Pharmacology S1 U2

receptor

agonist

antagonist

mechanism of action

side effects

contraindications

drug interactions

contraindications

pharmacokinetics

intended molecular target

absorption, distribution, metaboism, excretion

absorption

distribution

metabolism

excretion

free

albumin

aqueous diffusion

lipid diffusion

carrier mediated movement

endocytosis and exocytosis

drugs acid or base properties and the aqueous partirion coefficient

rate of diffusion=(available surface area*concentration radient)/(resistance of membrane*thivkness of membrane)

weak acid

weak base

lipid

pKa

pH= pKa+ log (A-/HA)

alkaline

sodium bicarbonate (NaHCO3)

Ammonium chloride (NH
4
Cl), Ascorbic acid
(Vit C), citric acid (e.g. cranberry juice

acidic

equilibreium

partition coefficient

part coefficient= drug organic/drig water

apparent partition coeffoicient (PC)

apparent PC= PC* fraction non-ionized drug

Ct

CT or Css

minimal effective concerration (MEC)

MEC

bioavailability (F)

amt absorbed/amt administered

• Route of administration
• Chemical-Physical properties of the drug
• Patient-specific factor

D1F1=D2F2

sites of loss

low MW (200-300 Da) and lipid soluble drugs may cross

not very selective (many drugs pass through and may
affect fetus)
• Subject to usual physicochemical properties (MW < 1000 Da, lipid solubility, free
vs protein-bound, etc.

a1-acid glycoprotein

dose mg/plasma drug conc (mg/ml)

lower; higher

metabolites

stable adducts

hydrophobic

phase 1 rxn

phase II rxn

liver (most), kidneysm lungs, skin, intrestines

prodrugs

tamoxifen, enalapril (ace inhibitors), L dopa

oxidation, reduction, hydrolysis

cytochrome CYP enzyme (Cytochrome P450)

donates electrons via NADPH to NADP+

CYP3A4

CYP2D6

CYP2E1

CYP2C9

induction

inhibition

induction

suicide inhibitor

CYP1A

CYP2E1

CYP3A4

CYP4A

cause induction to many if them

polar

intremediates; cytosol, microsomes

NAPQI

N-acetylcysteine (NAC)

2D6, 2C19, 2C9

slow acetylators

CYP3A4

CYP3A4

CYP1A1, 1A2, 2E1

P450`

decrease

decrease

increase

increase

males

t1/2

Kelim (rate of elimination)

Cl

rate of clearance (mL)/concentration of drug(min)

clearance/vd

rapid

1st order rxns

t1/2

t1/2= (ln(2)*Vd)/Cl`

etoh., aspirin, phenytoin

zero order

5

loading dose

Kd

higher

effective concentration 50

graded dose response curves

quantal dose response curve

agonist

competitive antagonist

noncompetitive active site antagonist

partial agonist

biased agonist

mixed agonist/antagonist

inverse agonist

spare receptors

Gas

Gai

Gaq

Ga12/13

polypharmacy

thrombosis

primaru hemostatoc plug

endothelin

von willebrand factor

PGI2

protein c and s

prpthrombin G2021A mutation

antiplatelet agents, anticoagulant, thrombolyitc agents

cyclooxygenase (COX) inhibitors, phosphodiesterase inhibitors, ADP receptor pathway inhibitors, GPIIb–IIIa antagonists, and thrombin receptor (PAR-1) antagonists.

