DRUGS AFFECTING THE CARDIOVASCULAR
SYSTEM
III. ANTIHYPERLIPIDEMIC DRUGS & ANTICOAGULANTS,
ANTIPLATELETS & THROMBOLYTIC DRUGS
Dr. Salma Abdelaziz Darwish
Lecturer of Pharmaceutical Chemistry
Faculty of Pharmacy
Alexandria University
• The major lipids found in the blood stream are cholesterol, cholesterol esters and
triglycerides (TGs).
• Excess plasma concentration of one or more of these compounds is known as
hyperlipidemia, which is the most prevalent indicator for susceptibility to atherosclerotic
lesions and coronary heart disease.
• Because lipid molecules (cholesterol and TGs) are water
insoluble, they must be packaged with hydrophilic
proteins and carbohydrates in special molecular complexes
known as lipoproteins to be transported in plasma.
➢ Hyperlipidemia results in an increased concentration of
the transport molecules (lipoproteins), a condition known
as hyperlipoproteinemia.
Lipoprotein Particle
2
• Cholesterol is the starting point for corticosteroids, sex steroids, and bile acids.
• Bile acids promote the intestinal absorption of lipids and fat-soluble vitamins.
• Plasma lipoproteins can be divided into seven classes based on size, lipid composition,
and apolipoproteins including chylomicrons, VLDL, LDL, and HDL.
Types of Hyperlipidemias
• Primary (familial) hyperlipidemia
• resulted from inherited genetic defects.
• Secondary hyperlipidemia
• unhealthy diet and a poor lifestyle regimen
• due to the use of drugs (β-blockers, certain oral contraceptives, glucocorticoids or
thiazide diuretics).
• As a result of diabetes mellitus, hypothyroidism, or hepatitis.
Management of Hyperlipidemia
•
Dietary and lifestyle modifications.
•
Pharmacologic interventions.
Treatment Strategy
• Decrease Fat & Cholesterol Intake.
• Enhance Cholesterol Excretion.
• Inhibit Cholesterol Biosynthesis.
• Increase HDL (good cholesterol).
• Decrease LDL (bad cholesterol) or
increase their uptake by the liver.
6
HMG-CoA Reductase Inhibitors (HMGRIs) or Statins
•
• Statins are competitive inhibitors of HMGR,
the rate-limiting enzyme in cholesterol
biosynthesis.
• Statins successfully compete with the
endogenous 3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA) substrate for access to the
HMGR active site.
Antihypercholesterolemic only Drugs:
1. Bile acid sequestrants
2. HMG-CoA reductase inhibitors (statins)
Antihypercholesterolemic & triglyceridemic Drugs:
SCoA
HMG-CoA
2 NADP+
2 NADPH
O
HMG-CoA
reductase CoA
COOH
H3C
OH
Mevalonic acid
• The substrate is also anchored by three hydrogen
bonds: Ser-684 and Asp-690 coordinate to the 3OH group, while the thioester oxygen atom
interacts with Lys-691.
1. Fibric acid derivatives
2. Niacin
7
•
The dihydroxyheptan(en)oic acid segment of the statins (polar head group) mimics the chemistry of HMG
and binds in a similar fashion to HMGR.
•
An ion–ion bond between anionic statins and cationic Lys735 is the anchoring interaction.
•
HO
COOH
O
• It is known that in the substrate binding process,
the carboxylate anion of HMG-CoA forms an ionic
bond to Lys-735 of the enzyme.
3. Ezetimibe
•
HO
H3C
Cholesterol
HMG CoA
reductase
inhibitors
→ The dihydroxyheptan(en)oic acid segment is essential.
Hydroxyls at chiral C3 and C5 have important interactions at HMGR and must have the proper absolute
configuration:
o C3 requires the R configuration.
o Optimal configuration at C5 depends on C6–C7 saturation status. Dihydroxyheptanoic acid statins have 5R
stereochemistry and dihydroxyheptenoic acids have the 5S configuration.
