Chap 34: Antiplatelet agents, drugs used in bleeding disorders

Introduction
- PLT regulated by 3 categories of substances

• agents outside plt, act on plt membrane receptors - catecholamines, collagen, thrombin, prostacyclin
• agents generated inside plt, act the same - ADP, prostaglandin D2, E2, serotonin
• agents generated inside plt, act inside plt - prostaglandin endoperoxides, Tx A2, cAMP/GMP

- hence the groups of antiplatelet agents

• PG synthesis inhibitor - aspirin
• ADP-induced plt aggregation inhibitor - clopidogrel, ticlopidine
• glycoprotein IIb/IIIa receptor blockers - abciximab, tirofiban, eptifibatide

ASPIRIN
- Tx A2 - arachidonate product --> plt change shape, degranulate, aggregate
- aspirin --> cyclooxygenase inhibitor irreversibly --> reduce tx A2
- other NSAIDs + salicylates --> do the same but action is reversible hence not used as antiplt


CLOPIDOGREL + TICLOPIDINE
- irreversibly block ADP receptors on plt
- use

• PTI with stent - prevent re-thrombosis
• prevention of vascular events - TIA, completed strokes, unstable angina

- SE

• GIT - nausea, dyspepsia, diarrhoea - 20% pt
• hemorrhage - 5%
• neutropenia - 1% (very serious) - regular monitoring WCC in first 3 months

- clopidogrel has fewer SE than ticlopidine - rarely assoc with neutropenia
- clopidogrel - dose dependent efx - hence need loading dose 300mg (80% plt inhibition) - 75mg maintenance - takes 7-10 days to reach antiplt efx hence the same time to wean off


Aspirin + clopidogrel resistance
- no objective studies
- varies from 5%-75% where thrombosis happens despite rx


GLYCOPROTEIN IIb/IIIa RECEPTOR BLOCKERS
- used in acute coronary syndromes
- IIb/IIIa complex acts as receptors for fibrinogen, vitronectin, fibronectin, and vWF --> as final common pathway of plt aggregation
- average plt has 50,000 copies of receptors --> ppl lacking these receptors = Glanzmann's thrombasthenia --> bleeding tendency

- abciximab - monoclonal antibody - used in PTI and ACS
- eptifibatide
- tirofiban - smaller molecule than eptifibatide - inhibit ligand binding to IIb/IIIa receptor


OTHER ANTIPLTs
- dipyridamole

• vasodilator
• inhibit adenoside uptake + cGMP phosphodiesterase activity
• by itself - no beneficial efx - need to combine with aspirin to prevent cerebrovascular ischaemia

- cilostazol - newer phosphodiesterase inhibitor --> promotes vasodilation + (-) plt aggregn


DRUGS USED IN BLEEDING DISORDERS
Vitamin K
- fat soluble, found in leafy green veges
- human get it from veges + gut bactera
- confers biologic activity on factor 2,7,9,10 by modifying them
- 2 forms - K1 and K2 - K1 found in food, K2 found in human tissue + synthesised by bacteria
- requires bile salt for absoprtion
- onset 6 hrs, compete by 24 hrs
- best given IV + po, not sc (erratic)
- given to all newborn to prevent hemorrhagic disease of newborn (common in premature infants)

Plasma fractions
- spontaneous bleeding occurs when factor activity <5-10% of normal
- commonest: hemophilia A and B (christmas disease, IX deficiency)
- preparation

• prepared from large pools of plasma
• viral transmission elimited/reduced by pasteurisation
• but not prion disease
• now uses recombinant technology

- clinical usage

• if hemorrhage to joint --> infuse factor VIII/IX to maintain 30-50% of normal concentration for 24 hrs
• soft tissue hematoma = minimum of 100% factor activity for 7 days
• hematuria = 10% activity for 3 days
• surgery/major trauma = 100% activity for 10 days
• has loading + maintenance dose
• desmopressin acetate - increases VIII activity with mild hemophilia /vWB disease --> can use in minor surgery like tooth extraction - given intranasal

- cryoprecipitate

• plasma protein fraction from whole blood
• treat deficiencies/qualitative abnorm of fibrinogen
• eg DIC/liver disease
• hemophilia A and vWB disease if desporessin not indicated and other stuff not available --> last resort as cryoprecipitate not treated to reduce risk of viral transmission

