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78 Cards in this Set
- Front
- Back
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what are the FOUR main assumptions of Receptor Theory
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1. receptor must possess STRUCTURAL and STERIC specificity
2. receptors are SATURABLE and FINITE 3. receptors must possess HIGH AFFINITY for its endogenous ligand at physiological concentrations 4. once the endogenous ligand binds to the receptor, SOME RECOGNIZABLE EARLY CHEMICAL EVENT MUST OCCUR |
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what is the concentration-response relationship
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1. the more receptors occupied, the greater the response to the ligand.
2. up to the point at which cell signaling mechanisms are saturated and cannot be further driven |
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what does the equilibrium dissociation constant say about the system.
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the concentration of ligand that produces 50% receptor occupancy at equilibrium
1. relationship between affinity, drug concentration, and receptor occupancy potent drugs: high affinity: low Kd weak drugs: low affinity: high Kd |
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what is the difference between potency and efficacy
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1. potency: (how fast it gets there) the concentration of ligand required to yield an effect
2. efficacy: (how high the ceiling is) the quantitative ability of a drug to produce a biologic effect |
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what is the difference between an ANTAGONIST and AGONIST
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1. antagonist: binds to receptor WITHOUT causing an effect, thereby preventing an active substance from gaining access (NO INTRINSIC ACTIVITY, NO DOWNSTREAM EFFECT)
2. agonist: occupy receptors and activate DOWNSTREAM effector mechanisms, producing a response |
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what is a competitive pharmacological antagonist
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1. binds to the same site as the agonist
2. CAN be overcome by increasing the concentration of agonist |
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what is an irreversible pharmacological antagonist
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CANNOT by overcome by increasing the concentration of agonist
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what is a physiological antagonist
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a drug that counters the effects of another by binding to a DIFFERENT RECEPTOR and causing an opposing effect
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what is a chemical antagonist
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a drug that counters the effects of another by BINDING TO THE AGONIST DRUG (inactivating it) and NOT the receptor
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what is the difference between FULL and PARTIAL agonist
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1. full: produces maximum biologic response and are maximally efficacious, INDEPENDENT of potency
2. partial: produce less than 100% of maximum biological response, even at max receptor occupancy |
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what is the difference between COMPETITIVE and NONCOMPETITIVE antagonism
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1. competitive: binding to receptor preventing agonist from binding
2. noncompetitive: both antagonist and agonist can bind to receptor, BUT antagonist prevents or reduces effect of agonist COMPETITIVE can be overcome with increased concentration of agonist |
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what is the difference between reversible and irreversible antagonism
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1. reversible: antagonist is readily dissociated from the receptor (antihistamine)
2. irreversible: antagonist forms a strong COVALENT bond with receptor (phenyloxybenzamine) |
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agonist and antagonist in relation to efficacy...how does an agonist graph look with presentation of competitive antagonist
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1. agonist: full or partial efficacy
2. antagonist: NO EFFICACY SHIFT TO THE RIGHT with presence of antagonist REDUCED POTENCY NO CHANGE IN EFFICACY |
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how does an agonist graph look with presentation of noncompetitive antagonist
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SHRINKING and RIGHT SHIFT
DECREASE in potency DECREASE in efficacy because receptors removed from available pool |
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what are spare receptors?
when are spare receptors said to be present? |
1. receptors that upregulate their complement of specific receptors to increase their sensitivity to ligands
2. shift graph RIGHT, altering apparent potency WITHOUT altering max efficacy 3. present when 50% of EC50 is less than the concentration of 50% of Kd |
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what is LD50/ED50 ratio?
