Y09. Pharmacopeia: Haematological Pharmacology

PAST QUESTIONS – Q02. Pharmacology of Haematological System (Click to Open)

SYLLABUS (Fourth Edition, 2023)

LEVEL 1	LEVEL 2	LEVEL 3
Anticoagulants		Anticoagulant Reversal Agents
Low molecular weight heparin (LMWH)	Apixaban	Idarucizumab
Unfractionated Heparin (UFH)	Bivalirudin	Protamine
Warfarin	Dabigatran	Vitamin K
	Rivaroxaban
Anti-platelet drugs
Aspirin		ADP receptor blockers
		Clopidogrel
		Ticagrelor
		Prasugrel
		GPIIb/IIIa inhibitors
		Abciximab
		Tirofiban
Blood Products		Fibrinolytics
Cryoprecipitate		Alteplase
Fresh Frozen plasma		Tenecteplase
Platelets		Antifibrinolytics
Red blood cells		Tranexamic acid

Fractionated plasma products
Albumin	Fibrinogen concentrate	Antithrombin III
	Prothrombinex	Factor IX
		Factor VIIa
		Factor VIII
		Intravenous Immunoglobulin

N.B. The Syllabus tables used in out Pharmacopeia seem incomplete, but that is intentional because we have only included groups/classes/drugs which are mentioned directly in the syllabus or have been asked before in the exams.

TRAINEE EXPECTATIONS

Trainees are expected to understand a drug’s pharmacology in the context of normal physiology, extremes of age (i.e., neonates, paediatrics, and the elderly), obesity, pregnancy (including foetal implications) and critical illness. An understanding of potential toxicity and relevant antidotes is also expected. Agents may be listed in more than one section when they are used for different indications.
This is not an exhaustive list of all drugs relevant to or important in ICU practice. Each drug or classes of drugs have been assigned a details of understanding level outlined below. This is a guide to the minimum level of knowledge expected for that drug.
For classes of drugs where examples are not specified, it is suggested a prototypical drug from the class be studied, as well as the relevant variations within the class exploring the major differences that exist between the agents in that class.

LEVELS OF UNDERSTANDING

Level 1	Level 2	Level 3
For these drugs, a detailed knowledge and comprehension of:	For these drugs a detailed knowledge of:	For these drugs a detailed knowledge of:
Class, Indications, and dose
Mechanism of Action
Pharmacodynamics and Adverse effects
Pharmacokinetics	Important pharmacokinetic differences or considerations when using in ICU
Pharmaceutics

CICMWrecks Tables (Click to Open)

MASTER TABLES	Anticoagulants
	Anticoagulant Reversal Agents
	Antiplatelet Agents
	Fibrinolytics / Antifibrinolytics
	Blood Products
	Fractionated Plasma Products and IVIg
INDIVIDUAL TABLES	Clopidogrel
	Aspirin
	Aspirin \| Clopidogrel
	Heparin \| LMWH
	LMWH \| Hirudin
	Warfarin
	Dabigatran \| Warfarin
	Tranexamic Acid
	Alteplase

MASTER TABLES

ANTICOAGULANTS

Pharmacopeia - Anticoagulants

	UNFRACTIONATED HEPARIN (UFH)	LOW MOLECULAR WEIGHT HEPARIN (LMWH)	HIRUDIN	WARFARIN	DABIGATRAN	APIXABAN	RIVAROXABAN	BIVALIRUDIN
GROUP	Anticoagulants	Anticoagulants	Anticoagulants	Anticoagulants	Anticoagulants	Anticoagulants	Anticoagulants	Anticoagulants
CICM Level of Understanding	Level 1	Level 1	Not in list (Historical question)	Level 1	Level 2	Level 2	Level 2	Level 2

INTRODUCTION	Heparin is an anioic, mucopolysaccaride, organic acid. It occurs naturally in the liver and mast cell granules. MW: 5000-25000 Daltons	Enoxaparin is a LMWH prepared from unfractionated heparin by controlled enzymatic or chemical depolymerisation Consists of smaller fragments of Heparin. MW: Average of 5000 Daltons	Is a naturally occurring peptide found in leaches saliva with anticoagulant properties recombinant techniques are used to create drugs in this class	Coumarin derivative	Competitive Direct Thrombin Inhibitor	Direct Xa inhibitor (free and bound) Blocks amplification phase	Direct Xa inhibitor (free and bound) Blocks amplification phase
USES	1. the prevention of venous thromboembolic disease 2. the priming of haemodialysis and cardiopulmonary bypass machines and for maintaining the patency of indwelling lines and the treatment of 3. DIC 4. fat embolism, and 5. in the treatment of acute coronary syndromes.	1. the prevention of venous thromboembolic disease 2. the treatment of acute coronary syndromes.		1. AF 2. Thromboprophylaxis in rheumatic or prosthetic valves 3. Prophylaxis and treatment of DVT/PE	1. Non-valvular AF 2. VTE prophylaxis in orthopaedic 3. VTE treatment	1. Non-valvular AF 2. VTE prophylaxis in orthopaedic 3. VTE treatment	1. Non-valvular AF 2. VTE prophylaxis in orthopaedic 3. VTE treatment


