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80 Cards in this Set
- Front
- Back
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Biotransformation
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Conversion of a pharmacologically active, lipophilic drug into one or more hydrophilic and OFTEN (but not always) inactive metabolite(s)
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Biotransformation facilitates?
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more rapid excretion of the drug via urine or bile
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Why is biotransformation not always synonymous with inactivation or with detoxification?
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1. Many drugs have pharmacologically active metabolites
2. Some drugs are formulated as inactive prodrugs; drug metabolite is pharmacologically active 3. Some drug metabolites have toxic properties |
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Name 3 sites of biotransformation : relative activity
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1. Liver - 100%
2. Lung - 10-20% 3. Kidney 8% |
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Types of biotransformation
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1. Phase I
2. Phase II 3. Combination reactions (phase I to phase II) |
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Phase I reactions are also called?
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degradation reactions
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What reactions are included in Phase I- degradation reactions?
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Oxidation, reduction, hydrolysis
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Phase II reactions are also called?
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Conjugation reactions (make it more water soluble)
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Combination reactions are?
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very common
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In oxidation, what enzymes are responsible?
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cytochrome P-450
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Where are the cytochrome P-450 enzymes located?
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in the membranes of the smooth ER
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What are other names for the cytochrome P-450 enzyme?
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microsomal enzymes or mixed function oxidases
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What does an oxidized drug look like?
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O2 + drug ---> drug-O + H20
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What contain several P450 isoenzymes?
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hepatocytes
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CYP3A4 isozyme
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is responsible for the biotransformation of 50% to 60% of clinically prescribed drugs, including opioids (fentanyl, alfentanil, sufentanil), benzodiazepenes (midazolam, diazepam), amide local anesthetics (lidocaine, ropivacaine), and calcium channel blockers
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2E1 isozyme
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is responsible for biotransformation of halogenated anesthetics
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CYP2D6 isozyme
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is responsible for biotransformation of codeine, oxycodone (Percocet), and hydrocodone (Vicodin) to their pharmacologically active metabolites - morphine, oxymorphone, and hydromorphone
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P450 enzymes are subject to?
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induction
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Induction means?
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Substances increase P450 enzyme activity
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What substances increase P450 activity and are referred to as inducers?
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barbituates, tobacco smoke, chronic alcohol ingestion, carbamazepine, St. John's wort
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induction leads to?
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enhanced biotransformation of the inducer as well as drugs metabolized by the particular P450 isozyme
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Inhibition of P-450 activity, what drugs?
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cimetidine, ketoconazole, SSRIs, erythomycin
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What environment factors inhibit P450 activity?
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grapefruit juice
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Inhibition of P450 activity may?
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enhance plasma levels of drugs metabolized by the affected enzyme
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Name 3 examples of P450-dependent oxidations
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1. Hydroxylation
2. Dealkylation 3. Deamination |
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Reduction occurs where?
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in the smooth ER
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In reduction, is cytochrome P450 involved?
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unclear
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When may reduction become important?
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when tissue PO2 is low
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Hydrolysis occurs how?
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nonmicrosomal enzymes (not inducible)
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What type of enzymes carry out hydrolysis?
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1. esterases: succinylcholine, procaine, esmolol, aspirin
2. amidases: lidocaine, procainamide |
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Conjugation reactions, name 4
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1. Glucuronidation
2. Acetylation 3. Sulfation 4. Amino acids |
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What is the most common conjugation reaction and why?
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glucuronidation due to the availability of glucose
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Glucuronidation involves what type of enzymes?
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microsomal enzymes, therefore inducible
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Glucuronidation is important for what drugs?*
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morphine, diazepam, acetaminophen, and lorazepam
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Of the conjugation reactions which reactions are carried out by nonmicrosomal enzymes?
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acetylation, sulfation, amino acids
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What would be an example of Phase I and Phase II biotransformation reactions?
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Hydrolysis followed by glucuronidation
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What factors may cause individual variations in drug metabolism?
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1. Genetic polymorphisms
2. Dietary/environmental factors may affect P-450 activity 3. Age 4. Gender |
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What are 4 examples of how genetic polymorphisms may cause variations in drug metabolism?
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1. CYP450 enzymes exhibit many allelic variations
2. Abnormal pseudocholinesterase 3. Slow acetylators vs. fast acetylators 4. racial/ethnic differences |
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What dietary/environmental factors may affect P450 activity?
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1. Inducers: tobacco smoke, industrial pollutants
2. Inhibitors: grapefruit juice |
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How does age affect drug metabolism?
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slower metabolism in children and elderly individuals
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How does gender affect drug metabolism?
