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Increased polarity and charge increases what drug property? Solubility
For PO drugs, is it better for them to be more hydrophobic or more lipophilic? Both! They are the same thing. Allows for easier membrane permeability.
what are hard drugs? drugs that are metabolized to biologically active metabolites.
what are soft drugs? drugs that are characterized by a predictable and controllable in vivo metabolism to non-toxic products after they have achieved therapeutic goal.
how are soft drugs designed? By building a metabolically sensitive group into the molecule that directs it to a pathway of deactivation/detoxification.
what are prodrugs? drugs that are inactive or less active drug analogs specifically metabolized to pharmacologically active drug.
Name ways in which metabolism poses a problem to drug action. -by inactivating the drug -producing toxic metabolites -decreasing half life -drug-drug interactions (competing for metabolizing enzymes or inhibiting/slow metabolism, inducing metabolism and decreasing drug concentration)
which type of drug reduces metabolism by incorporating a stable functional group at metabolically vulnerable sites? hard drugs - goal is to prevent metabolism, increase F, block formation of toxic metabolites, decrease drug elimination rate (inc half life)
How do you look at a structure and determine which sites have been "designed out" for a hard drug? You can't. - He won't ask us to.
What's the goal of a hard drug? to minimize metabolism.
Goals for which drug type? -minimize intra,inter-individual variability -reduced toxic metabolites -simplify PK -increase half life Hard drugs.
Metoprolol and betaxolol are examples of what type of drug? (hint: half life, F inc) - do they fall into one class or two? Hard drugs. BUT may also be considered soft drugs because they produce inactive metabolites that are cleared.
Is changing the drug structure always beneficial to half life? No. It can contribute to inactive metabolites, but also may produce toxic compounds that are undesirable.
ACE inhibitors are examples of what type of drug? Hard drugs. Ex: captopril and enalaprilat
Which type of drug is classified into "metabolism as a solution to problems with therapeutic agents?" Soft drugs and prodrugs.
What is soft drug design? Making a substance with a predictable metabolism producing inactive metabolites AFTER biological action is elicited. -Builds a "directing" molecule into structure.
What is the most commonly used hydrolytic enzyme for soft drug metabolism? Why are these most common? Esterases! -present in most tissues, offer fast rxn and low substrate specificity.
which type of drug is remifentanil? patients with what type of organ dysfunction can benefit from this drug? SOFT drug - rapidly inactivated opioid analgesic. Ester group is cleaved by esterases in serum and converted to inactive COOH within 3-5 min. - no renal/liver clearance is needed to inactivate/clear the drug (renal/liver dysfxn okay in pts)
what are prodrugs? inactive/less active drug analogs that are designed to be specifically metabolized to the pharmacologically active drug - through metabolic transformation.
how would you draw the "design" pathway for a prodrug? active drug (pharmacophore) bound to group attached to change drug properties --(in vivo cleavage of prodrug moiety)--> active drug + leftover prodrug cmpd
how are prodrugs beneficial? -improve deficient physiochemical properties like: +membrane permability +water solubility +rate of elimination +formulation difficulty etc
What type of drugs target the drug to certain organs or cells where the active drug is released (where action is required)? prodrugs.
for what problems can prodrugs help? (many examples) -adding polar/charged group to inc H20 solubility -inc lipophilicity (inc % drug abs) -inc/dec protein binding -dec clearance, metabolism (inc t1/2) -improve stability -INC BBB penetration -site specificity (tumor targetting) -modify taste, mode of
how can you convert an active drug containing an ALCOHOL to a prodrug? -convert -OH to Ester using ACYL group *pathway makes ester prodrug which is hydrolyzed by esterase and produces active drug with OH plus COOH cmpd
besides acyl groups, what other elements may be used to convert alcohols? sulfates and phosphates - they cleave back to alcohol using sulfatase and phosphatase.
imagine a prodrug drug with a phosphate group attached. what type of enzyme would cleave back to parent drug? (recall from notes which substituent group often uses sulfates/phosphates) enzyme: phosphatase. parent drug: alcohol
drugs that have added acidic or basic groups, that are charged at physiological pH, increase what drug property? water solubility.
are all drugs that contain sulfate/phosphate groups prodrugs? NO!!!!
