Drugs for Numbness and Weakness 2 (Vascular Pathologies) Flashcards
What are the 2 kinds of vascular pathologies. State the names of the conditions treated.
- arterial - peripheral arterial disease
- venous - varicose veins + deep vein thrombosis
State the 4 classes of drugs used to treat peripheral arterial disease
- anti-hypertensives
- antilipid therapy
- antiplatelet therapy
- pentoxyfylline
What are the 7 common side effects of pentoxifylline?
- Gastrointestinal discomfort
- Belching
- Bloating
- Nausea
- Vomiting
- Dizziness
- Flushing
Whate are rare but potentially serious side effects of pentoxifylline?
- Angina
- Palpitations
- Bleeding
- Arrhythmias
- Anxiety
- Hallucinations
State the MOA of pentoxyfylline in peripheral arterial disease
- non-selective PDE (phosphodiesterase) inhibitor that improves RBC deformability and reduces blood viscosity thus having haemorrheologic effect (improves blood flow)
- methylated xanthine derivative
- adenosine 2 antagonist
Name the drug used in antiplatelet therapy
ADP receptor blockers - clopidogrel
State the MOA of clopidogrel
ADP receptor blocker –> blocks P2Y12 recepotr –> prevents signalling pathways which prevent platelet activation and hence platelet aggregation
State the adverse effects of clopidogrel
Generally well tolerated
What is the benefit of ADP receptor blockers in IHD patients?
Reduction in the risk of atherothrombotic events in patients with IHD.
State the name of antilipid therapy used in peripheral arterial disease
HMG-CoA reductase - atorvastatin
State the MOA of atorvastatin in peripheral arterial disease
- inhibition of HMG reductase
- upregulates LDL-R on cell surface –> depletes extracellular cholesterol by increase number of specific cell surface LDL -R that can bind and internalise circulating LDL-C
State the adverse effects of atorvastatin in peripheral arterial disease
- muscle - myopathy, rhabdomyolysis
- liver - liver dysfunction
State the 2 drugs used as anti-hypertensives in peripheral arterial disease
ACE-inhibitors - captopril
ANGII Type 1 blocker - candesartan
State the MOA of captopril in peripheral arterial disease
- ACE-I inhibits conversion of ANGI to ANGII
- Decreased ANGII –> decreased vasoconstriction of SM –> decreased peripheral vascular resistance –> decreased BP
- Decreased ANGII –> decreased aldosterone secretion –> decreased Na+ and water retention –> increased urination –> decreased BP
- ACE-I also inhibits breakdown of bradykinin –> increased formation of NO and PG –> vasodilation –> decreased BP
State the adverse effecfts of captopril
- severe hypotension
- acute renal failure
- hyperkalaemia
- angioedema
- dry cough
In what situation should atorvastatin (antilipid) be used with caution
- pregnancy
- nursing mothers
- children or teens
State the MOA of candesartan in peripheral arterial disease
- ANGII type 1 blocker inhibits conversion of ANGI to ANGII
- Decreased ANGII –> decreased vasoconstriction of SM –> decreased peripheral vascular resistance –> decreased BP
- Decreased ANGII –> decreased aldosterone secretion –> decreased Na+ and water retention –> increased urination –> decreased BP
State the adverse effects of candesartan in peripheral arterial disease
- less dry cough
In what situation should candesartan (antihypertensive) be used with caution
pregnancy…
State the 2 classes of drugs used in treatment of varicose veins
varicose veins - engorged veins causing nerve compression
- mucopolysaccharide polysulphate –> treatment of inflamed, swollen varicose veins
- polidocanol –> treatment throguh sclerotherapy to narrow lumen of varicose veisn to force blood elsewhere
What is mucopolysaccharide polysulphate used for in varicose veins?
It is used to treat inflamed and swollen varicose veins due to its antithrombotic and anti-inflammatory properties.
What are the MOA of mucopolysaccharide polysulphate?