NSAID: cyclooxygenase inhibitor

inhibits the synthesis of prostaglandins (at cycloxygenase enzyme), thereby inhibiting the platelet granule release reaction and interfering with normal platelet aggregation
=.ovalently acetylating a serine residue near the active site of the COX enzyme, thereby inhibiting the synthesis of the cyclic endoperoxide and the various metabolites of the cyclic endoperoxide

in platelets np, irreversibly poisoned, new ones need to be made
-in endothelial cells yes

not permanent

antiplatelet agent to prevent arterial thrombosis leading to transient ischemic attack, stroke, and myocardial infarction

decrease platelet aggregability by inhibiting cAMP degradation, while activators of platelet adenylyl cyclase decrease platelet aggregability by increasing cAMP synthesis.

platelet phosphodiesterase inhibitor

combination of dipyridamole and warfarin can be used to inhibit thrombus formation on prosthetic heart valves, while the combination of dipyridamole and aspirin can be used to reduce the likelihood of thrombosis in patients with a thrombotic diathesis.

nay induce angina

Ticlopidine, clopidogrel, and prasugrel

covalently modifying and inactivating the platelet P2Y(ADP) receptor (also called P2Y12), which is physiologically coupled to the inhibition of adenylyl cyclase

prodrug ADP R pathway inhibitor

(1) secondary prevention of thrombotic strokes in patients intolerant of aspirin, and (2) in combination with aspirin, prevention of stent thrombosis after placement of coronary artery stents.

neutropenia, thrombocytopenia, and thrombotic thrombocytopenic purpura (TTP)

2nd gen thienopyridine, prodrug, must be oxidized by p450

interact with statins, proton pump inhibitors, and other drugs metabolized by these P450 isoforms

approved for secondary prevention in patients with recent myocardial infarction, stroke, or peripheral vascular disease. It is also approved for use in acute coronary syndromes that are treated with either percutaneous coronary intervention or coronary artery bypass graftin

irreversible antagonist P2Y12 ADP R

approved for use in acute coronary syndromes treated with percutaneous coronary intervention. Like clopidogrel, prasugrel is a prodrug and is used in combination with aspirin.

may increase the risk of bleeding relative to clopidogrel, especially in patients over 75 years of age or weighing less than 60 kilograms

use in patients with a prior history of stroke or transient ischemic attack because of an increased risk of intracranial hemorrhage

competitive antagonist at P2Y12 ADPR
-no hepatic activatuon requred
-orally taken

approved for use in patients with acute coronary syndromes.

dyspnea and bradycardia.

patients with histiry of intracranial hemorrhage

GPIIb-IIIa R antagonist

antagonizes the platelet GPIIb–IIIa receptor with high affinity

used to reduce ischemic events in patients undergoing percutaneous coronary intervention and to treat unstable angina and non-ST elevation myocardial infarction.

essentially irreversible GPIIb-IIIa receptir antagonist

reduces both long-term and short-term ischemic events in patients undergoing high-risk percutaneous coronary intervention

nonpeptide tyrosine analog that reversible GPIIB-IIIa R antagonist

patients with acute coronary syndromes

previously infused is already bound to platelets, infusion of fresh platelets after the drug has been stopped can reverse the antiplatelet effect.

bleeding

one must stop the drug infusion and wait for platelet function to return to normal

GPVI

platelets

GPVI antagonist

can bind to collagen and block the binding of platelet GPVI, thereby blocking this step in initiating primary hemostasis.
-also binds to other extracellular matrix proteins, such as fibronectin, laminin, and vitronectin, and it inhibits the binding of vWF to collagen, thereby blocking the other major step of primary hemostasis initiation.

this agent may have the ability to block pathologic thrombosis while maintaining systemic hemostasis, potentially giving it a unique advantage compared to other antiplatelet agents.

reversible thrombin R (PAR-1) antagonist

secondary prevention of myocardial infarction, death, and stroke in patients with a prior myocardial infarction or with peripheral artery disease.

CYP3A4

should not be administered to patients with a prior history of stroke, transient ischemic attack, or intracranial hemorrhage

ncrease the risk of bleeding when used in the treatment of acute coronary syndrome, limiting its clinical utility

least selective agents (warfarin and unfractionated heparin) to the most selective agents (selective factor Xa inhibitors and direct thrombin inhibitors).

bleeding

Vitamin K

(1) a precursor form of the target protein with its 9 to 12 amino-terminal glutamic acid residues, (2) carbon dioxide, (3) molecular oxygen, and (4) reduced vitamin K.

blocking epoxide redictase that mediates the regeneratuon of reduced vitamin K

epoxide reductase

VKORC1

often administered to complete a course of anticoagulation that has been initiated with heparin (see below) and to prevent thrombosis in predisposed patients.

