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136 Cards in this Set

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Which alcohol is the only one w/ clinical usefulness?
Ethanol: neurolytic agent and for tx of poisonings due to ingestion of other alcohols.
What does BAC depend on (EtOH)?
-quality of etOH
-consumption rate
-speed of absorption
-body weight
-% total body water
-rate of metabolism
Describe absorption of EtOH?
-Via simple diffusion in proximal intestines, also stomach (20-30%).
-rate of absorption is concentration dependent.
-delays in gastric emptying => decr absorption in prox intestines.
Describe distribution of etOH?
-enters systemic circulation => Liver => entire body
-Peak BAC @ 30-90 mins.
Describe metabolism of etOH?
-90% is oxidized to CO2 and H2O
-zero order kinetics(not time, conc dependent).
etOH oxidation specifics?
1st: gastric mucosa alcohol dehydrogenase.
2nd: hepatic enzamatic mechanisms. alcohol dehydrogenase (main) and microsomal enzyme oxidizing system(MEOS) (secondary) and catalase (tertiary).

-ADH is NAD+ limited
-MEOS is not NAD+ limited, has high Km for etOH.
Describe etOH elimination?
eliminated as CO2 and H2O.
-it's also expired quantitatively in respiratory gases.
Describe etOH's MOA?
nonspecific: since it's lipid soluble, it affects membrane proteins involved in neuronal signaling(Na/K ATPase, adenyl cyclase,voltage gated ion channels).

Specific effects:
-increased neuronal signaling at lower conc due to decr action of GABA to reduce inhibitory neurons signal(disinhibition) and incr release of DA in nucleus accumbens(pleasurable effect).

-decreased neuronal signaling at higher concentrations. Enhancement of GABA effects and inhibition of glut effects at NMDA receptor.
etOH CNS effects?
acute effects: low conc produces disinhibition => CNS stimulation. High conc produces impairment of the reticular activating system(RAS) => depression.

chronic effects: associated w/ serious neurologic & mental disorders. Abuse associated w/ vit-B deficiency leads to peripheral neuropathies.
etOH CV effects?
acute: cutaneous vasodilation w/ small doses; toxic doses => myocardial and respiratory depression.

Chronic: hypertension & irreversible cardiomyopathy.
etOH Hepatic effects?
acute: excess reducing equivalents incr NADH/NAD ratio => transient hyperglycemia, hyperlacticacademia, hyperuricemia, hyperlipidemia, and ketoacidosis.

Chronic:
-NADH induced inhibition of glycerophosphate dehydrogenase leads to incr glycerophosphate and esterification of fatty acids.
-decr oxidation of FA.
-Fatty liver
etOH GI effects?
acute: low conc => incr acid secretion. high conc => gastric irritation & pylorospasms(direct effect).

chronic: erosive gastritis and esophageal & duodenal abnormalities. Also pancreatitis.
etOH endocrine-reproductive system effects?
acute: ADH secretion is inhibited => diuresis. oxytocin secretion inhibited and LH and testosterone levels are decreased.

chronic: testicular atrophy, impotence sterility and gynocomastia due to hormone inhibition.
-excessive maternal etOH abuse during pregnancy => fetal alcohol syndrome.
etOH toxicity?
acute: related to BAC => CNS and CV depression. tx is supportive.

chronic: associated w/ incr mortalitiy. Liver dz, CNS neuropathies, incr risk for cancer.
Describe tolerance?
Either metabolic or pharmacodynamic.

Metabolic: increased capacity to metabolize etOH due to induction of hepatic cytochrome p450 2E-1

pharmacodynamic: cellular tolerance to etOH. membrane adaptation and behavioral adaptation also.
Describe etOH dependence?
psychological and physical dependence. the former leads to the latter.

-physical: due to chronic abuse => adaptive changes in neurotransmitters. downreg of GABA receptors and upreg of excitatory glut NMDA receptors and incr central NE activity. This leads to withdrawal if etOH ingestion is discontinued. Withdrawal syndrome = hallucinations, seizures, & delirium tremors.
How is withdrawal syndrome treated?
tx with counseling, clonidine(a2 adrenergic agonist), naltrexone(narcotic antagonist), disulfiram(aversive deterrent to etOH ingestion), acomprosate(NMDA receptor agonist; decr relapse rate), tiapride(DA receptor antagonist; blocks pleasurable effects).
etOH interactions?
due to disinhibition, avoid use in epileptic pts. Also avoid in hepatic or renal dz pts.
etOH effects on drug mechanisms?
Bioavailability:
-low conc => incr solubility of diazepam and AG antibiotics => incr bioavailability.
-high conc => induced pylorospasms which decr levels of any drug absorbed in proximal intestines.

metabolism: high conc can decrease metabolism of drugs like pentobarbital, phenobarbital, and phenytoin.
Chronic use can induce hepatic cytochrome P450 enhancing drug metabolism of drugs.
What is "aldehyde syndrome"?
Three drugs, disulfiram, metronidazol, & hypoglycemic sulfonylureas inhibit hepatic aldehyde dehydrogenase => buildup of acetaldehyde in body which causes cutaneous vasodilation, headaches, respiratory difficulties, n/v, sweating, cheast pain, blurred vision, hypotension, orthostatic syncope & confusion.
What drugs can potentiate the effects of etOH?
CNS: enhanced sedation w/ all CNS depressing agents.
GI: incr gastric irritation w/ salicylates.
endocrine: incr hypoglycemic response w/ sulfonylureas & biguanides.
CV: incr hypotensive response w/ nitrates.
methanol?
"wood alcohol" found in windshield washing fluid, solvent.

