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PMP 201 Patient-Centred Learning > Pharmaceutical Chemistry of cardiovascular system drugs II > Flashcards

Pharmaceutical Chemistry of cardiovascular system drugs II Flashcards

(58 cards)

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1
Q

Stroke

A
  • Blood supply to part of brain is cut off
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2
Q

Angina

A
  • Chest pains caused by reduced blood flow to heart muscles
  • Warning sign possible heart attack or stroke
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3
Q

Heart failure

A
  • Structural/functional abnormalities of heart resulting in reduced cardiac output
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4
Q

Heart attack/MI

A
  • Serious medical emergency where supply of blood to the heart is suddenly blocked by a blood clot
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5
Q

Example of stroke prevention and Arrythmias

A
  • Warfarin and DOACs
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6
Q

Example of antiplatelet drugs

A
  • Aspirin
  • Clopidrogel
  • Ticagrelor
  • All drug used in STEMI
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7
Q

Thrombolytic drugs

A
  • Alteplase
  • Reteplase
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8
Q

First method:
Dissolving of existing clot

A
  • Activation of plasminogen with thrombolytic agents which degrades insoluble fibrin
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9
Q

Second method:
Prevention of thrombus formation/extension

A
  • Inhibition of factor higher in cascade with heparin and other oral anticoagulants
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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
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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
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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
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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
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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
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15
Q

Chirality of warfarin

A
  • Racemic mixture (s) warfarin is 4 fold more potent as an anticoagulant compared to (R)
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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)
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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
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18
Q

Direct acting oral anticoagulants

A
  • Directly against certain coagulation factors
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19
Q

Direct thrombin (Factor IIa inhibitors )

A
  • Desirudin, Bivalirudin, Dabigatran
  • Binding directly or reversibly to the active site of thrombin
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20
Q

Factor Xa inhibitor

A
  • Apixaban
  • Betrixaban
  • Rivaroxaban
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21
Q

Binding of direct thrombin

A
  • Exosite 1 - binding dock of substrates such as fibrin
  • Catalytic site
  • Exosite 2 - Heparin binding domain
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22
Q

Bivalent DTIs

A
  • Binds to both catalytic site and ES1 called bridging
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23
Q

Univalent DTIs

A
  • Binds to the catalytic site
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24
Q

Factor Xa inhibitors

Study These Flashcards
A
  • Both free and clot bound forming FXa and are highly selective
25
Rivaroxaban complex crystal structure
- Gly219 forms hydrogen bonding with factor Xa inhibitor - Hydrophobic interaction between hydrophobic amino acids S1 and S4
26
Apixaban
- S4 pocket hydrophobic interaction - Glycine hydrogen bond no S1 hydrophobic interaction
27
Antiplatelet drugs
- Inhibit platelet activation and subsequent thrombus formation
28
COX-1 Inhibitor
- Thromboxane A2 potent vasoconstrictor induce platelet aggregation - degranulate - COX-1 converts arachidonic acid to prostaglandin H2 which is converted to TAX2
29
Aspirin
- Inhibits the bio synthesis by blocking TXA2 in platelets by irreversibly permanently inactivating cyclooxygenase
30
Nucleophilic acyl substitution aspirin
- Acylation of serine 350 - OH attack the aspirin ester - COX serine is the nucleophile and aspirin is electrophile
31
effect of acetylation of serine
- Blocking by acetyl group so normal substrate can no longer bind - Cause anti thrombotic effect for the life span of the platelet
32
Mechanism of binding
- H-bonds stabilizes the resultant tetrahedral intermediate - H-bond and ionic bond - Salicylic acid is a weak COX-1 inhibitor
33
Absorption of aspirin
- 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
P2Y Purinergic receptor antagonist
- P2X1 which is activated by ATP - P2Y1 and P2Y12 receptors which are activated by ADP
35
Binding of P2Y1 with ADP
- Changes in platelet shape initiates platelet agregation
36
ADP binding P2Y12
- Inhibition of adenyl cyclase causes decrease in cellular cAMP levels - Sustained platelet aggregation
37
Irreversible aggregation of P2Y12
- Binding to ADP active site e.g. Cloprodigrel
38
Reversable antagonist of P2Y12
- Binding to allosteric site such as ticgrelor
39
Thienopyridine
- Selective irreversible inhibition of ADP induced platelet aggregation block ADP binding
40
Ticlopidine
- Not effective in inhibiting platelet aggregation in vitro to the in vivo of patients platelets
41
Oxidization of Ticlopidine and clopidogrel
- 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
Prasugrel prodrug
- Activated to form irreversible inhibitor
43
Binding of ticagrelor
- Binds to remote allosteric site resulting in blocking conformational changes to receptor at ATP binds to site
44
Triazolopyridine ring
- Bio-isostere of purine ring - Increase in binding affinity by 100x
45
Cyclopentene
- Replaces the ribose that would increase half life
46
Large group attached to Triazolopyridine ring
- Improve PK and affinity to P2Y12 and metabolic stability
47
OH chain purpose
- Removed from plasma by CYP3A4/3A5 in vivo
48
Fibrin blood clots
- Dissolved by actions of the fibrinolytic system - Removal of unwanted clots without damaging the integrity of vascular system
49
Plasmin
- Non-specific protease enzyme that digests fibrin
50
Plasminogen activator
- Trypsin like serine protease cause cleavage of peptide bond
51
TPA inhibitor
- Stop the digestion of degraded fibrin
52
Alteplase
- 527 amino acids - 1 in N-terminus - 527 in C-terminus
53
Reteplase
- Removal of amino acids 1 to 172 compared to Alteplase
54
Nitrates
- Very volatile and moisture sensitive with explosive properties - Lipophilic good for emergency treatment rapid absorb
55
Nitric oxide
- Produced by vascular endothelial cell relax smooth muscles - Stimulates formation of cGMP
56
Interaction of nitrate containing drugs
- Free sulfhydryl groups SH causes formation of NO via nitrosothiol intermediate - Activation of cGMP soluable
57
Nicoradil
- Nicotinamide-nitrate ester - Treatment of angina pectoris and CHF - Dual mechanism smooth muscle relax property increase K+ conductance - Vasodilation of coronary arteries
58
Nicoradil formation
- 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

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