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males may metabolize some drugs more rapidly than females
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What disease can impair drug biotransformation?
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1. Liver disease: cirrhosis, hepatitis, cancer
2. Heart disease: reduced blood flow to the liver |
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What are the 2 most common routes of excretion?
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1. Renal
2. Biliary |
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Renal excretion is dependent on four processes, what are they?
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1. Glomerular filtration
2. Tubular secretion 3. Tubular reabsorption 4. pH and drug/drug metabolite trapping in tubule |
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What occurs in GF?
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non-protein bound (free) drug is filtered and elimination is dependent on GFR
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Tubular secretion
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1. Weak acids and bases
2. Active transport across tubular epithelium 3. Can enhance elimination of highly protein-bound drugs |
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Tubular reabsorption is the?
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return of filtered and/or secreted drug to circulation
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In tubular reabsorption, what drugs are extensively reabsorbed?
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lipid-soluble drugs
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Since lipid-soluble drugs are extensively reabsorbed this stresses the importance of?
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drug biotransformation to hydrophilic metabolites, which may then be excreted in the urine
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In pH and drug/drug metabolite trapping in tubule, what are excreted more rapidly in alkaline urine? acidic urine?
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weak acids, weak bases
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Weak acids are excreted more rapidly in alkaline urine, why?
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The equilibrium shifts to favor the ionized form which is the form that is not reabsorbed, therefore speeding up the excretion
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A weak base is excreted more rapidly in acidic urine because?
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the equilibrium shifts to favor the ionized form which is the form that is not reabsorbed
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Biliary excretion
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Unchanged drug or drug metabolites (eg, glucuronides) are secreted in the bile ---> small intestine
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In biliary excretion, what circulation may occur?
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enterohepatic circulation (ileum--> portal vein --> liver) may occur
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Most drugs exert their pharmacological effects by interacting with?
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receptors
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Most receptors are?
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proteins, either on cell membranes or within cells
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Drugs can act as receptor?
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agonists or antagonists
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Agonist
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is a compound that interacts with a receptor and produces a physiological (endogenous agonist) or pharmacological (exogenous agonist) effect
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Dissociation constant (Kd)
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The receptor has a certain binding affinity for the agonist, ie, the concentration of free agonist at which binding is half-maximal
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The lower the value of Kd, the?
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higher the binding affinity
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Full agonist
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exerts a maximal pharmacological effect without necessarily occupying all available receptors
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Partial agonist
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exerts less response than does a full agonist, and not necessarily because of reduced binding affinity
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Neutral antagonists
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these drugs interact with receptors, exert no agonist effect, and block or reverse the effects of agonists
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Competitive antagonist
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antagonism can be overcome by increasing concentrations of agonist; reversible binding of antagonist to receptor
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Noncompetitive antagonist
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antagonism cannot be completely overcome by increasing the concentration of agonist; irreversible binding of antagonist to receptor
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Receptors exist in equilibrium between?
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inactivated and activated states; there occurs spontaneous conversion from the inactivated to activated state
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Agonist bind to and stabilize?
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the active state of the receptor, therefore shifting the receptor equilibrium to favor the active site
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If a drug is a full agonist what occurs?
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they fully stabilize the active receptor state and produce a maximal effect
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If a drug is a partial agonist what occurs?
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they only partially stabilize the active receptor state and produce a submaximal effect, even at high doses
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If a drug is a neutral antagonist what occurs?
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it binds equally to the inactivated and activated receptor states and does not alter the baseline equilibrium
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Structure-activity relationships
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the ability of a drug to combine with a specific receptor is dependent on the molecular size, three-dimensional shape, and electrical charge of the drug
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Optical isomers (enatiomers) may ?
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not have the same binding affinity (Kd)
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What usually exist for agonists and antagonists?
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multiple receptors
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What receptors exist?
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1. Alpha and beta
2. nicotinic and muscarinic cholinergic 3. receptors for opioids, histamine, dopamine, and serotonin |
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What three bonds exist for drug-receptors?
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1. Covalent bond
2. Ionic bond 3. Hydrogen bond |
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Covalent bond
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stong bond, frequently irreversible; binding of phenoxybenzamine to alpha-1 adrenergic receptors is an example (uncommon)
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Ionic bond
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electrostatic interactions; important for drugs that are ionized at plasma pH
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Hydrogen bond
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-OH, -NH2 interact with electronegative groups (weakest form of interaction)
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The fraction of activated receptors is very low in the absence of a(n)?
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agonist
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Most receptors are in what state at rest?
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inactivated state
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