Study your flashcards anywhere!

Download the official Cram app for free >

  • Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off

How to study your flashcards.

Right/Left arrow keys: Navigate between flashcards.right arrow keyleft arrow key

Up/Down arrow keys: Flip the card between the front and back.down keyup key

H key: Show hint (3rd side).h key

A key: Read text to speech.a key


Play button


Play button




Click to flip

121 Cards in this Set

  • Front
  • Back

When cells are damaged, they release prostaglandins in inflammatory exudates. Cause of erythema (increase in local blood flow), increased capillary permeability, infiltration of leukocytes and other phagocytic cells in the acute inflammatory response. COX-2 induces inflammation. Administration of NSAIDs reduces the ACUTE inflammatory response. Inhibition of cyclooxygenase doesn't explain effectiveness of NSAIDs in treatment of chronic inflammation like rheumatoid arthritis that involves an autoimmune response, fibrosis, and tissue degeneration. Other mechanisms may be involved.

Discuss ANTIPYRETIC effects of NSAIDs.
Fever is generated by a variety of pro-inflammatory cytokines produced in many disease states. Preoptic hypothalamus responds to cytokines by producing PGE2 which triggers a febrile response. Synthesis of PGE2 is blocked by NSAIDs. Drugs reduce body temp only in febrile subjects and DO NOT alter body temp in normal individuals.

Discuss ANALGESIC effects of NSAIDs.
NSAIDs eliminate the hyperalgesic effects of prostaglandins released during the inflamm process. NSAIDs act at region of tissue damage where prostaglandins sensitize pain receptors (decrease threshold of C nerve fibers). NSAIDs also act within the DNS to modulate perception of pain. Effective for mild to moderate pain originating in integumental structures. Not effective against visceral pain. Tolerance and addiction are not seen.

Discuss Primary and Secondary Prevention of MI and Stroke via inhibition of platelet aggregation.
Low dose aspirin is used to prevent MI and stroke. Aspirin is acetylsalicylic acid (ASA) which acetylates the active site of COX isoforms and irreversibly inhibits the generation of eicosanoids. In the platelet, COX-1 leads to synthesis of thromboxane (TXA2), a potent activator of platelet aggregation. Since platelets don't synthesize new protein, normal platelet function is only restored after production of new platelets. Other NSAIDs reversibly inhibit platelet cyclooxygenase, limiting potential therapeutic effects but minimizing toxic bleeding episodes. Permanent effect of aspirin to block thrombosis makes it standard therapy for secondary prevention in patients post-MI or stroke.

If I'm already taking aspirin to prevent MI or stroke, what can I take for pain?
Ibuprofen and naproxen can interfere with ability of aspirin to access the active site of COX-1 and thus irreversibly inhibit TXA2 synthesis. What do we do? Give acetominophen, diclofenac or a coxib. Increase aspirin to antiinflammatory doses. Time the aspirin dose to precede the NSAID dose (2 hrs before) but sufficiently after the previous NSAID dose (6-8 hrs for ibuprofen, etc.)

Discuss DYSMENORRHEA treatment by NSAIDs.
Prostaglandins have powerful effects on smooth muscle including uterine smooth muscle. Overproduction of prostaglandins during menstruation can be the cause of painful muscle cramping. Directly related to increased PG synthesis in the uterus. Aspirin is relatively ineffective, but ibuprofen, naproxen, and other NSAIDs are widely used.

What is Bartter's Syndrome?
This disorder results from overproduction of renal prostaglandins. NSAIDs other than aspirin are effective.

How do NSAIDs treat Patent Ductus Arteriosis?
PG's are involved in maintaining the patency of the ductus arteriosus. NSAIDs like indomethacin and ibuprofen have been given to neonates to effect closure. Be very wary about using these drugs during pregnancy, particularly near-term pregnancy.

How do NSAIDs treat Acute Gouty Arthritis?
Not sure! But they do. Some NSAIDs (NOT aspirin) have been found to be very effective in treating the pain and other symptoms of acute gouty attacks.
(PHARM 10)

How do NSAIDs treat Familial Adenomatous Polyposis and Colorectal Cancer?
COX-2 is induced in some neoplastic tissue so NSAIDs reduce formation of polyps in affected patients and cause regression of existing polyps. Prostaglandins can modulate the initiation and/or progression of cancerous cells via several mechanisms. ALSO, regulation of gene expression by COX-independent mechanisms is a second mechanism by which NSAIDs can be antineoplastic. Peroxisome Proliferator-Activated Receptor δ (PPARδ) is repressed in cells expressing the tumor suppressor APC. PPARδ is a ligand-dependent activator of transcription. SULINDAC suppresses colorectal cancer, by inhibiting PPARδ. Sulindac also induced apoptosis in tumor cell lines and inhibited DNA binding ability of PPAR δ /RXRalpha heterodimers.
(PHARM 11)

How do NSAIDs cause toxicity w/regard to GI tract function?
Chronic use of aspirin and other NSAIDs results in gastroduodenal lesions and GI blood loss. 2 ways that NSAIDs can cause gastric or intestinal ulceration. 1st is by direct irritation of the mucosa, since these drugs are acids. The 2nd involves inhibition of PG synthesis (PGI2 and PGE2) by constitutively active COX-1 in the gut. NSAIDs compromise other gastric mucosal defenses. Mucus gel is present at the lumenal surface of the gastric epithelium, which is bicarb-rich and maintains a neutral pH at the epithelial cell surfaces. Epithelial cells migrate in response to injury and regenerate. Adequate blood supply provides bicarb. NSAIDs interfere with all of these: (1) COX-1 inhibition contributes to decreased mucus production, (2) decreased HCO3- secretion, and (3) impaired mucosal proliferation. Addition of exogenous PGE2 overcomes the NSAID-induced reduction in basal bicarbonate secretion. MISOPROSTOL, an oral PGE1 analog, reduces the incidence of NSAID-induced gastric ulceration. However, use of misoprostol is associated with diarrhea in up to 30% of patients.
(PHARM 12)

How do NSAIDs cause renal toxicity?
Normally prostaglandins aren't needed to maintain renal blood flow – only play a small role. But in some clinical settings renal cortical eicosanoids, particularly prostacyclin, are req'd to increase renal blood flow and keep GFR adequate. Administration of NSAIDs to patients w/compromised renal function (due to renal disease or congestive heart failure) may result in precipitation of acute renal failure. Produces oliguria and hyperkalemia out of proportion to renal failure. Associated with a low fractional excretion of sodium. NSAID-induced renal insufficiency is common among patients w/chronic illness. Risk factors for NSAID-associated renal failure: (1) Decreased effective arterial blood volume: congestive heart failure, cirrhosis, nephrotic syndrome, sepsis, hemorrhage, postoperative state, volume depletion. (2) Normal or increased effective arterial blood volume: chronic renal failure, glomerulonephritis, contrast-induced nephropathy, elderly age, obstructive uropathy, cyclosporine use.
(PHARM 13)

What do you do when patients are NSAID-intolerant?
Substitute acetominophen for NSAIDs. Use COX-2 selective NSAIDs. Substitution of salsalid for other salicylates. Prophylaxis of ulcers with proton-pump inhibitors (omeprazole). Use of misoprostol or high dose H2-blockers to minimize GI mucosal injury.
(PHARM 14)

Discuss aspirin sensitivity.
8-25% of middle-aged patients w/asthma, nasal polyps or chronic urticaria. Symptoms may range from a runny nose to bronchial asthma, to hypotension and shock. Deaths have occurred. Patients who are intolerant of one NSAID are often intolerant of others: cross-sensitivity.
(PHARM 15)

Discuss bronchoconstriction resulting from NSAIDs.
Administration of NSAIDs will cause bronchoconstriction in 1 out of 10 asthmatics. Constrictor and dilator substances in the bloodstream normally act on smooth muscle in the bronchus. PGE2 is a dilating substance. NSAIDs decrease the amt of PGE2, resulting in greater effect of the remaining constrictors. Also, since COX and 5-lipoxygenase share arachidonic acid as a substrate, inhibition of substrate might provide additional substrate to the LO pathway. This would result in an increase in the synthesis of LTC4 and LTD4 which are potent bronchoconstrictor substances.
(PHARM 16)

