inhibit cyclo-oxygenase from interacting with arachadonic acid to convert into prostaglandins
|
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|
Cyclooxygenase Inhibitors
|
-Chemically diverse
-Weak acids -Most inhibit both COX-1 and COX-2 -Unwanted side effects are due to inhibition of COX-1 -Do not inhibit tissue damage caused by release of lysosomal enzymes and toxic oxygen radicals |
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Aspirin and Salicylates
|
-Similar to Sodium Salicylates
-Absorbed in stomach and upper small intestine -Acid medium in stomach promotes absorption --keeps salicylate in non-ionized form --poorly absorbed in horse and cows -Salicylate binds albumin in serum --higher dosages result in higher concentration of un-bound drug |
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Salicylate
|
-Aspirin is converted to salicylate by esterases in tissues and blood
-Competitive inhibitor of arachadonic acid |
|
|
Irreversible COX inhibitor
|
-Aspirin
-Only NSAID to covalently modify COX -Acetylates COD, prevents enzyme binding to arachadonic acid -More effective COX-1 inhibition than COX-2 -Peroxidase activity is not affected -Scavenges oxygen free radicals --contributes to inhibition of prostaglandin synthesis |
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Other effects of Aspirin
|
-Analgesic: reduces pain by inhibiting pain stimuli and reducing inflammation
-Antipyrogenic: blocks pyrogen-induced prostaglandin synthesis -Platelet effects: inhibits COX-1, inhibits thromboxane synthesis in platelets, inhibits platelet aggregation --irreversible until new platelets are formed --Platelets do not have nuclei, no way to up or down-regulate production --no place for glucocorticoids to have effect |
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|
Aspirin Inactivation
|
-Inactivated by conjugation to glucuronic Acid
-Different species have different amounts of glucuronidation activity --lower glucuronidation activity leads to longer plasma half-life for aspirin --T1/2 is variable -Salicylate conjugates are cleared via kidney --excretion is faster in more alkaline urine -Conjugates to glutathione when glucuronic acid is absent |
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Adverse effects of Aspirin
|
-gastric Ulceration and GI disturbances
-COX-1 inhibition of gastric cytoprotection --prostaglandins stimulate bicarbonate and mucous secretions in gastric mucosa -Gastric irritation can be decreased by raising gastric pH to 3.5 or higher -Can administed misoprostol, Prostaglandin analog |
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|
Adverse effects of Aspirin at High Doses
|
-Salicylism
--dizziness, deafness, uncoupled oxidative phosphorylation, increased O2 consumption -Fever -Dehydration -Renal damage -Generalized hemorrhage -Convulsions or coma |
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Para-Aminophenols
|
-Acetaminophen: tylenol, paracetamol
-Phenacetin: breaks down to acetaminophen -Reversible inhibition of COX, COX-3?? -Competes with arachadonic acid binding -Effective analgesic and antipyrogenic, poor anti-inflammatory -Not very useful as anti-inflammatory agents in vet med -Rapidly absorbed in the GI tract -80-90% is conjugated to glucuronic acid -High doses cause accumulation of toxic by-product in liver |
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Adverse effects of Acetaminophen
|
-HIGHLY toxic to cats
-Oxidized in liver to toxic metabolite that depletes glutathione -Causes hepatic necrosis and methemoglobin formation -Hemolytic anemia -Denaturation of RBC membranes causes hypoxia |
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Phenylproprionic Acids
|
-Ibuprophen
-Naproxen -Carprophen -Competitive reversible inhibitors of COX --interfere with arachidonic acid binding -Compete with aspirin for plasma protein binding sites |
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|
Ibuprophen
|
-Moderate COX inhibitor
-More selective for COX-2 -Less toxic to has -Toxic to dogs --causes ulcers and kidney failure |
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|
Naproxen
|
-Approved for use in horses and dogs
-Works equally on COX-1 and COX-2 |
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|
Adverse effects of Phenylproprionic Acids
|
-Possible nephrotoxicity
-Nausea -GI toxicities -Peripheral edema |
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|
COXIBs
|
-COX-2 selective drugs
-Carprophen (Rimadyl) --least selective -Etodolac (Etogesic) -Deracoxib (Deramaxx) -Firocoxib (Previcox) -Robenacoxib (Onsior, for CATS) |
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|
COX-2 selectivity
|
-Make molecule a little larger so it can only fit into COX-2 binding site
-Will only inhibit COX-2 |
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|