-rapidly absorbed in stomach => distributed in total body H2O.

-Substrate for alcohol dehydrogenase leading to formation of formaldehyde => formic acid via aldehyde dehydrogenase.

-Toxicity: headache, vertigo, vomiting, dyspnea, blurred vision, respiration, and acid-base balance(acidosis).
-can produce blindness via destruction of retinal ganglion cells via inflamation.

tx is supportive, acidosis correction. can give etOH which is a substrate for alchohol dehydrogenase blocking it's action on methanol.
Isopropanol?
initial substrate for Alcohol dehydrogenase. oxidized to acetone.

Toxicity:fatal dose 8oz. S/E similar to etOH but more prominent. Intoxication lasts longer due to slower oxidation. CNS depression => coma.

ketoacidosis and ketones in urine confirms intoxicaion.
Ethylene glycol?
antifreeze and/or solvent.

converted to glycoaldehyde via Alcohol dehydrogenase then to glycolic acid via aldehyde dehydrogenase.

glycolic acid => glyoxylic acid => oxalic acid.

Toxicity: initial CNS depression followed by metabolic acidosis. Nephrotoxicity can occur due to deposition of oxalic acid in renal tubules.

tx: supportive w/ correction of metabolic acidosis. administer etOH to reduce formation of toxic metabolites.
Classification of skeletal muscle relaxants?
Neuromuscular junction
-botulinus toxin
-cis-atracurium
-vecuronium
-succinylcholine
CNS (spinal interneurons):
-diazepam
-baclofen
Skeletal muscle Contractile Process:
-dantrolene
Uses of skeletal muscle relaxants?
Blocks nerve to muscle conduction:
-endotracheal intubation assistance.
-adjunct in surgical anesthesia to decr reflex movements.
-facilitates assisted ventilation during surgery.

Blockade of spinal interneuronal conduction(central blockade):
-decrease motor reflexes(spasticity)
-decreases muscle hypertonicity.

Blockade of skeletal muscle contractile process:
-malignant hyperthermia prophylaxis
-spasticity
Name drug which works presynaptically?
Botulinus toxin (clostridium botulinum) blocks vesicular release of ACh. It cleaves proteins involved in exocytosis of synaptic vesicles w/ ACh
Name one drug which works postsynaptically?
Vecuronium: non-depolarizing competitive blocking agent.
-contains one positively charged quaternary ammonium permitting electrostatic attraction and binding to the negatively charged alpha subunit of ACh receptor thus blocking it competitively. They bind/block but do not stimulate receptor.
-Muscle relaxes due to lack of neuronal input. increasing ACh can reverse effects(via acetylcholinesterase)
Name another drug which works postsynaptically?
Succinylcholine:
-depolarizing non-competitive blocking agent. Contains two (+) charged quaternary ammonium groups which binds to alpha subunit of ACh receptor w/ both affinity and efficacy => depolarization of post-junctional membrane.
-produces transient disorganized muscle contraction appearing as fasciculations. It also enters motor endplate => Na channel flickering ion conductance triggering an action potential adding to fasciculations.
-Succinylcholine isn't broken down as rapidly as ACh so it holds the motor endplate in a constant depolorized state. Flaccid paralysis occurs because muscle require a cycling b/w repolarization/depolorization.
This is called the PHASE I BLOCK!!! added ACh adds to the effect.
-continued occupancy by succinylcholine leads to desensitization => membrane repolarization and now added ACh(acetylcholinesterase inhibition) reverses the effect. this is called PHASE II BLOCK.
describe pharmacokinetics for muscle relaxants?
All are administered parenterally(other than mouth) and onset is 1-7mins.

-duration of effect of competitive, nondepolarizing agents reflects diffusion away from active site => hepatic metabolism => renal elimination.

-succinylcholine has short duration of action due to hydrolysis via cholinesterase & diffusion from receptor.
Describe onset and duration of NMBA's
Succinylcholine, non-competitive, 1-1.5m onset, 6-10m duration.

Cis-atracurium, competitive, 4-6m onset, 45-60m duration.

Vecuronium, competitive, 3-4m onset, 35-45m duration.
How are estimations of neuromuscular blockades made?
Via indirect stimulation of a motor nerve with "trains of four" stimuli applied to the ulnar nerve to see thumb adduct. Estimate of transmission is made by using ratio of 4th and 1st amplitude responses in same train.
Vecuronium?
Non depolarizing competitive agent which is a newer "uroniums". inhalational anesthetics augment neuromuscular blockade, aminoglycoside also augments blockade and cholinesterase inhibitors antagonize blockade.
cis-atracurium?
Non depolarizing competitive agent

purified form of one isomer of atracurium. undergoes spontaneous metabolism in vivo via hofmann elimination(80%), the rest is eliminated by renal mechanisms.

inhalational anesthetics augment neuromuscular blockade, aminoglycoside also augments blockade and cholinesterase inhibitors antagonize blockade.
Succinylcholine Cl?
Depolarizing non competitive agent. Used for brief surgical procedures. rapidly hydrolyzed by plasma cholinesterases so only a small amount reaches NMJ.