Discuss prolonged bleeding time as a result of NSAIDs.
Since NSAIDs inhibit platelet aggregation, using them can prolong bleeding time. So avoid NSAID use prior to surgery, particularly aspirin. However, aspirin therapy has a powerful positive effect in the immediate post-surgical period after vascular surgeries such as coronary artery bypass, reducing subsequent MI by 48%, stroke by 50%, renal failure by 74% and bowel infarction by 62%.
(PHARM 17)

Discuss prolongation of gestation using NSAIDs.
Prostaglandins E and F are uterotropic. Biosynthesis by the uterus increases in hours prior to parturition from induction of COX-2 expression. Need prostaglandins to deliver the baby. Animals lacking prostaglandin receptors fail to deliver their offspring, despite the offspring proceeding normally to term.
(PHARM 18)

Discuss NSAID therapy to treat premature closure of the ductus arteriosus.
NSAID therapy closes patent ductus arteriosus in newborns. Possible to prematurely close the ductus by inappropriate use of NSAIDs in late-term pregnancy.
(PHARM 19)

Discuss ASPIRIN: Mechanism of Action
(1)Cyclooxygenase inhibition is aspirin's main MOA. Acetylsalicylic acid is the only NSAID that irreversibly acetylates and inactivates its principal cellular targets, COX. Duration of action exceeds its biological half life. Mechanism of action of salicylates can't be explained entirely by inhibition of COX b/c sodium salicylate and salsalate are weaker, reversible inhibitors of COX and still possess potent anti-inflammatory and analgesic properties. (2) Inhibition of NF-κB activation is shared by aspirin and sodium salicylate. Phosphorylation of IκB, a negative regulatory subunit, triggers its degradation, allowing NF-κB to translocate into the nucleus. Sodium salicylate or aspirin inhibit activation of NF-κB and IκB phosphorylation. (3) Alteration in leukocyte adhesion molecules: central event in initiation of inflammation is adherence of leukocytes to the vascular endothelium. NSAIDs affect cell surface expression of cell adhesion molecules. Inhibit induction of TNFα of mRNA for ICAM-1 and VCAM-1. NSAIDs also promote shedding of L-selectin on human PMNs and block activation of B2 integrins on PMNs by TNFα .
(PHARM 20)

Discuss ASPIRIN: Pharmacokinetics.
ASA is rapidly absorbed by the stomach (limited), upper duodenum (extensive). Rate of absorption is influenced by the physical form of aspirin, pH at site of absorption, and gastric emptying time (full vs. empty stomach). ASA is mainly absorbed in the duodenum, stays in soln at the high pH because it is ionized, large surface area available for absorption.
(PHARM 21)

Discuss ASPIRIN: Metabolism
ASA has a short plasma half-life 15 minutes, rapidly de-acetylated by esterases. Anti-inflamm dose of ASA exerts initial effect thru the parent cmpd and most of its total effect by the metabolite, salicylate. ASA has a strong effect on inhibition of platelet cyclooxygenase. Salicylates are metabolized primarily in the liver, via conjugation w/glycine or gluconuronic acid. Glucuronidation saturates at high plasma levels so that 1st order kinetics are replaced with zero order dose-dependent kinetics. Excreted by proximal tubule. Alkalinization of the urine can increase amt of ionized, unchanged salicylate in the urine and accelerate its elimination, which is a useful in poisoning. Excretion of conjugates of salicylic acid is not pH dependent.
(PHARM 22)

Discuss the clinical utility of salicylates.
Used for: analgesia (headache, arthritis, dysmenorrhea, neuralgia, myalgia). Antipyresis. Inhibition of inflammation in a wide variety of settings. Used as anti-inflammatory agents in rheumatoid arthritis and other collagen vascular diseases. A major indication for ASA (but not other NSAIDs) is the inhibition of platelet aggregation for prevention of MI.
(PHARM 23)

Discuss toxicity of ASA.
Daily administration of aspirin increases GI blood loss. Enteric-coated aspirin offers some degree of protection. Salicylism: mild chronic intoxication results in headache, dizziness, tinnitus, confusion, drowsiness, thirst, hyperventilation, nausea, and vomiting. Severe salicylate intoxication has respiratory effects. If doses are really high there may be direct depression of respiratory centers which can result in an increase in PCO2, vasomotor depression and decreased renal blood flow, w/severe metabolic acidosis. Electrolyte disturbances: combo of respiratory acidosis and metabolic acidosis, due to low bicarb from loss during compensation for respiratory alkalosis, followed by medullary depression resulting in increased PCO2 and lowered pH. Accompanied by an increase in blood acid due to ASA and its derivatives. Renal toxicity. Hepatic toxicity: salicylate use is rarely associated with cholestatic hepatitis. CNS disturbances, including seizures and coma.
(PHARM 24)

Discuss Reye's Syndrome
Rare but fatal consequence of viral infections. Acute encephalopathy associated with fatty degeneration of the liver. Association between development of Reye's syndrome and antecedent use of aspirin in children. So don't use aspirin in association with viral infections in children or adolescents.
(PHARM 25)

Don't use ASA in pregnant women or patients about to undergo surgery.
Causes increased bleeding time so avoid for one week prior to surgery. And can cause moms to have babies with lower birth weight and/or problems with gestation or delivery. Pre-partum use of salicylates will prolong the bleeding time of the mother and the fetus. May also cause premature closure of the ductus. Don't take ASA during the last 3 months of pregnancy.
(PHARM 26)

An ester of 2 salicylic acid molecules which is hydrolyzed in the small intestine or plasma to salicylic acid. Produces less GI irritation than aspirin. Doesn't antagonize platelets function as it is only a week COX inhibitor. Commonly used in collagen vascular diseases.
(PHARM 27)

Salicylates are used in the treatment of inflammatory bowel disease and exert their effects without being absorbed systemically. Sulfasalazine is a salicylate derivative that is cleaved into its active component by bacteria in the colon.
(PHARM 28)

Discuss Bismuth Subsalicylate
Active ingredient in Pepto-Bismol. Used as a source of bismuth in the treatment of H. pylori-associated peptic ulcer disease.
(PHARM 29)

Difluorophenyl derivative of salicylic acid. It is a competitive inhibitor of COX and is used as an analgesic.
(PHARM 30)

Discuss ACETAMINOPHEN: m.o.a.
Acetaminophen is used as an analgesic and antipyretic. It is a weak anti-inflammatory compound. Inhibits COX in the brain (hypothalamus) and is an effective antipyretic but not at peripheral sites of inflammation. Does not have significant anti-inflamm properties when used in safe doses. Can substitute for salicylates in promoting analgesia and antipyresis. It is often used in patients in whom aspirin is contraindicated (peptic ulcer) or when prolonged bleeding time is a disadvantage because it has much less (none?) adverse effects on the GI tract and platelets.
(PHARM 31)

Discuss ACETAMINOPHEN: pharmacokinetics and biotransformation
Rapidly absorbed from the GI tract. Half-life in plasma is 2 hrs. Metabolites include conjugates w/glucuronide and sulfuric acid in the liver. Small percentage of the drug undergoes CYP 450 mediated N-hydroxylation to form the metabolite N-acetyl-benzoquinoneimine, which conjugates with glutathione and is metabolized to mecapturic acid and excreted in the urine.
(PHARM 32)

Discuss ACETAMINOPHEN toxicity
Large doses of acetaminophen predisposes to the formation of large amounts of N-acetyl-benzoquinoeimine, which depletes glutathione. In the absence of glutathione, the reactive metabolite binds covalently to hepatocyte macromolecules leading to dysfunction of enzyme systems. This can lead to irreversible hepatic necrosis. Doses of 10 to 15 g are toxic and death occurs when single doses exceed 20 g. Evidence of hepatic damage can be delayed for several days. Treatment is the sulfhydryl cmpd N-acetylcysteine, which repletes intracellular glutathione levels. Antidote should be administered within 10-36 hrs after acetaminophen ingestion. Other toxic effects include renal tubular necrosis, hypoglycemic coma, and hypersensitivity rxns. No effects on cardiovascular and respiratory systems. No effects on acid-base balance.
(PHARM 33)