- Antithrombotic = Inhibits clotting factors by potentiating antithrombin activity
- Anti-inflammatory = Reduces capillary permeability and inflammatory mediators
- Improves Microcirculation = Promotes blood flow and tissue oxygenation
- Fibroblast Modulation = Enhances fibroblast activity and collagen synthesis, supporting wound healing
- Analgesic = Provides mild pain relief by modulating local inflammation.
State the adverse effects of mucopolysaccharide polysulfate
Local reaction
1. mild skin irritation (erythema, pruritus)
2. contact dermatitis with prolonged use
Systemic (rare)
1. hypersensitivity
2. systemic anticoagulation if used over large areas
What is the mechanism of action of polidocanol?
- non-ionic surfactant that causes localized endothelial damage and induces clot formation leading to sclerosis and obliteration of the vein.
- mild anaesthetic - causes less pain and discomfort compared to other sclerostants
What are potential adverse effects of polidocanol when used in sclerotherapy?
LOCAL
1. pain
2. redness
3. pruritus
4. hyperpigmentation
5. skin discolouration at the injection site
SYSTEMIC
1. allergic reaction (anaphylaxis)
2. n/v
3. headache
SERIOUS
1. thromboembolism
2. ulceration, or tissue necrosis if extravasation occurs
What is the primary treatment approach for deep vein thrombosis (DVT)?
- anticoagulants such as rivaroxaban, apixaban, or low molecular weight heparin
- warfarin, dabigatran or edoxaban.
What are common side effects of anticoagulants used for deep vein thrombosis (DVT)?
- bleeding
- bruising
- risk of haemorrhage
State the MOA of anticoagulants.
- blocks activation of clotting fibres
- prevents conversion of fibrinogen to fibrin
- prevents polymerisation of fibrin to form meshwork to stabilise and hold thrombus together
State the common oral anticoagulants used to treat DVT
- vitamin k antagonist - warfarin
- direct oral anticoagulant (DOAC) non-vitamin k antagonist - dabigatran, rivaroxaban
State the common parenteral anticoagulants used to treat DVT
- heparin
- low molecular weight heparin derivatives - LMWHs - enoxaparin
- hirudins - lepirudin (NOT IMPORTANT)
State the MOA of warfarin
Inhibition of vitamin K-dependent clotting factors (II, VII, IX, X) by inhibiting vitamin k reductase enzyme that reacivates oxidised vitamin k
What is the reversal agent for warfarin?
vitamin k!!!!
State the route of warfarin metabolism.
Can there be variability in response?
hepatic - primarily via CYP2C9
yes, variability occurs due to genetic polymorphisms in genes (CYP2C9 and VIt K Reductase Complex Subunit 1 - VKORC1)
State 2 things we should monitor to titrate dose of warfarin
- international normalised ratio (INR)
- prothrombin time
State the adverse effects of warfarin
- haemorrhage - bloody stool/urine, melena, excessive bruising, petechiae, persistent oozing from superficial injuries, excessive menstrual bleeding
- hepatitis (esp old dudes)
- cutaneous necrosis and infarction of breast, buttocks and extremities
State the contraindications of warfarin
- hypersensitivity
- active bleeding, risk of pathologic bleeding after major surgery
- severe or malignant HTN
- severe renal/hepatic disease
- subacute bacterial endocarditis/pericarditis/pericardial effusion
- pregnancy
cautions
1. breast-feeding women
2. diverticulitis, colitis
3. mild htn
4. mild renal/hepatic disease
5. drainage tubes in orifices
State some drugs and food that can interact with warfarin in DDI and DFI
INCREASE BLEED
- paracetamol long term therapy at high dose –> increase bleed
- allopurinol, NSAIDs, salicylates, PPI, metronidazole –> increase bleed
- traditional meds (gingko, reishi mushrooms, cranberry juice) –> increase bleed
DECREASE EFFICACY OF WARFARIN
- barbiturates, corticosteroids, spironolactone, thiazide diuretics –> decrease efficacy
- traditional meds (vitamin k, green tea) –> decrease efficacy
What is the role of vitamin K in Warfarin therapy?
Vitamin K is necessary for the synthesis of clotting factors inhibited by Warfarin.
What are the risks of combining NSAIDs with anticoagulants?
Increased risk of bleeding and gastrointestinal ulcers.
