5/18/15 Vd= amount of drug given [IV]/ [drug] plasma CL = (0.7 * Vd) /t1/2 LD = Css * Vd MD = Css * CL Competitive inhibitors the Km? Increase Noncompetitive inbhitors Km? Does not change. In enzyme kinetics, the vlue of Km reflect the ? of the enzyme for the substruate? Affinity In enzyme kinetics, Vmax is directly proportional to the? Enzyme concentration Competive inhibitor substrate? Resemble Noncompetive inhibitor substrate) Not resemble a substrate In enzyme kinetics, the higher the Km, the affinity? Lower 322 = 32 322- 32 = 290 245 290 = 45 45 + 32 = 77 77/7 11 46-11 = 35 = 76% As substurate concentration increases, velocity of reaction ? Increase, decrease, increases then plautes? Velocity of reaction increases as substratce concentration increases, and platuea when the enzyme is saturated Competitive inhibitors the Vmax? Do not change nonC inh Vmax? Decrease What is the formula for calculating the clearance of a drug? CL (L/min) = [rate of elimination of the drug (g/min)]/plasma drug concentration (g/L) What is the definiation of the half life of a drug? The time of elimination or constant infecustion required to change the amount of the drug in the body by one-half. USMLE: The T1/2 of a drug is 4 hours. How long must eht drug be infused at a constant rate before reaching 94% of Css (steady state concentration) 16 hours (4 half-lifes) USMLE After 3 half-lifes, given constant IV infusion of a drug, how close to steady state is the concentration of the drug? 87.5% of steady-state concentration. A drug with a medium volume of distrubtion of 15L is most likely to be found in the (blood, ECS/tissue) Extracellular space; these drugs disturbed throughout the total body water. USMLE: A drug has a bioavailability of 60%. What dosage is needed to ensure that 300 mg of the drug reaches the systemic circulation unchanged? 500 mg What ist he forumula for calculating the volume distrubiton of a drug? Volume of distribution = Vd =amount of drug in the body / plasma drug concentraction The bioavailabilty fo a drug taken orally is 70%. What 2 factors likely cause this decrease in bioaviabilty from the IV form? Incomplete absorption fo the drug and first pass metabolism Drugs with a low volume of distribution such as 4 to 8 L, are found in the (blood, tissue, ECS)? Blood ONLY!!! These drugs do not distribute outside the plasma After one half-life, given constant IV infusion of adrug, how close to steady state ist eh concentraction fo the drug? 50% of Css USMLE: in a 75 kg man, a drug has a Vd of 40L. It can be expected to be found in (blood/tissue/ECS) Tissue What is the formual for calculating the half life of a drug? Half life (T1/2) = (0.7 x Vd)/CL What si the formula for the Loading dose of ad rug? LD = (target plasma concenctration x volume of distribution) / bioavailability USMLE On pt has cirrhosis and another has chronic renal failure. How do the LD and MD of drugs change for these patients? For both heaptic and renal disease, LD? Does not change But maintenance dose decreases What is the formula for maintenance dose of a drug adminstred intravenously? MD = rate of the elmiatnion/bioaviailty (target paslama cocnenctration x clearance)/bioavailability) In zero-order elimination fo a drug from the body, what ist he relationship between the rate of elmaitnion an dthe drug concenctration? There is no relationship; the rate of elmiatino is constant regarlgdess of the drug concentraction What are 3 drugs that exhibit zero order elimation ) PEA is round like the 0 in zero order. Phenytoin Ethanol Aspirin In first order elmaitno fo fdrugs from the body, what ist he relationship between the rate of elmation and drug concentraction? Rate of the elmation if directly proprotioant to the drug concenctraation A constant fraction (rather than a constant amount) is eliminated Weak base get trapped in acidic environment USMLE: What substance is given to enhance the renal clrearnce weakly acidic drug i.e. aspirin, methotrexate, phenobarbital? Bicarbonate Weak acids get trapped basic environment What substance is given to enhance the renal CL of a weakly basic drug i.e. an amphetamine Ammonium chloride USMLE 3 hoursafter consuming a bottle of aspirin, a boy is put on IV saline with bicaronbate. By what mechanism doe sthis help him? Bicarbonate alkalnize the lumen of nephrons trapping acetylsalicylic acid, a weak acide that can be ionized in basic environments. The products of phase II metabolism of drugs are typically excrted by what organ? Kidney Phase II metabolism of drugs yield nonpolar/very polar/ slightly polar molecues thare inactive/often still active) Very polar, inactive What 