Other Flashcards
Phenothiazine
E.g Chlorpromazine, Prochlorperazine
- Antipsychotic
Indications - Schizophrenia, Anti-emesis, vertigo
MoA
▪ D2 receptor antagonists
▪ MAChR antagonists
▪ A1 and a2 adrenoceptor antagonists
▪ H1 receptor antagonists
▪ 5-HT receptor antagonists
▪ Inhibit uptake 1 of NA
Effects
▪ Sedation and neurolepsy (reduced motor activity)
▪ EPSE
▪ Hyperprolactinaemia
▪ Neuroleptic malignant syndrome
▪ Postural hypotension
▪ Increase appetite
▪ Anti-emetic
▪ Moderate anticholinergic effects
▪ Hypothermia
Droperidol
- Butyrophenone
- Dose 0.625-1.25mg IV
- Incompatible with thio
- Light protective ampoule
MoA
- D2 antagonist at CTZ
- Some HA, 5-HT and alpha antagonist activity
- Some post synaptic GABA antagonism
- Similar efficacy for N+V
PK
- High PO bioavailability 75%
- High protein binding
- Onset 5-15mins, sedating effect may last up to 12hrs
- Extensive hepatic metabolism
- Renal excretion, T1/2 3hrs
Adverse effects
- Sedation - tends to be at lower doses due to alpha antagonism
- EPSE - Parkinsonism, akathisia (restlessness), tardive dyskinesia, acute dystonia, neuroleptic malignant syndrome, neurolepsis
- Prolonged QT -> torsades
- Postural hypotension
- Extrapyramidal effects
Butyrophenones
E.g droperidol, haloperidol, domperidone (does not cross BBB)
MoA
- D2 antagonists (CTZ)
- Some 5HT, histamine and a-antagonist activity
Indications
- Psychosis
- Delirium
- Anti-emesis
- Neuroleptic anaesthetsia
Haloperidol
- 0.5-2mg IM/IV
- T1/2 10-20hrs
Effects
- Sedation
- Neurolepsy
- Extrapyramidal effects
- Neuroleptic malignant syndrome
- Anti-emetic effect
- Postural hypotension
- Prolonged QT interval -> torsades, dose-related effect
- Hyperprolactinaemia
Lithium
MoA
- Largely unknown - may act as a membrane stabilise or alter central NT function
- 95% excreted in urine, remainder in sweat
Effects
- Reversible ECG changes - T wave depression
- Lower seizure threshold in epileptics
- Polyuria/ polydipsia - antagonises ADH
- Hypernatraemia - ↑aldosterone secretion
- ↑Ca + ↑Mg
- Thyroid dysfunction
- Weight gain
- Nephrogenic DI with long term treatment
Toxicity
- N+V
- Ataxia
- Convulsions
- Coma
- Dysrhythmia
Neuroleptic malignant syndrome
MOA
- Can be triggered by all D2 antagonists
- Blockade of D2 receptors in corpus striatum
=> Spasticity of skeletal muscles
=> Excessive heat production
Risk factors
- Rapid ↑dose
- Long lasting forms
- Men <40yrs
- Postpartum women
- Genetic predisposition
Signs
- Slow onset 24-72hrs
- Muscle rigidity with ↑CK
- Hyperthermia
- Autonomic instability
- Delirium
Tx
- Discontinue precipitating drug
- Support care in ICU
- Dantrolene
- Dopamine agonists - bromocriptine
- IVF
Sodium valproate
Anticonvulsant - salt of carboxylic acid
MoA
- Stabilises the inactive state of voltage gated Na+ channels
- Inhibits enzymes that deactivate GABA -> stimulation of GABAergic inhibitory activity
Side effects
- GIT upset
- Hepatitis
- Pancreatitis
- Transient hair loss
- Thrombocytopenia
- Teratogenic
Phenytoin
- Anticonvulsant - hydantoin
- Irritant on injection
- Uses - epilepsy, trigeminal neuralgia, TCA overdose, digoxin-induced arrhythmia
MoA
- Stabilises the inactive state of voltage gated Na+ channels -> limits repetitive generation of APs
PK
- A - Slow PO absorption, PO bioavailability 70-100%
- D - Highly protein bound 90%
- M - metabolised by hepatic hydroxylation via CYP, saturable process (1st -> zero order kinetic), genetic polymorphism, small TI