•
The remainder of the statin structure (ring component) binds to hydrophobic and polar residues in a flexible
receptor pocket. There is 2 carbon distance between C5 and ring system
•
Affinity is enhanced 1000- to 10,000-fold compared to HMG-CoA ensuring effective enzyme inhibition.
•
LDL reuptake receptor expression is augmented, leading to increased LDL clearance.
•
The two most potent statins (rosuvastatin, atorvastatin) also lower serum triglycerides
• The coenzyme A moiety is involved in various
interactions with residues in a narrow hydrophobic
slot close to the active site.
8
• Compactin was isolated from Penicillium citrinum in the 1970s. It was identified as a potent HMGR inhibitor (10000-fold
higher affinity for the enzyme than the natural substrate).
• In 1978 Merck isolated mevinolin, an analogue of compactin (differing by one methyl group), produced by Aspergillus
terreus. Clinical trials of mevinolin began in 1980 and it was eventually marketed as lovastatin, a landmark in the
treatment of hypercholesterolemia.
• Simvastatin, approved in 1988, was prepared by semi-synthesis from lovastatin.
• Pravastatin was obtained from compactin by biotransformation and first marketed in 1991.
• These are type I statins, all ultimately derived from fungal metabolites
and having the general structure shown below.
• Naturally occurring statins have a
2’,6’-dimethylhexahydronaphthylene
ring system substituted with a
methylbutyrate ester at C8’.
• Addition of an α-CH3 = R to the
methylbutyrate group (lovastatin vs.
simvastatin) increases activity
two-fold.
The type I statins proved to be very effective at lowering cholesterol levels, but the
associated side-effects and difficult syntheses prompted further optimisation
work. This yielded the so-called type II statins, in which the decalin ring is replaced
by a larger hydrophobic moiety.
• It should be noted that, while lovastatin and simvastatin lack the polar 'head'
group shown in the generalised structure, these compounds are both prodrugs.
Their respective lactone rings are hydrolysed in vivo to produce the
corresponding hydroxy acid form.
Type I statins:
1. The decalin ring is essential for anchoring the compound to the enzyme
active site. Replacement with a cyclohexane ring resulted in a 10,000-fold
decrease in activity.
2. Stereochemistry of the ester side chain is not important for activity; however,
conversion of this ester to an ether results in a decrease in activity.
3. Methyl substitution at the R2 position increases activity (i.e., simvastatin is more potent than lovastatin).
4. 𝛃-Hydroxyl group substitution at the R1 position enhances hydrophilicity and may provide some cellular
specificity.
5. X-ray analysis studies show that the hydrophobic region of the statin cannot occupy the same part of the
HMGR enzyme as the coenzyme A unit of the natural substrate. The CoA binding pocket is too narrow for
this to be the case. Nor is there any other hydrophobic region that could accommodate the side-chain.
For these reasons it is concluded that the enzyme possesses significant flexibility.
When HMG-CoA substrate binds, an α-helical section of the protein folds over the active site, shielding it
from water and creating a narrow hydrophobic cleft that accepts the CoA section of the molecule.
When a statin binds, the enzyme alters its shape (induced fit) differently, with the formation of a shallow
hydrophobic binding region next to the active site as a result of the movement of two C-terminal α-helices
whose flexibility is a key factor.
▪ Type II statins are much easier to synthesise as they lack all but two of the stereogenic centres present in the type I series.
▪ PK studies have revealed a spectrum of effectiveness that depends, at least in part, on the hydrophobic nature of the
molecule.
▪ Lower hydrophobicity makes a statin more selective for liver cells, where most of the cholesterol biosynthesis takes place.
▪ Rosuvastatin is the most potent of the structures shown below. The sulfonamide group was added for the specific purpose
of making a drug that was less hydrophobic.
• Synthetic statins have heteroaromatic ring systems. Isopropyl (or cyclopropyl) and p-fluorophenyl
substituents contribute to receptor affinity.
• Statins with polar functional groups positioned to bind to Arg568 and Ser565 (rosuvastatin) show
significant increases in affinity and potency.