PHARMACEUTICS (PC)	s/c or i.v. - I.U. (not mg) due to variable potencies. 5000IU BD s/c or 5000IU IV then infusion-rate based on wttitrated (APTT)	Usually s/c, but can be given i.v. 20mg or 40mg BD s/c as prophylaxis, 1mg/kg BD s/c as therapeutic dose Monitor: Anti-Xa level		Racemic mixture of warfarin sodium (S enantiomer is 2-5x more potent) 0.5/1/3/5mg tablets Maximum effect 18-72 hours after dose Monitor: INR aim generally 2.0-4.5 depending on indication (most commonly 2-3)	PO (Dabigitran etexilate- prodrug) Monitor: Direct assays of Thrombin activity: - Thrombin time (TT) - Ecarin clotting time (ECT) - APTT 2.5x >control= increased risk of bleeding	PO Monitor: PT Anti-Xa	PO Monitor: PT Anti-Xa
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Activates antithrombin which then inhibits clotting factors thrombin and factor Xa	Activates antithrombin but due to shorter length preferentially inhibits factor Xa	is via direct irreversible binding to thrombin Causes a prolongation of bleeding time	Vitamin K is responsible for the gamma-carboxylation of glutamic residues of inactive precursors of clotting factors 2,7,9,10. Warfarin prevents the return of vitamin K to its reduced form, inhibiting the activation of these factors.	MOA: Competitive direct thrombin inhibitor. Blocks pivotal part of common pathway Gastric irritation (tartaric acid)	MOA: Direct Xa inhibitor, blocking the final common pathway of clotting cascade	MOA: Direct Xa inhibitor, blocking the final common pathway of clotting cascade
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	Bleeding, Heparin Induced Thrombocytopaenia, Osteoporosis, Transient transaminitis	Bleeding Needs adjustment in renal failure Less HITS and osteoporosis	Bleeding	1. Hemorrhage 2. Teratogenicity - More common and serious in first trimester 3. In third trimester it may cross the placenta and cause fetal hemorrhage.	Bleeding	Bleeding	Bleeding


PHARMACOKINETICS (PK)
PK: Absorption	reduced due to endothelial binding (SC), IV	up to 90% via SC (greater than heparin)	administered SC	- Rapidly and completely orally absorbed with bioavailability of 100% - Onset 8 hours post dose	5% PO bioavailability	50% oral bioavailability	80-100% PO bioavailability

PK: Distribution
Protein binding (PK: Distribution)	very high protein binding.	less prot bind than heparin		99% protein bound, predominantly albumin	35% protein bound	90% protein bound	95% protein bound
Volume of distribution (PK: Distribution)	Vd 0.05-0.1L/kg	Vd ~ 0.1L/kg		Vd 0.1L/Kg

PK: Metabolism	By heparinases in the liver, reticuloendothelial system and kidneys	Hepatic depolymerisation and desulfation to less active fragments		Completely hepatically metabolized Oxidation of L-form and reduction of D-form. Then conjugated with glucuronide.	Rapidly metabolized to active Dabigitran by hepatic and plasma esterases Not metabolized further	Hepatic metabolism (3A4) No active metabolites	Hepatic metabolism (3A4) No active metabolites

PK: Excretion	urine as inactive metabolites, little change in renal failure	urine as 40% of dose and 10% active fragments, dose adjustment in renal failure	excreted in the urine, dose adjustment required in renal failure	Metabolites excreted in urine and feces	Renal excretion	Renal and faeces (greater reliance on biliary elimination)	Renal and faeces
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	variable half life due to protein binding 30 - 150 mins depending on dose	2-4 times longer half-life than heparin dose independent half time		T1/2= 40 hours	T1/2= 12-17 hours	T1/2= 5-13 hours	T1/2= 5-13 hours


SPECIAL POINTS	Reversal: Protamine by slow infusion (1mg/100i.u. heparin). Cationic compound forms a stable covalent salt with heparin	Reversal: Protamine by slow infusion Less e¬ffective than heparin due to the preferential Xa action (1mg/1mg LMWH), but max effect is < 60%	Reversal: irreversible binding - no reversal agent dialysis with PMMA membranes works	Reversal: 1. Vitamin K 2. FFP 3. 4-factor PCC (Prothrombinex: 3-factor PCC available in Australia) Increase effect: 1. Cyp inhibitors- many antibiotics, cimetidine, amiodarone 2. Competitive plasma protein binding (Amiodarone, NSAIDs) 3. Decreased intake of vitamin K CYP2C9 genetic polymorphism Decrease effect: 1. CYP inducers- rifampicin, phenytoin, carbamazepine 2. Increased dietary intake of vitamin K CYP2C9 genetic polymorphism	Reversal: Idarucizumab Cons: 1. Many drug interactions 2. Excretion dependent on renal function Pros: 1. Predictable kinetics not affected by age, weight or gender 2. Oral 3. Monitoring generally not indicated 4. Reversal agent available 5. Lower bleeding risk than warfarin	Reversal: Andexanet alfa or 4-factor PCC (Prothrombinex 3-factor PCC available in Australia) Cons: 1. No specific reversal agent 2. Renal dose adjustment 3. Dose adjustment based on age and weight Pros: 1. Oral 2. Monitoring generally not indicated 3. Renal dose adjustment not required for eGFR >30 4. Lower bleeding risk than warfarin	Reversal: Andexanet alfa or 4-factor PCC (Prothrombinex 3-factor PCC available in Australia) Cons: 1. No specific reversal agent 2. Renal dose adjustment Pros: 1. Predictable kinetics not affected by age, weight or gender 2. Oral 3. Monitoring generally not indicated 4. Renal dose adjustment not required for eGFR >30 5. Lower bleeding risk than warfarin