A non-selective COX inhibitor not commonly used as an antipyretic or for acute inflammation. Still used to treat rheumatoid arthritis, acute gouty arthritis, and ankylosing spondylitis. Also treatment of patent ductus arteriosus and as a tocolytic agent in suppressing preterm labor. Produces CNS side effects including dizziness, headache, confusion, depression, psychosis, and hallucinations. GI side effects and impaired platelet function as usual.
(PHARM 34)

Discuss IBUPROFEN (Motrin, Rufen, Advil, Nuprin) and NAPROXEN (Aleve)
Approved for rheumatoid arthritis, osteoarthritis, analgesia, dysmenorrhea and fever, patent ductus arteriosus. Other propionic acid derivatives have the same spectrum of activity, including naproxen (Naprosyn, Aleve), fenoprofen (Nalfon), ketoprofen (Orudis), flurbiprofen (Ansaid), and oxaprofen (Daypro).
(PHARM 35)

Approved for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and acute gouty arthritis. Prodrug which is metabolized to the active sulfide form. Sulfide is excreted in the bile and then reabsorbed from the intestine (enterohepatic circulation). Enterohepatic cycling prolongs duration of action to 12-16 hrs. Causes little direct GI irritation. Its other toxicities are characteristic for non-selective COX inhibition.
(PHARM 36)

Approved for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, dysmenorrhea, analgesia and fever. It is a potent non-selective COX inhibitor.
(PHARM 37)

Approved only for analgesia, although it has typical NSAID properties (antipyretic, antiinflammatory). Given IM or IV as an analgesic post-surgery. Equivalent to morphine (10 mg) or meperidine (100 mg). Not associated with tolerance, respiratory depression or withdrawal effects. Can be used orally as an analgesic but only for a limited time (5 days) because of GI and renal toxicity. Also inhibits platelet aggregation. It is a non-selective COX inhibitor.
(PHARM 38)

Marketed for inflamm conditions in individs at risk for GI toxicity of non-selective NSAIDs or who are intolerant to non-selective NSAIDs. Have comparable analgesic and antipyretic effects to non-selective NSAIDs. Do produce some GI toxicity – dose dependent. Still affords a 78% reduction in risk of GI ulceration as compared to traditional non-selective NSAIDs. However, COX-2 selective drugs may increase risk of hypertension and thrombotic events in some patients. These compounds are considerably more expensive than the non-selective drugs.
(PHARM 39)

Discuss the COXIB Controversy
Most NSAIDs decrease platelet production of thromboxane (COX-1 dependent) which is a prothrombotic eicosanoid AND endothelial cell prostacyclin (COX-2 dependent) which is antithrombotic. Net effect is a slight prolongation of bleeding time due to a net inhibition of platelet aggregation but the balance between TXA2 and PGI2 is essentially maintained. Selective COX-2 inhibitors decrease production of PGI2 but not TXA2, so they could have a prothrombotic effect. Recent studies have raised concerns that selective COX-2 inhibitors may increase risk of thrombotic cardiovascular events so rofecoxib (Vioxx) was taken off the market. Additional studies have suggested that the less selective molecule, Celecoxib (Celebrex) does not have a prothrombotic effect and may be beneficial. Also, any prothrombotic effect of the coxibs can be overcome by the addition of low-dose aspiring to the coxib therapy. But adding aspiring to coxib therapy leads to significant GI toxicity. So coxibs should be used with great care in individuals at risk for MI or stroke.
(PHARM 40)

Protective and evolutionarily adaptive. Designed to prevent tissue injury. Pain signal is rapidly carried by myelinated Aδ fibers to lamina III of the spinal cord. These fibers may be specific for the mode of pain being transduced such as temperature or they may be polymodal, transmitting, for example, chemical as well as temperature stimuli. These fibers transmit largely somatic, but also some visceral input.
(PHARM 41)

Discuss C-Fibers
C-Fibers are unmyelinated and transmit “aching” pathological pain. They also largely transmit visceral pain impulses.
(PHARM 42)

Consequence of inflammation or may be caused by a primary or secondary neuropathic process. Tissue damage causes release of inflammatory chemical mediators such as substance P, which results in vasodilation, and extravasation of inflammatory such as macrophages and mast cells. Release an 'inflammatory soup' of chemicals such as bradykinin, 5-HT, prostaglandins, histamine, interleukins, nerve growth factors, hydrogen ions and adenosine. In addition to amplifying pain signal in affected nerves, these chemicals diffuse into surrounding tissues and lower the threshold for activation in bystander nerves. PERIPHERAL SENSITIZATION. Phenotypic changes occur in the nerve as a consequence of severe or chronic pain, resulting in insertion of new receptors and channels within the cell membrane. Gene activation can occur, results in sprouting of nerves and dendritic arborization both peripherally and centrally.
(PHARM 43)

Inflammation can result in long-term abnormal sensory responses that may be a consequence of long-term changes in the peripheral and central nervous system. Discuss ALLODYNIA, DYESTHESIAS, and CENTRAL SENSITIZATION
Aβ fibers, which transmit sensation of light touch by synapsing with lamina II neurons that project to the dorsal columns may sprout and synapse with deeper laminae III and IV neurons which normally synapse with c and Aδ pain fibers and project to the lateral spinothalamic tract carrying a sensation of pain to the brain. So the peripheral non-painful sensation of light touch is perceived centrally as pain, a phenomenon known as ALLODYNIA. Peripheral sensitization can result in the amplification of pain signals and HYPERALGESIC STATES. Insertion of new channels, receptors, and induction of new or different NT synthesis may play a role in the development of DYESTHESIAS, or unusual, burning, electrical or 'pins and needle sensations.' CENTRAL SENSITIZATION may be caused by disinhibition or by repetitive excitatory stimulation of central neurons resulting in an exaggerated nonlinear response of second order cells (called wind-up).
(PHARM 44)

Consequence of viral illnesses such as herpes zoster or HIV. Stroke involving specific regions of the thalamus may cause disinhibition and a central pain syndrome. “Phantom limb pain”, which may occur after an amputation, is a complex and poorly understood form of central pain. Trauma may cause damage to a nerve and form a NEUROMA, which may have a large number of receptors and ion channels within it resulting in pain amplification. Minor limb trauma may result in a CHRONIC REGIONAL PAIN SYNDROME (CRPS) that can be debilitating and is mechanistically poorly understood. Neuropathic pain is DIFFICULT to treat. Opioid insensitive. Frequently treated by using membrane stabilizers such as local anesthetics, antidepressants which may potentiate central inhibition of pain by further activating NE and 5-HT pathways and by administering anticonvulsants to decrease sodium conductance and excitatory synaptic activity. Cognitive and behavioral therapies may also be effective in helping patients cope with such pain.
(PHARM 45)

What genetic syndromes can make individuals prone to painful states?
A form of migraine headache has been associated w/a channelopathy. Single nucleotide polymorphisms may alter μ-receptor sensitivity to opioid agonists. Autoimmune disorders may result in sensory neuropathies. Metabolic deficiency states and hormonal levels alter pain perception. Toxins in the environment may have a similar effect.
(PHARM 46)

Discuss patient controlled analgesia.
Pain therapy cannot be directed at the μ-receptor alone. Must be multimodal and preemptive to be most effective. Patient controlled analgesia is the most effective way of delivering parenteral opioids. Provides patient with a locus of control over his/her pain. Minimizes delay in treatment. Results in more stable plasma drug levels. Patients who self administer opioid use LESS drug than patients who are prescribed 'round the clock' or 'as-needed' medication.
(PHARM 47)

What is the gold standard for pain control?
Opioids. No ceiling effect for opioids. Dose is limited only by adverse effects which include nausea, vomiting, constipation, respiratory depression, fatigue, cognitive impairment, urinary retention and pruritis. Some side effects can be treated by changing the opioid to one of a different class or by specific therapies. Respiratory depression may be treated by adding a NOLOXONE infusion. Pruritis might be treated by administering an antihistamine or a low dose opioid agonist-antagonist such as NALBUPHINE. Adding a psychostimulant such as DEXTROAMPHETAMINE may treat sedation or cognitive impairment.
(PHARM 48)