• Studies have shown that statins with a lower hydrophobic character (such as rosuvastatin) are
more selective for liver cells, where most cholesterol synthesis takes place, and that
such statins have fewer side effects.
✓ A polar sulphonamide group was added to rosuvastatin to make it more hydrophilic and
more tissue selective.
p-Fluorophenyl
> butyryl
Lipophilic is a
must
Heterocyclic
ring:
• indole pyridine,
pyrimidine, pyrrole,
quinoline
• Small ring with
polar heteroatom is
favoured
Alkyl
substitution:
small,lipophilic,
branched is
favoured
p-fluorophenyl cannot
be coplanar with
central aromatic ring
Five membered or
six membered
heterocyclic
Double bond has
optimal activity in
synthetic statins
Rosuvastatin is unique among the
statins in having an extra binding
interaction between the sulphone
group of the drug and Arg-568,
making it the most strongly bound
statin.
• Rosuvastatin bioavailability decreases in the presence of antacids
due to chelation of divalent and trivalent metal ions.
▪ In the binding of type II statins, the
isopropyl group present in most
examples binds to the same part of
the narrow hydrophobic region as the
decalin ring of the type I systems, but
there are extra interactions (van der
Waals type) with hydrophobic sidechains in this locality.
• Pleiotropic Statins
• Statins are pleiotropic drugs that have multiple beneficial
effects.
• Statins decrease levels of C-reactive protein (CRP), a
major biomarker of inflammation, and they have shown
promise in the treatment of inflammation-based
diseases, including CAD and vascular dysfunction
secondary to diabetic insulin resistance.
• Lipophilic statins may have a positive impact on bone
density
• Statin–NSAID
cotherapy
has
demonstrated
a
chemoprotective effect for some cancers.
▪ The
fluorophenyl
moiety
can
coordinate to Arg-590 of the enzyme
through dipolar and π-stacking
interactions.
▪ With atorvastatin, the carbonyl group
of the amide group provides an
additional H-bonding locus, while
rosuvastatin can do the same via its
sulfone group.
Fibrates
• Statins have demonstrated high degree of effectiveness and have good safety
record.
• Fibrates are fibric acid derivative agents and are used to lower plasma lipids and particularly triglyceride
levels.
• Fibrates activate peroxisome proliferator-activated receptor alpha (PPARα), is a transcription factor that
controls the expression of numerous genes involved in a many lipid metabolic pathways.
• Adverse Effects
• It is generally agreed that active PPARα is predominantly localized in the nucleus.
• They may elevate serum levels of hepatic enzymes and cause hepatitis.
• The PPARα subtype exerts its main functions in the liver, where the receptor is involved in various aspects of
lipid metabolism.
• They may cause muscle weakness (myopathy).
• PPARα agonists :
• reduce very-low-density lipoprotein (VLDL) production
• enhance the catabolism of triglyceride (TG)-rich particles, which indirectly decreases small dense lowdensity lipoprotein (LDL) particles
• enhance the formation of HDL particles and hepatic elimination of excess cholesterol.
• More specifically PPARα activators decrease plasma TG-rich particle levels by increasing the activity of
LPL which is the key enzyme in the hydrolysis of TGs.
• Side effects are thought to be caused by the inhibition of HMGR in other
tissues, particularly muscle cells, where a condition known as myalgia can
occur.
• A severe form of muscle toxicity is a condition known as rhabdomyolysis,
which can be fatal.
17
➢ Fibrates decrease serum triglyceride and VLDL levels.
➢ Fibrates also increase the level of HDL cholesterol
➢ Fibrates facilitate cholesterol removal from liver.
SAR
Hydrolysis
• Fibrates are phenoxyisobutyric acid or fibric acid derivatives .
• The fibrate anion predominates at pH 7.4.
Fenofibrate
prodrug
• Fibrate esters must hydrolyze to release the active anion.
• PPARα is flexible. A spacer of up to three carbons between isobutyrate and aryloxy groups is
permitted.
• Spacer groups augment molecular lipophilicity and promote gastrointestinal and hepatic membrane
penetration.