Because warfarin is highly albumin-bound in the plasma, co-administration of warfarin with other albumin-bound drugs can increase the free (unbound) plasma concentrations of both drugs. In addition, because warfarin is metabolized by P450 enzymes in the liver, co-administration of warfarin with drugs that induce and/or compete for P450 metabolism can affect the plasma concentrations of both drugs.
-pregnant women

prothrombin time (PT)

unfractioned standard heparin and lmw heparin

unfractional heparin

LMW heparin

antithrombin III

acting as a cofactor, accelerates the reaction by 1,000-fold. Heparin has two important physiologic functions: (1) it serves as a catalytic surface to which both antithrombin III and the serine proteases bind; and (2) it induces a conformational change in antithrombin III that makes the reactive site of this molecule more accessible to the attacking protease

LMW heparins, which have an average molecular weight of 3–4 kDa and contain fewer than 18 monosaccharide units, efficiently catalyze the inactivation of factor Xa by antithrombin III but less efficiently catalyze the inactivation of thrombin by antithrombin III. In contrast, unfractionated heparin, which has an average molecular weight of 20 kDa and contains more than 18 monosaccharide units, is of sufficient length to bind simultaneously to thrombin and antithrombin III and therefore efficiently catalyzes the inactivation of both thrombin and factor Xa by antithrombin III. Q

both prophylaxis and treatment of thromboembolic diseases. Both unfractionated and LMW heparins are used to prevent propagation of established thromboembolic disease such as deep vein thrombosis and pulmonary embolism.

parenterally, usually via intravenous or subcutaneous routes.

heparin induced thrombocytopoenia

HIT type I

HIT type 2

enoxaparin, dalteparin, and tinzaparin

renal insufficiency

selective factor Xa inhibitir (idirect)

prevention and treatment of deep vein thrombosis and is available as a once-daily subcutaneous injection.

renal insiufficency

directly inhibit factor Xa by binding to its active site and competitively inhibiting the enzyme (Fig. 51-15). All three of these agents bind factor Xa that is complexed with factor Va and calcium ions on phospholipid surfaces. As a result, these agents do not require antithrombin III as a cofactor for inhibition of factor Xa.

DOACs

approved for prevention of stroke in patients with non-valvular atrial fibrillation (i.e., atrial fibrillation not related to mitral stenosis or a prosthetic heart valve) and for prevention of deep vein thrombosis after hip or knee orthopedic surgery.

-drugs that compete with active sites of metabolism (Cyp2C9(Swarfarin), Cyp3A4(Rwarfarin)
-drugs that compete with albumin binding sites (antibiotics)
-anything that increases Vitamin K amounts can counteract the effects of warfarin therapy (vitamin K rich foods)
-anything that wipes out gut bacteria (systemic antibiotics)

direct oral anticoagulants (DOCAs)

patient’s weight; in patients with weights below 60 kg or above 120 kg, or with a BMI of greater than 40 kg/m2, dabigatran is contraindicated

Renal function, hepatic function, and monitoring for bleeding should be considered in all patients taking DOACs due to their potential effects on these processes.

Renal function, hepatic function, and monitoring for bleeding should be considered in all patients taking DOACs due to their potential effects on these processes.