Homeostasis of Platelet Aggregation
|
-Some coxibs can disrupt balance
-Shift balance towards platelet aggregation -Occurs when only COX-2 is inhibitied -has not been demonstrated to occur in animals, only in humans |
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|
Carprophen
|
-Rimadyl
-Only officially approved for dogs -Pain relief, joint pain, post-surgical inflammation -Proprionic acid -More selective for COX-2, inhibits COX-1 only slightly -Not approved for use in cats -Insoluble in water -Metabolized in the liver and excreted in the feces -T1/2 in dogs is 8 hours |
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|
Adverse Effects of Carprophen
|
-Gastric Ulceration
-Nausea, appetite loss, vomiting, diarrhea -Hepatopathy, liver toxicity --occurs within first 3 weeks --If ignored, can be life-threatening and irreversible damage --3-4x high concentration of liver enzymes in the blood -Labrador Retrieveres are over-represented -Make sure animal does not have liver damage before giving |
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|
Renal side effects fo Carprophen
|
-Due to COX-1 inhibition
-Excess water consumption and urination (PU/PD) -Loss of balance, hyperactivity, depression, and aggression |
|
|
Carprophen Conraindications
|
-Pre-existing liver, kidney disease or GI ulcerations
-Should not be used with other NSAID or corticosteroid drugs -Not recommended for pregnant or nursing females --has not been sufficiently tested |
|
|
Etodolac
|
-Approved for dogs
-T1/2 is 8-14 hours -Metabolized in the liver and excreted in feces -Extensive enterohepatic recycling -Side effects of GI ulceration |
|
|
Deracoxib
|
-Approved for use in dogs
-Control post-operative pain and inflammation -Relatively short half-life with low doses -Larger doses have longer half-life |
|
|
Firocoxib
|
-Previcox, Equioxx
-Approved for dogs and horses -T1/2: --8 hours in dogs --30-40 hours in horses -Hepatic clearance |
|
|
Selectivity Assays
|
-IC50 ratio: give idea for how selective a drug can be
-Concentration of a drug needed to inhibit processes by 50% -high ratio is more COX-2 selective -Ratio does not correlate to efficacy --drugs with large COX-1 action will also have COX-2 activity -Deracoxib has highest ratio, least COX-1 inhibition -Aspirin has lowest ratio, affects both COX-1 and COX-2 |
|
|
Most Common NSAID side effect
|
-Gastric Intolerance and Ulceration
-Especially in Dogs |
|
|
NSAIDs for Cats
|
-Not commonly used
-Cats do not tolerate any NSAID well -Robenacoxib and Meloxicam are only 2 approved |
|
|
Robenacoxib
|
-NSAID in cats
-New COX-2 selective inhibitor -Tablet and injectable forms -27 hour halflife -Metabolized in liver and excreted in feces -Adverse reactions in digestive tract reported |
|
|
Meloxicam
|
-NSAID in cats, relatively safe in dogs
-Considered COX-2 selective at low doses -97% is bound to plasma proteins -Metabolized in the liver -Eliminated in feces -Only approved for a single injection to relieve post-operative pain -Repeated use is associated with renal failure and death |
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|
Flunixin meglumine
|
-Banamine
-Irreversible, non-covalent COX inhibitor -Possibile weak inhibitor of 5-lipoxygenase -Powerful analgesic -Long duration, 24-36 hours -2 hours onset of action, maximum action at 12 hours -Administered IV or IM -Used mostly in horses and cattle -DO NOT use in cats |
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|
Flunixin meglumine Advantages
|
-More potent analgesic than other available inhibitors of prostaglandin synthesis
-Rapid onset and long duration of action --will have effect within 2 hours of administration, lasts 24-36 hours -Useful for relieving pain associated with musculoskeletal disorders, surgery, GI spasm, and endotoxic shock --helpful for colics |
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|
Flunixin meglumine Adverse effects
|
-Ulceration of tongue, lips, gums, palate, stomach
-Anorexia -CNS depression -May cause acute renal failure in dogs --unknown mechanism --need to ensure adequate hydration, avoid decreases in BP and blood volume |
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|
Phenylbutasone
|
-Irreversibly binds COX
--non-covalent -Metabolized to oxyphenobutasone active metabolite -Can stick around in the body for a long period of time -NOT approved for food animals -99% of drug binds to plasma proteins -Approved for dogs and horses --most popular NSAID in horses |
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|
Bute Duration of Action
|
-LONG duration of action
--24-72 hours -New COX has to be synthesized in order to synthesize more prostaglandins -Oxyphenbutazine metabolite persists in the body -Plasma bound drug can penetrate inflamed tissues -Excreted via kidneys |
