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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

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

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

PMP 201 Patient-Centred Learning (51 decks)

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