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ANTICOAGULANT REVERSAL AGENTS

Pharmacopeia - Anticoagulant Reversal Agents

	IDARUCIZUMAB	PROTAMINE	VITAMIN K
GROUP	Anticoagulant Reversal Agents	Anticoagulant Reversal Agents	Anticoagulant Reversal Agents
CICM Level of Understanding	Level 3	Level 3	Level 3

INTRODUCTION	Monoclonal antibody Fab fragment	Basic cationic protein	Fat soluble vitamin
USES


PHARMACEUTICS (PC)	IV 5g bolus	1mg=100U heparin	Leafy vegetables (K1) Synthesized in GIT by bacteria (K2) Can be administered PO or IV
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Direct binding to Dabigitran	Heparin is acidic anionic protein. Combines with heparin to form a stable, inactive salt cleared by RES. Not able to completely reverse LMWH	Vit K is a cofactor for gamma-carboxylation glutamic residues of Vit K dependent clotting factors (2,7,9,10)
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	Minimal Headache	1. Pulmonary Hypertension - Complement activation and TxA2 release- only heparin-protamine complex elicits this 2. Myocardial depression, decreased SVR (Histamine release) 3. Weakly anticoagulant in absence of heparin 4. Allergic reaction	Flushing, hypotension Warfarin reversal


PHARMACOKINETICS (PK)
PK: Absorption	IV only	IV only	- PO requires bile (fat soluble). Onset at 6 hours, max 24hours - IV onset 2 hours, maximal effect at 12 hours

PK: Distribution
Protein binding (PK: Distribution)
Volume of distribution (PK: Distribution)	Vd 9L	Vd 5L

PK: Metabolism	Hepatic metabolism	Metabolism unclear

PK: Excretion			Elimination: Urine and feces
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	T1/2= 1 hour (occasionally require second dose)	T1/2= 7min


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ANTIPLATELET AGENTS

Pharmacopeia - Antiplatelet Agents

	ASPIRIN	CLOPIDOGREL	TICAGRELOR	PRASUGREL	DIPYRIDAMOLE	ABCIXIMAB	TIROFIBAN
GROUP	Antiplatelet	Antiplatelet	Antiplatelet	Antiplatelet	Antiplatelet	Antiplatelet	Antiplatelet
CICM Level of Understanding	Level 1	Level 3	Level 3	Level 3	-	Level 3	Level 3

INTRODUCTION	COX inhibitor	ADP Receptor Antagonist - Thienopyridine	ADP Receptor Antagonist - Thienopyridine	ADP Receptor Antagonist - Thienopyridine Prodrug	PDE3 inhibitor	GP IIb/IIIA Inhibitor	GP IIb/IIIA Inhibitor
USES


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action	Platelet inhibition	Platelet inhibition	Platelet inhibition	Platelet inhibition	Platelet inhibition	Platelet inhibition	Platelet inhibition
PD: Mode of Action	Non-specific Irreversible platelet cyclooxygenase inhibitor (COX-1 and 2) via acetylation of serine residues → ↓formation PG precursors. - Inhibits formation of thromboxane (TXA) → inhibit aggregation - At higher doses prostacyclin (PFI2) synthesis also inhibited → vasoconstriction (but endothelium can regenerate COX)	Prodrug. Hepatic activation to active agent (Thiol derivative, by oxidation and hydrolysis) which is an ADP receptor antagonist - Irreversible inhibition of P2Y12 receptor at platelet surface → Inhibits activation of GPIIb/IIIa → Inhibits platelet activation	Allosteric, reversible antagonist at P2Y12-R (an ADP receptor), preventing activation of glycoprotein IIb/IIIa→ prevents platelet crosslinking	Irreversibly binds the P2Y12-R (an ADP receptor), preventing activation of glycoprotein IIb/IIIa→ prevents platelet crosslinking	Phosphodiesterase 5&3 inhibition in the platelet→ cAMP and intracellular Ca. It reduces the platelet's ability to adhere to damaged vascular endothelium by inhibiting adenosine uptake, potentiates the effects of prostacyclin and interferes with adhesion more than aggregation. Also causes potent coronary vasodilatation	Similar mechanism as tirofiban but monoclonal antibody	Antagonises the GpIIb/IIIa receptor, preventing the binding of fibrinogen and platelet crosslinking and aggregation.
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	Bleeding Bronchospasm, Renal toxicity Reye’s Syndrome, GI ulceration Caution with other anticoagulants	Bleeding TTP Agranulocytosis, Neutropenia Significant drug interactions as requires activation by CYP450			Haemorrhage, may cause hypotension, thrombocytopenia and myalgias. Dipyridamole can be incorporated into gall stones.	Haemorrhage, thrombocytopenia, human antichimeric antibody development, allergic reaction	Haemorrhage Difficulty reversing agent Dose adjustment in renal impairment


PHARMACOKINETICS (PK)
PK: Absorption	- PO. BA. 50%. - 300mg Loading. 100mg maint.	- PO. BA 50% - 600mg loading. 75mg maint.	BA=40%

PK: Distribution
Protein binding (PK: Distribution)	85% protein binding, pKa 3	95% protein binding,
Volume of distribution (PK: Distribution)	Vd 10L	Vd unknown

PK: Metabolism	- Converted to salicylic acid in GI mucosa and liver - Hepatic conjugation (saturable)	- Hepatic CYP450 2C19 + Esterases to Inactive metab	Metabolized by CYP3A4	Prodrug- 1 step metabolism Less susceptible to CYP polymorphism and CYP inhibition or induction than Clopidogrel	Undergoes hepatic conjugation to glucuronide.	Platelet function typically returns to normal 24-48 hours after infusion ceases	Limited metabolism in humans.