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|
Bute administration
|
-Orally or IV in dogs and horses
-Can cause local irritation and phlebitis if injected perivascularly |
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|
Bute Adverse Effects
|
-Oral and GI tract erosions, diarrhea, depression
-Death (if enteropathy leads to decreased blood volume, hypovolemic shock, circulatory collapse) -Do not use if patient has hematocytologic disorders --cardiac, renal, or hepatic dysfunction also no-go -Can cause permanent kidney damage if animal is dehydrated |
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|
Aspirin Unique Features
|
-Irreversible COX inhibitor
-Increased toxicity in Cats |
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|
Phenylbutazone Unique Features
|
-Most popular NSAID in horses
-Induces hepatic CYP450 enzymes -Idiosyncratic bone marrow toxicity |
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|
Acetominophen Unique Features
|
-Does not inhibit platelet function
-TOXIC in cats |
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Ibuprophen unique feature
|
-Enhanced ulcer formation in dogs
|
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Naxproxen unique features
|
-Enhanced ulcer formation in dogs
|
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|
Carprophen unique feature
|
-Idiosyncratic hepatotoxin
|
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|
Flunixin meglumine Unique features
|
-Potent analgesic agent for horses
|
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|
Tepoxalin
|
-Zubrin
-Cox inhibitor -Dual LOX/COX inhibitor? --inhibits 5-lipoxygenase -Approved for drugs -Lipophilic -Converted to an active carboxylated metabolite -Hepatic clearance -T1/2 in dogs is 12-14 hours |
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|
Dimethy Sulfoxide
DMSO |
-Non-COX inhibitor
-Clear, odorless liquid -Solvent for Aromatic and Unsaturated hydrocarbons, organic nitrogen cpds, and inorganic salts -Rapidly penetrates the skin -Breaks down to DMS and other metabolites --excreted via kidney -Some is expelled in breath --halitosis is common side effect, smells like garlic/oysters |
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DMSO therapeutic Features
|
-Anti-inflammatory
-Analgesic -Anti-microbial -Anti-fungal -Anti-diuretic -Anti-cholinesterase |
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DMSO Anti-inflammatory effects
|
-Not well understood
-Traps cytotoxic free radicals released from leukotrienes during injury and inflammation |
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DMSO Analgesic
|
-Thermal activity may relieve muscle and joint pain
-Appears to slow conductance of non-myelinated nerve fibers -Has anti-microbial, anti-fungal, anti-diuretic, and anti-cholinesterase function with unknown mechanism |
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|
DMSO Administration
|
-Topical
-Readily penetrates the skin -Causes hemolysis when injected IV in concentrations greater than 40% -Readily penetrates the skin, rapidly distributed to all parts of the body |
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DMSO Adverse Effects
|
-Can introduce external toxins into the body
--Wear gloves when administering -Can induce degranulation of mast cells -May cause cataracts in dogs -May be teratogenic |
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|
Enteric Nervous System
|
-Branch of Autonomic nervous System
-Receives input from SNS and PNS -Can act semi-autonomously, thought of as a 3rd division of the ANS -Myenteric plexus: GI motility -Submucosal plexus: secretion and absorption |
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Electrical Activity of the GI system
|
-GI smooth muscle activity is controlled on 3 levels
--Extrinsic Autonomic Nervous System --Intrinsic Nervous System --Receptors mediated by neuropeptides -ACh used for intrinsic and extrinsic systems --adrenergic stimulation decreases motility -Vasoactive intestinal Peptide, substance P, gastrin, motilin, and ghrelin modulate gasric and intestinal motility -Slow waves during resting -Spikes during activity, leads to depolarization |
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Laxatives and Cathartics
|
-Promote defecation
-Cleanse bowels for radiographic procedures, surgery, colonoscopy -Eliminate toxins during poisonings -Reduce fecal impaction, non-dietary constipation |
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Laxatives
|
-Elimination of soft formed stools
|
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Cathartics
|
-Elimination of more liquid stools
|
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Bristol Stool Chart
|
Type 1: separate hard lumps, like nuts