Gemfibrozil
Fenofibrate is more effective than gemfibrozil in lowering triglyceride levels.
Similar to HMGRIs, fibrates can cause myopathy, myositis, and rhabdomyolysis.
Although rare, the risk of these serious effects increases when these two classes
of agents are used together.
O
[Aromatic ring]-O-[Spacer group]
H3C
OH
CH3
Anticoagulants, Antiplatelets and Thrombolytics
•
2. Formation of a Platelet Plug (Primary hemostasis).
• Hemostasis is the mechanism that leads to cessation of bleeding from a blood vessel after injury.
•
When a blood vessel is damaged, the blood is exposed to collagen fibers in the basement
membrane of the vessel.
•
Platelets (thrombocytes) stick to collagen and become activated.
•
Activated platelets release chemicals such as adenosine diphosphate (ADP), and thromboxane
A2 (TXA2), that cause the aggregation of more platelets to the site of injury.
•
Platelet aggregation results in the formation of a platelet plug, which acts to stop the flow of
blood from the broken vessel.
• The mechanism of hemostasis can be divided into four stages.
1) Constriction of the blood vessel.
2) Formation of a temporary “platelet plug."
3) Activation of the coagulation cascade.
4) Formation of “fibrin plug” or the final clot.
• This clot seals the injured area, controls and prevents further bleeding while the tissue
regeneration process takes place. Once the injury starts to heal, the plug slowly remodels, and it
dissolves with the restoration of normal tissue at the site of the damage
(Note: The actions of thromboxane are balanced at the vessel level by the presence
of prostacyclin (PGI2), which is produced by COX enzymes in the vascular endothelial cells. PGI2 is
a strong inhibitor of platelet aggregation and also results in vasodilation.).
1. Vasoconstriction
• Vasoconstriction of a damaged blood vessel slows the flow of blood and thus helps to limit blood loss.
This process is mediated by:
• Local controls. Vasoconstrictors such as thromboxane A2 are released at the site of the injury.
• Systemic control.
Epinephrine released by the adrenal glands stimulates general
vasoconstriction.
Scan for supplementary explanatory video
3. Coagulation cascade (Secondary hemostasis )
✓ Thrombin is the key to the clotting
• Blood clotting is the transformation of liquid blood into a semisolid gel. Blood contains
about a dozen clotting factors.
Extrinsic pathway
Intrinsic pathway
mechanism, i.e. if thrombin is present
then clotting will proceed.
• These factors are proteins that exist in the blood in an inactive state, but can be activated
when tissues or blood vessels are damaged.
✓ Thrombin is derived from an inactive
precursor called prothrombin.
• The activation of clotting factors occurs in a sequential manner. The first factor in the
sequence activates the second factor, which activates the third factor and so on.
✓ There are two pathways that lead to the
conversion of prothrombin to thrombin;
the
• This series of reactions is called the coagulation cascade.
• Secondary hemostasis includes the two main coagulation pathways, intrinsic and
extrinsic, that meet up at a point to form the common pathway. The common pathway
ultimately activates fibrinogen into fibrin. These fibrin subunits have an affinity for each
other and combine into fibrin strands that bind the platelets together, stabilizing the
platelet plug.
intrinsic
pathway
and
the
extrinsic pathway.
The intrinsic pathway is activated through
exposed endothelial collagen, and the
extrinsic pathway is activated through
tissue factor released by endothelial cells
Scan for supplementary explanatory video
after external damage.
▪ Thrombosis occurs when blood clots block your blood vessels. There are 2 main types of thrombosis:
• Venous thrombosis is when the blood clot blocks a vein. Veins carry blood from the body back into the heart.
1.
• Arterial thrombosis is when the blood clot blocks an artery. Arteries carry oxygen-rich blood away from the
heart to the body.
▪ Venous thrombosis may be caused by:
- Disease or injury to the leg veins.
Anticoagulants; inhibit the action of the coagulation factors (heparin) or
interfere with the synthesis of the coagulation factors (for example, vitamin K
antagonists such as warfarin).
a) Coumarin derivatives: Warfarin
- immobility for any reason.