PK: Excretion	- Renal as salicylate	- Renal and faecal elimination			Mainly excreted as glucuronides in bile,5% excreted in urine	Platelet function typically returns to normal 24-48 hours after infusion ceases	Excreted in urine and faeces, mostly unchanged
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	- T1/2b 15~20 mins when first order - Dur: 4-6 hrs. (Effect on platelet aggregation will last life of current cohort of platelets (7-10 days)	- T1/2b 7 hours parent drug (30mins metab) Dur: life of platelet			HL 10-12 hrs		HL 1.9-2.2 hrs


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FIBRINOLYTICS / ANTIFIBRINOLYTICS

Pharmacopeia - Fibrinolytics / Antifibrinolytics

	ALTEPLASE	TENECTEPLASE	TRANEXAMIC ACID
GROUP	Fibrinolytic	Fibrinolytic	AntiFibrinolytic
CICM Level of Understanding	Level 3	Level 3	Level 3

INTRODUCTION	Recombinant tissue plasminogen activator	Recombinant tissue plasminogen activator	Synthetic Lysine Derivative Antifibrinolytic
USES			1. Trauma 2. Elective Arthroplasty 3. Hemophilia 4. Obstetric surgery 5. Menorrhagia 6. Recent evidence to suggest possible role in mild to moderate TBI


PHARMACEUTICS (PC)	administered IV and dosing depends on the indication (AMI and PE use bolus followed by infusion. Stroke uses infusion). All thrombolytics except streptokinase are prepared with heparin.	modified version of alteplase with several potential advantages over alteplase, such as a longer half-life and higher fibrin specificity	PO and IV 500mg tablet, 1g IV
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	It is a glycoprotein that only becomes activated when bound to thrombus bound-plasminogen. This activation then leads to the conversion of plasminogen to plasmin, which cleaves fibrin into fibrin degradation products, such d-dimers. This mechanism of activation decreases the systemic effects	It is a glycoprotein that only becomes activated when bound to thrombus bound-plasminogen. This activation then leads to the conversion of plasminogen to plasmin, which cleaves fibrin into fibrin degradation products, such d-dimers. This mechanism of activation decreases the systemic effects	Reversibly inhibits lysine binding sites on plasminogen → Inhibits conversion of plasminogen to plasmin, thereby preventing the breakdown of fibrin
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	Haemorrhage (cease drug, resuscitate +- tranexamic acid) Cardiovascular- reperfusion arrhythmias and hypotension during treatment of MI Reperfusion pain	Haemorrhage (Less than Alteplase) (cease drug, resuscitate +- tranexamic acid) Cardiovascular- reperfusion arrhythmias and hypotension during treatment of MI Reperfusion pain	1. Abdominal pain, especially on rapid bolus 2. Possible risk of increased VTE (exact risk is controversial) 3. Delayed seizures


PHARMACOKINETICS (PK)
PK: Absorption			BA 50%

PK: Distribution
Protein binding (PK: Distribution)			<3L PB
Volume of distribution (PK: Distribution)	Small Vd of 2-4L	Vd 2-4L	Vd- 9-12L, crosses into all tissues

PK: Metabolism	Undergoes hepatic metabolism to smaller peptides.	Hepatic metabolism	Minimally metabolized

PK: Excretion	Undergoes biphasic elimination, with rapid plasma clearance.	Biphasic elimination Slower renal clearance than alteplase	95% unchanged in urine
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)			T1/2 90min-3 hours


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BLOOD PRODUCTS

Pharmacopeia - Blood Products

	RED BLOOD CELLS (RBC)	FRESH FROZEN PLASMA (FFP)	PLATELETS	CRYOPRECIPITATE
GROUP	Blood Products	Blood Products	Blood Products	Blood Products
CICM Level of Understanding	Level 1	Level 1	Level 1	Level 1

PHARMACEUTICS (PC)	250-300ml/unit	1 unit= 200-300ml (contains all coagulation factors) Dose= 10-15ml/kg	1 unit is 60ml ‘Pooled platelets’ is 4 units	PHARMACEUTICS (PC) 250-300ml/unit 1 unit= 200-300ml (contains all coagulation factors) Dose= 10-15ml/kg 1 unit is 60ml ‘Pooled platelets’ is 4 units 1 unit - vWF, fibrinogen, fibronectin, vWF, factor 8, Factor 13