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therapeutic index:
1. a measure of the safety of a therapeutic agent HIGH INDEX=GOOD LOW INDEX=BAD |
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what is the largest class of receptors
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receptors that activate G-proteins
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what are intracellular RECEPTORS
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lipid-soluble or diffusible agents may cross the membrane and combine with an intracellular receptor that ultimately regulate gene transcription
corticosteriods, sex steriods, thyroid hormones, vitamin D, etc |
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what are intracellular ENZYMES
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ligands can bind to enzymes, altering their activity, which has direct effect on cell physiology
NSAIDS...like aspirin (cyclooxygenase blocker) |
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name the four membrane-spanning receptors
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1. ion channels
2. enzymes 3. receptors activating separate intracellular tyrosine kinase 4. receptors that activate G-proteins |
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what are the general determinants of absorption rates
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1. dissolution into aq. fluids at absorption site
2. lipid solubility 3. concentration gradient 4. blood flow at absorption site 5. surface area of absorption site |
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what is volume of distribution
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Vd= (amount of drug in the body)/(plasma drug concentration)
an indicator of how well the drug is distributed in the tissue IN RELATION to other drugs. NOT how much is reaching the site of action |
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what are the factors that influence volume distribution
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1. drug pKa
2. extent of drug-plasma protein binding 3. partition coefficient of the drug in fat (lipid solubility) 4. gender, age, disease state, body composition |
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what is the relationship of volume distribution with lipid solubility and half life
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DIRECTLY PROPORTIONAL
HIGH Vd= high lipid solubility and longer half life vis versa |
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what is drug clearance
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Cl= (rate of elimination of drug)/(plasma drug concentration)
the volume of plasma from which the drug is completely removed per unit time |
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what are the TWO most important organs for clearing drugs
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1. kidneys
2. liver |
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what are the factors affecting hepatic clearance
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1. blood flow
2. extent of plasma-bound drugs 3. high extraction ratio drugs (first pass) |
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what is first order kinetics
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1. constant fraction of the drug in the body is eliminated per unit time
2. rate of elimination is proportional to the amount of drug in the body 3. higher drug concentration, the greater the amount of drug eliminated per unit time MOST DRUGS are eliminated this way |
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what is zero order kinetics
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the rate of elimination is constant regardless of concentration
LINEAR GRAPH |
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what are the EIGHT important zero order drugs
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1. Phenytoin
2. Ethanol 3. Warfarin 4. Heparin 5. Aspirin 6. Theophylline 7. Tolbutamide 8. Salicylate |
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what is half life and how is it calculated
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time required for the amount of drug to fall to 50% of an earlier measurement
half life= (0.7 x Vd)/(clearance) this is for a single compartment |
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what are the general determinants of absorption rates
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1. dissolution into aq. fluids at absorption site
2. lipid solubility 3. concentration gradient 4. blood flow at absorption site 5. surface area of absorption site |
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what is volume of distribution
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Vd= (amount of drug in the body)/(plasma drug concentration)
an indicator of how well the drug is distributed in the tissue IN RELATION to other drugs. NOT how much is reaching the site of action |
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what are the factors that influence volume distribution
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1. drug pKa
2. extent of drug-plasma protein binding 3. partition coefficient of the drug in fat (lipid solubility) 4. gender, age, disease state, body composition |
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what is the relationship of volume distribution with lipid solubility and half life
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DIRECTLY PROPORTIONAL
HIGH Vd= high lipid solubility and longer half life vis versa |
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what is drug clearance
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Cl= (rate of elimination of drug)/(plasma drug concentration)
the volume of plasma from which the drug is completely removed per unit time |
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what are the TWO most important organs for clearing drugs
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1. kidneys
2. liver |
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what are the factors affecting hepatic clearance
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1. blood flow
2. extent of plasma-bound drugs 3. high extraction ratio drugs (first pass) |
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what is first order kinetics
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1. constant fraction of the durg in the body is eliminated per unit time
2. rate of elimination is proportional to the amount of drug in the body 3. higher drug concentration, the greater the amount of drug eliminated per unit time MOST DRUGS are eliminated this way |
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what is zero order kinetics
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the rate of elimination is constant regardless of concentration
LINEAR GRAPH |
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what are the EIGHT important zero order drugs
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1. Phenytoin
2. Ethanol 3. Warfarin 4. Heparin 5. Aspirin 6. Theophylline 7. Tolbutamide 8. Salicylate |
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what is half life and how is it calculated
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time required for the amount of drug to fall to 50% of an earlier measurement
half life= (0.7 x Vd)/(clearance) this is for a single compartment |
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first order kinetics: half life is CONSTANT regardless of concentration
zero order kinetics: rate of elimination is CONSTANT regardless of concentration |
first order kinetics: half life is CONSTANT regardless of concentration
zero order kinetics: rate of elimination is CONSTANT regardless of concentration |
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what is biotransformation
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metabolism of lipophilic drugs to hydrophilic derivatives
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what organ plays a major role first pass metabolism
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LIVER (HIGHEST enzymatic activity)
other: GI tract kidneys skin |
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what is added in phase 1 on metabolism
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functionalization reaction
introduction of a new functional group: -OH -SH -NH2 usually after this the drug is polar enough to be eliminated. if not it goes through phase II |
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what does phase 1 reaction require
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1. cytochrome P450 hemoprotein
2. NADPH-CYP450 reductase 3. NADPH 4. O2 |
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where does phase 1 metabolism occur? phase 2 metabolism?
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1. phase 1 metabolism occur in the SMOOTH ENDOPLASMIC RETICULUM of the LIVER
2. phase 2 metabolism occur in the CYTOSOL |
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what is the most abundant human isoform of CYP? what is it induced by?