-pts w/ myasthenia gravis are resistant to succinylcholine's effects. Do not use on pts w/ ocular disorders

-pts who have atypical cholinesterase exhibit a prolonged blockade.

-pts w/ burns or trauma respond w/ hyperkalemia when given succinylcholine.

-S/E: bradycardia, cardiac dysrhythmias, increased intraocular, intragastric & intracrainial pressures, myalgia, & myoglobinuria.
What is the MOA of centrally acting muscle relaxants?
-They depress activity of spinal and supraspinal interneurons in motor reflex pathways, not NMJ!!!!

-exact mechanism is unkwn. May be due to enhanced GABA mediated pre/post synaptic inhibition to decrease neuronal signal strength in motor circuits. OR decreased release of excitatory NT's (glut).
What are the clinical uses of CAMR's?
Agents are palliative and do not alter clinical course of primary lesions.

-Used to relieve spasticity due to excessive neuronal reflex activity from sprains, arthritis, myositis, and fibrositis. hypertonicity and rigidity are both reduced also.
Diazepam?
BZ which incr GABA mediated inhibitory synaptic transmission to decr spinal interneuronal signaling.

S/E: sedation, tolerance and dependence.
Baclofen?
an agonist at GABA-B receptor but this action in treatment is questionable.

Reduces the release of glut from spinal neuronal circuits => reduced interneuronal excitatory conduction. effective in treating flexor spasms and muscle rigidity of MS and spinal cord injury.

S/E: sedation, confusion, weakness, sudden withdrawal leads to auditory and visual hallucinations.
Describe the MOA of the peripheral acting muscle relaxants, Dantrolene?
direct effect on the excitation-contraction coupling mechanisms(not at NMJ).

-it decreases Ca++ release from the sarcoplasmic reticulum thereby permitting relaxation of hypertonic muscles.
Clinical uses for Dantrolene?
-Spasticity associated w/ upper motor neuron lesions.
-muscle relaxation in stroke, MS, dystonia, & postencephalitic athetosis(involuntary twisting) patients.
-prophylaxis for anesthetic induced malignant hyperthermia; these pts experience severe muscle spasms & contractures when triggered by anesthetic agents. Can be given as treatment or as prophylaxis.

S/E: muscle weakness and fatigue.
Define pain perception?
process where brain integrates both sensory and emotional components of nociceptive or neuropathic input.
Define analgesia?
relief of pain by either removing stimulus, blocking the generation of nerve impulses at sensory nerve endings, or reducing signal strength in pain pathways.
Define anesthesia?
loss of all sensation w/ or w/o loss of consciousness and is achieved by local application of agents achieved by blocking the generation of nerve impulses at sensory nerve endings or reducing signal strength in pain pathways.
How is pain transmitted to the brain?
activation of nociceptor nerve endings sending signal via primary sensory neurons then via both spinal and supraspinal pathways.

primary sensory nerves of dorsal root ganglion terminate in the dorsal horn of the spinal cord by forming a synapses w/ neurons projecting to supraspinal structures.
Name some neurotransmitters/neuropeptides involved in pain reception.
Glutamate=> NMDA & non-NMDA receptors.

Substance P along w/ calcitonin gene related peptide(CGRP) are co-released from primary afferents.

adenosine and Protein kinase C play modulatory role.

endogenous opiate peptides - modulates both ascending and descending signaling.

NE & 5HT mediate one component of thedescending control of pain relay circuit.

GABA decreases neuronal signal strength by increasing inhibitory conduction in pathways which mediate awareness.

Voltage dependent ion channels-mediate both excitatory and inhibitory pathways in pain reception.
Name the sites of analgesic/anesthetic action?
non-narcotic analgesics-central & peripheral prostaglandin synthesis.

Acetaminophen-central prostaglandin synthesis.

narcotic analgesics-opiate receptors.

Local anesthetics-Na channels

General anesthetics-K+,Ca++,Na+ channels & GABA receptors-Cl channel system.

Injectable anesthetics-GABA system

Ketamine-NMDA receptors

Methadone-opiate and NMDA receptors.
Describe local anesthesia?
Reversible depression of both central & peripheral nerve conduction in a circumscribed area.
What are the routes of administration of anesthetics?
intravenous anesthesia
topical anesthesia
infiltration local anesthesia
nerve block anesthesia
spinal subarachnoid anesthesia
epidural and caudal anesthesia
What three structural components determine the anesthetics properties?
lipophilic group(aromatic ring)
hydrophilic group(amine group)
hydrocarbon chain(ester or amide)

-unsaturated aromatic rings confer lipophilic properties and an amino terminus(tertiary amine) confers hydrophilic properties.

-lipophilic portion is essential for anesthetic activity.
What two groups are local anesthetics classified into?
esters(procaine HCl)
amides(lidocaine HCl)

esters are hydrolyzed by cholinesterases to water soluble metabolites and amides are metabolized in the liver.
What are features of local anesthetics?
-they are weak bases: pKa 8-9
-solutions are mixtures of unionized, lipid soluble form w/ ionized water soluble form.
-uncharged bases penetrate across nerve sheath: pH dependent re equilibration occurs in the interior of nerve to charged water soluble form => binding of active sites in nerve membrane.
Pharmacokintics of local anesthetics?
-local anesthetics are administered adjacent to the nerve fibers to be blocked
-onset, potency, & duration of action are determined by: dosage, site of injection, local blood flow, anesthetic formulation, pharmacological properties of the agent, and protein/tissue binding.
-diffusion away from the application site & metabolism determine duration of action.
How are esters metabolized?
By pseudocholinesterase => short half lives of procaine.