PHARMACODYNAMICS (PD)	Collection: Collected as whole blood samples in CPD (citrate, phosphate and dextrose) Preparation: Citrated, centrifuged, leucodepleted Generally irradiated ABO and rhesus matched Storage: 4’C for decreased metabolism and bacteria SAG-M - Saline (tonicity), adenine, glucose and manitol (keeps tonicity stable)	Collection: Collected as Whole blood or apheresis Preparation: Plasma that remains after removal of RBC/platelets Must be thawed (15-30min) prior to administration Contains citrate Storage: -30’C	Collection: Collected as Whole blood or apheresis Preparation: Platelets are typed in Australia Match for CMV status Can irradiate Storage: 20-24’C, continuously agitated	Collection: Collected as Whole blood or apheresis Cryo supinate used for TTP exchange Preparation: Insoluble proteins that precipitate when FFP is thawed. Storage: -25’C
PD: Side Effects / Toxicity	Effects of Storage: - Some red cells become spherical and have increased rigidity (10-20% lost on transfusion by 24 hours) - Buffering capacity lost due to lactic acidosis and leading to pH of 6.5 - Decreased 2,3-DPG - Paralysis of Na/K/ATPase leads to potassium concentration of 30mmol/L at 30 days - Glucose decreases (19 to 12) - Free haemoglobin increases		Effects of Storage: Risks infection due to temperature of storage. Storing beyond this time frame or below this temperature decreases platelet activation


PHARMACOKINETICS (PK)	Lifespan: 42 days (28 if washed)	Lifespan: 12 months Can be used for up to 5 days after being thawed	Lifespan: 5 days	Lifespan: 12 months

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FRACTIONATED PLASMA PRODUCTS AND IVIG

Pharmacopeia - Fractionated Plasma Products & IVIg

	ALBUMIN	FIBRINOGEN CONCENTRATE	PROTHROMBINEX (PCC)	ATIII	FACTOR IX	FACTOR VIIA	FACTOR VIII	INTRAVENOUS IMMUNOGLOBULIN (IVIg)
GROUP	Fractionated Plasma Product	Fractionated Plasma Product	Fractionated Plasma Product	Fractionated Plasma Product	Fractionated Plasma Product	Fractionated Plasma Product	Fractionated Plasma Product	IVIg
CICM Level of Understanding	Level 1	Level 2	Level 2	Level 3	Level 3	Level 3	Level 3	Level 3

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INDIVIDUAL TABLES

CLOPIDOGREL

Pharmacopeia - Antiplatelet Agents

	CLOPIDOGREL
GROUP	Antiplatelet
CICM Level of Understanding	Level 3

INTRODUCTION	ADP Receptor Antagonist - Thienopyridine
USES


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action	Platelet inhibition
PD: Mode of Action	Prodrug. Hepatic activation to active agent (Thiol derivative, by oxidation and hydrolysis) which is an ADP receptor antagonist - Irreversible inhibition of P2Y12 receptor at platelet surface → Inhibits activation of GPIIb/IIIa → Inhibits platelet activation
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	Bleeding TTP Agranulocytosis, Neutropenia Significant drug interactions as requires activation by CYP450


PHARMACOKINETICS (PK)
PK: Absorption	- PO. BA 50% - 600mg loading. 75mg maint.

PK: Distribution
Protein binding (PK: Distribution)	95% protein binding,
Volume of distribution (PK: Distribution)	Vd unknown

PK: Metabolism	- Hepatic CYP450 2C19 + Esterases to Inactive metab

PK: Excretion	- Renal and faecal elimination
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	- T1/2b 7 hours parent drug (30mins metab) Dur: life of platelet


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ASPIRIN

Pharmacopeia - Antiplatelet Agents

	ASPIRIN
GROUP	Antiplatelet
CICM Level of Understanding	Level 1

INTRODUCTION	COX inhibitor
USES


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action	Platelet inhibition
PD: Mode of Action	Non-specific Irreversible platelet cyclooxygenase inhibitor (COX-1 and 2) via acetylation of serine residues → ↓formation PG precursors. - Inhibits formation of thromboxane (TXA) → inhibit aggregation - At higher doses prostacyclin (PFI2) synthesis also inhibited → vasoconstriction (but endothelium can regenerate COX)
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	Bleeding Bronchospasm, Renal toxicity Reye’s Syndrome, GI ulceration Caution with other anticoagulants


PHARMACOKINETICS (PK)
PK: Absorption	- PO. BA. 50%. - 300mg Loading. 100mg maint.

PK: Distribution
Protein binding (PK: Distribution)	85% protein binding, pKa 3
Volume of distribution (PK: Distribution)	Vd 10L

PK: Metabolism	- Converted to salicylic acid in GI mucosa and liver - Hepatic conjugation (saturable)

PK: Excretion	- Renal as salicylate
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	- T1/2b 15~20 mins when first order - Dur: 4-6 hrs. (Effect on platelet aggregation will last life of current cohort of platelets (7-10 days)


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ASPIRIN | CLOPIDOGREL

Pharmacopeia - Antiplatelet Agents

	ASPIRIN	CLOPIDOGREL
GROUP	Antiplatelet	Antiplatelet
CICM Level of Understanding	Level 1	Level 3

