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148 Cards in this Set
- Front
- Back
what are the 4 areas covered by PHARMACOKINETICS
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ADME
Absorption Distribution Biotransformation Excretion |
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what is involved in pharmacodynamics
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this is the cell-cell signaling after the drug reaches its site of action
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what does the sustained pharmacological effect of a drug depend on ?
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the amount of drug that reaches treatment site and the time it spends on the receptor.
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what are the speed of drug availability from high to low
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IV > IM > SC > Oral
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what are the advantages of IV
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1. immediate availability
2. rapid distribution and response 3. bypasses the stomach and liver 4.can maintain constant blood levels and be given over long periods of time, even in unconscious patient 5. reduce irritation due to blood buffer |
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what are the disadvantages of IV
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1. cant be removed once in system
2. cant be self administered 3. must use sterile technique 4. can cause irritation, allergy, overdose |
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1.what is DRUG BIOAVAILABILITY
2. what things affect this? |
1.determination of the fraction of unchanged drug that reaches circulation.
2. first pass metabolism, formulation, route of administration,solubility, stability |
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1. what is first pass hepatic metabolism
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1. rapid and extensive metabolism of drugs given orally by the liver, which decreases the amount of drug that reaches circulation
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what is the formula for bioavailability
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bioavilability = f
f= auc oral / auc injected x 100 f= 1 = 100% if IV |
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to what kind of drugs does half life apply
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to those with 1st order kinetics
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1.what is the steady state of a drug
2. what happens to drug plasma concentration at steady state? 3. how many half lives are needed for steady state |
1.when rate of elimination = rate of input.
2. plasma drug concentration is constant 3. 4-5 |
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1.how long does it take to reach 90% steady state.
2. what is the therapeutic window |
1. 3.3 half lives
2. safe opening between minimum therapeutic and minimum toxic concentration |
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1. what is the minimum therapeutic concentration
2. what is minimum toxic concentration |
1. minimum concentration needed for efficacy
2. peak plasma concentration |
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1. how do we calculate therapeutic Index or Ti.
2. what is the the Ti bellow which a drug is concidered highly toxic |
1. Ti= [toxic] / [therapeutic].
2. bellow 10 |
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1. what is drug absorption
2. what is the efficacy of absorption dependant on? 3. what are the 4 mechanisms of absorption |
1. transfer of drug from site of injection to blood.
2. route of administration. 3. passive, active, facilitated, pinocytosis |
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1. in Passive diffusion what is the transfer of drug dependent upon?
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concentration gradiet, lipid:water partition coefficient.
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1. what is the one drug that engages in facilitated diffusion?
2. what are some particels that get in by pinocytosis |
1. l-dopa
2. Iron-transferrin, vit B12- intrinsic factor |
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1. what happens to acids and bases if pH is below pKa?
2. in what ionization state are drugs absorved? |
acis are unionized,
bases are ionized 2. unionized |
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1. in what part of the intestines are weak acids absorved?
2. how about weak bases |
weak acids are absorved in proximal intestine
weak bases are absorved in distal intestine |
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1. are ionized drugs water or lipid soluble?
2. how about non ionized |
1. water soluble and is excreted
2. lipid soluble and absorved |
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1. what are the phases of drug distribution and in what tissues they happen?
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High phase: happens in highly vascular tissue like brain, kidney liver
Low phase: happens in low vascular tissue like skin, soft tissue, bone |
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what is drug interaction
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this is what happens when a drug that is bound highly to plasma protein is displaced by a new drug.
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1. List drugs that have high plasma protein binding.
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NSAIDS
SULFONAMIDES DIGOXIN WARFARIN |
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1. why are sulfonamides contraindicated in neonates
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because it displaces bilirubin which enters CNS causing kernicterus
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what is the formula for volume of distribution ?
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Vd = dose administered/ plasma concentration at time 0
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what are the assumptions on the patient when doing volume of distribution study?
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70 kg
42 L body water. 28L Intracellular 14L extracellular |
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what are the 2 parts of the Phase 1 biotransformation
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1. Non microsomal: this is hydrolysis used for amide aneshetics, alcohol metabolism, and succinylcholine.