What are the most commonly prescribed parenteral opioids?
Morphine, hydromorphone, fentanyl, and meperidine. Meperidine has an excitatory intermediate normeperidine and may be associated with seizures if given as a continuous infusion or given repetitively. Fentanyl is highly potent but short acting. Tolerance develops rapidly to fentanyl. Hydromorphone is more sedating than morphine. All four of these opioids can cause itching.
(PHARM 49)

Why would NSAIDs or acetominophen be administered with opioids as ADJUVANTS?
They have “opioid sparing” effects. By co-administering these agents, a lower dose of opioid is needed to achieve the same pain score. The use of adjuvants may limit opioid related adverse effects as well. [NSAIDs all demonstrate a ceiling effect, meaning that there is no increase in analgesia beyond a certain dose. All NSAIDs may cause gastropathy, hepatopathy, and nephropathy. NSAIDs decrease GFR by decreasing efferent arteriolar tone. NSAIDs may attenuate central sensitization and may play an important role in pre-emptive analgesia.]
(PHARM 50)

TOLERANCE develops to opioids w/prolonged use and following administration of high doses for moderate periods of time. A higher dose of medication is needed to obtain the desired effect of pain relief. Sudden cessation of opioid in the tolerant individual will result in a physiologic withdrawal syndrome characterized by myalgias, diaphoresis, nasal stuffiness, anxiety, tachycardia, yawning, temperature intolerance and diarrhea. Can be avoided by tapering the drug slowly or by using medication that will modulate the sympathetic symptoms of withdrawal such as clonidine (an alpha 2 agonist) or beta-blockers.
(PHARM 51)

(1)Cross-Tolerance may be incomplete when converting a patient from one drug to another because of differential μ-receptor subclass avidity and so you should take this into account or you could give your patient an overdose. If a patient is converted from drug A to drug B, only a percentage of the equianalgesic dose should be administered. One can always increase the dose subsequently. Or else you could put the patient in respiratory depression.
(2) Addiction refers to a physiological craving for a drug because of the desired psychic effects. Rarely seen in patients w/acute pain and should never be a reason for withholding drug from patients who are in pain.
(3) Pseudoaddiction is manifested by a demand for more drug by patients who are being undertreated for their level of pain. It is commonly seen in patients who are tolerant and have a high dose requirement.
(PHARM 52)

Discuss Oral Opioids: Morphine, Hydromorphine, Codeine, Hydrocodone, and Oxycodone.
Bioavailabilities of these drugs vary and must be taken into account when switching from the parenteral route to the oral route. Many come as a fixed combo with acetaminophen. Have to be careful not to exceed to safe daily dosing of acetaminophen. Transdermal fentanyl can't be used in opioid naïve because it creates a sub-dermal depot that remains effective for 18 hours after removal of the patch. If initial dose chosen is too high, it will take a long time for the physiologic effect to abate. Morphine and oxycodone may be prescribed as continuous or sustained release preparations for patients with severe or chronic pain. These preparations have high abuse potential.
(PHARM 53)

Discuss METHADONE as an analgesic.
Novel and effective analgesic. Racemic mixture (L and D isomer) with avidity for both the μ-receptor (agonist) and the NMDA receptor (antagonist). It may be particularly suited to the treatment of neuropathic pain. Tolerance to methadone develops more slowly than for other opioids because of NMDA activity. Has a large volume of distribution at steady state and may have a very long half life (>100 hrs) making proper, safe dosing challenging. This is the only long-acting opioid available in liquid form, which is helpful for pediatrics.
(PHARM 54)

Discuss Local Anesthetics in the context of treating pain.
Great efficacy in treating pain. Regional nerve blocks as well as subarachnoid (spinal) or epidural routes using preservative free local anesthetics may be performed. Tachyphylaxis develops over time when infusions are used chronically. Adjuvants such as opioids, clonidine, ketamine, or neostigmine may have some utility when mixed with local anesthetics for conduction or central blocks.
(PHARM #55)

Distinguish between physiologic (good) pain, inflammatory pain ('the ache') and neuropathic pain:
(1)Physiologic pain is protective, evolutionarily adaptive, self-limited, results from direct stimulation of pressure, heat, and chemical receptors. It is transmitted mainly by myelinated Aδ fibers (“ouch”) and slower non-myelinated c-fibers (ache). Activation of Aβ or light touch fibers may inhibit painful impulses.
(2) Inflammatory pain occurs when tissue damage results in the release of inflammatory mediators. Results in a lowered activation threshold & an exaggerated response to painful stimuli. Spread of mediators to nearby uninjured tissues results in hyperalgesia or a lowering of the activation threshold of nearby normal nerves.
(3) Neuropathic pain is central or peripheral nerve dysfunction or injury resulting in a false signal of pain. Can be due to a mononeuropathy or a polyneuropathy. Can have multiple etiologies.
(PHARM #56)

How do we measure pain intensity?
Self report is still the gold standard. No universal measurement instrument is available. So we use categorical, numerical pain score, visual analog score. Facial expression is a sensitive indicator of pain. Also can use observations. Cry and vital signs can indicate pain in babies. The FLACC scale for babies assesses pain with regard to Face, Legs, Activity, Cry, Consolability.
(PHARM #57)

How do we treat inflammatory pain pharmacologically?
The ladder: NSAIDs/Acetominophen. Enteral Opioids. Parenteral Opioids. Adjuvants/non-pharmacological measures. Local anesthetics. Neuromodulation/neurolytic techniques. Therapy is not sequential. It is commonly multimodal.
(PHARM #58)

Why don't we give pain meds IM?
Because if the therapeutic option hurts, patients won't ask for it!!
(PHARM #59)

What are the most commonly used parenteral opioids? Oral?
PARENTERAL: Morphine, Hydromorphone, Fentanyl, and Meperidine

ORAL: Codeine, Oxycodone, Hydrocodone, Morphine
(PHARM #60)

What adjuvant medications are used in the treatment of nociceptive inflammatory pain?
NSAIDs: non-specific COX-1 and COX-2 inhibitors. Including Ibuprofen, Indomethacin, Naproxen, Diclofenac (more selective for COX-2) and Ketorolac (which can be given intravenously).
(PHARM #61)

We have to manage the side effects of opioids. What can we give for nausea? Pruritis? Sedation? Constipation? Urinary retention? Opioid tolerance? Respiratory depression?
(1)NAUSEA: ondansetron, granisetron (5-HT3 antagonist), metoclopramide (DA-antagonist), lorazepam, steroid, naloxone ( μ-antagonist); (2) PRURITIS: diphenhydramine, hydroxazine, nalbuphine (kappa-agonist, μ-antagonist), cyproheptadine (histamine and serotonin antagonist), naloxone ( μ-antagonist); (3) SEDATION: dose adjustment, use of adjuvants, methylphenidate, dextroamphetamine, modinafil, naloxone; (4) CONSTIPATION: water, fiber, laxatives; (5) URINARY RETENTION: catheter; (6) OPIOID TOLERANCE: opioid rotation; (7) RESPIRATORY DEPRESSION: naloxone
(PHARM #62)

What is pseudoaddiction?
Requests for medication which is a consequence of either inadequate pain relief or under-medication. May be a consequence of patient disbelief, inadequate dosing, or as a consequence of physiologic tolerance.
(PHARM #63)

In tolerant individuals, a withdrawal syndrome will develop if the opioid is acutely eliminated. So taper the drug off slowly, with clonidine to minimize the symptoms, which are?
Tachycardia, dysrhythmias, diaphoresis, sweating, nasal congestion, myalgias, diarrhea, malaise
(PHARM #64)

Remember: Cross-Tolerance is invariably INCOMPLETE!!!
Tolerance to a drug (ex. Morphine) in a given class (Opioids) confers some tolerance to others in the same structural or mechanistic category (Hydromorphone). But only SOME. Cross-tolerance is invariably incomplete.
(PHARM #65)

What is Loratab elixir? Percocet?
LORATAB ELIXIR: Contains acetaminophen. Dosed as hydrocodone.