INTRODUCTION	COX inhibitor	ADP Receptor Antagonist - Thienopyridine
USES


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action	Platelet inhibition	Platelet inhibition
PD: Mode of Action	Non-specific Irreversible platelet cyclooxygenase inhibitor (COX-1 and 2) via acetylation of serine residues → ↓formation PG precursors. - Inhibits formation of thromboxane (TXA) → inhibit aggregation - At higher doses prostacyclin (PFI2) synthesis also inhibited → vasoconstriction (but endothelium can regenerate COX)	Prodrug. Hepatic activation to active agent (Thiol derivative, by oxidation and hydrolysis) which is an ADP receptor antagonist - Irreversible inhibition of P2Y12 receptor at platelet surface → Inhibits activation of GPIIb/IIIa → Inhibits platelet activation
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	Bleeding Bronchospasm, Renal toxicity Reye’s Syndrome, GI ulceration Caution with other anticoagulants	Bleeding TTP Agranulocytosis, Neutropenia Significant drug interactions as requires activation by CYP450


PHARMACOKINETICS (PK)
PK: Absorption	- PO. BA. 50%. - 300mg Loading. 100mg maint.	- PO. BA 50% - 600mg loading. 75mg maint.

PK: Distribution
Protein binding (PK: Distribution)	85% protein binding, pKa 3	95% protein binding,
Volume of distribution (PK: Distribution)	Vd 10L	Vd unknown

PK: Metabolism	- Converted to salicylic acid in GI mucosa and liver - Hepatic conjugation (saturable)	- Hepatic CYP450 2C19 + Esterases to Inactive metab

PK: Excretion	- Renal as salicylate	- Renal and faecal elimination
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	- T1/2b 15~20 mins when first order - Dur: 4-6 hrs. (Effect on platelet aggregation will last life of current cohort of platelets (7-10 days)	- T1/2b 7 hours parent drug (30mins metab) Dur: life of platelet


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HEPARIN | LMWH

Pharmacopeia - Anticoagulants

	UNFRACTIONATED HEPARIN (UFH)	LOW MOLECULAR WEIGHT HEPARIN (LMWH)
GROUP	Anticoagulants	Anticoagulants
CICM Level of Understanding	Level 1	Level 1

INTRODUCTION	Heparin is an anioic, mucopolysaccaride, organic acid. It occurs naturally in the liver and mast cell granules. MW: 5000-25000 Daltons	Enoxaparin is a LMWH prepared from unfractionated heparin by controlled enzymatic or chemical depolymerisation Consists of smaller fragments of Heparin. MW: Average of 5000 Daltons
USES	1. the prevention of venous thromboembolic disease 2. the priming of haemodialysis and cardiopulmonary bypass machines and for maintaining the patency of indwelling lines and the treatment of 3. DIC 4. fat embolism, and 5. in the treatment of acute coronary syndromes.	1. the prevention of venous thromboembolic disease 2. the treatment of acute coronary syndromes.


PHARMACEUTICS (PC)	s/c or i.v. - I.U. (not mg) due to variable potencies. 5000IU BD s/c or 5000IU IV then infusion-rate based on wttitrated (APTT)	Usually s/c, but can be given i.v. 20mg or 40mg BD s/c as prophylaxis, 1mg/kg BD s/c as therapeutic dose Monitor: Anti-Xa level
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Activates antithrombin which then inhibits clotting factors thrombin and factor Xa	Activates antithrombin but due to shorter length preferentially inhibits factor Xa
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	Bleeding, Heparin Induced Thrombocytopaenia, Osteoporosis, Transient transaminitis	Bleeding Needs adjustment in renal failure Less HITS and osteoporosis


PHARMACOKINETICS (PK)
PK: Absorption	reduced due to endothelial binding (SC), IV	up to 90% via SC (greater than heparin)

PK: Distribution
Protein binding (PK: Distribution)	very high protein binding.	less prot bind than heparin
Volume of distribution (PK: Distribution)	Vd 0.05-0.1L/kg	Vd ~ 0.1L/kg

PK: Metabolism	By heparinases in the liver, reticuloendothelial system and kidneys	Hepatic depolymerisation and desulfation to less active fragments

PK: Excretion	urine as inactive metabolites, little change in renal failure	urine as 40% of dose and 10% active fragments, dose adjustment in renal failure
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	variable half life due to protein binding 30 - 150 mins depending on dose	2-4 times longer half-life than heparin dose independent half time


SPECIAL POINTS	Reversal: Protamine by slow infusion (1mg/100i.u. heparin). Cationic compound forms a stable covalent salt with heparin	Reversal: Protamine by slow infusion Less e¬ffective than heparin due to the preferential Xa action (1mg/1mg LMWH), but max effect is < 60%

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LMWH | HIRUDIN

Pharmacopeia - Anticoagulants

	LOW MOLECULAR WEIGHT HEPARIN (LMWH)	HIRUDIN
GROUP	Anticoagulants	Anticoagulants
CICM Level of Understanding	Level 1	Not in list (Historical question)

INTRODUCTION	Enoxaparin is a LMWH prepared from unfractionated heparin by controlled enzymatic or chemical depolymerisation Consists of smaller fragments of Heparin. MW: Average of 5000 Daltons	Is a naturally occurring peptide found in leaches saliva with anticoagulant properties recombinant techniques are used to create drugs in this class
USES	1. the prevention of venous thromboembolic disease 2. the treatment of acute coronary syndromes.