2, microsomal enzyme catalyzed reactions by cytochrome P450 family |
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what are the microsomal reactions dependent on
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endoplasmic eticulum
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what are some of the typical inhibitors of cytochrome P450
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grapefruit juice
cimetidine macrolide antibioticds azole antifungals |
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1.what are the typical inducers of Cytochrome P450
2. what drug will cause oral contraceptive failure |
barbituates
anticonvulsants except valporate rifampin 2. rifampin |
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what are the problems caused by cymetidine
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cymetidine inhibits 2C9 causing diazepam toxicity
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why cant a patient on statins drink grapefruit juice
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grapefruit inhibits statin metabolism causing rhabdomyelosis, causing renal failure
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1. what are some examples of Phase II biotransformation.
2. what is the role of Phase II |
glucorinidation by glucoronly transferas
sulfate conjugation by sulfotransferase AA conjugaction by transacylases 2. makes drugs water soluble which increases their excretion |
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what are some drugs that are transformed via glucorinidation
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acetaminophen, diazepam
morphine > morphine 6b-glucoronide increasing its effect |
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why dont we give chloramphenicol to neonates?
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babies cant glucorinate causing gray baby syndrome
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what drugs are metabolized by sulfation
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acetaminophen, methyldopa
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what drugs are metabolized by acetylation
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hydrazine, Isoniazid, Pyrazinamide Procainamide
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what are the drugs that cause SLE syndrome in slow acetylators
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HIP drugs
Hydralazine (vasodialator) Isoniazid (ant TB) Procainamide ( anti arrythmic) |
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what is the the rate of metabolism of drugs at low doses
how about high doses |
1st order, proportional to dose
0 order and independent of concentration |
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what 3 processes work during renal excretion
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Filtration
Secretion Reabsorption |
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1. what is normal GFR
2. what is the creatnine clearance for men and women. 3. what is the cutoff GFR for NSAIDS |
1. 120 ml/min
2. women: 87-104 Men: 90-140 3. 80 ml/min |
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what is the formula for Net Renal Excretion
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NRE= GFR of drug + ammount of drug actively secreted by kidney - amount of drug passively reabsorved in tubule because its lipid soluble
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what is net renal clearance equal to when there is no secretion or reabsorption
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NRC = GFR
NRC = free fraction x GFR and always assume 120 ml/min GFR |
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what are the drugs that follow 0 order elimination
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phenytoin, ethanol, salicylates
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what is the antidote to asprin overdose
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NaHCO3 to increase pH because aspirin is a weak acid
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what is the antidote to quinidine overdose?
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make urine acidic by vitamin C or cranberry juice to lower pH since quinidine is a weak base
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what is the formula for loading dose ?
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LD = Vd x Cp / f
vd= volume of distribution Cp= plasma concentration F= bioavilability |
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what is formula for maintenance dose
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MD = Cl x Cp / F
cl = clearance Cp= plasma concentration F = bioavailability |
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what is the difference between loading dose formula and maintenance dose?
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maintenance dose takes into account clearance which loading dose does not.
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what are the 5 basic principles of drug theory
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1. drug has to bing specifically
2.cant make new pathway, just modifly existing by activating or deactivating it 3. has to have a measurable effect 4. response of system is proportional to amount of drug given |
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what are the two main targets of drugs
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1. molecules for normal function such as enzymes, nucleic acids
2. molecules used for intercellular communication |
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what are some of the features of membrane bound receptors?
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1. has hydrophobic and hydrophylic segements.
2. acts as signal transducer 3. may have enzymatic properties 4. has lipid or carb mods to help it associate with membrane |
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Describe the a 7-Transmembrane G-protein coupled receptors.
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1. has 7 non polar Trans-memb regions
2. coupled g protein binds to the 3rd intracellular look and carboxy terminal 3. its a signal transducer 4. works in minutes |
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what is a receptor for NOREPI
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a,b adrenergic receptors 7TMS-GPCR
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what is the receptor for Serotonin
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serotonergic 5-HT
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what are the receptors for acetylcholine
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Muscarinic colinergic receptor M1-M5
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what is the receptor for histamine
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H1 and H2 receptors
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1 what do the As subunit of the Gprotein do?.
2. what are the receptors that activate this |
1. + adenyl cyclase > + cAMP
2. b1, b2, AR, glucagon |
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1 what do the Ai subunit of the Gprotein do?.
2. what are the receptors that activate this |
1. - adenyl cyclase > - cAMP
2. a2 AR, uOR |
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what does G-alpha-s do?
what does G-alpha-i do? |
1. + adenyl cyclase > + cAMP > + PKA >contraction
2. - adenyl cyclase > - cAMP > - PKA > relaxation |
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what is the role of phospholipase C
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dissociades IP3-DAG. IP3 goes and releases Ca+2 from SR and contraction of smooth muscle.