State the common direct oral anticoagulants (DOAC) non-vitamin k antagonists
- dabigatran
- rivaroxaban
State the MOA of dabigatran
dabigatran and its acyl glucuronide metabolites are** competitive reversible non-peptide antagonists of thrombin (factor IIa) **
dabigatran etexilate is the prodrug for dabigatran
State the reversal agent of dabigatran.
State the MOA of the reversal agent.
State the clinical use of the reversal agent.
idarucizumab.
MOA: humanised monoclonal Ab fragment that binds dabigatran and its acyl glucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin
Clinical use:
- reversal of anticoagulant effects of dabigatran in emergency surgery or life-threatening uncontrolled bleeding
Explain why dabigatran etexilate must be administered in enteric coating preparations
Dabigatran extexilate has very low bioavailability of 3-7% hence enteric coating helps enhance absorption into bloodstream.
State the MOA of rivaroxaban
rivaroxaban is a competitive reversible antagonist of activated factor X (Xa)
State the reversal agent of rivaroxaban
andexanet alfa!
is a recombinant modified human factor Xa decoy protein
Does dabigatran etexilate or rivaroxaban have faster reversibility of effects
rivaroxaban
the half life of dabigatran is 12-17 hours while that of rivaroxaban is a shorter 5-9 hours
State the adverse effects of the DOAC (direct oral anticoagulants) non-vitamin k antagonists
dabigatran - GI, bleeding
rivaroxaban - bleeding
State the common DDIs in the DOAC (direct oral anticoagulants) non-vitamin k antagonists
dabigatran
1. increase risk of bleeding - antiplatelets, anticoagulants, fibrinolytics, nsaids, ketocoonazole
2. reduced dabigatran level - rifampicin
rivaroxaban
1. increase risk of bleeding - antiplatelets, anticoagulants, nsaids, p-glyco-protein (P-gp), CYP3A4 inhibitors
2. reduced rivaroxaban level - P-gp, CYP3A4 inducers
What is the function of Antithrombin III in anticoagulation?
It enhances the inactivation of thrombin and other coagulation enzymes.
What is the advantage of low molecular weight heparins (LMWHs) over standard heparin?
- more predictable anticoagulant response
- lower risk of bleeding.
- longer half life (heparin = 1hr, lmwh = 4hr)
- higher bioavailability
What are the indications for Antithrombin III administration?
Used in hereditary antithrombin deficiency and in certain cases of heparin resistance.
State the MOA of heparin and LMWH (enoxaparin)
Heparin:
blocks surface contact triggered coagulation by potentiating action of ATIII and thereby inactivating thrombin
- binds tightly to ATIII and causes conformational change whcih exposes ATIII active site more for action by protease
LMWH (enoxaparin):
more selective in blockage of factor Xa and to a lesser extent thrombin (IIa)
What are the side effects of using Heparin?
- bleeding (esp IV heparin)
- heparin-induced thrombocytopenia –> heparin binds to platelet factor 4 (PE4) on activated platelet surface –> IgG Ab against heparin-PE4 complex
- osteoporosis with long-term use.
- increased risk of epidural or spinal hematoma and paralysis in patients receiving epidural or spinal anaesthesia or spinal puncture
State the contraindications of heparin and LMWH
- hypersensitivity
- active major bleeding
- thrombocytopenai or antiplatelet Ab
caution
1. elderly
2. risk of bleeding - prostethic heart valves, major surgery, regional or lumbar block anaesthesia, blood dyscrasis, recent birth, pericarditis, pericardial effusion, renal insufficiency (LMWH)
State the DDI DHI and DFI of heparin and LMWH
- increase risk of bleeding with antiplatelets, anticoagulants, fibrinolytics, nsaids, ssri
- increase risk of bleeding with various food and herbs such as chamomile, fenugreek, garlic, ginger, gingko and ginseng
State the reversal agent of heparin
protamine sulfate iv infusion
(incomplete reversal for LMWH)
Can heparin and LMWH be used in pregnancy?
YES!
unlike warfarin, heparin and LMWH do not cross the placenta and have not been associated with fetal malformations