3 types of bioche mical reaction sar einvovled in the phase I metabolism fo drugs? Reduction Oxidation Hydrolysis What enz sysmte mediates phase 1 metaoblism of drugs int eh body? cP450 USMLE: A 98 year old man is likely to have preserved which phase of drug metabolism? Phase II Do geriatric patietns lose the abilty for phase I or phase II drug metabolism first? Phase I (geratrict patietns have GAS of phase II: Glucuronidation Acetylation Sulfation What 3 types of biochemical reaction sare involve din the phase II metabolism fo drugs? GAS Conjation reactions Phase I metabolism of drugs yields (nonpolar/slightly polar/very polary ) molecues that are (inactive/often still active) Slightly polar, often still active) USMLE: An oncology patient receives a chemotherupatic agent. It likely has affinity for its receptor? Chemotheraptuci drugs highly potent High affinity for the receptor What is the definition fo ? Maximal effect a drug can produce? Efficacy Amount fo drug needed for agiven effect? Potency A drug that requires a very low dose to achieve its desired effected is considered? Potent How does the potency of a partial agonist relate tot eh potency of a full agonist of the same receptor? A partial agonist may be more potent than, less potean thtan or equally as potent as a full agonist In pharmcodyanicms, the addiotn of a nonC agonist (increase, decrease does not change) the efficacy of the agonist? Decrease When a competibve antagonist is given, the maximal effect of an agonist is (constant, decrease increased) Constant; maximal effect is achievable in the presence of a competitive antagonist if icnerased amoutns of the agonist are given How does the efficacy of a partial agonist realte to the efficacy of a fulla gonsti of the same receptor? A partial agonist has lower maximal effeciay than afull agonist Safer drugs have (higher or lower) therauptic index value? Higher What ist he formula that describte the TI of a drug? TI = LD50 (median toxic dose) / ED 50 (median effective dose) TD is same as LD (TILE) TITE What property of a drug is determined by its TI? Safety (drugs with higher therapeutic indices are less likely to cause toxicities ) USMLE: The lowest effective dose of a drug X is 200 mg/dL. If given at 600 mg/dL, drug X is lethal. What is the Therapeutic window of drug X? (minimum effective dose to minimum toxic dose) 400 mg/dL 600 - 200 What property of a drug is determined by its therautpic window? The range of a clinical drug safety PS axons on neurons in the peripheral ganglia? Synapse How many synapses are involved in activation of the adrenal medulla? One Hwo many neurons are involved in PS transmission formt eh spinal cord to the target organ? 2 A pt affected by botulumin toxin will be affected at which neurotnramistter/receptor groups? All neutrotransmitter/receptor gupos with acetylcholine as the neurotransmitter Which 2 componetnet of the symapthic nervous ystem are innverabed by cholinergic fibers? Sweat glands and Adrenal medulla What NT receptor mediates PS NS function at the periphaeral ganglia? Receptor? Nicotinic acetylcholine recpetors How many neurons are involved in the symapthic trnamsision from the spinal cord t the garget organ? 2 What are 4 cell tyeps in which which alpha and beta adrenric recptors mediate sympathietic tone? Cardiac Smooth muscle Glandular cells Terminal ends of neurons What NT mediates symapthic tone int eh renal vascular smooth muscle? Dopamine At the paravertebral ganglia, the NT acetyacyhole acts on nictoniec acyletchoni recptors to te hmediate SNS function What NT recptor mediates PST int eh cardiac muscle? Musc acetyl receptors What NT recptors mediate the symaptic NS function at the sweat glands? Musc acetyl receptors Somatic nerves arising form the spin innervate skeletal muscle. What NT receptor on skeletal muscle recives this input? Nictonic acetylchone recpetors What NT mediates SNS function at eh sweat glands? Acetylcholoine :_) What NT recptors mediates syspethic tone int eh renal vascular rsmooth muscle? D1 receptor Which types of nerves arise from the spinal cord and directly innerveat eskelta muscle? Somatic nerve What NT mediates Symp tone int eh cardiac muscle, smooth muscle an dglandualr clels? nEp what 2 substances are released into the blood from the adnreal medulla after the activation fo the symsptic nervous sytem? nEp and Ep preganglaionti csymspteic axons synapse on neurons in the paravertebral ganglia what NT mediates PSNS function? Acetylcholine Are muscarinic acehtylchlin recptors lingade gated sodium ptosum channels or G protein couled recptors? M acet rectprso G protein couple drecptors