PERCOCET: Contains acetaminophen. Dosed as oxycodone.
(PHARM #66)

What are commonly used long-acting opioids?
MS-Contin: morphine continuous release

Oxycontin: oxycodone continuous release

Kadian: MS-sustained release

Methadone: mu agonist/NMDA antagonist
(PHARM #67)

What might we use to treat neuropathic pain?
Anticonvulsants, Tricyclic antidepressants, Local anesthetics, Autonomic blockade, NMDA antagonists, Methadone, PT/OT
(PHARM #68)

If you were giving epidural anesthesia, why would you give clonidine as an adjuvant.
Increased intensity of block, no ileus, no hypotension, no pruritis, no urinary retention, must be preservative free, drug interactions.
(PHARM #69)

What is the aim of anesthesia?
To achieve in the brain a partial pressure of the agent (anesthetic) in order to obtain the desired effect (to render a patient pain free during a surgical procedure). Partial pressure is a measurement of the amt of anesthetic because many of the anesthetic agents are volatile (gases).
(PHARM #70)

What is the Minimum Alveolar Concentration?
Concentration of anesthetic in the brain that prevents movement of 50% of subjects in response to a standard surgical incision. Potency of different anesthetics is compared in terms of their MAC.
(PHARM #71)

Remember the universal gas equation!!
PV = nRT

The pressure exerted by a gas is inversely related to the volume in which it is contained and directly proportional to the # of moles in the container. Volatile anesthetics exert pressure when they are contained in the lungs, blood, and brain. Think of pressure rather than drug concentration. If 2 gases are mixed together in a container, each gas exerts a pressure as if it were alone. PT = PA + PB
(PHARM #72)

Solubility of a Gas in a Liquid. Discuss the Partition Coefficient and the Relationship between Solubility and Partition Coefficient.
Solubility is the volume of gas dissolved in a unit volume of liquid at a stated temperature. The amount of gas dissolved in a liquid is proportional to the partial pressure in a gas phase and the partition coefficient of the gas. The partition coefficient is the ratio of the solubility of an agent for two media, such as blood and brain or lung and blood at equilibrium. Halothane has a blood-gas partition coefficient of 2.3 which means that the number of moles in the blood phase is 2.3X the number of moles in the gas phase (lung). Solubility is the volume of gas dissolved in a unit volume of liquid at a stated temperature. The partition coefficient is the ratio of the volume of gas in two phases at a stated temperature.
(PHARM #73)

Gas A constitutes 20% of volume of the container. Gas B constitutes 75% of the volume in the container. Plasma vapor constitutes 5% of the volume. What is the partial pressure exerted by each of these gases?
When considering how this determines how much gas moves from the gas phase of the lung into the liquid phase in the blood, the partition coefficient of the anesthetic gas between liquid (blood) and gas (λL1-G) must be considered. Finally, there is a 3rd phase, the tissue phase (brain). Transfer of anesthetic gas to the tissues is governed by the same principles. Liquid (blood) anesthetic equilibrates with tissue anesthetic. The amt that enters the tissue is dependent on the partial pressure in the liquid (blood) and the liquid-tissue partition coefficient (λL2-L1).
Gas A: 20% x 760 mm Hg = 152 mm Hg; Gas B: 75% x 760 mm Hg = 570 mm Hg; Vapor: 5% x 760 mm Hg = 38 mm Hg; Gas A (λL1-G) = 0.5 # molecules in gas = 20, # molecules in liquid = 10; Gas B (λL1-G) = 0.2 # molecules in gas = 75, # molecules in liquid = 15
Gas A (λL2-L1) = 10 # molecules in liquid = 10, # molecules dissolved in tissue = 100; Gas B (λL2-L1) = 1 # molecules in liquid = 15, # molecules dissolved in tissue = 15; At equilibrium if we started with 20 molecules of Gas A in the lung, there would be 10 molecules in the blood and 100 molecules in the tissue (brain). However, the partial pressure for each of the gases is the same in each of the 3 different phases at equilibrium. At equilibrium, the partial pressure of all the tissues is equal to the partial pressure of the anesthetic gas in the inspired gas and in the alveolar gas.
(PHARM #75)

Discuss the effects of ventilation on input of anesthetic from the inspired gas to the alveoli and hence, equilibration of inspired anesthetic (Fi) with alveolar anesthetic (FA), where FA/Fi = 1 at equilibration.
The initial rise with all anesthetics is rapid because there has been little uptake of the anesthetic into the blood to oppose it. As uptake occurs, removal of anesthetic from the lungs into the blood opposes the effects of ventilation to drive alveolar concentration upward until a balance is reached between input and uptake. With anesthetics that have a higher solubility (halothane), there is a greater uptake into the blood and the initial rise in FA/Fi slows markedly compared to a less soluble anesthetic like N2O. The slower phase of increase results in slower uptake into tissues (brain) and slower onset of equilibration (slower anesthetic induction).
(PHARM #76)

As ventilation increases from 2 to 4 to 8L/min, what happens to equilibration between alveolar gas and inspired gas partial pressure of halothane, which has a high solubility in the blood? What about nitrous oxide, a less soluble gas?
It occurs more quickly, so FA/Fi rises much more quickly. Can't equal 1 because some of the inspired gas is dissolving into the blood. Halothane has a high solubility in the blood. An insoluble agent such as nitrous oxide is much less affected by the increase in ventilation because as a result of its low solubility in blood, it rapidly reaches equilibrium between alveolar gas and inspired gas and therefore, between alveolar gas and the blood, even at low ventilation rates.
(PHARM #77)

Discuss the concept of OVERPRESSURE
Starting out with a higher concentration (partial pressure) of anesthetic that is needed to maintain a constant state of anesthesia. It is similar to giving a loading dose of a drug. Equilibrium is reached much more quickly if you begin with an overpressure. Decreases the time for onset of anesthesia. Then the concentration is reduced to the level needed to maintain anesthesia to avoid overdose.
(PHARM #78)

What factors affect anesthetic uptake from alveoli to blood?
Uptake = λ (solubility of gas in blood) x Q (cardiac output) x [(PA-PV )alveolar to venous partial pressure difference]/PB (barometric pressure)

If any component of uptake approaches 0, uptake approaches 0, and the effects of ventilation to drive the alveolar anesthetic concentration rapidly upward is unopposed speeding equilibration between alveolar gas tension and inspired gas tension. Low solubility or low cardiac output (shock) would do so.
(PHARM #79)

The solubility of the anesthetic agent affects its uptake from the lung into the blood (measured as the blood/gas partition coefficient).Discuss!
With a very soluble anesthetic, many more molecules must be taken up into the liquid phase before the partial pressure in the blood is in equilibrium with the partial pressure in the lung. For example, enflurane has a partition coefficient of 1.9, meaning that each ml of blood holds 1.9x 1 ml of alveolar gas. Results in a large fall in alveolar partial pressure as highly soluble anesthetic enters the blood. So the rate at which the alveolar partial pressure reaches equilibrium with the inspired partial pressure is much slower with a highly soluble agent than with an agent that is not very soluble in the blood. So it takes longer for equilibrium to occur between inspired anesthetic gas and alveolar gas and therefore, a longer time until anesthesia is induced (equilibrium between the blood and the brain) with a highly soluble anesthetic than with a less soluble anesthetic.
(PHARM #80)

What is the effect of increased cardiac output on uptake of anesthetics from alveoli to the blood?
As CO increases the transfer of anesthetic from alveoli to the blood is increased, reducing alveolar anesthetic pressure. So the rate at which equilibrium occurs between alveolar gas and inspired gas decreases when cardiac output is increased. FA/Fi (fraction of anesthetic gas in the alveoli/fraction of inspired anesthetic gas) reaches equilibrium more rapidly with halothane at a cardiac output of 2 than at a cardiac output of 18. So it will take longer for anesthesia to occur at a higher cardiac output. Increasing CO is analogous to increasing anesthetic solubility which means more anesthetic must be dissolved before partial pressure in blood reaches equilibrium with alveolar gas. A less soluble gas (such as nitrous oxide) is less affected by a change in CO than a more soluble gas (such as halothane).
(PHARM #81)