--hard to pass Type 2: sausage-shaped but lumpy Type 3: Like a sausage but with cracks on surface Type 4: like a sausage or snake, smooth and soft Type 5: Soft blobs with clear-cut edges Type 6: Fluffy pieces with ragged edges, mushy stool Type 7: Watery, no solid pieces, entirely liquid |
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Types of Laxatives and cathartics
|
-Stimulants
-Surfactant laxatives -Lubricants -Bulk forming laxatives -Osmotic Agents |
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Stimulants
|
-Promote accumulation of water and electrolytes in lumen of the colon
-Stimulate intestinal motility, muscle contraction -Slow onset of action (6 hours) -Ex: Bisacodyl --intestinal and bacterial enzymes convert into active metabolite |
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Bisacodyl
|
-Diphenthylmethane derivative
-Slow onset of action, works in colon -Rapidly converted by intestinal and bacterial enzymes into active desacetyl metabolite |
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Docusate
|
-Anionic surfactants that have detergent-like action
-Acts as stool-wetting and stool-softening agent -Allows mixing of water, lipids, and fecal material -Stimulates intestinal water and electrolyte secretion to soften stools |
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Surfactant laxatives
|
-Hydrophilic end and long tail
-Anionic -Detergent-like action -Stool-wetting and stool softening agent -Allows mixing of water, lipids, and fecal material -Stimulates intestinal water and electrolyte secretion to soften stools |
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Lubricants
|
-Soften and lubricate fecal material to facilitate expulsion
-Mineral oil |
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Mineral Oil
|
-Lubricant
-Aliphatic hydrocarbon, obtained from petroleum -Indigestible and not absorbed by intestine -Needs to be taken for 2-3 days for effect -Can cause malabsorption of fat-soluble vitamins and drugs |
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Bulk Forming Laxatives
|
-Dietary fiber
-Indigestible plant cell wall material -Not digested in intestine, but absorb water and expands, increases bulk -Expansion stimulates stretch reflex, stimulates expulsion -Day onset of action -Flatulence is side-effect -Need to stay hydrated, material absorbs water out of lumen |
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|
Osmotic Agents
Hypertonic Agents |
-Cause osmotic movement of water into gut lumen
-Hypertonic agents cause osmotic movement of water into the gut lumen --Mg, Tartarate Na salts, lactulose, glycerine, sorbitol, mannitol, polyethylene glycol --Movement of water into lumen increases stool volume --Stimulates mechanoreceptors and results in increase in peristaltic activity -Potential for dehydration exists |
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Osmosis
|
-Movement of water across a semi-permeable membrane from areas of high concentration to areas of low concentration
-Moves from Low concentration of solute to high concentration of solute -Seeks equilibrium of concentration |
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Osmotic Agents
Isotonic Agents |
-PEG electrolyte solution
-Isotonic water in, water out -results in copious watery stools -No movement of fluid into intestine -No dehydration, no differential osmotic pressure |
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|
Magnesium Hydroxide
“Milk of Magnesia” |
-Has laxative action
-Cause diarrhea -Draw fluid into the lumen of intestine -Distention of bowl due to increased fluid in intestine induces peristalsis |
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|
Anti-diarrheal agents
|
-Oral rehydration
-Opioid agonists -Bismuth salicylates -Kaolin-pectin suspensions |
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|
Oral Rehydration for Diarrhea
|
-Main risk in acute diarrhea is dehydration
-Need to replace fluids and electrolytes lost |
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|
Opioid Agonist for diarrhea
|
-Act on Mu and Delta receptors in myenteric plexus
-Decreases motility of large intestine -Allows more time for water resorption -Activate Mu receptors and increase sphincter tone -Imodium, Lomotil --structurally similar to demerol, potentially addictive --sold in combination with atropine to induce unpleasant side-effects and decrease abuse potential |
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|
Bismuth Subsalicylate
Anti-diarrheal |
-treats mild to moderate diarrhea
-Mechanism is not understood -Absorption of toxins by bismuth? -Antiinflammatory effect of salicylate? -Used in dogs, horses, cattle -NOT in cats |
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|
Kaolin-pectin suspensions
|
-Anti-diarrheal
-Colloid suspension with kaolinite --Absorbs water -Decreases fluidity of fecal material -need to be sure to stay hydrated -Give orally every 4-6 hours -Used in dogs, cats, horses, cattle, swine, sheep, birds |