that act through second messengers Are N Acetcyl recptors : Ligand-gatede Na/K channeles Adenyl cyclase catalyzes the converstion of ATP into what molecule? cAMP what 5 types of recptors are couples with Gs protein? B1, B2, H2, V2, D1 Gi is MAD and theyre all 2s M2, A2, D2 Gq is all the 1s except Bob and Dan which is B and D So if I give you any number 1 except B and D it will be Gq The rest will fit into Gs What enzyme is activated directly downstream of the Gq coupled receptors? Phospholipase C What enzyme is activated directly downstream of Gs coupled receptor? Adenylyl cyclase ( What are the major effects of alpha receptor activation? Vascular smooth muscle? Increases Pupillary dilator muscle? Contracts dilate mydriasis Insteintaal and bladder sphcinter muscle? Contracts To what class of G prtoeins are H2, V1 and V2 repctors linked? Qiss (kiss) and qiq (kick) till youre siq (sick) of sqs (sex) S, q and s respectively What enzyme is inhbited directly downstream of Gi-coupled recptors? Adenyl cyclase What 5 types of recptors are coupled with Gq proteins? (HAVe 1 M&M) H1, A1, M1 and M3 To what class of G prtoeins are D1, D2 and H1 recptors? D1 = Gs D2 = Gi H1 = Gq Qiss and qiq till youre siq of sqs What final effecto renyzme is activated by recptor that are coupled with Gs prtoeins? Protein kinase A What effect does V1 recptor activation have on vasduclar smooth muscle? Vascular smooth msucl eocntraction? Increase ( Actgivation of what G protein couple drepctors can increase vascular smooth msucl eocntraction? Alpha 1 and V1 recptor increase contraction Relaxation? Mediated? B2 and D1 (renal only) Where are M1 recptors located? Enteric nervous system and CNS What are the effects of H1 recptor activation? Pruritus, pain, nasal and bronchial mucus production, contarctoin of bronchioles What is the effect of V2 recptor activation? Water permatiblyt Increase Reabsorption of the collectinb tubles of the kidney Where are they located? V2 is found in the 2 kidneys To what class of G prtoeins are M1, M2 and M3 recptores linked? Gq, Gi Gq What are the major functions of B1 recptor activation Herat rate? Increase Contractility increase too Renin relase form the kidneys? Increase Lipolysis of adipose tissue Increase What is the effect of H2 recptor activation? Gastir cacid secretion? Increases What enzyme is activated by DAG (diacylglyercol) Protein kinase C What are the effect of M3 recptor activatin? Exocrine gland secretion? Increase Gut peristalitic Bladder? Contracts Bronchoconstriction Miosis Pupiillar accomdiation To what class of G prtoeins are alpha1, A2, B1 and B2 recptors linked? Gq Gi Gs Gs What ist he effect of increased inositol triphosate (IP3) ont eh ICC of calcium? Increaset eh inintracuellar calcium concentraction smooth muscle contraction What 3 types of repctors are coupled with Gi proteins? MAD M2, A2, D2 Gi is MAD and theyre all 2s M2, A2, D2 Gq is all the 1s except Bob and Dan which is B and D So if I give you any number 1 except B and D it will be Gq All the 2s beside the MAD are going to be Gs B1 and D1 Gs What ist he major function fo B2 recptor activation toeh bodys vasucatlur? Vasodilate What effect does M2 repctor activation have on cardiac function? Decrease HR and Contractily of the atria? Decreases What final effector enzyme is inhibited by recptors that are coupled with Gi proteins? PKA What are the major functions of A2 recptor activation? Synpathic outflow Decrase Insuli release? Decrease Phospholipase C catalyzes the cleavnce of membrane lipids into what molcuels? PIP2 which his futher divided into IP3 and DAG What is the majoir function fo B2 recptora cgiation on the respiratory system? Bronchodilation What effect does the activation of ATII recptors in the presynaptic sympsthic nerve timernal have on nEP relase? Stimulates nEp release nEp-mediated activation of A2 recptors on the preasyantpic SN termains is ane xmapel of what ytpe of feegacvk? Negative feedback Tyrosine precurose to the formation of which NT? DOPA, DA, nEp What is the order for their synthesis? Tyrosine, DOPA, DA, nEP What 3 receptor types modulate the presyantpic relase of nEp from the noradregneric nerve temrinals? AGII recptors, A2, M Tyrosine is converted itno DA via what intermidate precursor? DOPA: DOPA can be used as pharamoclig canget to increase CNS DA The entory of what ion into the nerve terminal induces the release of acetylcholine into the synaptic cleft? Calcium What effect doet she activation fo M2 repctor in presynaptic symspthic nerve temrainls have on nEp relase? Inhibits What enzyme breaks down Act int the synaptic cleft? Ach-esterase 2 products