Fibrinolytic inhibitor
- aminocaproic acid (EACA) - competitively inhibit plasminogen activation - po and rapidly cleared
- tranaxemic acid

• analog of EACA
• 15mg/kg loading, then 30mg/kg QID
• uses - adjunct therapy for hemophilia, bleeding from fibrinolytic therapy, prophylaxis for intracranial aneurysm, postop bleed (GI, prostatectomy, bladder hemorrhage, drug induced cystitis)
• SE: intravascular thrombosis

-

Chap 34: Fibrinolytic drugs

Introduction
- rapidly lyse thrombin by catalysing plasminogen --> plasmin
- plasmin itself cannot be used due to inhibiting enzymes

Pharmacology
- streptokinase

• made by streotpcocci - converts inactive plasminogen to plasmin

- urokinase

• human enzyme synthesized by kidney

- anistreplase

• anisoylated plasminogen streptokinase activator complex
• complex of purified human plaminogen + bacterial streptokinase
• allows rapid IV injection, allows greater clot selectivity

- tissue plasminogen activators

• preferentially activates plasminogen THAT IS BOUND TO FIBRIN
• in theory - only lyses formed thrombus - avoids systemic activation
• alteplase - recombinant DNA technology --> human tPA
• reteplase - same as alteplase with several amino acids deleted - less expensive to produce but less fibrin-specific than t-PA
• tenecteplase - mutant form of t-PA with longer T1/2

Thrombolytic drugs for AMI
- 20% reduction in mortality for pt with AMI
- PCI (intervention) = PTCA +- stent - better but if not available = thrombolysis
- pt selection is critical

• dx of AMI - clinical + ECG
• pt with STEMI and new onset BBB has best outcomes
• earlier the better, within 6 hrs onset of AMI

Other indication and dosage
- PE with hemodynamic instability
- severe DVT - SVC syndrome, ascending thrombophlebitis of iliofemoral vein - severe edema
- intraarterial PVD
- AMI:

• streptokinase: loading dose 250K units, then 100K U/hr for 24-72 hrs; beware antistreptococcal antibodies - fever, allergic reaction

- acute ischaemic stroke

• <3hrs>
• ensure not hemorrhagic infarct - better outcome
• check dosage as higher dosage 1.5million units --> increased bleeding risk

- d

Chap 34: warfarin + the coumarin anticoagulants

Chemistry + Pharmacokinetics

- formed from spoiled sweet clover silage --> hemorrhagic disease in cattle

- researchers found toxic agent = bishydroxycourarin

- synthesised derivative = warfarin (Wisconsin Alumni Research Foundation, arin from coumarin)

- initially used as rodenticides

- pharmacokinatics

• 100% oral bioavailability
• T1/2 36 hrs = hence take 2-3 days to establish the levels
• 99% albumin bound

- MOA

• block g-carboxylation of glutamine residue in factor 2,7,9,10, protein C, S --> inactive
• also oxidises Vit K
• Vit K needs to be reduced to be active - warfarin blocks activity of Vit K
• mutational change to Vit K epoxide reductase = genetic resistance to warfarin in human, especially rats
• 8-12 hr delay in warfarin action
• T1/2 of factor 2,7,9, 10 are 60, 6,24,40
• larger initial dose of warfarin to 0.75mg/kg hasten anticoagulant efx, above that effect is independent

- toxicity

• crosses placenta --> hemorrhagic disease of fetus, birth defect
• reduced protein C activity --> thrombosis --> cutaneous necrosis in skin, breast, fatty tissue, intestine, extremities

- warfarin resistance

• progression/recurrence of thrombotic event with therapeutic INR
• cancer pt most at risk, typically GIT ca --> can change to LMWH
• can have INR target raised

- drug interactions

• most drugs do
• but NOT ethanol, phenothiazines, benzos, paracetamol, opioids, indocid, most abs except (flagyl different)

- reversal

• may need longer FFP/factor VIIa due to long T1/2

-

Chap 43: Direct thrombin inhibitors

Introduction
- binds to active site of thrombin - rather than through antithrombin like heparin
- hirudin

• leech saliva
• available as recombinant form as lepirudin
• used by surgeons to prevent microvascular thrombosis - reattaching digits
• lepirudin used in pt with HITS
• monitored using APTT

- bivalirudin

• rapid onset + offset
• short T1/2 - used in PTCA

- argatroban - like above, used in pt with HITS
- ximelagatran - oral agent, no monitoring needed

