Chem
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| What is another name for phase 1 reactions | biotransformation
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| what are the 3 types of phase 1 reactions | oxidation, hydrolysis, reduction
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| what is the goal or end result of phase 1 reactions? | to create a more polar cmpd that is easily excreated by the kidneys
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| It is important to know that during Phase 1 reactions, placing _______ on drug molecules enables Phase 2 reactions to occur. | hydroxyl or carboxy groups
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| Oxidation of drugs employs the ______ and this is known as _______ system. | hepatic microsomal enzymes, cytochrome P-450 enzyme
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| what occurs during phase 1 oxidation reactions? | oxygen is introduced to molecule, or oxidative state of molecule is changed so its oxygen content is increased; oxidation results in LOSS of electrons (OIL RIG)
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| what happens to the oxygen molecule that is introduced to the compound during oxidation reactions? | oxygen molecule is split - one atom oxidizes each molecule of the drug and the other is incorporated into a molecule of water
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| what molecule is the electron donor during phase 1 oxidation reactions? | nicotinamide adenine dinucleaotide (NAD)
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| Oxidative metabolism reactions are catalyzed by _____ | the enzymes of the cytochrome P450 system.
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| what are 5 examples of oxidative metabolism | hydroxylation, deamination, desulfuration, dealkylation, dehalogenation
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| what occurs during hydroxylation? | a phase 1 oxidation reaction: a chemical process by which one or more hydroxyl groups (-OH) are introduced into a compound.
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| what is an example of hydroxylation? | Aliphatic hydroxylation of a minor metabolite of Phenobarbital converting it to an alcohol. This makes it more polar so it can be excreted.
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| what occurs during deamination? | a phase 1 oxidation reaction: involves the removal of the amino radical from a compound
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| describe 3 examples of deamination reactions: | 1. amino acid cytosine converts to uricil 2. 5-methylcytosine converts to the amino acid thymine 3. norepinephrine and epinephrine leads to vanillymandelic acid (VNA) (also called 3-methyl-4-hydroxyphenylglycol)
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| what occurs during desulfuration | the removal of the sulfur atom and the substitution of an oxygen atom.
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| what is an example of desulfuration | Thiobarbiturates (Thiopental) can undergo desulfuration to form oxybarbiturates and further breakdown into active metabolites. Thio = sulfur.
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| what occurs during phase 1 hydrolysis reactions? | Hydrolysis is the addition of water to an ester or amide to break the bond and form 2 smaller molecules
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| name two example of hydrolysis reactions | 1. Esters + water --> acid + alcohol (ester hydrolysis) 2. Amides + water --> acid + amine **local anesthetics **amides rarely undergo hydrolysis
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| what are some commonly used anesthetics taht undergo phase 1 hydrolysis reactions? (name 6) | succs, cocaine, neostigmine, remifentanil, esmolol, cisatracurium
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| reduction pathways use what enzymes | enzymes of CYP 450 system
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| what occurs during reduction reactions? | When insufficient amounts of oxygen are present to compete for electrons, these enzymes transfer electrons directly to a substrate rather than to oxygen. Reduction is GAIN of e-; the reduced drug creates a free radical that attach to a cell --> toxic
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| describe the outcomes of halothane when undergoing oxidation and reduction pathways | • Oxidative pathway leads to Trifluoroacetic acid (TFA) • Reductive pathway leads to several metabolites thought to be responsible for hepatotoxicity in animal models (controversial)
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| what is another name for phase 2 reactions: | synthetic/conjugation reactions
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| what generally occurs during phase 2 reactions? | body synthesizes a new compound by donating a functional group usually derived from an endogenous acid. the new cmpd is the conjugate of the drug product from phase 1 reactions
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| the new cmpd in phase 2 reactions is a conjugate with what endogenous acids or groups? (name 4) | glucuronic acid, sulfuric acid, glycine acetic acid, or a methyl group.
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| Hepatic microsomal enzymes responsible for biotransformation of numerous agents reside mainly in the _________(CYP 450) | smooth endoplasmic reticulum
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| what is another name for the CYP450 system? | MIXED-FUNCTION OXIDASE SYSTEM.
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| there are ___ iso-enzymes involved in drug metabolism and they are _______ | 6 CYP1A2, CYP2D6, CYP2C19, CYP2E1, CYP2C9, CYP3A
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| Small differences in the ______of the different iso-enzymes lead to differences in drug metabolism and account for genetic variability among individuals’ ability to metabolize agents. | amino acid sequences
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| what is enzyme induction | increased enzyme activity by stimulating the enzymes over a period of time ; usually produced by exposure to certain drug or chemical compounds.
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| name 4 other drugs besides ETOH that are capable of causing enzyme induction | Phenobarbital, phenytoin, rifampin, carbamazepine
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| how can microsomal enzymes be inhibited? | exposure to certain drugs and chemicals which lead to an accumulation of the substrate (drug) agent. This can cause elevated plasma levels and potentially greater activity and toxicity. These drugs inhibits enzymes that metabolize other drugs.