An uncharged/polar alcohol that transforms to an aliphatic/aromatic group becomes (more/less) hydrophoblic and has (inc/dec) PO absorption. -MORE hydrophobic -INC oral absorption
how can you convert an active drug containing a CARBOXYLIC ACID to a prodrug? -convert -COOH to ester prodrug using ALCOHOL group (OH-R) *pathway makes ester prodrug which is hydrolyzed by esterase and produces active drug with COOH plus OH-R cmpd
basic groups on esters (inc/dec) pKa? hydrophobic esters (inc/dec) lipophilicity? -basic groups inc pKa -hydrophobic esters inc lipophilicity
Long-chain aliphatic alcohols and sterically hindered alcohols give prodrug esters that are (more slowly/more fast) cleaved by esterases. MORE SLOWLY.
T/F EWG on alcohol/small alcohols give prodrug esters that are less rapidly cleaved by esterases. False. They are more RAPIDLY cleaved by esterases.
how can you convert an active drug containing an AMINE to a prodrug? -convert -NH2 to AMIDE prodrug using ACYL group (X=O-R) *pathway makes AMIDE prodrug which is hydrolyzed by AMIDASE and produces active drug with NH2 plus COOH-R cmpd
T/F Simple amides are much more stable to hydrolysis than esters. TRUE!
T/F Many amides are good substrates for amidases. FALSE!! An exception is acetamide group (N-acetyl) which is NOT a prodrug and is usually stable to amidases.
T/F Amides that resemble amino acid based amides are typically more susceptible to amidase cleavage. True! We won't have to predict if amide will be cleaved on exam though.
Note: other types of prodrugs are possible for drugs containing amines. what is one example? IMINE prodrug. it's non enzymatic drug to spontaneous hydrolysis to amine and aldehyde. - no intra/inter patient variability since its non enzymatic
how can you make a prodrug from active drugs containing diols/carbonyl groups? -diols can be converted using ketone or aldehydes. -ketones give ketal prodrugs (R'+R=C) -aldehydes give acetal prodrugs (R'=H) -both type of prodrug undergo non-enzymatic hydrolysis to form parent drug + ketone or aldehyde
what is one advantage of non-enzymatic conversion of prodrug to parent drug? Intra and inter patient variability is minimized since reactions don't depend on enzymes!
prednisolone and methyprednisolone are poorly water soluble drugs. what can you add to them to make them water soluble? (ex: of carrier linked prodrug) -sodium succinate ester must be added to methylprednisolone and/or prednisolone.
which enzyme do you use to convert AMINO ACID AMIDE OF BENZOCAINE (a prodrug) to BENZOCAINE (a local anesthetic) -an amidase (amide)
how do you convert an OPEN-CHAIN AA PRODRUG OF DIAZEPAM (very water soluble) to the active drug (which has low water solubility)? -an amidase. (peptidases hydrolyze the prodrug to an intermediate which spontaneously cyclizes to provide the drug).
Fluocinolone acetonide is a prodrug that allows dermal abs by "hiding" the hydroxyl groups as esters or acetonides. Once the drug is absorbed through the skin, how is the active drug revealed? -By esterases or hydrolysis.
Dipivefrin is a prodrug for epi. Which type of enzyme is used to increase corneal permeability? (prodrug for imp. abs/distribution) -aqueous humor (yay pharmacology) esterases. turns esters into alcohols.
if a drug contains a COOH, the linkage to the carrier is an ester which decomposes via which enzyme? esterase!
tumor cells possess higher concentrations of phosphatases and amidases when compared to normal cells. why is this beneficial? it allows us to base drug design off of the enzymes available at the target site = prodrugs for site specificity.
what is a drug that has been modified into a prodrug to protect it from first pass metabolism? propranolol; propranolol was transformed into an hemisuccinate ester which blocks glucuronide formation and allows for an 8 fold increase in plasma levels of active drug.