Blood flow => diffusion away from injection site affects duration. reducing blood flow => increase duration of block.
How are amides metabolized?
By the liver via cytochrome P450 => hydrolysis of amide linkage. Hepatic blood flow, liver disease, and competition by other drugs for P450 all effect amide metabolism.

Blood flow => diffusion away from injection site affects duration. reducing blood flow => increase duration of block.
Durations of procaine and lidocaine?
Procaine = 20m alone and 56m w/ Epi(vasoconstrictor).

Lidocaine = 75m alone and 228m w/ Epi.
What's the MOA of local anesthetics?
-they bind to, and block voltage gated Na+ channels => altered nerve fiber conduction.

-They bind to receptor sites near the intracellular end of Na+ channel and block the channel in a time/voltage dependent fashion.: specifically they bind to Na+ channels in the inactivated-closed state to prevent their change to activated-open state. this effect is greater in rapidly firing axons than in resting fibers.
Describe the sequence of events for blockade by a local anesthetic?
-binding to receptor site in voltage gated Na+ channel
-Blockade of Na+ channel and decreased Na+ conductance.
-Depression of electrical depolarization rate.
-failure to achieve threshold potential => failure to propagate an action potental.
Describe the electrical changes in a nerve following anesthetic binding.
-increased threshold for electrical excitability
-decr rate of rise of depolarization phase of AP.
-lengthen refractory period.
-Resting membrane potential in not affected.
Describe the order of blockade in nerve fibers?
Order of block is based on nerve size and myelination.

-Ad,B,C fibers being the smallest and least myelinated are blocked first => pain sensation is reduced before motor function is blocked. Aa motor fibers are larger and heavily myelinated so they are last on the order of block.
How does toxicity w/ local anesthetics occur?
Absorption into the systemic circulation can occur.

-Toxicity occurs by the same MOA used in clinical efficacy, binding to voltage gated Na channels.

-Toxicity is directly related to blood levels of anesthetic.

-greater lipid solubility => longer duration of action & greater potential for toxicity.

-decreased blood flow at injection site(Epi), plasma proteins which serve as sinks for free drugs are ways to minimize systemic toxicity.
What are signs of toxicity w/ local anesthetics?
CNS:initially - salivation & tremors. Convulsions occur w/ incr blood concentrations. CNS mediated hypertension and tachycardia followed by hypotension.

CV: Direct effect on cardiac and sm muscle via cardiac voltage gated Na channels => alterations in pacemaker activity & conduction blockade.

Treatment: restore ventilation and circulation then give BZ used to treat seizures.
What is neurotoxicity?
placement of local anesthetics in the epidural or subarachnoid space => transient numbness, radicular irritation of lumbosacral nerves or myotomal weakness. Permanent injury after local anesthetic use is rare.
Allergic rxn w/ local anesthetic?
With Ester type locals => bronchospasm and anaphylaxis.

-CV dz may lower threshold for cardiac toxicity as will therapy w/ drugs which inhibit myocardial impulse propagation.

Hepatic metabolism of amide locals can be decreased by reducing liver blood flow & by taking drug which are also substrates for p450.
Specifics on Procaine HCl?
first synthetic local anesthetic; an Ester.

Hydrolyzed by pseudocholinesterase => gives procaine short half-life.
Specifics on Lidocaine HCl?
First amide local anesthetic.

metabolized in liver

liver dz or decr hepatic blood flow decreases its metabolism.

Has intrinsic vasodilator properties.
Pharmacokinetics of Aspirin?
-ASA is absorb mainly in the proximal intestines, some in the stomach. Absorption is determined by pH at mucosal surface(acidic is better), tablet dissolution rate, & gastric emptying time.

-ASA is rapidly hydrolyzed to acetate + SA via esterases. Peak plasma conc occur at 1-2hr.

-free SA is distributed throughout most body tissues, 80-90% is bound to plasma proteins though
Describe the metabolism of salicylate?
-In liver, salicylate is conjugated w/ gly or glucuronic acid. Half life for SA is 2-3h in low doses & 15-30h in high/toxic doses. Dose dependent elimination is result of livers limited ability to form conjugates.

Free SA is excreted in urine and is pH dependent. Alkaline urine => higher excretion %.
Ibuprofen?
propionic acid derivative.

-rapidly absorbed after oral intake.
-1-2h peak concentration; 2h half-live.
-99% are bound to plasma proteins.
-metabolized in liver.
-concentration in synovial fluid is higher than plasma conc.
-95% of propionic acid derivatives are excreted in urine.
Describe analgesic and anti inflammatory actions of ibuprofen & aspirin.
-they decrease prostaglandin(PG) synthesis via inhibition of the enzymes COX I & II at central and peripheral sites.
-COX I is constitutive and expressed in most tissues. PG's protect gastric mucosa by putting a brake on acid production. PG also influence salt/water excretion by altering renal blood flow and direct effects on renal tubules.