- E - metabolites excreted in urine
Effects
Dose dependent
- Anti-convulsant
- Class Ib anti-arrhythmic
- Hypotension, heart block, arrhythmia
- N+V
- Sedation
- Tremour
- Vertigo
- Slurred speech
- Ataxia
- Nystagmus - sign of toxicity
- Rapid infusion -> hypotension, heart block, asystole
Idiosyncratic
- Rash
- Gum hyperplasia
- Acne
- Blood dyscrasias
- SLE
- Hepatotoxicity
- Allergic reaction
- Peripheral neuropathy
- Trigger of porphyria
Other
- Teratogenic
- Hypoglycaemia
- Hypocalcaemia
Carbemazepine
MoA
- Stabilise inactive state of voltage gated Na channels and limits generation of AP
Adverse effects
- Drowsiness
- Antidiuretic effect
- Hepatitis
- Teratogenic
- Hepatic enzyme induction
Lamotrigine
Anticonvulsant - triazine
MoA
- Stabilises the inactive state of voltage gated Na channels -> ↓release of aspartate and glutamate (excitatory NT)
- Hepatic metabolism to inactive metabolites
- Rarely causes SJS
Levetiracetam
Mechanism different to other anticonvsulants
- Inhibits intracellular Ca release
PK
- 95% excreted in urine
- Does not interact with CYP
Adverse effects
- Somnolence
- Headache
- Nasopharyngitis
Anti-parkinsonian drugs
Levodopa (precursor of dopamine)
- 1% crosses BBB -> converted to dopamine
- Rest rapidly decarboxylated to DA in liver
=> DA does not cross BBB
=> ↑plasma conc of DA -> ↑S/E
=> Coadministered with peripheral decarboxylase inhibitor (carbidopa) -> ↑proportion of levodopa crossing BBB, ↓S/E
- Reduced effect after 1-5yrs of tx due to DA depletion/ disease progression
- Adverse effects - postural hypotension, arrhythmias, nausea, abnormal involuntary movements (dyskinesia, oculogyric crisis), behavioural disturbance
Carbidopa (peripheral decarboxylase inhibitor)
- Pharmacologically inactive alone
- Combined with levodopa (e.g sinemet - levodopa + carbidopa)
- Inhibit dopa decarboxylase
Bromocriptine (dopamine agonist)
- Hypoprolactinaemia
- ↓secretion of GH
- Adverse effects - orthostatic hypotension, dyskinesia, nausea
Benztropine (Anticholinergic)
- Cross BBB -> ↓central excitatory ACh activity
- Modest effects
- May help control tremour
- Not useful for muscle rigidity and bradykinesia
- Anticholinergic S/E
Amantadine (antiviral)
- Unknown MoA
- May improve muscle rigidity and bradykinesia
Domperidone (dopamine antagonist)
- Does not cross BBB
- Given with levodopa to ↓peripheral S/E
- Antiemetic properties
Selegiline
- Selective irreversible MAO-B inhibitor
- MAO-B deaminated DA
Serotonin
5-hydroxytryptamine (5HT)
- 90% located in GI enterochromaffin cells
- 10% in CNS and platelets
Endogenous monoamine NT
- Pathways for GI motility, appetitie, emesis, pain, mood
- Vasoactive - dual actions of vasoconstriction + vasodilation; vasoconstriction of cerebral, splanchnic, renal + pulmonary vessels; vasodilation of damaged blood vessels
Synthesis
- L-tryptophan -> 5-hydrpxytryptophan (tryptophan hydroxylase) -> 5-HT (aromatic acid decarboxylase)
- Metabolised by MAO after re-uptake into pre-synaptic terminal
Metablism
- Liver to 5-HIAA (5-hydro-indole-acetic-acid)
=> MAO
=> Aldehyde dehydrogenase
Renal excretion
Serotonin syndrome
MoA - excessive serotonin activity at central and peripheral 5-HT receptors
Triggers
- SSRIs + MAOi/ TCA/ pethidine/ tramadol
Signs + Sx
- Rapid onset
- Cognitive - confusion, agitation, hallucination
- Autonomic - sweating, hyperthermia, HTN, ↑HR
- Somatic - hyperreflexia, myoclonus, tremour
Tx
- Discontinue precipitant
- Supportive care in ICU - BZD, direct acting inotropes, short acting anti-HTN