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|
Vomiting
|
-Protective mechanism to remove toxins from the body
-Can be humorally mediated or neurally mediated |
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|
Humorally-mediated emesis
|
-Kidney failure
-Liver disease -Endotoxemia -Digoxin toxicity -Apomorphine |
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|
Neurally-mediated emesis
|
-GI infection
-GI toxicity -GI inflammation -Malignancy |
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|
Physiology of events during vomiting
|
-contraction of abdominal muscle
-Crainal movement of diaphragm -Contraction of pylorus and antrum -Relaxation of gastroesophageal sphincter -Relaxation of the cricopharyngeus -Closure of the glottis -Respiratory inhibition -Closure of the nasopharynx -Main concern is aspiration of vomitus |
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|
Physiology of Emesis
|
-Highly regulated protective reflex
-Coordinated in emetic center in lateral reticular formation in medulla --Lower order process -Afferent inputs: --chemotrigger zone --Vestibular system --peripheral sensory receptors in stomach and intestine --higher CNS nervous system centers |
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|
Signals promoting vomiting
|
1. Chemotrigger zone
2. Ear vestibular nucleus 3. Gut sensory receptors 4. Gut irritant receptors |
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|
Metabolic consequences of Vomiting
|
-Dehydration
-Electrolyte imbalances --Hypokalemia --hypochloremia --hyponatremia --Alkalosis, increased blood pH due to loss of acids |
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|
Drugs controlling emesis
|
-A2 Adrenergic antagonists
-Dopamine antagonists -5-HT3 serotonin antagonists -Opioid antagonists -Antihistamines -Anticholinergics -Neurokinin-1 antagonists -Cannabinoids |
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|
A2 adrenergic antagonists and Emesis
|
-Compounds are Antagonists for multiple receptors
-Chlorpromazine -Prochlorperazine -Weak dopamine receptor antagonism -Weak histamine receptor antagonism -Weak cholinergic receptor antagonism -Blocks vomiting reflex at emetic center at CRTZ -Used mainly in dogs and cats as antiemetic |
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Side effects of A2 adrenergic Antagonists as anti-emetics
|
-mild sedation due to histamine receptor blockade
-Hypotension due to A1 receptor blockade -Contraindicated in horses due to ataxia |
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|
Dopamine Antagonists and Emesis
|
-Anti-emetic action due to blocking D2
--Receptors in CRTZ -At high doses blocks 5-HT3 serotonin receptors --can contribute to anti-emetic properties -Prokinetic, increases peristalsis in jejunum and duodenum --due to muscarinic activity, D2 antagonism, and 5-HT4 receptor agonism -Side effects include hyperactivity, tremors, and constipation |
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|
Serotonin Antagonists and emesis
|
-Ondansteron and Granisteron
-Anti-emetic action due to blocking serotonin receptors in CRTZ and GI tract -Oral or IV dosage used to control nausea due to radiation and chemotherapy -Side effects include transient headache, constipation, and dizziness |
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Opioid Antagonists and emesis
|
-Butorphanol (torbugesic)
-Synthetic opioid receptor antagonist -Acts on opioid receptors in emetic center and higher CNS centers, blocks receptors for anti-emetic effect -Sedation is common side-effect -Used to prevent emesis after chemotherapy |
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|
Anti-histamines and Emesis
|
-Dimenhydrinate (Gravol, Dramamine)
-Mainstay therapy for nausea caused by motion sickness -Anti-emetic activity due to blockade of H1 histamine receptors in CRTZ -Sedation is common side-effect (CNS H1 receptors) -Not effective in cats -Used to prevent vomiting due to motion sickness |
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|
CRT zone in Cats
|
-Signal from vestibular nucleus in ear goes directly into emetic center in cats
-Does not go to CRT zone, impulse is not mediated by CRT zone -In dogs, vestibular nucleus impulses pass through CRT zone to emetic center |
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|
Meclizine
|
-Dramamine II
-Therapy for nausea caused by motion sickness -Anti-emetic activity due to blockade of central H1 histamine recptors -Sedation is a less common side effect -Used to treat vertigo due to inner ear infections |
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|
Anti-cholinergics and emesis blocking
|
-Scopolamine