-Cox II is inducible and activated by mediators released during tissue damage; responsible for inflammatory response.
What's aspirin and ibuprofens effects on Cox I, II?
Both Cox I and II are inhibited by them => reduced inflammation induced PG synthesis(beneficial PG in gastric muscosa and kidneys are also reduced).
What are other effects of aspirin and ibuprofen?
-they inhibit migration of PMN leukocytes and macrophages into inflammation sites
-stabilization of lysosomal membranes.
-inhibition of ab-ag aggregation.
How does aspirin and ibuprofen reduce elevated body temperature?
-They inhibit PG synthesis in the hypothalamus. Bacterial pyrogens stimulate IL1 => stimulates PG synthesis in hypothalamus. PG(E2) elevates body temperature.
How does aspirin and ibuprofen reduce platelet aggregation?
Reduced aggregation reduces the incidence of stroke and recurrence of myocardial infarction(Aspirin).

-ASA acetylates COX I in platelets irreversibly blocking synthesis of thromboxane A2.
-Platelets do not synthesize new COX I enzymes so effect last for the life of the platelet 8-10days.
-Effects only w/ aspirin!!
Adverse effects of aspirin?
-gastric irritation
-prolonged bleeding time
-dehydrated pts or pt's w/ renal dz can show a reversible decr in GFR or interstitial nephritis and edema.
-Children w/ chicken pox or flu like illness are 25x more likely to develop Reye's Syndrome.
-hypersensitivity rxn: asthma, skin rashes, angioedema, anaphylactoid rxn
What's Reye's Syndrome?
deadly dz in children & teenagers occurring in the aftermath of a viral infx.

-aspirin and viral illness appear to damage mitochondrial membranes in genetically predisposed pts => hepatic injury and encephalopathy.
Adverse effects of ibuprofen?
-There's no gastric irritation, bleeding time issues, or Reye's syndrome complications w/ ibuprofen.
-hypersensitivity rxn possible
-reduced renal blood flow and edema, reversible decr GFR, interstitial nephritis, and nephrotic syndrome may occur in pts w/ preexisting dz or dehydration.
-Birth defects in 1st trimester, higher risk of heart defects or other congenital anomalies.
What about aspirin toxicity?
mild toxicity => headache, dizziness, mental confusion, tinnitus, n/v. All are dose dependent.

Severe toxicity => hyperventilation due to incr CO2 production(ASA uncouples oxidative metabolism in sk muscles which incr CO2 & it stimulates medullary respiratory center).
-Respriatory alkalosis is compensated for by incr Na & K bicarbonate excretion => disturbances in acid-base balance. Can lead to coma & death if left uncorrected.
-alkalization of urine will incr excretion of SA.
NSAID Drug interations?
-EtOH + NSAIDs = possibility of GI bleeding
-anticoags are displaced from plasma proteins by aspirin => increased anticoagulant activity.
-salicylate induced displacement leads to incr free drug w/ tolbutamide, chlorpropamide, phenytoin.
-small doses inhibit tubular secretion of uric acid blocking the uricosuric effect of probenecid.
-ibuprofen can interfere w/ anti-platelet effect of ASA.
Describe the Pharmacokinetics of acetaminophen.
-rapid, complete absorption from GI tract. Peak conc in 30-60min w/ 2-3hr half life.
-evenly distributed throughout most body fluids; binding of drug to plasma proteins is 20-50%.
-Most is metabolized via hepatic conjugation; glucuronic acid(60%) and sulfuric acid(40%).
-4-5% metabolized via cytochrome P450 system to N-Acetyl-benzoquinoneimine (NABQ)
Acetaminophen pharmacological action?
Has analgesic and antipyretic actions but lacks anti inflammatory properties(probably due to peroxide concentrations found at inflammatory sites which inactivate the drug).
-Unknown mechanism since it weakly inhibits COX I & II. May be selective for supposed COX III enzyme.
-Neutrophil activation or platelet function are not altered.
Acetaminophen adverse effects?
-Usually well tolerated
-Sometimes a skin rash or other allergic rxn.
Acetaminophen toxicity?
-Most serious is fatal hepatic necrosis => primary cause of acute liver failure.
-Toxic doses exceed capacity for glucuronidation so more is converted to NABQ via hydroxylation. NABQ binds to SH- groups in hepatic proteins producing cellular damage and hepatic necrosis.
-clinical signs of hepatic damage comes 2-4days post ingestion.
-chronic alcohol intake increase capacity of liver to N-hydroxylate acetaminophen to NABQ => lowering of threshold of acetaminophen liver damage.
-glutathione, which normally binds NABQ to inactivate it, is depleted in alcoholics => further increase in severity of liver injury.