what is a common strategy to slow hydrolysis? -think of two instances in patient dosing when this would be beneficial. to add a long chain aliphatic ester to the drug. -for treatment of psychoses where patients require medication for extended amts of time, where pt compliance is low
how are bioprecursor prodrugs beneficial? -example in notes was for nucleotide activation. +6-mercaptopurine has a 50% remission rate for acute childhood leukemias. it works by inhibiting several enzymes of purine biosynthesis. +also acyclovir and ganciclovir aSee notes for detailed explanati
which element plays an important role in the blood coagulation cascade? Ca2+
define thrombus. define embolus. thrombus: clot adhered to vascular wall. embolus: free floating clot.
thrombotic conditions are the largest medical cause of morbidity. what are examples in this category? MI, heart disease, unstable angina, surgical procedures where anticoags are critical to avoid thrombus/embolus, atherosclerosis -> rough vascular surface -> formation of thrombus
Endogenous heparin is not detected in plasma under normal conditions. Exogenous heparin is. What is heparin used for? an anticoagulant.
describe the structure of heparin. -40 monosaccharide units with an avg MW of 12-14,000. -specific pentasaccharide sequence found in 30% of heparin chains, which binds to serine protease inhibitor (serpin) (ANTITHROMBIN). -serine proteases are inhibited by antithrombin.
how does antithrombin inhibit serine proteases? cleaves an arginine-serine peptide bond and forms a covalent 1:1 inactive complex = anticoagulant.
which factor is inactivated when a specific pentasaccharide sequence within heparin binds to antithrombin III? 10A is inactivated.
the significance of antithrombin binding pentasaccharide is two-fold. what's one reason? 1. full length heparin chains (with the pentasacc.) bind antithrombin and thrombin. leads to 1000 fold inc in rate of antithrombin inactivating thrombin. thrombin mediated conversion of fibringoen to fibrin is inhibited = anticoag.
the significance of antithrombin binding pentasaccharide is two-fold. what's another reason? when pentassach. binds to antithrombin, antithrombin undergoes a conformational change which facilitates the interaction bw antithrombin and serine proteases which inc antithrombin-mediated inhibition of proteases (10A).
review: what are the long heparin sequences containing the pentasaccharide needed for? -what is the unique pentasaccharide part of heparin needed for? -long chain needed to optimially inhibit thrombin. -unique part needed to inhibit other serine proteases (eg 10A).
short reasoning: how does heparin act as an anticoag? -antithrombin binds to an inhibits thrombin. -heparin catalyzes this interaction and is then released to continue in the cycle.
overview: heparin mediated inactivation of other serine proteases (eg 10A). antithrombin binds heparin and a conformational change occurs --> actiavted antithrombin (not specific, but selective inhibitor of 10A) is now more effective inhibitor of serine proteases (10A)
what are LMWH? heparin that has been depolymerized by some method so that the polysaccharide chains are shorter; MW ~500.
what is the mechanism of action of LMWH? -shorter chains cannot effectively bind both antithrombin and thrombin on one chain THUS THEY DO NOT EFFECTIVELY PROMOTE ANTICOAG VIA INHIBITION OF THROMBIN. -does have the critical pentassach. to activate serine protease inhibitor antithrombin..10A inhi
is enoxaparin/Lovenox a heparin or LMWH? -how is it made? LMWH - benzylation of COOH followed by alkaline hydrolysis.
what type of drug is dalteparin/fragmin? how is it made? LMWH - nitrous acid depolymerization. MW 4-6000
what type of drug is ardeparin/normiflo? how is it made? LMWH - peroxidative cleavage. MW 55-6500
Nadroparin/Fraxiparine, Reviparin/Clivarine, Tinzaparin/Innohep are all what class of drugs? LMWH - soil enzymes can be used to make LMWH
why is danaproid a unique drug? it is a mix of non-heparin LMW glycosaminoglycans; since it lacks heparin it has reduced cross-sensitivity that can cause problems with heparin induced thrombocytopenia.
why can LMWH be used in outpatient therapy? -improved therapeutic profile -SC administration
what are advantages to LMWH therapy? -fewer effects on platelets (less action on throbmin)=less bleeding problems -less nonspecific binding to plasma proteins =inc F after SC admin -more predictable anticoag response, less interpt variability -longer DOA of anti-factor 10A activity
how does use of LMWH lower the risk of thrombocytopenia? -lower risk of immune sensitization -full length heparin binds to platelet factor 4 in body which can cause a immunological response (Ab formed) leading to HIT with or w/o thrombosis
how do synthetic pentasaccharides work? they are specific for binding and activating antithrombin. an example is Fondaparinux/Arixtra
which heparin can be inactivated with protamine? how are other heparins inactivated? Heparin itself can be inactivated with protamine. -LMWH's, synthetic polysaccharides, other anticoags are hard to inactivate.