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| name 2 examples of drugs that inhibits metabolism of other drugs | Antibiotic erythromycin inhibits metabolism of theophylline Cimetidine (tagamet) inhibits metabolism of many drugs.
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| what are the 2 categories of barbiturates? | thiobarbiturates; oxybarbiturates
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| name the 2 thiobarbiturates including brand name | thiopental (pentothal); thiamylal (surital
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| what are 3 other ways thiopental can be written | sometimes written Na TPL, sodium thiopental, or STP
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| name 4 oxybarbiturates including brand names | methohexital (brevital), pentobarbital (nembutal), secobarbital (seconal), phenobarbital
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| barbiturates are all derived from ______, which is formed from ___ and _____ | barbituric acid; urea & melonic acid
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| describe the mechanism of action of barbiturates | The mechanism of action of barbiturates is linked to GABA, an inhibitory neurotransmitter in the CNS. Barbiturates result in chloride ion movement into nerve cells.
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| how can oxybarbiturates be converted to thiobarbiturates | Replacement of the oxygen atom at position #2 with a sulfur atom converts the oxybarbiturate to a thiobarbiturate. Thiobarbiturates contain SULFUR.
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| describe the chemical structure of a barbiturate with more hypnotic activity; what is an example of this | • A barbiturate with a branched chain substitution on the #5 carbon atom usually has greater hypnotic activity than the corresponding drug with a straight chain; eg. thiopental
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| describe the chemical structure of a barbiturate with more anticonvulsant effects; what is an example of this | • Substituting a phenyl group at position #5 of the benzene ring of barbituric acid enhances the anticonvulsant effects of the drug. Eg. Phenobarbital
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| describe the chemical structure of a barbiturate with more rapid onset and shorter duration of action; what is an example of this and what is an adverse effect of this | • An addition of a methyl radical group to the nitrogen atom on carbon #5 of barbituric acid ring results in a compound with a more rapid onset and a shorter duration of action. adverse effects: more convulsant effects; eg. methohexital (brevital)
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| methohexital (brevital) is known for more convulsant effects - however, which characteristic of brevital positively offsets this adverse effect? | because the drug is ultra-short acting, the involuntary skeletal muscle movements are short lived.
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| describe the general pathway of how barbiturates are broken down | most significant metabolic pathway involves the oxidation of the side chain groups at the #5 carbon. Oxidation produces thiopental carboxylic acid which is inactive. This converts the lipid soluble barbiturate into a water soluble compound.
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| thiobarbiturates undergo what pathway/reaction | desulfuration (phase 1 oxidative reaction)
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| describe the 4 step process of the chemical breakdown of thiopental (pentothal) | 1. desulfuration converts thiopental to the oxybarbiturate pentobarbital 2. oxidation of side chain groups at #5 carbon; converts pentobarb to thiopental carboxylic acid 3. conjugation with glucuronic acid 4. excreted as glucuronide by kidneys
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| what are 2 other names for propofol? | diprivan 2,6 diisopropylphenol (an alcohol)
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| propofol is a milky white solution of: | 10% soybean, 2.25% glycerol, and 1.2% purified egg phosphatide
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| Propofol only lasts _____regardless of containing preservatives. | 6 hrs
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| Astra-Zeneca reformulated propofol by adding the preservative ______ | EDTA (ethylenediaminetetraacetate)
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| Baxter labs added a ____to propofol to help retard bacterial growth. | 0.025% sodium meta-bisulfite
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| describe protein binding activity of propofol | highly protein bound
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| what are some effects or side effects of propofol | antiemetic hypotension; apnea
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| Metabolized by ______in the liver, but the clearance rate exceeds hepatic blood flow, suggesting ______of metabolism. | conjugation; extra-hepatic sites
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| what is another name for etomidate | amidate
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| what is etomidate classified as? what does it do | non-barbiturate anesthetic; produces a hypnotic state
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| describe the chemical structure of etomidate | is considered an ethyl ester of a carboxylated imidazole derivative.
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| what types of patients benefit from etomidate and why | Maintains cardiovascular stability and has a wide range of safety. Great for CV patients (propofol – hypotension).
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| what are side effects of etomidate | pain on injection and myoclonia (tremors in body, usually extremities and head); adrenocorticol effects
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| describe the metabolism of etomidate | It is metabolized by liver microsomal enzymes and plasma esterases. Ester hydrolysis is the primary mode of metabolism in the liver and plasma.
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| describe the solubility of etomidate and how it usually exists in the plasma | Etomidate is highly lipid soluble and exists primarily in the non-ionized form in the plasma.