Treatment: induction of vomiting or gastric lavage should be performed followed by administration of oral charcoal. Hemodialysis if caught in first 12hrs. Also, administration of sulfhydryl compounds increases hepatic content of glutathione.
What about compounds containing acetaminophen and aspirin?
Abuse of these can cause renal tubular necrosis. Nephropathy results from p-aminophenol, a metabolite of acetaminophen, which concentrates in the hypertonic renal papillae.
Ketorolac?
-NSAID, Rapidly absorbed orally or IM. Peaks at 30-60min w/ halflife of 4-6hrs. 99% bound to plasma proteins. Metabolized in liver(conjugated w/ glucuronic acid); 60% excreted unchanged.
MOA of Ketorolac?
Inhibition of COX I and II PG synthesis => analgesic, antipyretic and anti-inflammatory actions. Analgesic effect is more potent than antipyretic or anti-inflammatory effects. USE FOR ACUTE PAIN.
S/E of Ketorolac?
-GI discomfort, dizziness & headache.
-inhibits platelet aggregation => prolonged bleed time
-Bronchospasms may occur w/ administration to asthmatic pts or those w/ nasal polyposis or aspirin sensitivity.
-increased incidence of gastric ulcers and renal impairment reported when taken longer than 5 days.
Describe the opiate receptor in general.
-High conc of them are located in the CNS and know to be involved in pain transmission.
AREAS: dorsal horn of spinal cord, periaqueductal gray, rostral ventral medulla, and some thalamic nuclei.
-Also located in the peripheral tissues.
Describe opiate receptor's characteristics.
-Structural specificity: small changes in drug molecule => big changes in binding properties.
-Stereospecificity: Only the l (-) isomer binds w/ high affinity.
-Reversibility: drugs can be displaced by other drugs in high concentrations w/ binding affinity for receptor.
What are the three subtypes of opiate receptors?
Mu, Kappa, and delta.
-All are members of the G-protein coupled family.
What are the three endogenous opiate peptides(opiopeptins)?
beta endorphin
-large peptide taken off from proopiomelanocortin enzymatically. Located in pituitary and hypothalamus & concentrated around 3rd and 4th ventricles. it's released into CSF during painful episodes.

dynorphins
-formed from prodynorphins & localized within nerve endings of CNS pain pathways.

enkephalins
-pentapeptides from proenkephalin breakdown. present throughout CNS pain areas and appear to regulate transmitter release inhibiting transmission of pain stimuli.
What are the properties of endogenous opiopeptins?
-they bind w/ high affinity to opiate receptors
-can be reversed w/ opiate receptor antagoists.
-Cross tolerance exhibited to narcotic agonist administration.
-Dependence w/ choronic use.
-withdrawal rxn is induced w/ antagonist in dependent subjects.
Describe narcotic absorption & distribution.
-Absorption is usually poor due to 1st pass metabolism & glucuronidation.
-IM administartion is complete w/ max blood levels in 15-30min.
-transdermal & epidural administration is effective also.
-Distribution is based on blood flow. CNS levels are influenced by BBB, lipid solubility of opiate, protein binding of opiate, and rapid hepatic conjugation.
Describe narcotic metabolism & elimination.
-Hepatic conjugation w/ glucuronic acid => water soluble product. Morphine-6-glucuronide is an active product.
-Codine demonstrates good oral:parenteral potency ratios due to structural protection from conjugation.
-Elimination via kidneys w/ water soluble metabolites and in bile w/ glucuronide conjugates.
Describe the cellular actions of narcotics.
-All actions are due to binding of opiates to receptors at pre/post synaptic sites.
-opiate receptors are coupled to various types of GTP-dependent proteins.
-binding of opiate => dissociation of GDP regulator from G-protein freeing GTP subunit to activate adenylate cyclase, phospholipase and/or protein kinases.j
-quantitative response is determined by agonist affinity and/or # of receptors activated.
-presynaptic agonist => decrease voltage gated Ca++ influx => reduced excitatory neurotransmitters released.
-postsynaptic agonist effects produce incr K+ conductance via activation of receptor operated K+ currents leading to hyperpolarization & reduced signal strength.
Describe the CNS effects from narcotics.
-analgesia: inhibits nociceptive reflexes at spinal and supraspinal sites by interacting w/ mu and kappa receptors => raised threshold for pain & diminished rxn to pain. Continuous dull pain is relieved more than sharp pain.
-Sedation: drowsiness and sedation is based on age, debilitation, other drugs. May also decr anxiety.
-Mood changes: euphoria
-Respiratory effect: Leads to dose dependent depression of respiration(decr sensitivity of respiratory center to CO2). Decrease in rate, minute volume, and tidal exchange.
What are other separate central effects to narcotics?
-miosis due to increase parasympathetic activity.
-n/v due to direct stimuation of CTZ for emesis in area postrema of medulla. All mu agonist produce n/v.
-cough suppression from direct depression of cough center in medulla.
-truncal rigidity due to increased decending motor impulses.
Describe the peripheral effects of narcotics.
-peripheral effects of morphine is due to activation of mu receptors. minimal effects on CV system in supine patient.
-small and large intestine tone is increased(spasm) & propulsive contractility decreased.
-constriction of biliary smooth muscle & spincter of oddi leads to increase biliary tract pressure.
-Urinary retension from increase tone in ureter, detrusor muscle of bladder, and vesicle sphincter.
-Histamine release => produces cutaneous flushing and loss of body heat but depends on opiate used.
Drug action at specific receptors?
Morphine: agonist at mu, kappa, & delta.

Fentanyl: agonist at mu.

methadone: agonist at mu.

butorphanol: partial agonist at mu.

nalbuphine: partial agonist at mu.

buprenorphine: partail agonist at mu.

Naloxone: antagonist at mu, kappa, and delta.
Describe tolerance w/ narcotics.
-can develop in 1-3 wks w/ repeated administration.
-tolerance is gained to all effects except for miosis and constipating effects.
-cross tolerance occurs to all opiates
-less tolerance gained w/ partial agonist/antagonists.
-tolerance related to reduction in the receptor-ion channel coupling in the membrane w/ incr drug use.
Describe dependence w/ narcotics.
-parallels tolerance development.
-cell processes linked to the receptor activation become hyperexcitable w/o continued presence of agonist at receptor site => withdrawal or abstinence syndrome.
-dependent patient + antangonist = withdrawal.
What are the dz/drug interactions w/ narcotics?
-hepatic and respiratory dz are factors due to respiration depression & increased drug effects.
-contraindicated in head injury w/o assisted ventilation.
-pts w/ pancreatitis may experience further increased biliary tract pressure.
-narcotics + CNS depressants = potentiation of sedative effects.
What about toxicity in narcotic use?
Triad of symptoms:
depressed respiration, pinpoint pupils, coma.