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what is the role of G protein coupled receptor Kinase?
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it phosphorylates the G-protein receptors which does 2 things
1. prevents further activation of receptor 2. serves as binding site for B-arrestin which internalyzes receptor and either degrades it or recycles it back to the surface |
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what is desensitization / tachyphylaxis
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decreased effect of repeat dose of drug. its seen with short term stimulation.
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what is down-regulation and tolerance
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its a long lasting decreased respose, because the receptors are degraded by lysosome. seen in long term chronic usage of drug.
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1. what is sensitization
2. what is this a result of ? |
1.increased response due to more receptor availability.
2. receptor blockade or decreased release of endogenous ligand as a result of drug treatement. |
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what are the characteristics of Ligand-gated Ion channel (ionotropic Receptors)
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1. made of multiple protein subunits which come together to make a pore
2. they are very fast acting ion channels that are controlled by ligands 3.they alter cell membrane potential |
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give an example of a ionotropic receptor
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nicotinic Ach receptors
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describe the Tyrosine Kinase Receptors
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1. they have a EC hormone binding domain, and IC tyrosine, serine, or guanylate cyclese domain
2. when activated they form dimers altering cell growth Name |
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Name some examples of tyrosine kinase receptors
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Insulin
Epidermal growth factor. EGF Platelet derived growth factor PDGF Atrial natriuretic factor (ANF) |
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describe the Cytokine receptors
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like tyrosine kinases but have JAK which are separate mobile kinase molecules.
they are involved in release of inflammatory mediators and hematopoietic factors |
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what are some endogenous activators of Cytokine receptors
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GH
erythropoietin INF |
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what does ligand binding do to the Cytokine Receptors
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1. dimerizes them, JAKs then phosphorylate tyrosine residues
2. JAKs phosphorylate STATS which dimerize and go to DNA and alter transcription |
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what are the functional domains of Intracellular receptors
what is their primary function |
Hormone binding domain
Dna binding domain transcription activating domain alter gene transcription in hours/days |
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what are some examples of Intracellular receptors
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glucocorticoids
mineralcorticoids sex steroids Vitamin D Thyroid hormone |
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when it comes to drugs, what is the deifference between ionic and hydrogen, van der waals binding
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ionic attracts the molecule, H-bonds and van der walls keeps it in the pocket
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what is Kd
what is the relationship between Kd and binding affinity |
1. binding affinity. its the concentration of drug needed to bind 1/2 of the receptors.
Low kd = high binding affinity |
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can a drug that has high affinity for one receptor still bind to others?
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yes. affinity for one does not mean cant bind to something else thats why we have side effects
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1. what kind of biological responses can we get from a drug
2. is every drug-receptor interaction lead to response |
1. biochemical, physiological, or both
2. no, only specific ones. |
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what is affinity
what is the formula for it? |
1. describes strenght of receptor and ligand.
2. Kd = [L] [R] / [LR] |
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describe the Cytokine receptors
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like tyrosine kinases but have JAK which are separate mobile kinase molecules.
they are involved in release of inflammatory mediators and hematopoietic factors |
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what are some endogenous activators of Cytokine receptors
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GH
erythropoietin INF |
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what does ligand binding do to the Cytokine Receptors
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1. dimerizes them, JAKs then phosphorylate tyrosine residues
2. JAKs phosphorylate STATS which dimerize and go to DNA and alter transcription |
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what are the functional domains of Intracellular receptors
what is their primary function |
Hormone binding domain
Dna binding domain transcription activating domain alter gene transcription in hours/days |
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what are some examples of Intracellular receptors
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glucocorticoids
mineralcorticoids sex steroids Vitamin D Thyroid hormone |
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when it comes to drugs, what is the deifference between ionic and hydrogen, van der waals binding
|
ionic attracts the molecule, H-bonds and van der walls keeps it in the pocket
|
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what is Kd
what is the relationship between Kd and binding affinity |
1. binding affinity. its the concentration of drug needed to bind 1/2 of the receptors.
Low kd = high binding affinity |
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can a drug that has high affinity for one receptor still bind to others?