Chap 43: Drugs in coagulation II - anticoagulants - Indirect thrombin inhibitors

INDIRECT THROMBIN INHIBITORS
- binding of antithrombin --> enhances inactivation of Xa --> reduced thrombin formation
- UFH, LMWH, synthetic fondaparinux

Heparin
- heterogenous mixture of sulfated mucopolysaccharides
- binds to endothelium + plasma proteins
- binds to antithrombin --> accelerate 1000x inactivation of clotting factors, esp IIa, IXa, Xa
- UFH - composed of high molecular weight heparin (HMWH) + LMWH

• HMWH - inhibit all 3 factors as above --> marked anticoagulants
• LMWH - inhibit activated factor X - less efx on thrombin
• but trials show that LMWH are as effective as UFH --> hence used

- HITS

• systemic hypercoagulable state
• 1-4% of ppl treated with UFH minimum 7 days
• surgical pt - high risk
• thrombosis - venous and arterial (not so common)
• suspect when - PLT dropping, having new thrombus despite heparin
• Rx with direct thrombin inhibitor/fondaparinux

- monitoring

• UFH - aPTT
• LMWH - no need as weight beight measurement, unlike UFH - but levels can be determined by anti-Xa units

- reversal of heparin action - protamine

• protamine sulfate (basic peptide) - binds to heparin --> stable complex --> no anticoagulant activity
• 1mg protamine sulfate to 100 unit of heparin
• LMWH - partial neutralisation - limited studies 1mg protamine to 1mg enoxaparin
• protamine does NOT reverse fandaparinux

Chap 34: Drugs used in coagulation I - basic principles

BLOOD COAGULATION CASCADE
Intruduction
- end products - fibrin formation
- central role - thrombin
- thrombin

• cleaves peptides from fibrinogen to convert it into fibrin clot
• activates upstream clotting factors - more thrombin formation, activates factor XIII that stabilises clot
• platelet activator
• activates protein C pathway - enhances anticoagulation efx --> no thrombosis causing downstream ischaemia

Initiation of clotting - the tissue factor-VIIa complex
- main initiator = factor VIIa (TF)
- tissue factor

• transmembrane protein
• expressed outside vasculature, intravascularly not active
• exposure to damaged endothelium/blood = binding of factor VIIa + TF = complex --> activation of factor X, IX

- coagulation happens in activated cell surfaces mediated by Ca2+ --> EDTA is a chelator, used in test tubes
- antithrombin (AT) - endogenous anticoagulant --> inactivates IIa, IXa, Xa, XIa, XIIa

- Prot C & S - endogenous anticoagulant --> inactivates Va, VIIIa

- factor V leiden = mutation of factor V = resists inactivation by protein C + S --> thrombophilic

Fibrinolysis

- fibrin digestion by plasmin

- injury --> endothelium releases t-PA --> activates plasminogen to plasmin --> remodels thrombus and limits extension

- t-PA, urokinase, streptokinase - activates fibrinolytic system

- aminocaproic acid - inhibits fibrinolysis

- heparin + oral anticoagulants --> do not affect this pathway

Chap 55: Cancer chemotherapy

CELL CYCLE KINETICS
Introduction
- tumor stem cells

• subpopulation within tumor cells
• has ability to proliferate repeatedly --> hence metastasis
• chemotherapy agents aimed at targeting tumor stem cells
• by definition non-TSC is sterile (they are irreversibly differentiated) ie not target of ctx

- cell cycle specific (CCS) drugs

• effective against proliferating cells - G1 - hematological malig
• solid tumors with predominantly rapidly dividing/in growth faction

- cell cycle non-specific (CCNS) drugs

• many binds to DNA or damage microtubule good for both proliferating and non-proliferating cells - G1 and G0 (resting stage)
• but G1 stage cells would be more sensitive

Resistance to cytotoxics
- primary resistance

• no response on 1st exposure
• due to genomic instability
• brain ca, RCC, melanoma

- acquired resistance

• mutation in chemosensitive tumor cells
• expression of normal gene - MDR1 gene
• expression of abnormal gene - multidrug resistance protein 1 (MRP1) gene

POLYFUNCTIONAL ALKYLATING AGENTS
- bisamines, cyclophosphamide, mechlorethamine, melphalan, chlorambucil
- MOA