what is thrombate used for? -IV admin of antithrombin used in clinical setting for anticoag therapy.
what are Hirudin and Hirudin-Like Thrombin inhibitors? Hirudin - direct, competitive inhibitor of thrombin. thrombin cleaves arg-glycine peptide bond in fibrinogen = fibrin monomer. Hirudin binding to thrombin blocks catalytic site in throbmin that catalyzes cleavage of fibrinogen to fibrin. **CANT TURN OFF*
T/F Bivalirudin/Angiomax is a LMWH. FALSE! It is a hirudin-like thrombin inhibitor that binds the catalytic site and the anion binding exosite of circulating and clot-bound thrombin. -20 AAs long -Binds reversibly, competitively, and is slowly cleaved by thrombin
T/F Argatroban/Acova is a small molecular direct inhibitor of thrombin. TRUE! The phe-pro-arg peptide sequence in fibrinogen is recognized and cleaved by thrombin. -It is a peptidomimetic of this tripeptide sequence -Competitive, reversible, inhibitor of thrombin catalytic site
what are examples of direct inhibitors of factor 10A? oral anticoags that inhibit catalytic activity of factor 10A: rivaroxaban, apixaban, betrixaban
what class of drugs is rivaroxaban? how does it work? -direct inhibitor of factor 10A. -inhibits free F10A and bound F10A -rapid onset of action, high F, highlyl selective, direct inhibitor -interrupts in/extrinsic paths -does NOT inhibit thrombin, no effects on platelets
compare and contrast drugs selective for F10A vs. LMWHs. drugs selective for F10A: structurally different from LMWH, different properties from LMWHS HOWEVER, therapeutically similar to LMWH due to inhibition of F10A
patients with what condition can be dosed with rivaroxaban? (note: still in clinical trials) does not need any liver conversion, so potentially in patients with liver dysfunction
what are the two main classes of drugs that fall into the category of VITAMIN K ANTAGONISTS? (Oral anticoags) -Coumarins -Indanediones
how do coumarin's work? -block the gama-carboxylation of glutamate residues in prothrombin and factors II, VII, IX, X and endogenous anticoag protein C.
how do coumarin's work as vitK antagonists? -block the reduction of VitK epoxide to its active hydroquinone form. Biosynthesis of active prothrombin depens on an adequate supply of this form of VitK. -VitK ant inc blood clotting time.
why are dicarboxyl groups important in/on VitK Antagonists? They bind Ca2+ and this Ca2+ binding is essential for their activity.
what is the structure of warfarin sodium? Draw it! Go verify structure in notes...can't paste picture.
What does it mean if a patient on VitK antagnosits have elevated VitK levels? They are overdosed. (corret me if I'm wrong here..)
Aspirin and COX inhibitors are examples of what class of drugs? Antiplatelet drugs!
how does aspirin inhibit the production of TXA2? -TXA2 is an icosanoid that induces platelet aggregation. -The major platelet enzyme (COX) produces TXA2. -Inhibition of TXA2 production has an antiplatelet effect.
how does aspirin inhibit COX? -draw the structure of aspirin -Aspirin acetylates an active site serine of COX blocking production of TXA2. -Knocks out COX for ~14 days due to irreversible qualities of drug. -Platelets don't synthesize new protein so inhibition lasts until new platelets are created.
what class of drugs is dipyridamole/persantine? what do you add to dipyridamole to make aggrenox? -Antiplatelet drugs. -add dipyridamole to aspirin to make aggrenox = combined, additive antiplatelet effect. -inhibits phosphodiesterase 3 which degrades cAMP to AMP in platelets and blood. resulting increase in cAMP levels - inhibition of platelet agg
what class of drugs does cliostazol/peletal belong to? what's it's job? -antiplatelet drug. -inhibits PDE3 and suppresses degredation of cAMP = inc in cAMP in platelets and blood vessels.
what are 2 examples of inhibitors of ADP mediated platelet aggregation? -Ticlopidine, Clopidogrel (PO) -used for reduction of MI/stroke. -small clots are potential toxicity
how do clopidogrel and ticolpidine work? -ADP activates platelets by activating GPCR leading to change in platelet shape and initiates platelet aggregation events (complex activation). C + T irreversibly modify ADP receptor inhibiting ADP receptor binding and blocking formation of the complex.