-Topane alkaloid with antimuscarininc activity -Blocks muscarinic receptor mediated emetic impulses from vagal affferent pathways to emetic center -Effective for travel sickness |
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|
Propantheline, Isopropamide
|
-Anti-cholinergics used in dogs and cats to treat vomiting
-Not as effective alone as when combined with other medicines -Side effects include tachycardia, loss of visual accommodation, urine retention, constipation, and xerostomia |
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|
Neurokinin1 Receptor Antagnoists and Emesis
|
-Maropitant
-Neuropeptide Substance-P is cognate ligant for NK-1 -Activation of NK-1 in CRTZ induces vomiting -Used for motion sickness and comiting |
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|
Aprepitant
|
-"Emend"
-Neurokinin-1 antagonist used to treat vomiting -Chemotherapy-induced nausea and vomiting -Prevents post-operative nausea and vomiting in humans |
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|
Cannabinoids and Emesis
|
-Binds to CB1 and CB2 GPCR receptors in higher centers in the brain
-CB1 receptors are pre-synaptic modulatory receptors -Marinol has been approved for treatment of refractory nausea and vomiting in chemotherapy patients |
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|
Emetics
|
-Cause vomiting
-Expel non-corrosive poisons from stomach prior to induction of general anesthesia --80% of stomach contents are expelled -Centrally acting emesis -Peripherally acting emetics |
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|
Centrally acting Emetics
|
-Apomorphine:
--Non-sepective dopamine agonist related to morphine --Can be given IV, IM, SC --Stimulates CRTZ --Can cause paradoxical excitement in cats --contraindicated in cats -Xylazine: --A2-adrenergic agonist --Induces vomiting in cats, then mild sedation --dose for emesis is lower than dose for sedation |
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|
Peripherally acting Emetics
|
-Local irritants
-NaCl: saturated solution of table salt, induces vomiting in dogs and cats -H2O2: induces vomiting in cats -Syrup of Ipecac: induces vomiting in 15-30 minutes --peripheral irritant, has some central actions --contrainidcated for use in cats |
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|
Ayahuasca
|
-Psychoactive infusion from vine in S. America
-Used in shamanic rituals for religious ceremonies -Also has purgative properties |
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|
Sites of Action of Inhaled Anesthetics
CNS |
1. Spinal cord and Brainstem
--Inhibition of sensory processing --inhibition of nociceptive signaling --Inhibition of motor response to noxious stimulation, immobility 2. Brain --hypnosis and amnesia --analgesia 3. Interrupts communication between thalamus and cerebral cortex --patients cannot perceive pain |
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|
Lipid Theory of General Anesthetic Action
|
-Interactions with lipid matrix of the membrane
-Expands volume of lipid membrane by interacting with it --puts pressure on ionic channels, inhibits ion channels and prevent AP generation -Changes membrane physical state, change in consistency --prevents ion channels from functioning appropriately |
|
|
Ion Channel Mechanism of Action
|
-Trans-membrane ion channels
-Gates are closed, inhibits movement of ions across cell membrane -When a ligand binds to receptor, gates open and ion can move down-gradient across cell membrane -"Resting Membrane": closed ion channel -"Activated Membrane": open ion channel |
|
|
Effects of Anesthetics on Membrane Integrity
|
-Membrane area expansion
--increased pressure on ion channels, prevents opening -Fluidization of phospholipid bilayer -Inhibition of conversion into space-saving gel phase |
|
|
Protein Theory of Anesthetic Mechanism of Action
Excitation |
-Anesthetics act on proteins in lipid bilayer
-Direct interactions with hydrophobic sites on specific membrane protein channels --lipophilic anesthetics interact with hydrophobic sites more -Binding Causes conformational changes in ion channel -Can stabilize ion channels in closed state --closed ion channel, no ions move into cell -Ex: Central nicotinic ACh receptor, NMDA receptor |
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|
Protein Theory of Anesthetic Mechanism of Action
Inhibitory |
-Enhance function of inhibitory amino acid receptors or ion channels
-Increases influx via GABAa and Glycine receptors --make membrane potential more negative -Decreases excitability of the CNS -Potentiation of inhibitory currents via GABAa receptor and Glycine receptor |
|
|
Protein theory of Molecular Action and Effects on Nociceptive Signaling
|
-Inhibits glutamatergic synaptic transmission in dorsal horn of the spinal cord