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CYP3A4
induced by barbiturates, rifampicin, glucocorticoids |
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what CYP is induced by ethanol
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CYP2E1
plays a major role in ethanol metabolism |
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what is the enzyme and cofactor that is responsible for GLUCURONIDATION
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MOST IMPORTANT of all the PHASE II conjugations!!!!
enzyme: UDP-glucuronosyl transferase (UGT) cofactor: UDP-glucuronic acid (UGA) |
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what is the enzyme and cofactor that is responsible for SULFATION
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transfer SO3 to drug
enzyme: sulfotransferase cofactor: PAP-sulfate |
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what is the enzyme and cofactor that is responsible for ACETYLATION
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transfer acetyl group to drug
enzyme: N-acetyltransferase cofactor: acetyl-CoA |
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what is the enzyme and cofactor that is responsible for GLUTATHIONE conjugation
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transfer glutathione to drug
enzyme: glutathione-S-transferase cofactor: glutathione |
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what is the enzyme and cofactor that is responsible for METHYLATION
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add methyl to drug
enzyme: S-adenosylmethionine cofactor: transmethylase |
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what is enzyme induction
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induction resulting from selective increase in synthesis of CYP450-dependent drug oxidizing enzymes
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what is the result of enzyme induction
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1. increase biotransformation
2. decrease in plasma conc. 3. decrease drug activity if metabolite is INACTIVE 4. increase drug activity if the metabolite is ACTIVE DECREASE THERAPEUTIC EFFECT |
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what is the most common form of enzyme inhibition
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1. competition for the same isozyme
2. leads to serious adverse effects |
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what a suicide inhibitors
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drugs that are metabolized to products that IRREVERSIBLY inhibit the metabolizing enzyme
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what are the THREE routes of excretion
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1. urine: most important for nonvolatile drugs and their metabolites
2. bile: most important for drugs/metabolites which are actively transported by hepatocytes 3. sweat, tears, repro fluid, etc are minor routes |
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how does decreased cardiac output affect metabolism
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1. reduces hepatic perfusion
2. decrease delivery of drug to the liver for metabolism |
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how does increase body fat affect metabolism
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1. INCREASE Vd
2. tend to prolong clearance time 3. promotes accumulation of highly lipid-soluble drugs |
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what are the THREE factors that affect bioavailability
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1. first pass metabolism
2. incomplete absorption 3. distribution to other tissues before entering the systemic circulation |
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how is bioavailability calculated
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F=[desired route]/[IV route]
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loading dose formula
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LD= Vd x TC
loading dose=vol. distribution x target conc. |
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dosing rate formula
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DR=RoE=Cl x TC
Dosing rate=rate of elimination =clearance x target conc. |
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maintenance dose formula
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maintenance dose=dosing rate x dosing interval
MD=DR x DI |
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correct dose formula
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corrected dose=avg. dose x (patient creatinine clearance/100)
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what are the conditions that affect pharmacokinetics to the fetus
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1. lipid solubility: lipophilic readily diffuse across the placenta
2. MW: under 500 can cross, 500-1000 difficult time crossing, greater than 1000 very poorly 3. placental transporters: can carry large molecules to the fetus 4. protein binding: drugs bound to plasma proteins may have a decreased rate of transfer to fetus 5. drug metabolism: placenta is a site of drug metabolism |
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how does decreased cardiac output affect metabolism
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1. reduces hepatic perfusion
2. decrease delivery of drug to the liver for metabolism |
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how does increase body fat affect metabolism
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1. INCREASE Vd
2. tend to prolong clearance time 3. promotes accumulation of highly lipid-soluble drugs |
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what are the THREE factors that affect bioavailability
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1. first pass metabolism
2. incomplete absorption 3. distribution to other tissues before entering the systemic circulation |
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how is bioavailability calculated
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F=[desired route]/[IV route]
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loading dose formula
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LD= Vd x TC
loading dose=vol. distribution x target conc. |
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dosing rate formula
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DR=RoE=Cl x TC
Dosing rate=rate of elimination =clearance x target conc. |
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maintenance dose formula
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maintenance dose=dosing rate x dosing interval
MD=DR x DI |
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correct dose formula
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corrected dose=avg. dose x (patient creatinine clearance/100)
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what are the conditions that affect pharmacokinetics to the fetus
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1. lipid solubility: lipophilic readily diffuse across the placenta
2. MW: under 500 can cross, 500-1000 difficult time crossing, greater than 1000 very poorly 3. placental transporters: can carry large molecules to the fetus 4. protein binding: drugs bound to plasma proteins may have a decreased rate of transfer to fetus 5. drug metabolism: placenta is a site of drug metabolism |