Choline and acetate What enzyme is responsible for the formation of acetylcholine? ChAT Choline acetyltrasnferase What are its 2 substrates? Acetyl-CoA and choline Which 3 mechainsims are used to clear nEp from the synaptic cleft? Diffusion, metabolism and reuptake The entry of what what ion into the nerve temrianl induces the release of nEp into the synaptic cleft? Calcium Tyrosine transporters are located in the nerve temrianls of what type of cells? Noradrengic cells Tyrosine is precursor nEp DA is converted into nEp in presynaptic vesicles Indirecit chlinvergic agonist increase endogenous acetylchoine by inhbitiing what enzyme? Acetylcholinestase Pilocparine is to acet-esterase? Resistant Why is pyridstoigment used to treat myasthenia gravis Increase endogenous acetylcholine and muscle strength (pyriddostimgein gets rid of a MG) 4 direct cholinergic agonists? Betahnocol Carbachol Pilocarpine Methacoline Carbachol and pilocarpine are effective for the rx of open-ange glaucoma b/c they actgivae what muscle? Ciliary muscle of the eye You suspect a 22 yo has asthma. How does a methacoline challenge test work? Methacolhine inhale stimulate muscarinic repctors and induce bronchoconstriction diagnose asthma What is the mechians of action of bethanecol? Activate Bladder and bowel Pt with MG develos frequent asthma attacks. Which medication could be underlying these sxs? Cholinomietics (used to treat MG like pyridstigmine) esxacerbate asthma What are the clinical indication for use of neostigmine? MG, Postoperative and neurogenic ileus and urinary retention. Reversal of neuromsucluar junction blockage (postoperative) Which pharm agent is used to rx atropine overdose? Physostigmine. Why? MOA? b/c it corsses the BBB and is able to reverse central and peripheral nervous system effects. What 2 direct agonist cholimiments drugs can be used to rx glaucoma? Carbochol Pilocarpine Name 5 indirect cholinergic agonists? Neostigmine Pyridostimin Edrophonium Diagnose MG : now dif between MG and cholinergic toxicity So if someone has organophosphate toxicity and they have a lto of Actylcholine it will rpesent as MG and b/c nicotinic recptors gets desenstiizied and if you give them edorhonium and nothing changes then its toxicity and if it gets better its MG. Physostigmine Donepezil Which antichlinease is used to diagnose MG? Edrophonium Why? The effects last for minutes and if weakenss is transicetly reversed it is diagnostic of myasthineic gravis What effect does neostigmine have on the CNS? None it does ? Does not penetrate the BBB Neo CNS = no CNS Pilocaprine is effective fo trthe Rx of closed angle galucome b/c it activae what muscle? Pupillary sphincter What are the clinical indication for use of bethanocol? Postoperiative and neurogenic ilus and Urinary retention Organopshoate poisoing is due to? Inbhitoin of acety-0ease? Irreversible A pt is exposed to parathion and devloep sxs. what ist he antitdtoe? Atropine + pralidoxime What sxs indicate chliensease ibhtior poisotine? DUMBBELSS Diarrhea Urination Miosis Bronchospasma. Bardycardia Exaction fo skelet muscle/CNS and then paralysis thats why edrophonium is used b/c the nicotinc recptors get desensitized quicker Lacrmation Sweating Salivation What medications can be given for organophaose (oftesn found in inseiction ) poisoing and how do they work Atropine and pralidoxime. The symeos of organosphaose poising i.e. parhatyoin are caused by inbhitoin fo what enzyme? Acetylchoelinstease What ist he mechainism of clinical application for oxybutynin? Muscarinic antaongised used to reduced urgency in mild cystitis and reduce bladder spasm On the damn toilet seat On = oxybutynin Darifencien Solifenicine Tropsium You gave haloperidof for? Schiz but the pt developed Parksons like motor effects. What drug could you add to treat this? benztropine what ist he mechanism and lcincial application for glycopyrrolate? Muscarnisms antagonis used to reduce airway secrertions and drooling What ist he clincila paplciation and MOA of atropine, homatropine and tropicamide? These drugs mydraisis and cycloplegia? By antaognizesing muscarinic recptors in the eye Which M agnostist is most commoly used to trate motion sickness? Scopolamine What is the MOA and clincail application for benztorpine? M antagonis reduce sxs? Parkins dsease Tremor and rigidity Bradycardia is due to lack fo DA and not Ach A boys severe asthma attack is unresponsive to albuterol. What other med that acts as a M antoagnist can be used? Ipratropium M antosed => used rx asthma and COPD I PRAY I can breath soon What is the effects of atropine ont eh stomach? Decrfeaed acid secretion