- Cyproheptadine - antagonist
Serotonin receptors
Mostly metabotropic GPCR - except 5HT3 (ligand gated ion channel)
- Both excitatory and inhibitory
5-HT1
- GiPCR -> ↓cAMP
- 5HT1A and 5HT1B
=> CNS - behavioural effects (sleep, thermoregulation)
=> Buspirone (1A) - promotes CNS excitation = antidepressant/ anxiolytic
=> Ergotamine (1B) - cerebral vasoconstriction for migraine
=> Paracetamol (1B) - analgesic
- 5HT1D
=> CNS - vasoconstriction of cerebral vessels
=> Agonist - sumatriptan for migraine
5-HT2
- GqPCR -> ↑IP3/DAG
- 5-HT2A
=> CNS, intestine
=> Platelets - aggregation response
=> Agonist - LSD -> CNS excitation
=> Antagonist - cyproheptadine (antihistamine)
- 5-HT2B
=> Gastric fundus - contraction
=> Methylsergide (2B/C) - tx of carcinoid syndrome diarrhoea
- 5-HT2C
=> CNS - choroid plexus ↑CSF production
5-HT3
- Ligand gated Na + K channel
- PSNS (incl vagal and splanchnic afferent)/ NTS/ area postrema - N+V, anxiety)
- Antagonist = ondansetron (antiemetic)
5-HT4
- GsPCR -> ↑cAMP
- CNS + GIT - GIT secretion and peristalsis
- Metoclopramide - ↑gastric motility + LOS
5-HT5-7
- GsPCR -> ↑cAMP
- CNS
Serotonergic Drugs
Direct action
- Serotonin agonists
=> Sumatriptan (5HT1B + 5HT1D agonist)
=> Paracetamol (5HT1B agonist)
- Serotonin antagonist
=> Ketanserin (5HT2 antagonist)
=> Ondansetron (5HT3 antagonist) - Mixed effect
=> Metoclopramide (mixed 5HT3 antagonist (high doses) and 5HT4 agonist)
Indirect action
- SSRI/ SNRI
=> Inhibit 5-HT reuptake at pre-synaptic membrane
=> Anti-depressant/ anxiolytic
- TCAs
=> Inhibit neuronal reuptake of 5HT - MAOIs
=> MAO-A deaminates 5-HT
=> Inhibits 5-HT metabolism
=> Anti-depressant - Tramadol
=> Indirect agonist - facilitates 5-HT release from pre-synaptic membrane
=> Block reuptake of NA + 5HT
=> Analgesia
Anticoagulants
Indirect thrombin inhibitors
- Heparins - UFH, LMWH
- Synthetic pentasaccharide derivative - fondaparinux
- Vit K antagonists - warfarin
- Direct factor Xa inhibitors - rivaroxiban, apixaban
Direct thrombin inhibitors
- Univalent - dabigatran, argatroban
- Bivalent - hirudin, lepirudin
Unfractionated heparin
- Naturally occurring glycosaminoglycan
- Derived from bovine lung or porcine intestine
- Variable MW 5000-25000Da
- Dose titrated to 1.5-2.5x normal APTT, begin infusion at 15units/kg, bolus of 5000 IU
MoA
- Reversibly bind to antithrombin III (ATIII) -> conformational change of ATIII molecule -> 1000 fold ↑ of activity of ATIII -> inactivation of FXa (at low concentrations) + inactivation of FIXa, FXIa, + FXIIa (as conc rises)
- Formation of Heparin-ATIII-FIIa complex -> inactivation of FIIa (FII = prothrombin, FIIa = thrombin)
- Anti-FXa : anti-FIIa ratio = 1:1
- Stimulates release of TFPI
- Impairs plt aggregation mediated by vWF and collagen
- Inhibits plt function by direct binding to plt
PK
- A - ineffective PO, avoid IM due to haematoma, SC and IV reach similar peak Cp - slower onset for SC. 40% bioavailability for SC
- D - low lipid solubility, does not cross BBB + placenta, highly protein bound - 1/3 to AT-III, 2/3 to albumin, fibrinogen, proteases. Immediate onset post IV
- M - non-linear, rapid saturable phase due to cellular degradation by macrophages which internalise heparin and grade it. Saturation when all receptors used and further Cl depends on new receptor synthesis. Accounts for poor bioavailability after low dose SC injection (slow rate of absorption barely exceeds capacity of cellular degradation).
