Pharm Flashcards
Explain how NSAIDs can increase risk of cardiovascular events; MI, stroke, heart failure
(1) Affects on hemostasis
COX-2 selective NSAIDs -> cause an imbalance between anti-thrombotic mediators and prothrombotic mediators.
COX-2 selective NSAIDS block the COX-2 site which inhibits the binding of AA and subsequent production of anti-thrombotic prostacyclins (PGI2) - These are generally produced by endothelial cells and smooth muscle cells - would normally cause vasodilation and inhibition of platelet aggregation.
This results in the unopposed action of COX-1 which produces prothrombic mediators in platelets - mainly TXA2 - causes activation and aggregation of platelets and vasoconstriction.
(2) Affects in kidneys
PGE2 normally functions in sodium hemostasis by inhibiting resorption of sodium into the blood from the ascending loop of henle.
Therefore blocking PGE2 production can result in increased sodium resorption -> increased blood pressure, worsens heart failure, dilutional hyponatremia, reduces efficacy of anti-hypertensives.
How might NSAIDs contribute to gastric ulcer formation/ GI upset
Mainly due to inhibition of COX-1
Results in reduced synthesis of PGE2 and PGI2. These would normally function to increase mucous production and inhibit gastric acid secretion.
Ways to avoids these ADR’s
- use COX-2 selective NSAID
- Co-prescribe a PGE2 analogue Misoprosotol
- Co prescribe a PPI
How does Aspirin (an NSAID) work as an anti-platelet
Aspirin inhibits COX-1 isozyme within platelets by acetylating serine residue in the cyclooxygenase binding site. -> prevents production of TXA2 -> inhibits platelet aggregation/activation and expression of GIIb/IIIa on platelet surface.
*Platelets do not have a nucleus and therefore they cannot synthesise proteins and when the cyclooxygenase binding site on the COX-1 isozyme is acetylated and inactivated it remains so for the lifetime of the platelet (7-10 days).
Outline the mechanism of action of clopidogrel and prasugrel as anti-platelets
These are prodrugs which are activated to a thiol-containing metabolite.
Irreversibly binds to P2Y12 receptor on platelets.
This inhibits binding to ADP which prevents expression of GIIb/IIIa to which fibrinogen would normally bind.
MOA of ticagrelor as an anti-platelet.
Ticagrelor reversibly interacts with the P2Y12 component of the ADP receptor. Ticagrelor does not prevent ADP binding but when bound to the P2Y12 receptor prevents ADP-induced signal transduction
MOA of abciximab as an antiplatelet
Binds to GIIb/IIIa on surface of activated platelets -> inhibits binding of fibrinogen.
MOA of nitroglycerin in causing vasodilation
Can be given sublingually
-Nitrates are converted to nitric oxide in the body.
-Increases activity of cGMP -> inactivation of inositol phosphate pathway -> reduction in intracellular calcium concentrations -> prevents smooth muscle contraction and so causes vasodilation.
What is meant by Prothrombin Time, how is it measured and what is the normal PT?
List 3 things that can affect PT
-Prothrombin time refers to how quickly a blood clot can form following initiation of coagulation with thromboplastin/tissue factor.
-Assesses function of Extrinsic + Common pathway
-Can detect abnormalities in Factors II, V, VII, X
-Normal PT is between 10-13s (INR 0.8-1.1) if not on anti-coagulant medication
(1) Liver disease
(2) Vitamin K deficiency
(3) Genetic abnormalities resulting in Factor deficiency.
(4) Warfarin
Outline the MOA of direct Xa and direct thrombin inhibitors (DOACs)
What pathway do they inhibit
Direct Xa - Apixaban/Rivaroxaban
-> Binds to active site of factor Xa thereby preventing the formation of prothrombinase complex and subsequent activation of prothrombin to thrombin.
Direct Thrombin (Dabigatron)
-> Binds to free and clot associated thrombin thereby preventing activation of platelets, clotting factors and fibrinogen -> fibrin
Outline the MOA of opioids (morphine)
Opioids carry out analgesic affects by inhibiting nociceptive transmission within the spinal cord - mediated through binding to Mu receptors (GiPCR)
(1) Pre-synaptic neuron: Reduces cAMP -> suppresses activity of voltage-gated calcium channels resulting in reduced influx of calcium -> no nociceptive neurotransmitters released (Glutamate, Substance P, CGRP)
(2) Post synaptic neuron: activates inward potassium channels which leads to hyperpolarisation of the neuron.
(3) Activates descending inhibitory pathways. In the periaqueductal grey/ rostral ventromedial region of medulla, opioids cause disinhibition of GABA’ergic interneurons resulting in increased activity of monoaminergic descending pathways which inhibit nociceptive transmission.
How does morphine cause respiratory depression
(1) It depresses the central chemoreceptors of the medulla thereby reducing their sensitivity to rising PaCO2 levels.
(2) In can depress the respiratory centres of the brainstem, particularly the pre-botzinger complex in ventral resp group which is the rhythm/frequency generator of breathing.
Mediated via Mu receptors
Low dose methotrexate MOA
Low dose methotrexate causes reduced folate production and suppresses neutrophil, macrophage and cytokine activity.
On entry into the cell it becomes polyglutamated.
It’s immunosuppressant effects come about through inhibition of AICAR transformylase enzyme which results in accumulation of extracellular adenosine. This causes activation of A2a receptor.
Its anti-folate effects come about through inhibtion of dihydrofolate reductase.
List 4 ADRs to methotrexate
Bone marrow suppression
Mucosal ulcer formation
Hepatotoxicity
GI: nausea, vomiting, diarrhea
How does methotrexate cause bone marrow suppression
Its anti-folate effects result in reduced availability of folate required for purine/pyrimadine synthesis for new cells in the bone marrow.
2 benefits of folate supplementation when on methotrexate
Reduced mucosal and GI disturbance
Some prevention against hepatotoxicity
NO prevention against bone marrow suppression
