pharmacology Flashcards
overview of all the drugs
1) antiplatelets: dipyridamole, aspirin, clopidogrel, ticagrelor
2) anticoagulants: OAC, warfarin, dabigatran, rivaroxaban, heparin
3) fibrinolytics: alteplase
MOA of dipyridamole
1) increase cAMP within platelet -> inhibit platelet activation and aggregation
- adenosine reuptake inhibitor: increase plasma adenosine activation of A2 receptor
- phosphodiesterase 3 (PDE3) inhibitor: reduce cAMP degradation within platelet
2) vasodilation
PK of dipyridamole
- fast onset after oral
- short duration of action (need modified release)
- fast reversal: useful for haemorrhage/bleeding risk
dipyridamole AE
headache, hypotension (vasodilation), dizzy, flushing, GI (N/V/D)
dipyridamole CI/caution
- CI hypersensitivity
- caution hypotension/severe CAD
dipyridamole DDI
1) increase cardiac adenosine levels = trigger reflex tachycardia
2) decrease cholinesterase inhibitor = aggravate myasthenia gravis
3) bleeding risk (+ other anticoagulant/antiplatelet esp heparin)
aspirin MOA
irreversible COX inhibitor (COX-1 > COX-2)
- inhibit platelet production of thromboxane A2
- platelet X nucleus = X synthesis of new COX enzyme = lesser COX-1 producing thromboxane A2 = lesser platelet aggregation
why lower dose of aspirin more effective than higher dose?
higher dose block PGI2 production longer, ideally low enough dose to irreversibly inhibit COX-1 then cleared form body so won’t inhibit COX-2 as much
aspirin AE
1) upper GI
- inhibit COX-1 production of protective PG in stomach
- gastric ulcer, bleeding
2) increased risk of bleeding and bruising
aspirin CI/caution
- pt w platelet/bleeding disorder
aspirin DDI
caution when combine w other antiplatelet/anticoagulant
clopidogrel MOA
ADP P2Y12 inhibitor: irreversibly bind to ADP binding site of P2Y12 receptor
clopidogrel PK
- delayed onset and interindividual variability: CYP2C9
- effect last 7-10 days (lifespan of platelet)
clopidogrel AE
- hemorrhage, bleeding
- bruising, dyspepsia, bronchospasm, dyspnea, hypotension
clopidogrel CI/caution
- hypersensitivity
- active pathologic bleeding
- bleeding risk
- variant alleles (CYP2C9)
clopidogrel DDI
1) warfarin, NSAID, salicylate increase risk of bleeding
2) macrolides reduce antiplatelet effect
3) strong-moderate CYP2C19 inhibitor (PPi, fluoxetine, ketoconazole)
4) rifamycin: increase antiplatelet effect
ticagrelor MOA
ADP P2Y12 inhibitor: reversibly bind to different binding site to inhibit G protein activation and signalling
ticagrelor AE
haemorrhage, bleeding, bradycardia, dyspnoea, cough
ticagrelor CI
1) hypersensitivity
2) severe hepatic impairment
3) breastfeeding, intracranial haemorrhage, active pathologic bleeding
ticagrelor caution
bleeding risk, elderly, moderate hepatic failure
ticagrelor DDI
1) anticoagulant, fibrinolytic, long term NSAID increase bleeding risk
2) aspirin < 100 mg/day reduce ticagrelor effect but increase bleeding risk
3) CYP3A4 inducer (dexamethasone, phenytoin): decrease serum conc and antiplatelet effect
4) CYP3A4 inhibitor (clarithromycin, ketoconazole) increase serum concentration and AE
how Vit K works
- active form activate II, VII, IX, X -> oxidise to inactive form
- Vit K reductase activate inactive form
- Vit K cofactor involved in post-translational carboxylation of prothrombin to prothrombin by GGCX
- meanwhile Vit K hydroquinone converted to Vit K epoxide in presence of O2 & CO2
- epoxide reduced by VKOR(C1) to Vit K and is converted back to Vit K hydroquinone by VKR
MOA of warfarin
- inhibit Vit K reductase
- good at blocking extrinsic pathway
- S-enantiomer active stereoisomer
- act on VKOR and possibly VKR
warfarin PK
- onset depends on how much active Vit K available
- hypercoagulable state4-5 days (protein C & S prevent blood clotting but inhibited by warfarin)
- highly plasma protein bound
- hepatic CYP2C9 metabolism (genetic polymorphism = variability)
- urine and shit excretion
warfarin AE
1) haemorrhage/bleeding
- blood in stool/urine, bruising, petechiae, persistent oozing from superficial wound, excess menses
- regular INR monitoring and dose adjustment required
2) hepatitis
3) cutaneous necrosis & infarction of breast, butt, extremities
- reduced blood flow to adipose tissue
- 3 - 5 days after initiation
warfarin CI
- hypersensitivity
- active bleed, bleed risk, recent major surgery
- severe/malignant HTN
- severe renal/hepatic disease
- pregnancy
warfarin caution
breastfeeding women
warfarin drugs that increase bleeding risk
1) long term paracetamol (> 2 wks) at high dose (> 2g/day)
2) allopurinol, NSAID, salicylate, PPi, metronidazole
warfarin food that increases bleeding risk
gingko, ginseng, reishi mushroom, cranberry juice
drugs that reduce efficacy of warfarin
barbiturate, corticosteroid, spironolactone, thiazide diuretics
warfarin interaction w Vit K containing stuff
supplement, green tea, food
warfarin interaction w antimicrobials
- higher biome load = metabolise more warfarin = need higher dose of warfarin, INR decrease
- inflammation = metabolise less warfarin = INR increase
- bactrim (Sulfamethoxazole/trimethoprim), ciprofloxacin = INR decrease by 25%