-No nociceptive inputs to the dorsal horn of the spinal cord -Inhibits nociceptive signaling |
|
|
Nociceptive Signaling of Pain
|
-1st order neuron from free sensory nerve endings into dorsal horn of spinal cord
-2nd order neuron from spinal cord up to brain -3rd order neuron with brain |
|
|
Inhibition of Nociceptive Signaling
|
-Isoflurane administration decreases excitatory currents in neurons
-decreases activity of neurons responsible for transmitting sense of pain |
|
|
GABAa receptor
|
-Inhibitory NT, causes membrane hyperpolarization
-Inhbits excitability, hyperpolarizes membrane -Allows Cl into the cell, increases Cl permeability -Decreased excitability at the brain level -Sedation, amnesia, muscle relaxation, anticonvulsion |
|
|
Glycine Receptor
|
-Inhibitory NT, causes membrane hyperpolarization
-Increases Cl permeability -Has effect on spinal reflexes and startle responses -Major inhibitory receptor in spinal cord |
|
|
Neuronal Nicotinic ACh receptor
|
-Excitatory NT
-Highly permeable to monovalent cations and Ca -Modulates NT release -Association with memory, nociception, and autonomic functions |
|
|
Serotonin Receptor
|
-increases excitability by inhibiting K leaking out of the cell in the resting state
-Roles in arousal and possibly emesis |
|
|
Glutamate Receptors
|
-NMDA subtype
-AMPA/Kainate subtype -Fast excitatory neurotransmission -Cation conductance for Ca and Mg -Inhibition prevents perception, learning, memory --No perception and memory |
|
|
Group 1a compounds
|
-Provide amnesia and hypnosis
-No major role in pain transmission or loss of motor functions --minimal analgesia and immobility -Etomidate, propofol, Benzodiazepines |
|
|
Group 1b Compounds
|
-Provide amnesia, hypnosis, and immobility
-Not much analgesic effect -Isoflurane, Sevoflurane, barbituates -Affect GABAa, Glycine, Glutamate, Nicotinic ACh receptots, and K-channels |
|
|
Group 2 Componds
|
-Ketamine, NO
-Not very specific -Provide analgesia -Provides amnesia? -Do not provide hypnosis or immobility |
|
|
Dosing Inhaled Anesthetics
|
-Determined by Minimum Alveolar Concentration (MAC)
|
|
|
Minimum Alveolar Concentration
|
-Concentration of anesthetic that provides 50% of patients with immobility when a supramaximal noxious stimulus is applied
-Will cause the given effect in 50% of the patients -given as volume% or partial pressure -MAC is agent-specific, depends on drug -Can be species specific -Correlates inversely to oil/gas partition coefficient --More soluble anesthetics are more potent --less soluble anesthetics are less potent, need higher concentration to reach same behavioral endpoint -Give cushion to give more safety --1.3-1.4x MAC will give ED95 (surgical MAC) |
|
|
MAC value for different agents in Dog
|
Isoflurane: 1.28-1.5
Sevoflurane: 2.1-2.36 Desflurae: 7.2-10.3 N2O: 188-297 |
|
|
MAC value for agents in Cat
|
Isoflurane: 1.28-1.63
Sevoflurane: 2.58-3.41 Desflurane: 9.79-10.27 N2O: 255 |
|
|
MAC value for agents in Horse
|
Isoflurane: 1.31-1.64
Sevoflurane: 2.31-2.84 Desflurane: 7.02-8.06 N2O: 205 |
|
|
MAC value for agents in human
|
Isoflurane: 1.15
Sevoflurane: 1.58-2.05 Desflurane: 6.00 N2O: 104 |
|
|
Isoflurane MAC% in different species
|
Dog: 1.28-1.5
Cat: 1.28-1.63 Horse: 1.31-1.64 Human: 1.15 |
|
|
Sevoflurane MAC% in different species
|
-Dog: 2.1-2.36
-Cat: 2.58-3.41 -Horse: 2.31-2.84 -Human: 1.58-2.05 |
|
|
Desflurane MAC% in different species
|
Dog: 7.2-10.3
Cat: 9.79-10.27 Horse: 7.02-8.06 Human: 6.00 |
|
|
N2O MAC% in different spcies
|
-Not soluble AT ALL
-Need a hyperbaric chamber to get pure N2O concentrations to work -Not potent on own, can be used as adjuvant -Dog: 188-297 -Cat: 255 -Horse: 205 -Human: 104 |
|
|
Factors Affecting MAC value
Decreased inhalant needed |
-Old age
-Pregnancy due to endogenous opioid release -Hypothermia -Hypotension due to poor perfusion -Hypoxemia due to poor perfusion -Hyponatremia -CNS depressant drugs/analgesics |
|
|
Factors Affecting MAC value
Increased inhalant needed |
-Hyperthermia
-Hypernatremia -CNS stimulants |
|
|
Pharmacological Effects of Inhaled Anesthetics
|
-Gradual generalized depression of CNS
-Spinal cord goes 1st, then brain -Iso is more potent than Sevo, more potent than Des --N2O is much less potent -In terms of analgesia, N2O is MUCH more potent that Iso, sevo, or des |
|
|
Cerebral Effects of Isoflurane
|
-Cerebral metabolic rate decreases
-Seizure occurrence decreases -Increased ICP -Increased cerebral blood flow and increased preservation of cerebral blood flow autoregulation -More responsive to CO2 |
|
|
Cerebral Effects of Sevoflurane
|
-Decreased cerebral metabolic rate
-Decreased seizures in most --increased seizures in cats and children -increased ICP -Increased cerebral blood flow -Slightly increased CO2 responsiveness |
|
|
Cerebral Effects of Desflurane
|
-Decreases cerebral metabolic rate