• transfer alkyl groups to varius cellular components --> likely DNA --> cell death (N7 position of guanine in DNA)
• cells most susceptible to alkylation at G1

- Resistance

• increased cell ability to repair DNA lesion, reduced permeability, increase gluthathione (inactivates alkylating agent)
• resistance to 1 alkylating agent = all generally

- SE

• direct vesicant efx - at site of injection (into peripheral v is ok - diluted immediated)
• systemic toxicity - affects fast growing tissues (bone marrow, GIT, reporudctive system)
• emetogenic - mediated by 5HT - use 5HT antagonist (ondansetron)

Related drugs acting as alkylating agents
- procarbazine

• oral agent
• use: Hodgkin's, NHL, brain tumors
• leukemogenic, teratogenic, mutagenic --> increased risk of 2ary cancer

- dacarbazine

• melanoma, HD, soft tissue sarcome

- altretamine
- cisplatin

• inorganic metal complex - discovered serendipitously that Pl inhibit division and induce filamentous growth of E coli
• exact mechanism unknown but likely alkylating agent
• solid tumors - small cell/NSCLC/oesophageal/gastric/H+Neck/GU - testicular, ovarian, bladder
• + bleomycin/etoposide --> cure nonseminomatous testicular ca
• nephrotoxic --> needs hydration

- carboplatin

• 2nd generation platinum analogue --> same spectrum of solid tumors
• toxicity --> myelosuppression, significantly less renal toxicity + GI toxicity than cisplatin
• don't need IV hydration --> widely replaced cisplatin

- oxaliplatin

• 3rd generation platinum
• MOA same
• used for tumors resistant to carbo + cis
• FOLFOX (5-FU, leucovorin) - advanced colorectal ca
• neurotoxic --> dose-limiting, peripheral sensory neuropathy (reversible)

ANTIMETABOLITES
- tumors has some quantitative differences in metabolism from norm cells
- inhibit nucleotide and nucleic acid synthesis
- methotrexate

• antifolate - binds to dihydrofolate reductase --> DNA inhibition
• toxicity - not metabolised, hence toxicity = dose administered
• efx of MTX reversed by leucovorin (5-formyltetrahydrofolate)

- premetrexed

• antifolate like MTX
• + cisplatin for mesothelioma/single agent in NSCLC
• myelosuppression, skin rash, mucositis, diarrhoea, fatigue

PURINE ANTAGONIST
- 6-MP and 6-TG

PYRIMIDINE ANTAGONIST
- 5-FU
- capecitabine
- cytarabine
- gemcitabine

CLINICAL PHARMACOLOGY FOR CHEMOTHERAPY
Introduction
- depends on

• growth fraction
• spontaneous cell death rate
• most cell in G0?
• hypoxic stem cells?
• cell cycle specific?
• hormonal control?
• drug metabolised by liver (cyclophosphamide) or tumor (capecitabine)?

- generally given in 3-4 wk pulse therapy - reason for norm cells to repair itself but not tumor - complete hematologic and immunologic recovery btw courses

The Leukemias
- acute childhood - good px
- acute adult
- chronic myeloid leukemia
- chronic

Breast cancer
- radiotherapy
- chemo
- hormonal - herceptin (trastuzumab) for HER-2 receptor +ve pt

Lung cancer
- NSCLC (majority - 75-80%) vs SCLC
- NSCLC - if advanced - bad px, best rx is avoid smoking + early detection
- SCLC - responds excellently to platinum

Testicular cancer
- platinum based therapy --> contributed much
- PEB - cisplatin, etoposide, bleomycin x3 cycles --> lead to cure

Melanoma
- relatively drug resistant
- dacarbazine, temozolomide, cisplatin most active
- high dose IL-2 has led to cures

Secondary malignancies + cancer chemotherapy
- AML commonest, happens as learly as 2-4 yrs, peaks 5 + 9 yrs
- alkylating agents, procarbazine, etoposide, ionizing radiation --> all leukaemogenic
- others not that much

Chap 53: Antiprotozoal drugs

TREATMENT OF MALARIA
Introduction
- 4 species but falciparum causes nearly all significant cx and deaths
- resistance a major issue with falciparum
- parasite life cycle