What is the effect of anesthetics tension gradient between alveoli and venous blood (PA-PV) on uptake?
If blood flowed only to the brain, equilibration would occur quickly because the brain has large blood flow relative to its size. Solubility of anesthetic agents is high in the brain but there is a small volume to fill. The blood leaving the brain within a short time would have a higher and higher partial pressure, and the tension gradient between blood returning to the alveoli from the brain and the partial pressure of anesthetic in the alveoli will decrease and rapidly reach equilibrium. Equilibrium between alveolar gas, blood, and tissue would be established quickly. However, CO goes to different tissue groups with different solubilities and different blood flows, not just the brain. The brain and other vessel rich (heart, splanchnic bed) groups are only 10% of total body mass but receive 75% of cardiac output. Muscle is 50% of total body mass and receives 20% of CO. Fat and other vessel poor groups are 40% of body mass but receive only 5% of CO. So, brain pool fills first, then muscle pool more slowly. The fat pool takes a long time to fill and may never fill, because of large bulk relative to flow and because anesthetics are more soluble in fat than in muscle. So the more obese a patient is, the slower the onset of anesthesia, because venous blood leaving fat tissue will have a low partial pressure of anesthetic contributing to a decreased PV in the lung, so (PA-PV) remains large.
(PHARM #82)

What factors determine speed of recovery from anesthesia?
(1)Anesthetic gas is turned off and inspired gas does not contain anesthetic. Venous blood returning to the lungs will release gas into alveoli along a tesnion gradient. Arterial blood from lung to tissues will have a very low anesthetic pressure and so anesthetic in the tissues will enter the bloodstream to be transported back to the lung. The more soluble the agent in the tissue, the slower the release into the blood and the slower the recovery or wake-up. (2) Hyperventilation will remove the anesthetic from the lung more quickly and create a large difference between alveolar gas tension and venous gas tension and will accelerate removal of the gas from the blood. (3) Each tissue has a different partition coefficient and blood flow so removal of anesthesia from each tissue group follows a different time course. Wake up from anesthesia depends on time for removal of anesthetic from the brain but there may still be anesthetic in other tissues.
(PHARM #83)

Discuss Diffusion Anoxia
Anesthetic gases are eliminated from the blood to the alveoli diluting the inspired gases in the alveoli. Most anesthetic agents are used along with nitrous oxide. During recovery, large volumes of nitrous oxide leave the blood and displace gases in the alveoli. It dilutes the carbon dioxide in the alveoli, diminishing the respiratory drive. If the patient is breathing room air, a decrease in the oxygen in the alveoli will also occur resulting in an hypoxic gas mixture in the lung (diffusion hypoxia). To prevent this, at the end of the anesthetic procedure, patients are administered 100% oxygen.
(PHARM #84)

What is general anesthesia? What are the phases of administration of a general anesthetic?
A pharmacologically induced state of analgesia, amnesia, muscle relaxation, hyponosis (induced consciousness), and altered autonomic regulation. The three phases are induction, maintenance, and emergence. Anesthesia may be induced and maintained by having a patient breathe anesthetic patient in oxygen or a mixture of oxygen and nitrous oxide. OR patient may be anesthetized by injecting a hypnotic agent IV and using an anesthetic vapor to maintain the anesthetized state. Eliminates the need for the patient to breathe a noxious gas while awake. Remember that anesthesia is NOT sleep!! It is a complex, pharmacologically attained state from which pain will not cause arousal. Classically described sleep stages do not occur during anesthesia.
(PHARM #85)

What is balanced anesthesia?
Use of an IV hypnotic agent followed by a combo of IV administered drugs to maintain anesthesia. May include a narcotic to ensure analgesia, a benzodiazepine for amnesia, and a muscle relaxant to prevent movement and ensure optimal relaxation for surgery. A mixture of nitrous oxide and oxygen may supplement analgesia and hypnosis. A variety of vasoactive substances may be needed to maintain proper hemodynamics: esmolol, a beta blocker, to prevent unnecessary tachycardia, or sodium nitroprusside, a primary arteriolar vasodilator, to prevent hypertension. A balanced technique might be needed because some patients cannot tolerate the adverse hemodynamic effects of “deep” inhalational anesthesia. Often a combination of light general anesthesia and regional blockade, local anesthetic continuously infused via the epidural space, is used. Advantages of this technique include lower levels of stress hormones and post-operative pain relief since the regional block is continued during the recovery period.
(PHARM #86)

Discuss the mechanism of action of inhalational anesthesia.
UNKNOWN!!! But...(1) Neurotransmitter modulation: anesthetics may alter the release, reuptake, or post-synaptic binding of neurotransmitters. (2) Voltage-gated ion channels: at concentrations of inhalational agents which are relevant to general anesthesia, voltage gated ion channels (such as sodium, potassium, and calcium channels) demonstrate very small depolarizing shifts in the steady-state activation curve and very small hyperpolarizing shifts in the steady-state inactivation curve. (3) Ligand-gated ion channels: Glutamate is a major excitatory NT. Its ionotropic receptor channel can be classified according to 3 selective agonists: NMDA, KA, and AMPA. Ketamine is neuroselective for the NMDA receptor. All glutamate receptors are insensitive to inhalational agents. Neuronal nicotinic ACh receptor – at high doses, most inhalational agents will stabilize a desensitized form of this receptor.
(PHARM #87)

Discuss possible mechanisms of inhalational anesthetics (cont'd):
Potentiation of inhibitory synaptic transmission: Attention has been focused on the GABAA and glycine receptors on the basis of electrophysiological studies. Pentobarbital, halothane, enflurane, isoflurane, and propofol all enhance the action of GABA by increasing the open probability of the GABAA Receptor Channel. Glycine is a major inhibitory NT in lower CNS centers such as the brainstem and spinal cord. At relevant concentrations of inhalational agents, the affinity of glycine for its receptor has been shown to increase.
(PHARM #74)

How long does it take for the anesthetic tension (partial pressure) in the lung to equal the anesthetic tension in the inspired gas?
This is the time constant. Alveolar partial pressure governs the partial pressure of anesthetic in all body tissues. At equilibrium, all must approach and ultimately equal the alveolar partial pressure. The buildup of anesthetic partial pressure in the lungs is opposed by the anesthetic uptake into the circulation. Time constant = Volume of “Circuit”/Gas inflow rate. Takes 4 time constants for the tension in the alveoli to reach 98% of the tension in the inspired gas. If fresh gas flow is increased from 4L/min to 8L/min, the time constant is decreased and the alveolar “wash in time” is decreased. This decreases time to the onset of anesthesia.
(PHARM #88)

Discuss mechanisms of inhalational anesthetics: Membrane Perturbation
Lipid solubility seems to correlate well with anesthetic potency. Inhalational anesthetics intercalate within the membrane and potentially exert effect on the lipoprotein bilayer causing membrane expansion and potentially altering membrane viscosity, dipole potential, and critical hydrogen bond formation. This alters the conformation of ion channels. Applying hydrostatic pressure increases the anesthetic dose needed to attain anesthetic state and impairs ionic conductance. But recent work suggest that this isn't actually the case because effects of anesthetics on lipid bilayers at clinically relevant concentrations are very small and can be mimicked by temperature changes of less than 1 degree celcius. SO: seems more likely that anesthetics bind to protein pockets or clefts with specific dimensions. More likely that anesthetic agents act at protein binding sites.
(PHARM #89)

What is Minimum Alveolar Concentration (MAC)?
Minimum Alveolar Concentration (MAC) is a statistical index of anesthetic potency. Allows for comparison between different agents. MAC = alveolar concentration of agent at 1 atmosphere pressure which is needed to abolish movement in 50% of patients in response to a skin incision. MAC is closely related to the oil: gas partition coefficient, which is an index of lipid solubility.
(PHARM #90)

Discuss Guidel's 4 Stages and Planes of Anesthesia:
Stage 1: Amnesia/Analgesia
Stage 2: Delirium/Excitement
Stage 3: Surgical Anesthesia
Stage 4: Overdose/Apnea
(Stage 1) Amnesia/Analgesia: Pupils small, nystagmus. Muscle tone and reflexes are intact. (Stage 2) Delirium/Excitement: Patient is unconscious. Pupils are dilated and divergent. There is muscular movement; vomiting. Increased respiration rate, blood pressure, heart rate. Airway reflexes are intact: laryngospasm. (Stage 3) Surgical Anesthesia: Small pupils, with gaze fixed and midline. Increased frequency and regularity of respiration; decreased tidal volume. Net result is decreased minute ventilation. There is loss of protective airway reflexes. (Stage 4) Overdose/Apnea: There are shallow or absent respirations. Dilated, non-reactive, mid-position pupils. Suppression of CNS activity. Cardiovascular collapse.
(PHARM #91)