- A broken bone (fracture).
- Certain medicines (such as certain birth control medicines).
- Obesity.
- Autoimmune disorders that make it more likely your blood will clot.
- Inherited disorders
▪ Arterial thrombosis may be caused by a hardening of the arteries (atherosclerosis). This happens when fatty or
calcium deposits cause artery walls to thicken. This can lead to a buildup of fatty material (plaque) in the artery
walls. This plaque can suddenly burst (rupture), followed by a blood clot.
b) Heparin-based: Fondaparinux
c) Direct Thrombin Inhibitors (DTIs): Dabigatran etexilate
d) Direct Factor Xa Inhibitors: Rivaroxaban
2.
Antiplatelets;
▪ Arterial thrombosis can occur in the arteries that supply blood to the heart muscle (coronary arteries). This can
lead to a heart attack. When arterial thrombosis occurs in a blood vessel in the brain, it can lead to a stroke.
a) COX-1 inhibitor: Aspirin
▪ Antithrombotic agents are subdivided into antiplatelet agents and anticoagulants.
b) PDE3 inhibitors: Cilostazol and Dipyridamole
• Antiplatelet agents inhibit clot formation by preventing platelet activation and aggregation, while
c) P2Y purinergic receptor inhibitors: Clopidogrel and Ticagrelor
• Anticoagulants primarily inhibit the coagulation cascade and fibrin formation.
Therapeutics within each category differs with respect to the mechanism of action, time to onset, duration of
effect and route of administration.
▪ Thrombolytics, clot busters or fibrinolytics are emergency medications that break up blood clots. They are
used in cases of heart attack and stroke to decrease the damage caused by the clot.
d) GP IIb/IIIa antagonists: Tirofiban
3.
Thrombolytics: Urokinase, Streptokinase, Alteplase
• Warfarin, a coumarin, is slightly
acidic forming a water-soluble
sodium salt at C4 enol.
• The product is used as a racemic
mixture although the S-isomer is the
more active form (4X R).
• Vitamin K is essential to the blood clotting
cascade by serving as a cofactor for the γcarboxylation
of
vitamin
K-dependent
coagulation factors (including factors II, VII, IX
and X) generated in the liver. (glutamic acid
(Glu) → γ-carboxyglutamic acid (Gla).
• γ-carboxyglutamic acid is needed for the
function of factors II, VII, IX, and X
• Warfarin blocks the interconversion of
vitamin K and vitamin K 2,3-epoxide
(inhibit vitamin K reductase),
• specifically preventing the reduction of
vitamin K 2,3-epoxide to vitamin K quinone,
the rate limiting step in the recycling of
vitamin K.
O
O
• The onset of action of warfarin is delayed (3 to 5 days) until clotting factors
already present are cleared (slow acting).
• They are taken orally in small doses for long-term control of blood clotting.
O
OH
Warfarin
Diagram only for
illustration!!
• Heparin is a natural-occurring polysulfated polysaccharide found in the mucosal
tissues, produced primarily in the liver and lung (usually obtained from pigs or
cows).
• Various forms of heparin-based products exist including:
✓unfractionated heparin (UFH),
✓low molecular weight heparin (LMWH),
✓synthetic pentasaccharide fondaparinux®(chemically related to LMWH)
• Heparin-based drugs exist as polysulfate ions at physiological pH and may
appear as various salts (e.g., Na+, Ca2+, Li+).
• Heparin-based anticoagulants for human use are all water-soluble sodium salts
administered parenterally (IV, SC).
• Heparin-based products cause a conformational change in antithrombin III (AT
or ATIII) peptide through ion–ion bond
• The conformationally modified AT exhibits an accelerated binding to thrombin
and factor Xa.
• Heparin is then released from the AT~thrombin/AT~factor Xa complex leaving an
inactive form of thrombin and/or factor Xa (heparin is a catalyst).
• Fondaparinux is a synthetic analog of the
pentasaccharide sequence found within heparin
chains and is a specific inhibitor of activated FactorXa.