Treatment: ABC's and administration of antagonist.
What are the narcotic antagonist and their characteristics?
naloxone: full agonist binds to mu, kappa, and delta receptors but has no action or effect on receptors (efficacy). Halflife of 1-2hrs following IV administration.

-naltrexone: pure antagonist which is longer acting and taken p.o.
what are narcotic agonist-antagonist.
binds to mu, kappa, or delta receptors as a pure or partial, agonist or an antagonist.
Buprenorphine?
acts as a partial agonist in the absence of morphine. May antagonize the effect of morphine based on dose.
Precautions of full antagonists?
-reversal of beneficial effects when trying to reverse respiratory depression(unmasking of analgesia.
-may have shorter halflive than morphine =>respiratory depression will reoccur
-precipitation of withdrawal.
What are the components of the anesthetic state?
amnesia
sedation/loss of consciousness
analgesia
hyporeflexia
muscle relaxation
What type of general anesthetics are in use?
inhalational anesthetics: sevoflurane
desflurane

inhalational analgesics:
NO

intravenous agents:
anti-anxiety BZ - midazolam
dissociative agent - ketamine
anesthetic agent - propofol, etomidate.
What are the Guedel stages of anesthesia?
Induction:
I. analgesia
II. delirium

Maintenance:
III.surgical anesthesia
Plane-1 Sleep
Plane-2 sensory loss
Plane-3 muscle tone loss
Plane-4 Intercostal paralysis

Coma/Death:
IV. medullary paralysis
What about newer anesthetics?
they have lower blood solubility which produces faster and less progression through the stages of anesthesia.
What's the underlying mechanisms for the different stages of anesthesia?
Stage I: selective sensitivity of neurons in the substantia gelatinosa accounts for analgesia(spinothalamic tract neurons).
Stage II: blockade of inhibitory neurons leads to delirium stage.
Stage III: progressive depression of ascending pathways in reticular formation accounts for surgical anesthesia stage.
Stage IV: at higher concentrations the medullary vasomotor & respiratory centers are depressed.
Describe the kinetics of gaseous anesthetic uptake and distribution.
onset of anesthesia depends on the rate of change of concentration of inhalational agent in alveolus vs. blood vs. brain and vice versa for offset.

-The rate of onset/offset of anesthesia is dependent upon the speed of equilibration in each of the compartments(rate of onset/offset-blood solubility[blood/gas partition coefficient])

-The depth of anesthesia depends upon the concentration of the agent in the brain(depth-concentration in brain[oil/gas partition coefficient])
describe inspired, alveolar and blood concentrations of anesthetics when obtained via inhalation.
inspired concentration: determined by flow of carrier gases and vapor pressure of anesthetic agent.

alveolar concentration:
determined by inspired concentration and minute volume and functional residual capacity. Also determined by blood flow since this removes the drug from alveolar space

Blood concentration:
determined by alveolar concentration and permeability of alveolar membrane. Solubility in blood is also important and is related to blood-gas partition coefficient.
-Blood-gas partition coefficient determines how rapidly the solubility equilibrium is reached b/w alveolus vs. blood. Induction w/ agents that have low coefficients(sevoflurane, desflurane) occurs more rapidly than w/ agents that have high coefficients.
describe brain concentrations of anesthetics when obtained via inhalation.
-determined by blood concentration and solubility of agent in brain. This is related to lipid solubility of agent. The oil-gas partition coefficient is the index of solubility of the agent in the brain.

Sevoflurane
blood/gas=0.65
oil/gas=50
MAC=2

Desflurane
blood/gas=0.45
oil/gas=20
MAC=6
What is minimal alveolar concentration?
MAC: concentration of anesthetic measured in end tidal gas which prevents response to standard painful stimulus in 50% of humans.
-in clinical situations, agents are given in multiples of MAC. MAC requirements can be minimized by co-administering inhalation analgesics or IV narcotics.
Describe metabolism and elimination of inhaled anesthetics.
-hepatic metabolism varies w/ agent. Minimal biotransformation occurs w/ desflurane & NO. 2-5% of sevoflurane is metabolized.
-metabolism of sevoflurane generates fluoride ions.
-most agents are eliminated quantitatively in expired gasses. Metabolites and organic/inorganic fluorides are eliminated by the kidney.
What are the mechanisms of anesthetic action.
-lipid solubility correlates w/ potency. inhaled agents don't have unique structural configurations that provide a particular structure-activity relationship, only lipid solubility.
-Electropysiological changes: agents decrease excitatory synaptic transmission(EPSP's) by entering the lipid-protein matrix of neuronal membranes where they reversibly disprupt (K+,Na+,Ca++) channel function. agents also increase inhibitory synaptic transmission(IPSP's). Low conc of inhalational anesthetic agents facilitate the action of GABA to increase GABA activated chloride ion influx. At higher conc, they directly activate GABA Cl- channel receptor complex to increase chloride flux.
Describe the CNS effects from inhalational anesthetics.
-they produce an irregularly descending depression of the CNS.
-Higher cortical centers, ascending reticular activating system and spinal cord are affected first; the medullary area is depressed at high concentrations => respiratory and circulatory arrest.
-Most inhalational agents produce a small incr in cerebral blood flow due to decreased cerebral vascular resistance
Describe the CV system effects from inhalational anesthetics.
-Sevoflurane decreases conractility and cardiac output at 1 MAC concentration. desflurane produces minimal depression.
-all inhalational agents decrease VSM tone => reduced BP in a concentration-dependent manner.
-Desflurane can increase BP when rapid increases in anesthetic concentration occur.
Describe the respiratory system effects from inhalational anesthetics.
-All agents produce a concentration-dependent respiratory depression via:
=direct depression of respiratory center.
=decrease in sensitivity of medullary respiratory center to CO2