diseases that affect warfarin
1) liver disease
- decrease clotting factor synthesis & warfarin metabolism
- INR increase
2) fluid retention
- liver congestion (decrease liver function), gut malabsorption of warfarin
- INR increase then decrease
3) fever
- increase metabolism of clotting factors
- increase INR
4) thyroid disease
- HYPERthyroid = increase clotting factor turnover = increase INR
- hypothyroid = decrease clotting factor turnover = decrease INR
lifestyle factors and warfarin
1) alcohol
- CYP450 inhibitor = increase INR
2) chronic alcoholism
- induce CYP450 = decrease INR
3) sudden increase in physical activity
- increase metabolism = decrease INR
4) smoking
- CYP450 inducer = decrease INR
genetic polymorphism for warfarin
1) CYP2C9
- increase metabolism = higher dose of warfarin
2) VKORC1
- increase susceptibility of enzyme to warfarin-induced metabolism = lower dose of warfarin
indication for Pgx for warfarin
1) existing clot (left ventricular thrombosis)
2) outpatient commencement of warfarin
3) DDI present
4) questionable adherence
INR monitoring for warfarin
- dependent on clotting factors II, XII, X
- why take after 3 days of initiation? factor II take 3 days to reach optimal level
loading warfarin
- achieve ideal INR faster
- load with enoxaparin to reduce hypercoagulable state
dabigatran etexilate general
- non Vit K antagonist
- good at blocking common pathway
- prodrug metabolised to dabigatran
dabigatran etexilate MOA
- competitively and reversibly inhibit thrombin (Factor IIa)
reversal of dabigatran etexilate
idarucizumab
- reverse dabigatran for emergency surgery/urgent procedure/life-threatening or uncontrolled bleeding
- MOA: bind to dabigatran and acyl glucuronide metabolite with higher affinity than dabigatran to thrombin
dabigatran etexilate PK
- large excreted unchanged
- low F so use enteric coated (swallowed whole)
- only DOAC that is dialysable cuz not very protein bound
dabigatran etexilate AE
- bleeding, GI symptoms (dyspepsia)
dabigatran etexilate DDI
rifampicin, carbamazepine, St, John’s Wort (reduce dabigatran levels, switch to warfarin)
rivaroxaban MOA
- competitively reversible antagonist of activated factor X
reversal of rivaroxaban
andexanet alfa (Factor Xa decoy)
rivaroxaban PK
hepatic metabolism (CYP3A4), excreted mainly in urine
rivaroxaban AE
bleeding
rivaroxaban DDI
1) antiplatelet, thrombolytics, anticoagulant, PGPi, CYP3A4i (macrolides): increase bleeding risk
2) PGP inducer, CYP3A4 inducer (Rifampicin), St. John’s Wort: reduces rivaroxaban levels
heparin and LMWH MOA
- heparin inactivate thrombin (IIa), factor IXa, Xa, XIIa
- LMWH inactivate factor Xa and IIa (lesser extent)
- both best at blocking intrinsic pathway
reversal of heparin and LMWH
protamine sulfate IV
- highly basic peptide stably bind to negatively charged heparin -> neutralised
- incomplete reversal of LMWH
LMWH PK
- higher F and longer t1/2
- mostly excreted in urine
heparin and LMWH AE
1) LMWH lesser chance of thrombocytopenia
2) bleeding
- anticoagulation effect disappear after few hours
- increased risk of epidural/spinal hematoma & paralysis in pt receiving epidural/spinal anesthesia/spinal puncture
- heparin induced thrombocytopenia
** bind to PF4 on activated platelet surface
** form IgG antibody against complex
heparin and LMWH special population
X for pregnancy cuz cross placenta
heparin and LMWH CI
hypersensitivity, active major bleeding, thrombocytopenia
heparin and LMWH caution
elderly, risk of bleeding, renal insufficiency
heparin and LMWH interactinos
1) increase risk of bleeding
- antiplatelet, anticoagulant, fibrinolytics, NSAID, SSRIs
- chamomile, fenugreek, garlic, ginger, gingko, ginseng
MOA alteplase
- act as tPA for resolution of clot
reversal of alteplase
tranexamic acid, aminocaproic acid
- compete for lysine binding site on plasminogen & plasmin -> block interaction with fibrin
alteplase vs endogenous tPA
- longer t1/2 = more convenient dosing
- bind preferentially to clot-associated plasminogen -> Activate platelet at clot
alteplase AE
- haemorrhage, bleeding
- ventricular arrhythmia, hypotension, oedema
- cholesterol embolisation, venous thromboembolism
- hypersensitivity (recombinant protein), anaphylaxis
alteplase CI
- active bleeding
- prior intracranial haemorrhage
- recent (within 3 months) intracranial/intraspinal surgery, serious head injury/stroke
alteplase caution
1) if fibrin meshwork breakdown too quickly -> clot break up too fast in clumps instead of gradual release of trapped stuff -> risk fragments circulating in blood -> embolus/block other small vessels
- ONLY used to treat pre-existing clots causing imminent risk of irreversible death/damage
- other clots degrade slowly with endogenous tPA
2) major surgery within 10 days
3) risk of bleeding
4) cerebrovascular disease
5) mitral stenosis
6) atrial fibrillation
7) acute pericarditis
8) subacute bacterial endocarditis
alteplase DDI
- increase risk of bleeding w antiplatelet (esp dipyridamole, aspirin) or anticoagulant (esp warfarin, heparin)
- nitroglycerin reduce levels of alteplase
