Pharmaceutical Chemistry of cardiovascular system drugs II Flashcards
1
Q
Stroke
A
- Blood supply to part of brain is cut off
2
Q
Angina
A
- Chest pains caused by reduced blood flow to heart muscles
- Warning sign possible heart attack or stroke
3
Q
Heart failure
A
- Structural/functional abnormalities of heart resulting in reduced cardiac output
4
Q
Heart attack/MI
A
- Serious medical emergency where supply of blood to the heart is suddenly blocked by a blood clot
5
Q
Example of stroke prevention and Arrythmias
A
- Warfarin and DOACs
6
Q
Example of antiplatelet drugs
A
- Aspirin
- Clopidrogel
- Ticagrelor
- All drug used in STEMI
7
Q
Thrombolytic drugs
A
- Alteplase
- Reteplase
8
Q
First method:
Dissolving of existing clot
A
- Activation of plasminogen with thrombolytic agents which degrades insoluble fibrin
9
Q
Second method:
Prevention of thrombus formation/extension
A
- Inhibition of factor higher in cascade with heparin and other oral anticoagulants
10
Q
Warfarin
A
- Vit K is essential co-factor for post translation carboxylation of Glu on N-terminus of specific clotting factors (II, VII, IX, X) and anticoagulant protein C
11
Q
Conversion to activate clotting factor
A
- Addition of carboxylic acid acting as a chelating of Ca2+ by vit K dependent carboxylase
- Conversion of decarboxylase prothrombin to prothrombin
12
Q
Vitamin K regeneration
A
- Vitamin K 2,3 - quinone reductase and Vitamin K 2,3 - epoxide reductase are regenerated to form Vitamin K
13
Q
Warfarin and Vitamin K antagonist
A
- Block the activity of both enzymes blocking recovery of vitamin K and addition of extra carboxylic acid
14
Q
Coumarin derivatives
A
- Water insoluble lactones similar to vitamin k
- Position 3 and 4 have OH group substitution
- Acidity of H allows formation of water soluble salts
- Substituent in 3 effects PK
- Narrow therapeutic index potential drug food interaction
- Delayed effect for warfarin
15
Q
Chirality of warfarin
A
- Racemic mixture (s) warfarin is 4 fold more potent as an anticoagulant compared to (R)
16
Q
Metabolism of (S) Warfarin
A
- (S) metabolized by hepatic CYP29 add OH to position 6/7 (inactive)
- Transform ketone group to alcohol (active form)
17
Q
Metabolism of (R) Warfarin
A
- CYP3A4 ketone reduction metabolize ketone to alcohol
- CYP1A2 OH metabolize position 6
- CYP2C19 OH metabolize position 7
- Induction and inhibition influence activity
18
Q
Direct acting oral anticoagulants
A
- Directly against certain coagulation factors
19
Q
Direct thrombin (Factor IIa inhibitors )
A
- Desirudin, Bivalirudin, Dabigatran
- Binding directly or reversibly to the active site of thrombin
20
Q
Factor Xa inhibitor
A
- Apixaban
- Betrixaban
- Rivaroxaban
21
Q
Binding of direct thrombin
A
- Exosite 1 - binding dock of substrates such as fibrin
- Catalytic site
- Exosite 2 - Heparin binding domain
22
Q
Bivalent DTIs
A
- Binds to both catalytic site and ES1 called bridging
23
Q
Univalent DTIs
A
- Binds to the catalytic site
24
Q
Factor Xa inhibitors
A
- Both free and clot bound forming FXa and are highly selective
25
Q
Rivaroxaban complex crystal structure
A
- Gly219 forms hydrogen bonding with factor Xa inhibitor
- Hydrophobic interaction between hydrophobic amino acids S1 and S4
26
Q
Apixaban
A
- S4 pocket hydrophobic interaction
- Glycine hydrogen bond no S1 hydrophobic interaction
27
Q
Antiplatelet drugs
A
- Inhibit platelet activation and subsequent thrombus formation
28
Q
COX-1 Inhibitor
A
- Thromboxane A2 potent vasoconstrictor induce platelet aggregation - degranulate
- COX-1 converts arachidonic acid to prostaglandin H2 which is converted to TAX2
29
Q
Aspirin
A
- Inhibits the bio synthesis by blocking TXA2 in platelets by irreversibly permanently inactivating cyclooxygenase