T/F Clopidogrel and Ticolpidine require metabolic converstion to active metabolite. TRUE. They are prodrugs that require P450 metabolic activation.
Abciximab/Reopro is a direct GPIIB/IIIa antagonist. what does it do? -its a Fab fragment of a monoclonal Ab that binds to the GPIIb/IIIa complex on platelet surface. -admin via IV drip -binding may sterically inhibit complex from interacting with fibrinogen or cause conformational changes/inhibit interaction with fibrino
Tirofiban/aggrastat is a direct GPIIB/IIIa antagnoist. how does it work? -interaction between fibrinogen and complex is mediated by binding of complex to tripeptide sequence found on fibrinogen. -Competitvely binds to RGD binding site in GPIIB/IIIA complex and inhibits fibrinogen-complex interactions and platelet aggreg
what class of drugs is eptifibatatide a part of? direct GPIIb/IIIa antagonist. -cyclic heptapeptide -binding to RGD binding pocket in complex blocks fibrinogen - complex interactions resulting in inhibition of platelet aggregation.
what are thrombolytic drugs? proteases that degrade clots or activate endogenous proteases that will degrade clots.
how are thrombolytic agents dosed? by IV to rapidly dissolve blood clots by proteolytic cleavage.
how is plasminogen converted? plasminogen is converted to plasmin and plasmin degrades fibrin clots.
what is anteplase/activase? a recombinant tissue plasminogen activator (tPA) -protease that is selective for converting fibrin-bound plasminogen to plasmin -tPA gives active form of plasmin
what is reteplase/retavase? a mutant form of tPA having the first 172 AA removed leading to longer half life than alteplase (activase) due to reduced hepatic elimination.
what is urokinase/abbokinase? a protease that directly activates plasminogen to fibring and fibrinogen (check this..not sure)
what are special properties about urokinase/abbokinase? -its a kinlytic -has a half life of 15 min -human protein that does not show antigenicity that can arise with bacterial derived streptokinase -not selective for fibrin-bound plasminogen
what is streptokinase? -a thrombolytic enzyme purified from streptocci -forms complex with plasminogen -complex activates plasminogen to produce plasmin and plasmin is a protease that dissolves fibrin clots.
what is the primary difference between urokinase and activase? -tPA drugs must bind fibrin in the thrombus and then they act on plasminogen to covert it to plasmin. -urokinase can directly act on plasminogen.
what is anistreplase? -an anisoylated plasmin streptokinase activator complex. -involves a plasmin-streptokinase complex where the active site of the complex has a p-anisoylated lysine residue. -the p-anisoyl group in the catalytic site inactivates the complex.
how is the p-anisoyl group of anistreplase cleaved? -by non-enzymatic first order kinetics to give active form of complex. -compared to giving just streptokinase, the drug has a longer active lifetime in the body. -gives complex time to bind to fibrin clot before it is activated
what do coagulants do? (think simple) stop bleeding. also called hemostatics.
what properties make vitamin k a cood coagulant? -safe in many populations -promotes coagulation via promoting gamma carboxylation of glutamate residues -can stop bleeding due to warfarin -short half life (oral admin) -can take 24h to see effect
what is protamine? -used to reverse action of heparin (inactivates) -arginine rich proteins from salmon sperm -can also bind other coag factors but does not effectively reverse current LMWHs very well/at all
what is amino caproic acid? -competes for lysine binding sites on plasminogen and blocks binding of plasmin to fibrin - simply competition.
why are a number of coag factors given IV to promote coagulation in certain diseases? -for direct replacement of a coagulation factor including: +factor IX +factor 7a +antihemophilic factor and complex with von willebrand factor etc.
Created by: michelle.stammet