• Due to its small size , fondaparinux exerts inhibitory
activity specifically against factor-Xa and has no
effect on thrombin.
Fondaparinux ®
• Fondaparinux is eliminated renally as unchanged drug with a half-life of 17–21 h in healthy
subjects with normal renal function. Thus, the anticoagulant effect of fondaparinux will
persist for 2–4 days after stopping the drug and even longer in patients with renal
impairment (dose adjustment).
• As with other anticoagulants, the major side effect associated with fondaparinux is
bleeding. There currently is no specific antidote for fondaparinux. In the event of major
bleeding, fresh-frozen plasma may be considered.
• Fondaparinux has not been reported to cause thrombocytopenia, a condition seen
with heparin as it does not affect platelet function unlike the heparins.
• Fondaparinux is the first selective factor Xa inhibitor that is approved for the
prophylaxis of DVT (deep vein thrombosis) , which may occur in patients
undergoing hip fracture surgery or hip or knee replacement surgery
• Fondaparinux is administered via subcutaneous injection with a single daily dose
and shows complete absorption. (Administered subcutaneously, fondaparinux
has 100 % bioavailability and is distributed into blood volume.)
• Peak fondaparinux levels occur 2–3 h following subcutaneous administration)
• Dabigatran
etexilate
is
a
peptidomimetic orally active DTI.
non-
• Dabigatran is a potent, competitive DTI
that reversibly and specifically binds both
clot-bound and free thrombin, inhibiting
thrombin-induced platelet aggregation.
• It is a highly polarized, hydrophilic
molecule that is not absorbed after oral
administration. The commercial product
is formulated as a lipophilic prodrug,
dabigatran
etexilate,
to
promote
gastrointestinal absorption prior to
metabolism to the active drug, dabigatran
Prodrug
Esterase
• The Factor-Xa inhibitors, including rivaroxaban share a similar mechanism of
action. They are competitive, selective and potent direct Factor-Xa inhibitors that
bind in a reversible manner to the active site of both free-floating Factor-Xa and
Factor-Xa within the prothrombinase complex, thereby attenuating thrombin
generation.
• The prothrombinase complex consists of FXa, factor Va, prothrombin, and Ca2+,
on a phospholipid surface.
• These agents are not prodrugs and do not require activation.
• The FXa inhibitors are highly specific inhibiting at a single site, the convergent step
of the intrinsic and extrinsic pathways.
• It does not interfere with existing thrombin levels, thus
improving safety.
• The direct FXa inhibitors are orally active drugs.
Morpholinone greatly improves activity versus morpholine, piperazine, or pyrrolidinone
Platelet activation as it relates to blood clot formation:
• The thrombus is formed at the site of a damaged wall in the vasculature.
• Normal endothelial cells in vascular wall provide prostacyclin, which stimulates the
conversion of adenosine triphosphate (ATP) to cAMP, preventing platelet aggregation.
• In injury, GP receptors (Glycoprotein receptors) bind substances such as von
Willebrand factor and collagen, activating the platelets.
• The GP IIb/IIIa receptors cross-link platelets via fibrinogen binding.
• As the platelet degranulates, additional aggregating substances (secondary chemical
messengers) including TXA2, thrombin, serotonin (5-HT), and ADP are released,
The four classes of anticoagulants often have overlapping treatment
indications, which include:
• prevention/treatment of Venous thromboembolism (VTE)
• deep vein thrombosis (DVT)
• Pulmonary embolism (PE)
which recruits additional platelets, thus amplifying the aggregation process.
• ADP by binding to P2Y1 and P2Y12 promote and sustain platelet aggregation,
respectively.
• Aspirin is an irreversible inhibitor of platelet COX-1 enzyme, thus inhibiting TXA2
synthesis.
• Acetylation occurs on a serine residue deactivating the enzyme for the life of this
platelet (7 to 10 days)
• In higher doses, COX-2 in the vessel wall is inhibited, decreasing production
of PGI2. This counteracts the cardiovascular benefits of platelet COX-1 inhibition.
Dose for aspirin’s antiplatelet
effect is from 50 to 100 mg/day
(below analgesic effects).