Atropine toxicity Skin dry stuck in a dessert so the sun makes you hot and dry and red. And see water source so thats delusion and its always blurry. Flushed Red as a beet Dry as bone What is the effect of atropine on GI motility? Decreased motility Atropine etoixcity can cause urinary retention. Which is typicall seen in prostatic hyperplasia can calso cause neonatal hyperthermia. What ist he effect of atropine ont eh airway mucosa? Secretions? Decreased A pt with jimson weed poisoning is likel y to be? Disoriented Mad as a hatter A pt starts on a bardycarid drug. She experience severe right sided eye pain. What dur gist h she taking and what side effect is this? Atropione acute angle-closure glaucoma Body temperatue atropine toxicity ? Increased Hot as a hare Dessert sun hot What are the efets of atropine ont eh eye? Pupil dilation. Cyclpleiga What is the effect of atropine eont eh baldder in a pti with cystitis? Decreased urgency Why woud DA be used to Rx a hsptialized pt with a BP of 80/40 and no urine production in the past 24 hours? Increased in BP while maintine renal perfusion What effect t does nEp have on renal perfusion? Decrease renal perfusion A man has daytime sleepiness. Hallucaiotnoins before/after sleep and catalplexy. What indirect symapthotmietic do use to reat him? Amphetamine By what mecniams does ampethamein exert its symapthomietmnic effect? Stimulate the relase of stored catehoclmaines Hypertensive crisis pheo Ritodrine acts on Ritodrine(discontinued preparation:Yutopar) is atocolyticdrug, used to stoppremature labor B2 UTERINE RELAXATION What are the three clinical appcilation fo ephedrine? Nasal congestion Urinary incontinence Hypotension What is the lcincial application for albutoreol? Acute asthma A pregnant 20 yo at 32 weeks gestation breaks her water which med can be used to delay the onset of labor? ritodrine, Terbutaline which reduce premature uterin contractison what are the clinical apcliation sof Ep? Anaphlysix Open angle glaucoma Asthma Hypotension Which tyeps of recptors are activated by Ep? A1, @, B1 and B2 What ar the effects of cocaine when used topically? Vasoconstriction Local anehsteic What ar the clincail aplciation of phenylephrine? Treate nasa degoneaetion Causes vasoconstriciotn Dilate pupils In the effect of nEp on B recptors gerter than equal to or less tan its effect on alpha recpeotrs? Less than. High dose Ep To dif between them you give an alpha 1 blocker and if it becomes By what mechiancim does cocaine exet it sysmsptehomimiet effect? Inhibits cathcoamoen uptake int eh nerve terminal, do not use ?beta blocers can cause unposed alpha1 activation By what mecihani does ephdeinre exert its symapthomimietn effect? Ephedrine indir4ct syampthomeitc tha tsitmualte the relase of sotred catechomains Phyealphine is an agonist for which repctor? Alpha 1> A2 What arteh clinical indication for amepthmaines? Nacrolpesy Obesity ADHD Isoproterenol is an agonist for which recptors? B1 = B2 Dobutamine is an agonist for which recptor? Strong agonist of B1 and weak agonsti of A1, A2 and B2 What arteh clinical applciations for dobuamtie? HF, cardiac stress testing A, P, I can be used to rx nasal congestion? Phenylephrine Am,ph, Eph, and Coca are indirect sym DA treats HF What is the clincali application for isoproteronole? Bradyarrthymias Torsades de pointes Which types of recptors does DA activate, and how stonrlgy does it acitave themr elative to one another? D1 greater than B greater than A recpetors Does nEp have greater affinity for alpha adnreic recptors or B1 recpeotrs? Alpha adren recpetors Which types of recptors are activated by nEp? A1, A2 and B1 (with lower affinity) Metaproternole, albuyterol and salmeterol and terbuatlin are agonsti for which recptors? B2 > B1, Albutoerl and salmtoerol are used to treat? Asthma and COPD What are th eefects of nEp on systolic and diastolic BP, PP, and HR? Systolic/diastolic BP? Increase PP? Increase Systolic more than diastolic) HR? Reduce via reflex bradycardia In the effect of isoproternoln on B recptors gerta than, = or < its effect on alpha recptors? > What are the effects of isoprtoeroneo on systolic and diastolic BP, PP and HR? Transiently increase (an dthen decrease) systolic decreases diastolic PP? Increase HR? Incrase What is the effect of clonide and alpha methyl dopa on central adnrenig coutlfow? Decrease central andreglic fluidc, Alpha2 agonists What are the clincail indications of clonidine and alpha methyldopa? HTN with renal disease b/c they do not decrease blodof lwo tot eh kdineys what is the clinical application and MOA of mirtazapine? Alpha-selective blocer rx depression