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| describe the adrenocorticol effects of etomidate | etomidate was attributed to adrenocortical hypofunction and hence decreased levels of cortisol. The decrease in cortisol levels was said to last 4 days after the initial administration. The adrenocortical hypofunction is reversible
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| what is ketamine a derivative of | phencyclidine
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| what does ketamine generally do to the patient 20-50 years old | caused serious psychic disturbances, including hallucinations and delirium. Ketamine produced a dissociative state of anesthesia (split personality) in which the patient is in a catatonic state.
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| what is the S (+) isomer of ketamine responsible for? | • The S (+) isomer was found to have less spontaneous motor activity, patients were calm in the recovery room and had few complaints of pain.
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| what is the R (-) isomer of ketamine responsible for? | • The R (-) isomer caused more instances of combativeness and delirium on emergence from anesthesia; the R isomer was also said to have caused the reported hallucinations
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| describe the metabolism of ketamine | metabolized by the hepatic microsomal enzyme systems. Demethylation and hydroxylation produce a glucuronide derivative that undergoes conjugation to produce a water soluble compound that is eliminated renally.
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| acid is a proton donor and base is a proton acceptor is what definition | bronsted-lowery definition of an acid and base
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| how is the strength of an acid determined? | by the extent of its dissociation in aqueous solution
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| what is the equation for pH | pH = - log [H+]
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| name four example of a strong acid | hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid
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| what is an example of a weak acid | acetic acid (vinegar)
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| name examples of acids produced by the body (name 7) | hydrochloric acid, lactic acid, carbonic acid, ketoacids, pyruvic acid, uric acid, proteins
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| many bases are what? or consist of what? | metallic hydroxides metal + -OH (hydroxl group) produce hydroxide ions when placed in water
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| name examples of strong bases | lithium hydroxide (manic-depression), sodium hydroxide, potassium hydroxide (caustic to veins), barium hydroxide (CO2 absorbers)
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| name examples of bases produced in they body | bicarbonate, phosphate, proteins, ammonia
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| what is a buffer | A buffer is a solution whose pH changes very little when small amounts of hydrogen ions or hydroxide ions are added to it. (“shock absorber”)
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| the body uses which 3 buffer systems? | carbonate, phosphate, and proteins (albumin); ammonia is a buffer in renal tubules.
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| name 6 long acting non depolarizing NMB agents | D-tubocurarine, metocurine, gallamine, pancuronium, doxacurium, pipercuronium
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| name 4 intermediate acting non-depolarizing NMB agents | atracurium, vecuronium, mivacurium, rocuronium
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| Succinylcholine is 2 molecules of acetylcholine joined together. They are linked together by ________ | acetate methyl group
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| compare the general structure of succs to non-depolarizing agents | succs is long, slender and flexible; non-dep agents are bulky and rigid
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| The NMB agents contain one or more positively charged ______ | quaternary ammonium groups. That is 4 carbon atoms attached to one nitrogen atom
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| Because the non-depolarizing neuromuscular agents posess quaternary ammonium groups, they do not cross the _______ | BBB, GI epithelium or placental barriers.
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| what portion of the NMB agent mimics acetylcholine | The + charge on the quaternary ammonium portion mimic the quaternary nitrogen of acetylcholine. This + charge is the reason for the attraction of these molecules to the negatively charged cholinergic receptor on the skeletal muscle.
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| Because there is a lack of specificity of the NMBDs for just skeletal muscle, the positively charged quaternary ammonium group may also attach where? | cardiac receptors and receptors in autonomic nervous system. Therefore you will also see cardiac and nervous system effects.
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| The specificity of a drug for the autonomic receptor vs. the neuromuscular junction (cholinergic receptor) is influenced by _______ | the length of the carbon chain separating the 2 positively charged ammonium groups. The number of positively charged ammonium groups varies with the individual drugs.
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| name the mono-quaternary NMBDs | d-tubocurarine, vecuronium
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| name the bisquaternary NMBDs | succinylcholine, doxacurium, atracurium, cisatracurium
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| name the triquaternary NMBDs | gallamine
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| describe the structure of NMBDs that are steroidal compounds | molecular configuration similar to steroids but don’t act like hormones. Steroidal compounds are composed of 3 six-sided rings (benzene rings) and 1 five membered ring
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| name the NMBDs that are steroidal cmpds | Pancuronium, vecuronium, pipercuronium (90 min paralytic; not used today), rocuronium
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| describe the breakdown of succs by plasma cholinesterase | Succinylcholine is broken down by plasma cholinesterase into succinylmonocholine and choline. These are further broken down by plasma cholinestersase into succinic acid and choline. These metabolites are inactive.
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| describe the breakdown of mivacurium chloride | metabolized by plasma cholinesterase and eliminated in the bile and urine
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| describe the breakdown of rocuronium bromide | eliminated by deacetylation via the liver
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| describe the breakdown of atracurium besylate | undergoes Hofmann elimination (pH and temperature dependent) in the plasma and tissues
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| describe the breakdown of vecuronium bromide | elimination via 3 compartment model
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| describe the breakdown of pancuronium bromide | undergoes triphasic elimination via kidney through glomerular filtration
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