30
Q
Nucleophilic acyl substitution aspirin
A
- Acylation of serine 350
- OH attack the aspirin ester
- COX serine is the nucleophile and aspirin is electrophile
31
Q
effect of acetylation of serine
A
- Blocking by acetyl group so normal substrate can no longer bind
- Cause anti thrombotic effect for the life span of the platelet
32
Q
Mechanism of binding
A
- H-bonds stabilizes the resultant tetrahedral intermediate
- H-bond and ionic bond
- Salicylic acid is a weak COX-1 inhibitor
33
Q
Absorption of aspirin
A
- Carboxylic acid on aspirin with a Pka of 3.5 in stomach
- Hydrolyzed via esterase in the GI mucosa, liver and plasma
- COX-1 inhibition platelets in portal system before deacetylation
34
Q
P2Y Purinergic receptor antagonist
A
- P2X1 which is activated by ATP
- P2Y1 and P2Y12 receptors which are activated by ADP
35
Q
Binding of P2Y1 with ADP
A
- Changes in platelet shape initiates platelet agregation
36
Q
ADP binding P2Y12
A
- Inhibition of adenyl cyclase causes decrease in cellular cAMP levels
- Sustained platelet aggregation
37
Q
Irreversible aggregation of P2Y12
A
- Binding to ADP active site e.g. Cloprodigrel
38
Q
Reversable antagonist of P2Y12
A
- Binding to allosteric site such as ticgrelor
39
Q
Thienopyridine
A
- Selective irreversible inhibition of ADP induced platelet aggregation block ADP binding
40
Q
Ticlopidine
A
- Not effective in inhibiting platelet aggregation in vitro to the in vivo of patients platelets
41
Q
Oxidization of Ticlopidine and clopidogrel
A
- Oxidized by CYP34A receptors and CYP2B6 enzymes
- Formation of Tiolactones then ketone is hydrolyzed into thiol metabolite which is reactive
- Formation of covalent disulfide bond with critical cystine residue in ADP site of P2Y12 prevent binding
42
Q
Prasugrel prodrug
A
- Activated to form irreversible inhibitor
43
Q
Binding of ticagrelor
A
- Binds to remote allosteric site resulting in blocking conformational changes to receptor at ATP binds to site
44
Q
Triazolopyridine ring
A
- Bio-isostere of purine ring
- Increase in binding affinity by 100x
45
Q
Cyclopentene
A
- Replaces the ribose that would increase half life
46
Q
Large group attached to Triazolopyridine ring
A
- Improve PK and affinity to P2Y12 and metabolic stability
47
Q
OH chain purpose
A
- Removed from plasma by CYP3A4/3A5 in vivo
48
Q
Fibrin blood clots
A
- Dissolved by actions of the fibrinolytic system
- Removal of unwanted clots without damaging the integrity of vascular system
49
Q
Plasmin
A
- Non-specific protease enzyme that digests fibrin
50
Q
Plasminogen activator
A
- Trypsin like serine protease cause cleavage of peptide bond
51
Q
TPA inhibitor
A
- Stop the digestion of degraded fibrin
52
Q
Alteplase
A
- 527 amino acids
- 1 in N-terminus
- 527 in C-terminus
53
Q
Reteplase
A
- Removal of amino acids 1 to 172 compared to Alteplase
54
Q
Nitrates
A
- Very volatile and moisture sensitive with explosive properties
- Lipophilic good for emergency treatment rapid absorb
55
Q
Nitric oxide
A
- Produced by vascular endothelial cell relax smooth muscles
- Stimulates formation of cGMP
56
Q
Interaction of nitrate containing drugs
A
- Free sulfhydryl groups SH causes formation of NO via nitrosothiol intermediate
- Activation of cGMP soluable
57
Q
Nicoradil
A
- Nicotinamide-nitrate ester
- Treatment of angina pectoris and CHF
- Dual mechanism smooth muscle relax property increase K+ conductance
- Vasodilation of coronary arteries
58
Q
Nicoradil formation
A
- Reflex reaction converting ester to amide via nucleophilic acyl sub
- Addition of nucleophile gives tetrahedral intermediate eliminate leaving group form amide
- Addition of nitrate group