Discuss factors affecting MAC (minimum alveolar concentration)
(1)Decreases with extremes of age.
(2) Decreases with hypothermia and increases with hyperthermia.
(3) Decreases with preanesthetic administration of narcotics, benzodiazepines, and barbiturates.
(3) Decreases with acute ethanol intoxication, increases with chronic alcoholism.
(4) The effect of nitrous oxide concurrently administered with a potent agent is additive (70% nitrous oxide + 1 MAC potent agent = 1.7 MAC)
(PHARM #92)

Discuss the Blood:Gas Solubility Coefficient
The blood:gas solubility coefficient is THE MOST IMPT characteristic of an anesthetic which determines the onset and offset time. The rate that partial pressure within a liquid changes to approach the partial pressure of the adjacent gas phase is quickest for an insoluble agent. Since anesthetic effect is related to the partial pressure of gas within brain tissue, and Pbrain = Palveolar = Parterial, substances which reach equilibrium rapidly within the alveolus are associated with rapid induction and rapid emergence. So DESFLURANE, the least soluble potent agent, has the quickest onset and offset time.
(PHARM #93)

Distinguish between gas and vapor.
A gas is referred to as a vapor when it is below its critical temperature and a gas when it exceeds this temperature. The critical temperature is that above which it can't be liquefied by an increase in pressure. So the physical characteristic that distinguishes a gas from a vapor is critical temperature, NOT boiling point.
(PHARM #93-2)

Name the only gas commonly used in anesthesia. Name vapors commonly used. Why are vapors called potent agents? Why is Nitrous Oxide NOT a potent agent?
Nitrous oxide is the only gas used in anesthesia, administered with oxygen and air. 3 vapors commonly used are isoflurane, desflurane, and halothane. Isoflurane and desflurane are ethers. Halothane is an alkane hydrocarbon. Sevoflurane is another vapor that was recently approved for clinical use.

Vapors are called POTENT AGENTS because they are complete anesthetics (cause analgesia, amnesia, atonia, hypnosis) and achieve anesthetic effect at a low alveolar concentration (0.75-7%), allowing the anesthesiologist to use a high inspired concentration of oxygen if needed. Nitrous oxide is NOT a potent agent since a very high inspired concentration is required to achieve anesthetic effect (108% at high atmospheric pressure) which would allow no room for delivery of oxygen at all.
(PHARM #94)

Discuss the Physical Characteristics of the Following Inhalational Agents: Nitrous Oxide, Desflurane, Sevoflurane, Isoflurane, and Halothane, with regard to their blood:gas partition coefficient, their O:G, and their minimal alveolar concentration (MAC).
Nitrous Oxide: B:G 0.47 --- O:G 1.4 --- MAC 108
Desflurane: B:G 0.42 --- O:G 18.7 --- MAC 7.25
Sevoflurane: B:G 0.68 --- O:G 47.2 --- MAC 2
Isoflurane: B:G 1.4 --- O:G 98 --- MAC 1.15
Halothane: B:G 2.4 --- O:G 224 --- MAC 0.75
(PHARM #95)

Nitrous oxide is an anesthetic. It is NOT a potent anesthetic. Alveolar respiration is maintained while on nitrous oxide. It is a mild myocardial depressant in healthy patients. It activates the sympathetic nervous system. (SIDE EFFECTS) Nitrous oxide impairs DNA synthesis when given for a prolonged period of time. 1000 ppm. Prolonged exposure may result in megaloblastic anemia and neuropathies. Nitrous oxide is highly diffusable into air-filled spaces and may increase the size of a pneumothorax or pneumocephalus.
(PHARM #96)

Inhalational anesthetic. (RESPIRATORY) Halothane is a potent bronchodilator. Causes a stereotypical increase in respiratory rate and decrease in tidal volume. Depresses the normal response to hypoxia and shifts the CO2 curve down and to the right. It is commonly used in pediatrics for inhalation induction. (CARDIOVASCULAR) It is a potent negative inotrope. Ventricular end-diastolic pressures increase. It has little direct effect on systemic vascular resistance. It causes a dose-dependent decrease in mean arterial pressure, like all potent agents. It markedly inhibits baroreceptor function. Halothane DECREASES sympathetic outflow. It causes a decrease in HR by this mechanism. It decreases rate of conduction making reentry more likely. It decreases SA-node automaticity as well. It sensitizes the heart to the arrhythmogenic effects of circulating catecholamines. (NEUROLOGIC) The EEG pattern is slowed and of high amplitude. Cerebral blood flow increases so intracranial pressure may increase with its administration. Decreases cerebral metabolic rate for oxygen. Has muscle relaxant properties. (SIDE EFFECTS) All vapors may trigger malignant hyperthermia. Halothane is metabolized to a trifluoroacetic acid conjugate, which may bind to hepatic proteins and act as a hapten allowing for the development of an acute autoimmune hepatitis. Exceedingly rare but may be fulminant.
(PHARM #97)

Inhalational anesthetic. (RESPIRATORY) Effective bronchodilator. Impairs hypoxic drive. Shifts the CO2 response curve further to the right than halothane. Very irritating to the airways. (CARDIOVASCULAR) It is different from halothane because it is an ether. Stabilizes the myocardium, less arrhythmogenic. Positive chronotrope and decreases inotropy less than halothane does. This coupled to a decrease in systemic vascular resistance results in better preservation of cardiac output. It still causes a dose-dependent decrease in blood pressure. Less depression of baroreceptor function than halothane.
(PHARM #98)

Inhalational anesthetic. Desflurane is very similar to isoflurane in terms of physiologic effects. Has the lowest blood:gas partition coefficient of any inhalational agent, so an advantage is rapid wake-up. Not used for inhalational induction since it is very pungent and is associated with a high incidence of breath holding, coughing, and laryngospasm.
(PHARM #99)

Inhalational anesthetic. Sevoflurane has NO odor and is a very smooth agent for inhalational induction. It is a very cardio-stable drug and its blood:gas partition coefficient confers fairly rapid induction and emergence characteristics. (SIDE EFFECTS) All vapors may trigger malignant hyperthermia. Sevoflurane undergoes biotransformation and hydrolysis in soda lime (which is used for CO2 absorption in anesthesia machines) to potentially toxic intermediates. (Sevoflurane, like halothane, is metabolized to trifluoroacetic acid conjugates, but I don't think it works as a hapten to cause autoimmune hepatitis – that's just halothane.)
(PHARM #100)

What is Malignant Hyperthermia?
All vapors may trigger malignant hyperthermia. Increased metabolic rate associated w/marked and rapid development of fever, hypercarbia, and hypoxemia. Patient may develop skeletal muscle rigidity and myonecrosis. Free myoglobin may crystallize in renal tubules leading to renal failure in survivors. Mechanism is unknown. Familial and associated with some myopathies. Families and patienst who may be susceptible to MH can safely be anesthetized by non-triggering intravenous agents. Dantrolene is an antidote which can be life-saving.
(PHARM #101)

Life-saving antidote to malignant hyperthermia which can be caused by vapors (potent anesthetics).
(PHARM #102)

Intravenous anesthetic. STRUCTURE: isoproyl phenol. PROPERTIES: rapid induction, rapid awakening, significant anti-emetic properties. USES: Short procedures and procedures outside the operating room. SIDE EFFECTS: cardiovascular properties similar to barbiturates (depression). Can contribute to bradycardia.
(PHARM #103)