PHARMACEUTICS (PC)	Usually s/c, but can be given i.v. 20mg or 40mg BD s/c as prophylaxis, 1mg/kg BD s/c as therapeutic dose Monitor: Anti-Xa level
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Activates antithrombin but due to shorter length preferentially inhibits factor Xa	is via direct irreversible binding to thrombin Causes a prolongation of bleeding time
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	Bleeding Needs adjustment in renal failure Less HITS and osteoporosis	Bleeding


PHARMACOKINETICS (PK)
PK: Absorption	up to 90% via SC (greater than heparin)	administered SC

PK: Distribution
Protein binding (PK: Distribution)	less prot bind than heparin
Volume of distribution (PK: Distribution)	Vd ~ 0.1L/kg

PK: Metabolism	Hepatic depolymerisation and desulfation to less active fragments

PK: Excretion	urine as 40% of dose and 10% active fragments, dose adjustment in renal failure	excreted in the urine, dose adjustment required in renal failure
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	2-4 times longer half-life than heparin dose independent half time


SPECIAL POINTS	Reversal: Protamine by slow infusion Less e¬ffective than heparin due to the preferential Xa action (1mg/1mg LMWH), but max effect is < 60%	Reversal: irreversible binding - no reversal agent dialysis with PMMA membranes works

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WARFARIN

Pharmacopeia - Anticoagulants

	WARFARIN
GROUP	Anticoagulants
CICM Level of Understanding	Level 1

INTRODUCTION	Coumarin derivative
USES	1. AF 2. Thromboprophylaxis in rheumatic or prosthetic valves 3. Prophylaxis and treatment of DVT/PE


PHARMACEUTICS (PC)	Racemic mixture of warfarin sodium (S enantiomer is 2-5x more potent) 0.5/1/3/5mg tablets Maximum effect 18-72 hours after dose Monitor: INR aim generally 2.0-4.5 depending on indication (most commonly 2-3)
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Vitamin K is responsible for the gamma-carboxylation of glutamic residues of inactive precursors of clotting factors 2,7,9,10. Warfarin prevents the return of vitamin K to its reduced form, inhibiting the activation of these factors.
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	1. Hemorrhage 2. Teratogenicity - More common and serious in first trimester 3. In third trimester it may cross the placenta and cause fetal hemorrhage.


PHARMACOKINETICS (PK)
PK: Absorption	- Rapidly and completely orally absorbed with bioavailability of 100% - Onset 8 hours post dose

PK: Distribution
Protein binding (PK: Distribution)	99% protein bound, predominantly albumin
Volume of distribution (PK: Distribution)	Vd 0.1L/Kg

PK: Metabolism	Completely hepatically metabolized Oxidation of L-form and reduction of D-form. Then conjugated with glucuronide.

PK: Excretion	Metabolites excreted in urine and feces
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	T1/2= 40 hours


SPECIAL POINTS	Reversal: 1. Vitamin K 2. FFP 3. 4-factor PCC (Prothrombinex: 3-factor PCC available in Australia) Increase effect: 1. Cyp inhibitors- many antibiotics, cimetidine, amiodarone 2. Competitive plasma protein binding (Amiodarone, NSAIDs) 3. Decreased intake of vitamin K CYP2C9 genetic polymorphism Decrease effect: 1. CYP inducers- rifampicin, phenytoin, carbamazepine 2. Increased dietary intake of vitamin K CYP2C9 genetic polymorphism

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DABIGATRAN | WARFARIN

Pharmacopeia - Anticoagulants

	DABIGATRAN	WARFARIN
GROUP	Anticoagulants	Anticoagulants
CICM Level of Understanding	Level 2	Level 1

INTRODUCTION	Competitive Direct Thrombin Inhibitor	Coumarin derivative
USES	1. Non-valvular AF 2. VTE prophylaxis in orthopaedic 3. VTE treatment	1. AF 2. Thromboprophylaxis in rheumatic or prosthetic valves 3. Prophylaxis and treatment of DVT/PE


PHARMACEUTICS (PC)	PO (Dabigitran etexilate- prodrug) Monitor: Direct assays of Thrombin activity: - Thrombin time (TT) - Ecarin clotting time (ECT) - APTT 2.5x >control= increased risk of bleeding	Racemic mixture of warfarin sodium (S enantiomer is 2-5x more potent) 0.5/1/3/5mg tablets Maximum effect 18-72 hours after dose Monitor: INR aim generally 2.0-4.5 depending on indication (most commonly 2-3)
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	MOA: Competitive direct thrombin inhibitor. Blocks pivotal part of common pathway Gastric irritation (tartaric acid)	Vitamin K is responsible for the gamma-carboxylation of glutamic residues of inactive precursors of clotting factors 2,7,9,10. Warfarin prevents the return of vitamin K to its reduced form, inhibiting the activation of these factors.
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	Bleeding	1. Hemorrhage 2. Teratogenicity - More common and serious in first trimester 3. In third trimester it may cross the placenta and cause fetal hemorrhage.


PHARMACOKINETICS (PK)
PK: Absorption	5% PO bioavailability	- Rapidly and completely orally absorbed with bioavailability of 100% - Onset 8 hours post dose

PK: Distribution
Protein binding (PK: Distribution)	35% protein bound	99% protein bound, predominantly albumin
Volume of distribution (PK: Distribution)		Vd 0.1L/Kg

PK: Metabolism	Rapidly metabolized to active Dabigitran by hepatic and plasma esterases Not metabolized further	Completely hepatically metabolized Oxidation of L-form and reduction of D-form. Then conjugated with glucuronide.