(1) proteolytically converts fibrinogen to fibrin; (2) activates factor XIII, which cross-links fibrin polymers to form a stable clot; (3) activates platelets; and (4) induces endothelial release of PGI2, t-PA, and PAI-1.

lepirudin, desirudin, bivalirudin, argatroban, and dabigatran

Lepirudin binds with high affinity to two sites on the thrombin molecule—the enzymatic active site and the “exosite,” a region of the thrombin protein that orients substrate proteins. Lepirudin binding to thrombin prevents the thrombin-mediated activation of fibrinogen and factor XIII. Lepirudin is a highly effective anticoagulant because it can inhibit both free and fibrin-bound thrombin in developing clots and because lepirudin binding to thrombin is essentially irreversible
-direct thrombin inhibitor

for use in the treatment of heparin-induced thrombocytopenia.

renally excreted

bleeding is the major adverse effect of lepirudin, and clotting times must be monitored closely.

-bleeding
-patients may develop anti-hirudin antibodies, limiting the long-term effectiveness of this agent as an anticoagulant

Desirudin

binds to both the active site and exosite of thrombin and thereby inhibits thrombin activity
-Thrombin slowly cleaves an arginine–proline bond in bivalirudin, leading to reactivation of the thrombin (not permanent)

anticoagulation in patients undergoing coronary angiography and angioplasty and may reduce rates of bleeding relative to heparin for this indication.

renally and 25min half life

binds only to the active site of thrombin (i.e., it does not interact with the exosite)
-small molecule inhibitor for thrombin

heparin-induced thrombocytopenia

-biliarysecretion: can be used in patients with renal insufficiency
-continuous intravenous infusion

direct thrombin inhibitor
-prodrug that is metabolized to an active species that, like argatroban, binds competitively to the active site of thrombin

approved for prevention of thromboembolism in patients with non-valvular atrial fibrillation
-ndicated for the treatment of established deep vein thrombosis and pulmonary embolism

significant bleeding

actvated protein C (APC)

recombinant activated protein C

treatment of patients with severe sepsis who demonstrate evidence of acute organ dysfunction, shock, oliguria, acidosis, and hypoxemia.

increases the risk of bleeding.

patients who have recently undergone a surgical procedure and in those with chronic liver failure, kidney failure, or thrombocytopenia.

Thrombolytic Agents

hemorrhage of varying severity

forms a stable, noncovalent 1:1 complex with plasminogen. The complexation reaction produces a conformational change in plasminogen that exposes this protein’s proteolytically active site. Streptokinase-complexed plasminogen, with its active site exposed and available, can then proteolytically cleave other plasminogen molecules to plasmin.

-capable of eliciting an antogenic response in humans apon a repeated adminiatration
-can resukt in systemic fibrnolysis

having taken streptokinase before

treatment of ST elevation myocardial infarction and for treatment of life-threatening pulmonary embolism.

T-PA

treatment of patients with ST elevation myocardial infarction or life-threatening pulmonary embolism. It is also approved for the treatment of acute ischemic stroke.

Tenectplase

Reteplase

Protamine

analogues of lysine that bind to and inhibit plasminogen and plasmin.

promote hemostasis in situations where fibrinolysis contributes to bleeding.
-used to reduce perioperative bleeding during coronary artery bypass grafting
-may not increase the risk of postoperative acute renal failure

Andexanet alfa

Idarucizumab

activate Gs coupled receptors on vascylar smoot myuscle

endothelial cells

preproendothelin to big endothelin to ET1 (endithelin converting enzyme)

vasoactive agents

prostacyclin, NO, atrial natruretic peptide

binds ETa and ETb receptors (Gqs) which mediate vasoconstriction

B2 receptors (higher affinity)

G2 coupled H2 receptors; vasodialation

Gq coupled HI receptors, NO generation

arteries; little venous system effects

lusitropic agents

smooth muscle: inhibit Ca2+ influx through L type channels

decreased automaticity SA node and conduction Av node

decreased afterload and myocardial O2 demand

increased

vasodilation increase, afterload decrease, mypcardial O2 demand decrease

dihydropryridines, benzodiazepines, phenylalkylamines

extracellular side by using a binding site buried in the lipid bilayer.
-a1 ion pore forming subunit is where the allosteric site located

binds the ion pore (a1) from extracellular side of channel