Intraveous anesthetic. STRUCTURE: phenylcyclidine derivative similar to PCP. PROPERTIES: Potent amnestic, potent analgesic. USES: Originally designed for use on healthy patients who have suffered major trauma because it stimulates the sympathetic nervous system. SIDE EFFECTS: Marked sialorrhea so usually given with an antisialogogue. (Sialorrhea is drooling, excessive production of saliva.) Myocardial depression; its activation of the sympathetic nervous system usually overrides this effect, however. Emergence phenomena such as hallucinations which can be countered by co-administration of benzodiazepines. Increased intracranial pressure. Causes dissociation between limbic and thalamic symptoms so that patients appear cataleptic. Catalepsy: a physical condition usually associated with catatonic schizophrenia, characterized by suspension of sensation, muscular rigidity, fixity of posture, and often by loss of contact with environment.
(PHARM #104)

Intravenous anesthetic. STRUCTURE: imidazole. PROPERTIES: Rapid induction and emergence. Remarkably cardiovascularly stable. No increased intracranial pressure. USES: Used with head injuries associated with increased intracranial pressure due to brain edema or intracranial hematoma. SIDE EFFECTS: High incidence of post operative nausea and vomiting. Inhibition of adrenal 11-beta-hydroxylase activity, causing a decrease in serum glucocorticoid and mineralocorticoid levels, even after a single dose. Myoclonus on injection. Myoclonus: an abrupt spasm or twitch of a muscle or group of muscles.
(PHARM #105)

Remember, anesthesia is NOT sleep!! So what is it?
Anesthesia is not sleep. Pain will not cause arousal from surgical levels of anesthesia. The EEG pattern is different from sleep. REM/NREM patterns are not present. Anesthesia is a pharmacologically induced state of analgesia, amnesia, atonia, hypnosis, and altered autonomic regulation.
(PHARM #106)

How do general anesthetics work?
No firm consensus. Attention has focused on neural membranes, ion channels and the systems that regulate them. Inhalational anesthetics appear to effect inhibitory ion channels. Ethanol and volatile anesthetics act on GABA-A and glycine receptors. A potentiating site exists near the extracellular regions of transmembrane domains 2 and 3 of these receptors. A single amino acid substitution at two positions removes this potentiating, inhibitory effect.
(PHARM #107)

What receptors mediate anesthesia?
(1)GABA AGONISTS: Barbiturates; Benzodiazepines; Propofol; Etomidate; Volatile Agents
(2) NMDA ANTAGONISTS: Ketamine, Nitrous Oxide
(3) NICOTONIC ACH RECEPTOR: Volatile agents stabilize a desensitized form of nAChR
(PHARM #108)

Discuss the inhaled anesthetic gases. Name five vapors or potent agents and one gas.
Vapors: Halothane, Desflurane, Isoflurane, Sevoflurane, & Enflurane.

Gas: Nitrous oxide
(PHARM #109)

Discuss Nitrous Oxide, an Anesthetic Gas
Slightly sweet or no smell, well tolerated. Increased RR, decreased tidal volume. Alveolar ventilation is maintained. At anesthetic doses, ventilatory response to CO2 breathing is depressed. May directly decrease myocardial performance. Activates the sympathetic nervous system. It is used in sub-anesthetic concentrations as a sedative at 50% concentrations with O2. Used as an adjuvant at up to 70% concentrations with a potent agent or an opioid (“nitrous narcotic technique”). Problems associated with N2O include its high MAC of 108% and its diffusion in nitrogen containing spaces (air-filled spaces). Pathologies associated with Nitrous Oxide include organogenesis, megaloblastic anemia, and subacute combined spinal cord injury/peripheral neuropathies. Requires prolonged exposure above a threshold of 1000 ppm to achieve these pathologic effects.
(PHARM #110)

Why are anesthetic vapors called “potent agents”?
Potent agents are complete anesthetics. They achieve anesthetic effects at a relatively low alveolar concentration (partial pressure) and thus allow the use of a high concentration of oxygen. Potency is related to the oil:gas partition coefficient. High solubility in oil or lecithin implies high potency.
(PHARM #111)

Discuss the Blood:Gas partition coefficient.
The rate at which the partial pressure changes to approach the partial pressure in an adjacent phase is quickest for an insoluble agent. Low blood:gas solubility = rapid induction and emergence.
(PHARM #112)

(Cardio Effects) It is a negative inotrope and chronotrope. It inhibits baroreceptor function. It causes a marginal reduction in systemic vascular resistance. It causes a dose-dependent decrease in blood pressure. It sensitizes the myocardium to epinephrine. (Respiratory Effects) It is a potent bronchodilator. Respiratory rate increases as tidal volume decreases, and minute ventilation decreases. Results in a depressed hypoxic response. (Neuro Effects) Causes a high amplitude, slow wave EEG. Increases cerebral blood flow (CBF). Impairs autoregulation but decreases cerebral metabolic rate (uncouples cerebral blood flow from cerebral metabolic rate of oxygen consumption). May increase intracranial pressure (ICP). (Muscular Effects) Has muscle relaxant properties.
(PHARM #113)

(Cardio Effects) Positive chronotrope; small decrease in inotropy; marked decrease in systemic vascular resistance (SVR). Cardiac output is better preserved. Dose dependent decrease in BP. Less depression of baroreceptor function than with halothane. Stable cardiac rhythm. (Respiratory Effects) Potent bronchodilator at higher concentrations. Impaired ventilatory response to hypoxia and its augmentation by CO2 breathing is suppressed. (Neuro Effects) Decreases cerebral metabolic rate of oxygen consumption (CMRO2). Increase in CBF (cerebral blood flow) may be attenuated by hyperventilation. (Muscular effects) Relaxant properties.
(PHARM #114)

Advantages: Highly stable molecule with negligible metabolism. Physiologic effects are very similar to isoflurane. May increase intracranial pressure. Lowest B:G partition coefficient of any inhaled anesthetic: rapid recovery. Disadvantages: airway irritant. As compared with nitrous oxide, desflurane has a comparable B:G partition coefficient (0.42 as compared with 0.47 for nitrous oxide). However, desflurane has a MUCH better MAC: 6% vs. 108% for nitrous oxide.
(PHARM #115)

Newest inhalational agent available in the USA. Has supplanted halothane as the drug of choice of inhalational induction of anesthesia. Stable cardio-respiratory characteristics. Little significant change in HR, BP, or cardiac output. No myocardial sensitization to epinephrine. Uniquely suited for inhalation induction. Little odor, very smooth inhalation. Rapid onset and offset. Only negative: has toxic breakdown products in soda lime.
(PHARM #116)

Discuss the problems with vapors (potent inhalational anesthetics)
(1)Metabolism: halothane, sevoflurane, and ENF are broken down into TFA conjugates (trifluoroacetic acid). Free fluorine, free bromine.
(2) Halothane hepatitis.
(3) Malignant hyperthermia.
(4) Potential for ozone depletion.
(5) Low level toxicity for OR personel.
(PHARM #117)

Discuss Total Intravenous Anesthesia (TVA)
Classical agents include: Barbiturates for induction and sedation; Opioids for induction, maintenance and analgesia; Benzodiazepines for induction, sedation, and anterograde amnesia. When combined, may require vasoactive agents to maintain hemodynamic stability during anesthesia. Newer agents include Propofol for induction and maintenance; Ketamine for induction, maintenance, analgesia and sedation; Etomidate for induction alone.
(PHARM #118)

Intravenous anesthetic. An isopropylphenol. Lipid soluble. “Milk of amnesia.” Induction time: 30 seconds. Awakening: 4-8 minutes. Anti-emetic properties, minimal residual sedation. Cardiovascular effects similar to the barbiturates.
(PHARM #119)

Intravenous anesthetic. Imidazole derivative. Induction time: 30 seconds. Awakening: 6 minutes. Hydrolyzed to inactive intermediates. Cardiovascular stability. Decreases cerebral blood flow (CBF) and CMRO2. No effect on intracranial pressure. Causes myoclonus, seizures. Causes adrenal suppression. Etomidate blocks 11-beta-hydroxylase, stopping production of cortisol and aldosterone.
(PHARM #120)

Intravenous anesthetic. Phencyclidine (PCP) derivative. Dissociation between thalamic, limbic, and cortical systems. Rapid onset: patients appear cataleptic. Intense analgesia and amnesia. Hypertonus. Respiratory effects. Increased secretions. Primary myocardial depressant but activates sympathetic nervous system. Emergence phenomenon and hallucinations.