-Increases ICP and cerebral blood flow -Decreases seizures |
|
|
Adverse effects of Inhaled Anesthetics on Respiratory System
|
-Cause respiratory depression
-Decrease ventilation, iso more than sevo and des --increased PaCO2 -Decrease RR (more objective measurement) -Causes Bronchodilation -All cause dose-dependent respiratory depression |
|
|
Adverse effects of Isoflurane on Cardiovascular System
|
-Significant decreases in myocardial contractility
--Less Ca available for contraction cross-bridging -Decreased systemic vascular resistance -Decreased BP -Increases HR |
|
|
Adverse Effects of Sevoflurane o Cardiovascular System
|
-Significantly decreases myocardial contractility
-Decreased systemic vascular resistance -Decreased BP -Decreases HR at lowed MAC, increases at MAC greater than 1.5 |
|
|
Adverse effects of Desflurane on Cardiovascular System
|
-Significantly decreases myocardial contractility
-Decreased systemic vascular resistance -Decreased BP |
|
|
Adverse effects of Inhaled Anesthetics on Kidneys
|
-Decreased renal blood flow due to decreased cardiovascular performance
-Decreased urine output |
|
|
Adverse Effects of Inhaled Anesthetics on the Liver
|
-Decreases hepatic blood flow
--Desflurane decreases much more than iso and sevo -Decreases injectable drug metabolism by 50-70% --CYP450 system -Can cause hepatotoxicity, usually negligible for iso, sevo, and des |
|
|
Adverse effects of Inhaled Anesthetics on Skeletal Muscle
|
-Decrease skeletal muscle tone
--due to decreases in CNS -Great muscle relaxants -Augment neuromuscular blockade by NDNMB |
|
|
Adverse effects of Inhaled Anesthetics on Fetuses
|
-Decreased uteroplacental blood flow
-Hypoxia to fetus! -May me mutagenic? Cause changes in gene expression --associated with malformations? |
|
|
Clinical Highlights of Isoflurane
|
-Most used inhaled anesthetic
-CHEAP -Useful for mask induction --non irritating to airways --Also pungent odor -Minimal metabolism, no direct toxic effects |
|
|
Clinical Highlights of Sevoflurane
|
-Effects are similar to isofluorane
-More expensive that Iso -Less soluble in blood and tissues than iso --can achieve changes in anesthetic depth faster --faster induction and slightly faster recovery -No pungent order, best choice for mask or inhalant inductions -Potentially less hypotensive -Causes less respiratory depression |
|
|
Sevoflurane and Renal/Hepatic Toxicity
|
-Hepatic metabolism to inorganic Fluoride
-Has potential to cause renal and hepatic damage -Renal toxicity has been demonstrated in rats -No evidence of fluoride-induced renal or hepatic toxicity in humans, dogs, monkeys, horses -not a major concern |
|
|
Sevoflurane and Compound A
|
-Breakdown of Sevo forms vinyl-ether compound (Compound A)
-Causes renal damage in rats -No evidence that Compound A causes toxicity in clinical vet med -No large enough concentration of Compound A to cause kidney damage |
|
|
Desflurane Clinical Highlights
|
-Least soluble inhalant anesthetic
--Very rapid induction and recovery -Extremely expensive, prohibitively expensive -Pharmacodynamic profile is similar to isoflurane --less CO depressant -Irritating to airways -Need special vaporizer due to volatility of gas -Needs time to warm up -Basically no metabolism |
|
|
N2O Clinical Highlights
|
-Gas at sea level
-Very weak anesthetic in animals --Have to deliver a high concentrations to have an effect -Has analgesic properties -Limited respiratory and cardiovascular depression -Stimulates sympathetic nervous system --may improve CO and arterial blood pressure -Has MAC sparing effects |
|
|
N2O MAC Sparing effects
|
-When used with other inhalants, requires less concentration of other inhalant
-More N2O, less inhalant you have to give -Inhalants cause respiratory and cardiovascular depression --using N2O can reduce effects |
|
|
N2O disadvantages
|
-Increased risk for arrhythmia
-Direct myocardial depression --increases in sympathetic tone counteract and provide cardiovascular stimulation -N2O diffuses into closed gas spaces --into gut and distends gut --into pleural space, causes pneumothorax -Risk for hypoxemia in large animals -Diffusion hypoxia -Bone marrow depression and changes in blood composition |
|
|
Balanced Anesthesia
|
-Combining injectable anesthetics, inhalation anesthetics, and regional anesthetics can provide for faster recovery
-Hypnosis and amnesia -Analgesia -Muscle relaxation -Absence of somatic or autonomic responses to noxious stimuli |
|
|
Balanced Anesthesia Protocols
|
-Injectible anesthetics with or without adjuncts
-Inhalation anesthetics -Regional anesthesia -Potent opioids, a2 agonists, ketamine, or lidocaine CRI --has MAC sparing effects -Neuromuscular blockers -Can have a dose reduction of individual drugs -Decreases adverse effects of any one drug -Will get more rapid recovery |