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yes. affinity for one does not mean cant bind to something else thats why we have side effects
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1. what kind of biological responses can we get from a drug
2. is every drug-receptor interaction lead to response |
1. biochemical, physiological, or both
2. no, only specific ones. |
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what is affinity
what is the formula for it? |
1. describes strenght of receptor and ligand. AKA equilibrium dissociation constant
2. Kd = [L] [R] / [LR] |
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what is efficacy?
does this predict the magnitude of resposne? |
how likely a ligand/receptor interaction will lead to a response.
no, just b/c a ligand binds, does not mean response |
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1. what is an agonist.
2. does it have to have affinity and efficacy? |
it binds to a receptor and produces a biological response
2. it has to have affinity but efficacy can varry |
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1. what is a full agonist?
2. what is the efficacy of a full agonist? |
1. generates the maximum response a system is capable of by activating 100% or less of the receptors
2. affinity and efficacy = 1 |
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1. what is a partial Agonist?
2. what is the efficacy and affinity or a partial agonist |
1. substance that at its max and 100% receptor coverage produces less than maximum response
2. they have variable degrees of efficacy and affinity |
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what is an inverse Agonist:
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a substance that essentailly turns off the system, even bellow baseline rates to an absolute 0.
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what are allosteric agonists or enhancers.
where do they bind? |
1.enhance the affinity and/or eficacy of agonists by bunding to receptors and changing their conformation.
2. on a site distinct from the agonist binding site. |
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what is an example of a allosteric agonis or enhancer
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benzodiazepines, sensipar
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what is chemical antagonism
give an example |
direct chemical interaction between 2 substance, in which one is inactivated
chelating agent, dimercaprol |
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what is physiologic anataonism
give an example |
2 agonists that act independent of each other to cause opposite effects.
acetocholine and epinephrine |
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what is the difference between chemical and physiologic anatagonists and inverse agonist
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physical and chemical bring the system to baseline, while inverse antagonists shut off the system
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what is indirect antagonism
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a substance that inhibits a biological response by acting a a site beyond the receptor
Ex: Ca channel blockers. they dont inhibit the signal just the ca+ release |
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what is the most encountered form of antagonist in clinical practice
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they block the receptor site from the agonist. they have high affinity but no efficacy
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what is the difference between equilibrium and non equilibrium competitive anagonists
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equilibrium compete for site of action but higher doses of agonists will diminish its effects. irreversible antagonists bind tight and cant be moved (aspirin, h pump blockers)
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what do allosteric antagonists do?
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they alter the affinity and/or efficacy of agonists by altering receptor confirmation eg CNS drugs
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how does the linear graph of dose-response data look?
how about log graph. why is this preferred? |
1. hyperbolic
2. sigmoidal. because more dose ranges can be presented. |
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why do we prefer dose-response curves over concentration-response
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its hard to measure concentration of drug at site of action
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can you compare potency (ED50) and affinity (Kd).
how is potency used as far as drugs |
there is no direct relationship.
to determine the effectivess of 2 drugs acting on the same system |
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what hapens if a tissue has many spare receptors for a drug versus those that have a few spare receptors
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tissues with more spare receptors will react to a lower concentration of a drug than those who have few spare receptors, so even a partial agonist can have a full response in those with many spares
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how does a competitve antagonist appear on a graphical curve
how does a irreversible antagonist appear |
as a rightward shift of the curve, but the system can still achieve a maximum response
appears as a decrse in efficacy with curve shifting down |
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how does indirect antagonism appear on a curve
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just like a irreversible antagonist with a depressed curve
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how is the partial agonist defined in terms of affinity and efficacy
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when a partial agonist is in the system with the full agonist, it acts as a antagonist, bringing the activity of the full agonist down to the level of the partial agonist.
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what is the innervation of blood vessels
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parasympathetic
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under normal physiological conditions, what is the dominant nervous system
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PSNS
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what are the 4 nerves that carry PSNS
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occulomotor, facial, glossopharengial, vagus
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in the Autonomic Nervous system, what is the neurotransmitter released by the preganglionic neurons
what is kind of receptor that this binds to? |
Acetocholene
nicotinic |
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1.in the SNS, what is the neurotransmitter released by the post ganglionic neurons.