-All inhalational anesthetic agents decrease tidal volume:
=an incr in respiratory rate occurs but is insufficient for the decrease in tidal volume. these agents produce a increase PaCO2 w/o mechanical ventilation.
Describe the neuromuscular system effects from inhalational anesthetics.
-skeletal muscle relaxation occurs in a concentration-dependent manner
-this is due to reduced signal strenght in spinal interneurons which is related to increased GABA effects.
Describe the GI system effects from inhalational anesthetics.
incidence of n/v is variable from patient to patient and depends on extent on the length of anesthetic administration.
Adverse effects Desflurane?
CV: rapid increases in anesthetic concentraton produces activation of the sympathetic nervous system. transient incr in HR and BP.

Respiratory: high incidence of airway irritation. pretreatment w/ narcotics decreases this S/E.

Toxic byproducts:
CO forms from rxn of desflurane w/ material which absorbs CO2(soda lime)
-CO formed depends on temp and moisture of CO2 absorption material.
Adverse effects of Sevoflurane?
-under low flow conditions, it can also react w/ CO2 absorber, soda lime, in the anesthetic circuit. Compound A is formed from the rxn w/ soda lime, especially w/ increased temperature in the gas delivery circuit.
Nitrous oxide?
-a potent inhalational analgesic agent.
-Used in combo w/ other anesthetic agents, it's inadequate alone.
-Has rapid onset/offset of effects due to limited solubility in blood.
Describe analgesia w/ NO?
Analgesia occurs w/ inspired concentrations of 20% but used in conc up to 70%.
-Used to lower conc of other anesthetic. the analgesic MOA is unknown.
Effects of NO on organ systems?
NO has no significant effect on CV, respiratory, hepatic, renal, or autonomic nervous system. It does have CNS effects due to disinhibition of inhibitory pathways hence it's name, "laughing gas".
What are NO's limitations of use?
-Hypoxia occurs when used in concentrations over 80%. Diffusional hypoxia occurs when NO is rapidly terminated w/o supplemental O2 leading to diffusion of NO from blood to alveolar space => low O2 pressure in the alveoli.

S/E: n/v, decreased fertility in women.
Describe the IV agent, midazolam.
-a BZ that reduces anxiety and sedates the patient(enhances GABA chloride flow but doesn't produce analgesia.)
-Combined w/ NO or narcotics to produced clinical anesthesia.
-Has minimal CV or Respiratory depression.
IV Propofol?
-Has rapid induction.
-doesn't provide analgesia so must be used w/ NO or potent narcotics.
-halflife of 30-90min and has rapid recovery w/ less "hang over".
-MOA: increases ihibitory synaptic transmission via facilitation of GABA receptor . Produces dose-dependent CNS depression.
What are the S/E of Propofol?
-Dose dependent depression of respiration w/ possible apnea.
-Depression of CV system => hypotension & reduced systemic vascular resistance. (15-30% reduction in CO, SV etc)
-has anti-emtic properties
-injection site irritation & allergic rxn.
IV Etomidate?
-rapid onset of sleep/recovery(t1/2=2-5hrs) but lacks analgesic properties so requires NO or narcotics.
-MOA: increase inhibitory synaptic transmission via GABA receptor. Doesn't reduce excitatory transmitter release.
-S/E: minimal CV, respiration depression. produces excitatory phenomenon(involuntary muscle movement, tremor). Marked suppression of adrenocortical function for 4days post use along w/ n/v.
IV Ketamine?
-produces a cataleptic trance like state where pt appears awake(dissociative anesthesia).
-rapid acting w/ return to consciousness in 15mins, complete recovery is longer.
-provides profound analgesia!!
-MOA: noncompetitive antagonist of NMDA glut receptors. Decreases excitatory synaptic transmission by reducing synaptic Ca++ channel conduction.
SE's of IV Ketamine?
-CV stimulation(incr BP, HR, etc) due to direct stimulation of CNS => increased sympathetic outflow.
-increased cerebral blood flow & ICP.
-Minimal respiratory depression.
-Muscle tone increased
-disagreeable dreams/hallucinations weeks after use.
describe IV opiate use?
-produces marked analgesia w/ sedation.
-"conscious sedation": IV opiate + anti-anxiety agent.
-"neuroleptanesthesia": analgesia and amnesia from fentanyl and droperisol.
-MOA: activation of opiate receptors(spinal, supraspinal) => reduced impulse transmission in pain pathway.
-S/E: respiratory depression, CV depression and skelekal muscle rigidity due to decreased inhibitory neuronal activity.