Acetylsalicylic acid (Aspirin)
P2Y12 Purinergic Receptor Inhibitors
• Platelets possess three PDE isoforms (PDE2, PDE3 and PDE5),with different
selectivity for cAMP and cGMP.
• The P2Y12 receptor is a platelet surface receptor that, when activated by ADP, results
• cAMP and cGMP are two critical inhibitory intracellular second messengers
regulating fundamental platelet processes
in activation and aggregation of platelets.
• The isoforms PDE1, 2 and 3 hydrolyse both cAMP and cGMP. However, PDE3
has higher affinity to the cyclic nucleotide compared to PDE1 and PDE2 but a
much lower efficacy of hydrolysis for cGMP, behaving essentially as a pure cAMP
PDE.
Cilostazol
• Clopidogrel, a thienopyridine derivative, binds specifically and irreversibly to the
platelet P2RY12 purinergic receptor, inhibiting ADP-mediated platelet activation and
aggregation.
• Both drugs inhibit PDE3, thus increasing the level of cAMP in platelets.
• After oral administration, clopidogrel is rapidly absorbed. Owing
• Both drugs inhibit extracellular adenosine uptake by adjacent cells, thus
increasing adenosine binding to platelet adenosine A2 receptors stimulating
cAMP synthesis.
to its extensive metabolism, clopidogrel is not detected in human
• Dipyridamole is used in combination with aspirin to treat thrombosis.
plasma. Clopidogrel is a prodrug that is absorbed in the intestine
• Also used in combination with warfarin in treating patients with prosthetic heart
valves.
Dipyridamole
• Cilostazol is approved for treating intermittent claudication (a peripheral artery
disease resulting from blockage of blood vessels in the limbs)
pyrimidopyrimidine derivative
• It is a prodrug which following metabolic activation (CYP oxidation) yields irreversible
inhibitor of P2Y12.
and is activated in the liver.
FDA has a boxed warning of a potential for reduced
effectiveness among poor metabolizers using clopidogrel.
Clopidogrel
However, the thienopyridine clopidogrel, the most widely used P2Y12 inhibitor, has a
number of important limitations:
• The thio metabolite bind irreversibly with a cysteine, which is near the ADP binding site
in P2Y12, thus blocking ADP binding (irreversible inhibition).
Thio metabolite
Active
1- The irreversible inhibition of platelets (a thienopyridine characteristic) that persists
throughout the lifetime of the platelet may complicate management in patients who
might require surgery and would therefore be at increased risk of bleeding.
2- Clopidogrel requires hepatic conversion to an active metabolite (a thienopyridine
P2Y12
characteristic), resulting in delayed onset of effect and posing the potential for
variable interindividual platelet effects associated with variable metabolism.
3- Mean levels of inhibition of adenosine diphosphate (ADP)-induced platelet
aggregation observed with clopidogrel are modest and responses to this agent
are variable, including hyporesponsiveness that has been associated with
2-Oxo clopidogrel
increased risk of adverse clinical outcomes
Ticagrelor, is the first reversibly binding oral P2Y12 receptor
antagonist and has the potential to address many of the
limitations of thienopyridine therapy.
(A and B) ADP binds to the
P2Y12
receptor,
resulting
in
conformational change and G-protein
activation.
(1) It is not a prodrug and therefore does not require metabolic
activation, has a rapid and reversible concentrationdependent inhibitory effect on the P2Y12 receptor,
Ticagrelor
(2) It provides greater and more consistent inhibition of ADPinduced platelet aggregation
(3) It offers the potential for greater flexibility in the management
of patients at risk for thrombotic events due to rapid onset
and offset of antiplatelet effect; and
Clinical Application of P2Y Purinergic
Receptor Inhibitors
(4)
• Reduction of MI and stroke in patients
with a history of recent MI or stoke.
•
It may also exert antithrombotic activity beyond platelet
inhibition by inhibiting P2Y12-mediated vasoconstriction in
vascular smooth muscles.