2. what kind of receptors does it activate |
1. Nonepinephrine
2. adrenergic receptors |
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what is the neurotransmitter released by the PSNS post ganglionic neurons
what kind of receptors does it bind to? |
acetocholine
muscarinic |
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what is the control over sweat glands?
|
sympathetic, using a muscarinic acetocholene receptors.
|
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what kind of receptors are the muscarinic receptors
what kind of receptors are the nicotinic receptors |
muscarinics are G-protein coupled receptors
nicotinic receptors are ligand gated ion channels |
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1.what are the excitatory muscarinic receptors
2. what G-protein do they have 3. what does activation do? |
1. M1, M3, M5
2. Gq/II activation of PLC 3. + IP, DAG > +Ca++, + PKc |
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1.what are the inhibitory muscarinic receptors
2. what G-protein do they have 3. what does activation do? |
1. M2, M4
2. Gi/Go inhibition of AC 3.- cAMP, hyperpolarization, inhibition of voltage gated calcium channel |
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where are the collinergic receptors a1, a2 located, what do they do?
|
a1 smooth muscle, vasoconstriction
a2 presynaptic neurons. inhibit presynaptic neurons, and decrease neurotransmitter release |
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where are the collinergic receptors B1, B2, B3 located and what do they do?
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B1- heart, heart stimulation
B2-vascular smooth muscle like bronchioles, relax the smooth muscle B3-in adipose tissue, causes liplysis |
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what is the constrictor pupillae under the control Of
what is the action of this muscle |
PSNS M3 mostly
Miosis, constriction of pupil |
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what us the dialator pupilae under the control of
what is the action of this muscle |
SNS a1 receptor
midriasis |
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what is the Ciliary muscle under the control of?
|
PSNS M3 > contraction
SNS B2> relaxes lens |
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what is accomodation under the control of?
how can we block accomodation |
PSNS
blocking muscarinic with atropine |
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what does the cilliary epithelium do
what nervous system controls this. how can we stop aqueous humor production |
blood supply to make the humor
SNS adrenergic a, b and muscarinic receptors activation of a1, a2 >vasoconstriction |
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why do we use b-blockers for glaucoma?
name a b- blocker used for glaucoma |
b2 vaodialtes , increasing aqeous humor, so if block it, will vasoconstrict
atropine |
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what are the lacrimal glands under the control of ?
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only PSNS through CNVII.
|
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how can we increase the aqueous humor drainage
|
muscarinic agonists and acetocholene esterase inhibitors.
|
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what kind of innervation does bronchial smooth muscle have
what kind of receptors does it also express |
PSNS
b2 |
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what drug can we use for bronchodialation?
what receptor does this work throug |
epinephrine
b2 |
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how does bronchoconstriction happen in the lungs
|
PSNS through M3 receptor
|
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what system is mucosal secretion under the control of?
what do a-agonists do what do b-agonists do |
SNS
a- decreases secretion b- increases secretions |
|
what is the system that controls the heart.
what innervates the SA node what innervates the AV node |
parasympathetic
SA is R vagus AV is L vagus |
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where does the SNS innervate the heart
|
all over specially in SA Node and ventricles
|
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what are the 4 parameters that determine the overall effect of autonomic drugs on the heart
|
1. Direct effect on the heart
2. Vascular effects 3. redistribution of blood 4. reflex phenomena |
|
what is the effect of SNS on SA node
how about PSNS |
+ HR
- HR |
|
what is the effect of SNS on Atria
how about PSNS |
+ contractility, + conduction velocity
- contractility, shortened AP duration |
|
what is the effect of SNS on AV node
how about PSNS |
+ automaticity + conduction velocity
- conduction velocity, AV block |
|
what is the effect of SNS onHIS- Purkinje system
how about PSNS |
+ automaticity + conduction velocity
none |
|
what is the effect of SNS on ventricles
|
+ automaticity + conduction velocity, + rate of ventricular pacemakers
- slight decrease in contractility |
|
what system controls the vasculature
thorugh what receptor what is the primary effect |
SNS
alpha, beta alpha constricts, beta dialates |
|
what is the dominant tone in the GI system
what is the effect of sympathetic tone on the GI |
PSNS> + GI motility
SNS > - GI motility |
|
what is the predominant response on insulin during exercise
why is this? |
alpha 2 mediated inhibition on insulin dominates over b2 response.
promote muscle glycogenolysis by the epinephrine B2 effect. this allwos muscles to work and still maintain glycemia for brain function |
|
what is the SNS effect on detrusor and sphincter
how about PSNS |
Detrusor b2 relaxes, sphinceter a1 contracts
detrousor M3 contracts. sphincter M2/M3relaxes. |
|
what system predominates in filling phase of bladder
how about mictruition |
SNS
PSNS |
|
what is the effect of SNS in renin production
|
increase via b1 receptors
decrease via b1 receptors |