• anopheline mosquito --> inoculates sporozoite --> into blood stream --> invade liver cells --> schizonts mature in liver --> merozoites released from liver --> invade RBC --> gametocytes develop in RBC --> taken by mosquite
• it's the RBC infection that causes clinical illness
• falciparum + malariae --> 1 cycle of liver cell invasion --> then liver infection stops in 4wks --> treatment of erythrocytic parasites will cure infection
• vivax + ovale --> dormant hepatic stage (hypnozoite) --> needs to treat RBC and hepatic parasites to achieve cure

- drug classification

• tissue schizonticides - kills developing/dormant liver forms
• blood schizonticides - kills RBC parasites
• gametocides - kills sexual stage and prevent transmission to mosquitoes

- chemoprophylaxis and treatment

Chroloquine
- for rx and chemoprophylaxis, drug of choice for sensitive falciparum and other species
- MOA

• blood schizonticide + gametocytes (for v,o,m not f), not active for liver
• unclear MOA
• resistance - very common in f, increasing in v due to mutation of transporter (to bring drugs into RBC)

- clinical

• Rx: drug of choice in sensitive f and non-f, rapidly terminates fever (in 24-48 hrs) and clears parasite from blood (48-72hrs)
• used in resistant falciparum cos eliminates symptoms quickly - but some has partial genetic immunity
• primaquine is added for v and o to kill liver schizonts
• chemoprophylaxis - preferred agent in sensitive f
• amebic liver abscess - after failing flagyl

- SE

• C/I in psoriasis/porphyria - can precipitate acute attacks
• not used in retinal/visual field abnorm/myopathy
• otherwise - renal, liver, eye (blurring of vision), blood (G6PD def)

Quinine & Quinidine
- 1st line for f malaria esp severe disease cos resistance is uncommon
- derived for cinchona tree in South America (used for intermittent fever)
- quinidine is stereoisomer of quinine
- MOA

• blood schizonticide for all
• gametocidal for v and o (not f)
• NOT liver schizonticide
• overall unknown
• resistance - uncommon only in SEA (esp Thai-Burma border) - but still has partial efx

- clinical uses

• parenteral rx of severe f malaria - IV/IM - should change to po once pt improves
• po rx - use as 1st line in resistant area, if not use chloroquine, need to add on other agent (doxycycline in adults or clindamycin in kids) to shorten duration to 3 days
• babesiosis - 1st line therapy with clindamycin

- SE

• cinchonism - neuro stuff (tinnitus, headache, nausea, dizzy, flush, visual)
• hypersensitivity reaction
• blood - hemolysis, WCC drop, agranulocytosis, thrumbocytopenia
• hypoglycemia - induce insulin
• blackwater fever - marked hemolysis, hemoglobinuria due to quinine - pathogenesis unknown - ?hypersensitivity reaction to drug

Mefloquine
- effective for chloroquine-resistant f malaria
- recommended chemoprophylactic drugs
- blood schizonticidal f and v, not liver/gamet
- resistance uncommon except SEA (Thai burma)
- C/I - epilepsy, psych disorder, arrhythmia, cardiac conduction defects

Primaquine
- liver schizoncidal - only drug to eradicate dormant liver form of vivax, ovale
- gametocidal against 4 human malaria sp
- minimally RBC-cidal but insignificant
- resistance - PNG, SEA, central and south america - resistant vivax - needs repeated therapy for radical cure (eg for 14 days)
- clinical use

• radical cure of acute v and o - add blood agents like chloroquine
• terminal prophylaxis of v and o - prevent relapse
• PCP infection - add clindamycin

- SE

• C/I - granulocytopenia, methb, G6PD def

Antibiotics
- tetracycline + doxy - RBC-cidal, not liver
- clindamycin - slowly active in RBC

Artemisinin & derivative
- active component of herbal medicine of China - antipyretic for 2000 yrs 青蒿素
- analogues - artesunate (water soluble), artemether (lipid soluble)
- rapid blood schizonticidal - not liver
- resistance is not an issue
- important in MDR falciparum malaria - only drug against quinine-resistant strains
- short T1/2 hence not used in chemoprophylaxis
- expensive and widely avaible
- clinical use

• needs combination to treat highly resistant f malaria - with mefloquine

TREATMENT OF AMOEBIASIS
- Entamoeba histolytica
- spectrum of disease - asymptomatic intestinal infection/colitis/dysentry/liver abscess
- treatment options

• metronidazole & tinidazole
• iodoquinol
• diloxanide furoate
• paromomycin sulfate
• emetine & dehydroemetine

- d