Ticagrelor binds to the P2Y12 receptor at a site distinct from
the ADP-binding site, and does not prevent binding of ADP. It
appears to inhibit ADP-induced receptor signalling in a
noncompetitive manner.
• Acute coronary syndromes (commonly
used in combination with aspirin).
➢ Major adverse effect of clopidogrel, and
ticagrelor is bleeding which could lead to
fatal/life-threatening outcomes.
(C) Binding of the clopidogrel active
metabolite to the P2Y12 receptor is
irreversible, rendering the receptor
nonfunctional for the life of the platelet.
(D) Ticagrelor binds reversibly to
P2Y12 at a site distinct from the ADPbinding site and inhibits ADP signaling
and receptor conformational change by
“locking” the receptor in an inactive
state; the receptor is functional after
dissociation of the ticagrelor molecule.
ADP can still bind at its binding site, and
the degree of receptor inhibition (and
inhibition of ADP-induced signaling) is
dependent on the concentration of
ticagrelor.
Glycoprotein IIb/IIIa Receptor Antagonists
cangrelor
Ticagrelor
Key elements in the medicinal, chemical journey from ATP through the ATP analog cangrelor to the
CPTP (cyclopentyl-triazolo-pyrimidine) ticagrelor:
• Introducing affinity-enhancing 5,7-hydrophobic substituents
• Replacing the labile triphosphates group
• Changing the core purine to a triazolopyrimidine, increasing affinity 100-fold
• Introducing the trans-2-phenylcyclopropylamino substituent, increasing affinity more than 10-fold
• The platelet surface is covered with inactive GP IIb/IIIa receptors.
• GP IIb/IIIa receptors exist in an inactive conformation, but conformational
change can be initiated by various platelet agonists including thrombin,
collagen, and TXA2.
• Activation of the receptor results in cross-linking of platelets through
bonding to fibrinogen thus mediating aggregation.
• Chemically diverse antagonists are capable of bonding to GP IIb/IIIa
receptors to block the platelet aggregation.
• Tirofiban is a non-peptide that binds to GP IIb/IIIa at the site that interacts
with the arginine–glycine–aspartic acid (RGD) sequence of fibrinogen.
• It is parenterally administered and exhibits a reduced risk of bleeding
because of its short biological half-life.
Thrombolytic Drugs
• Acute MI or stroke requires the digestion of insoluble fibrin clots.
• The common standard of treatment calls for the use of thrombolytic drugs for
these and other conditions associated with clot formation.
• Blood clots are designed to be temporary.
• After the vessel is healed and the blood
clot is no longer needed. The clot is
removed in the following way:
• The clot itself stimulates the secretion of
tissue plasminogen activator (tPA),
which catalyzes the activation of
plasminogen to plasmin which is an
enzyme that dissolves clots (cleaves
fibrin).
Thrombolytic drugs act through their catalytic role as tissue plasminogen
activators (tPAs) in generating plasmin.
• Alteplase (tPA)
• It is produced commercially using recombinant DNA technology. It is used clinically to dissolve clots
in coronary arteries following a heart attack. It is also used to dissolve clots in the brain following
stroke.
• Alteplase is very specific for plasminogen bound to fibrin with a preference for older clots (clot
selective).
• Streptokinase
• It is a protein purified from culture broths of Group C β–hemolytic
streptococci bacteria. Alone, it has no enzymatic activity. To be active, it
must form 1:1 complex with plasminogen, which then converts
uncomplexed plasminogen to the active enzyme, plasmin.
• Streptokinase is not a human enzyme and might initiate immune
response (hypersensitivity reactions).
• Urokinase
• It is isolated from cultures of human fetal kidney cells. Urokinase
is usually employed in patients who are sensitive to streptokinase
(Note: Urokinase is not a foreign protein and is therefore
nonantigenic).
• Streptokinase and urokinase act on free (circulating) plasminogen
inducing a generalized thrombolytic state.
Streptokinase
Plasminogen
Streptokinase-plasminogen
complex
Plasminogen
+
Plasmin
+
Mechanism of action of
streptokinase.
Fibrin
Degradation
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