PK: Excretion	Renal excretion	Metabolites excreted in urine and feces
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	T1/2= 12-17 hours	T1/2= 40 hours


SPECIAL POINTS	Reversal: Idarucizumab Cons: 1. Many drug interactions 2. Excretion dependent on renal function Pros: 1. Predictable kinetics not affected by age, weight or gender 2. Oral 3. Monitoring generally not indicated 4. Reversal agent available 5. Lower bleeding risk than warfarin	Reversal: 1. Vitamin K 2. FFP 3. 4-factor PCC (Prothrombinex: 3-factor PCC available in Australia) Increase effect: 1. Cyp inhibitors- many antibiotics, cimetidine, amiodarone 2. Competitive plasma protein binding (Amiodarone, NSAIDs) 3. Decreased intake of vitamin K CYP2C9 genetic polymorphism Decrease effect: 1. CYP inducers- rifampicin, phenytoin, carbamazepine 2. Increased dietary intake of vitamin K CYP2C9 genetic polymorphism

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TRANEXAMIC ACID

Pharmacopeia - Fibrinolytics / Antifibrinolytics

	TRANEXAMIC ACID
GROUP	AntiFibrinolytic
CICM Level of Understanding	Level 3

INTRODUCTION	Synthetic Lysine Derivative Antifibrinolytic
USES	1. Trauma 2. Elective Arthroplasty 3. Hemophilia 4. Obstetric surgery 5. Menorrhagia 6. Recent evidence to suggest possible role in mild to moderate TBI


PHARMACEUTICS (PC)	PO and IV 500mg tablet, 1g IV
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Reversibly inhibits lysine binding sites on plasminogen → Inhibits conversion of plasminogen to plasmin, thereby preventing the breakdown of fibrin
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	1. Abdominal pain, especially on rapid bolus 2. Possible risk of increased VTE (exact risk is controversial) 3. Delayed seizures


PHARMACOKINETICS (PK)
PK: Absorption	BA 50%

PK: Distribution
Protein binding (PK: Distribution)	<3L PB
Volume of distribution (PK: Distribution)	Vd- 9-12L, crosses into all tissues

PK: Metabolism	Minimally metabolized

PK: Excretion	95% unchanged in urine
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	T1/2 90min-3 hours


SPECIAL POINTS

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ALTEPLASE

Pharmacopeia - Fibrinolytics / Antifibrinolytics

	ALTEPLASE
GROUP	Fibrinolytic
CICM Level of Understanding	Level 3

INTRODUCTION	Recombinant tissue plasminogen activator
USES


PHARMACEUTICS (PC)	administered IV and dosing depends on the indication (AMI and PE use bolus followed by infusion. Stroke uses infusion). All thrombolytics except streptokinase are prepared with heparin.
PC: Chemical
PC: Presentation


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	It is a glycoprotein that only becomes activated when bound to thrombus bound-plasminogen. This activation then leads to the conversion of plasminogen to plasmin, which cleaves fibrin into fibrin degradation products, such d-dimers. This mechanism of activation decreases the systemic effects
PD: Route & Doses
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects
PD: Side Effects / Toxicity	Haemorrhage (cease drug, resuscitate +- tranexamic acid) Cardiovascular- reperfusion arrhythmias and hypotension during treatment of MI Reperfusion pain


PHARMACOKINETICS (PK)
PK: Absorption

PK: Distribution
Protein binding (PK: Distribution)
Volume of distribution (PK: Distribution)	Small Vd of 2-4L

PK: Metabolism	Undergoes hepatic metabolism to smaller peptides.

PK: Excretion	Undergoes biphasic elimination, with rapid plasma clearance.
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)


SPECIAL POINTS

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Y09. Pharmacopeia: Haematological Pharmacology

CICMWrecks Tables (Click to Open)

MASTER TABLES

ANTICOAGULANTS

Pharmacopeia - Anticoagulants

ANTICOAGULANT REVERSAL AGENTS

Pharmacopeia - Anticoagulant Reversal Agents

ANTIPLATELET AGENTS

Pharmacopeia - Antiplatelet Agents

FIBRINOLYTICS / ANTIFIBRINOLYTICS

Pharmacopeia - Fibrinolytics / Antifibrinolytics

BLOOD PRODUCTS

Pharmacopeia - Blood Products

FRACTIONATED PLASMA PRODUCTS AND IVIG

Pharmacopeia - Fractionated Plasma Products & IVIg

INDIVIDUAL TABLES

CLOPIDOGREL

Pharmacopeia - Antiplatelet Agents

ASPIRIN

Pharmacopeia - Antiplatelet Agents

ASPIRIN | CLOPIDOGREL

Pharmacopeia - Antiplatelet Agents

HEPARIN | LMWH

Pharmacopeia - Anticoagulants

LMWH | HIRUDIN

Pharmacopeia - Anticoagulants

WARFARIN

Pharmacopeia - Anticoagulants

DABIGATRAN | WARFARIN

Pharmacopeia - Anticoagulants

TRANEXAMIC ACID

Pharmacopeia - Fibrinolytics / Antifibrinolytics

ALTEPLASE

Pharmacopeia - Fibrinolytics / Antifibrinolytics

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