=> Metabolism via heparinases in liver and kidneys
- E - renal excretion, T1/2 90mins
Effects
- Direct anti-inflammatory effect
Dose-dependent
- Haeomorrhage
- Hypotension - following rapid IV
- Osteoporosis - after prolonged use, binds osteoclasts and osteoblasts
- Skin necrosis
- Hyperkalaemia - ↓aldosterone secretion
- Alopecia
Idiosyncratic
- Allergic reactions
- Type I thrombocytopenia (HIT)
=> Non-immune
=> Within 4days of therapy
=> Rarely clinically significant
=> Cessation not required, spont recovery
- Type II thrombocytopenia (HITT)
=> Immune
=> 4-14 days of therapy
=> Heparin + platelet factor 4 -> complex bound to IgG -> plt aggregation and thrombosis
=> High mortality 30%
=> Recurs immediately with recommencing heparin, i.e sensitised
LMWH - enoxaparin
- Derived from UFH
- MW 2000-8000Da
MoA
- Heparin-AT complex inhibits factor Xa
- Less inhibition of thrombin (IIa) vs UFH
- Anti-FXa : Anit-FIIa = 4:1
PK
- A - near complete SC bioavailability
- D - 10% protein bound to plasma protein, remained bound to ATIII. Minimal crossing of placenta, VD close to blood volume, peak effect 2-4hrs, offset 12hrs prophylactic, 24hr therapeutic (OD or BD dosing compared to heparin infusion)
- M - minimal hepatic metabolism
- E - renal excretion, T1/2 5hrs. Dose reduction if CrCl <30ml/min
Effects
- Slightly superior anticoagulant vs UFH
- Some cross reactivity for HITT
- Protamine only partially effective at reversing (max <60%)
Advantages cf UFH
- Single daily dose (longer T1/2B)
- Lower risk of bleeding
=> Lower affinity for plasma proteins
=> More predictable effect of Xa
=> Lower affinity for vWF
=> Less effect on plt
- Less risk of HIT/ thrombocytopenia
- Monitoring usually not required (can monitor anti-Xa in renal impairment or critically ill)
- Better bioavailability and absorption SC
- Does not cross placenta
Disadvantages
- Only SC admin
- Difficult/ expensive monitoring
- Reduce dose in renal failure
- Protamine only partially reverses (mostly reverses anti-FIIa effect)
Heparin therapy monitoring
Unfractionated heparin
- Narrow TI
- Unpredictable effective dose
- APTT
=> Measure intrinsic and common pathway factors
=> XII, XI, X, IX, VIII
LMWH
- Difficult
- APTT not altered
- Anti-FXa levels
Fondaparinux
Synthetic pentasaccharide derivative
MoA
Five polysaccharide units that form the active site of heparin -> 300x ↑in ATIII activity on FXa
- No direct activity against thrombin (IIa)
PK
- Rapidly absorbed after SC administration - 100% bioavailability
- Not metabolised
- Renal excretion, T1/2B 15hrs (OD dosing)
PD
- No thrombocytopenia (no affinity to plt factor 4)
Protamine
- Mixture of LMW cationic proteins derived from salmon sperm
- 10mg/ml clear colourless solution
- 1mg reverses 100units of heparin, 5mg/min max safe infusion rate
- Also used in some insulins, e.g protaphane. Insulin + protamine -> ↓onset and ↑duration
MoA
- Positively charged -> forms inactive complex with heparin - strongly basic protamine binds with strongly acidic heparin to form a stable salt complex with covalent bonds
- Complex is cleared by reticuloendothelial system
- Incomplete/ inconsistent reversal of Xa inhibition (does not neutralise all LMWH found in UFH mixture)
PK
- Clearance is more rapid than heparin (T1/2 60mins cf 90mins for heparin) - heparin rebound may occur
- Onset within 5mins, duration 2-3hrs
- Heparin-protamine complex may be broken down in the reticuloendothelial system
CVS
- Myocardial depressant
- Bradycardia and hypotension secondary to complement activation and leukotriene release
- Rapid IV admin -> hypotension, bradycardia, dyspnoea, flushing
RS
- Pulm HTN - Complement activation and TXA2 release -> pulm vasoconstriction and possible bronchoconstriction
- May impair RV output and lead to pulmonary oedema
Allergic reaction
- Anaphylaxis - IgE mediated, sensitisation: Ag on APC -> T-cell -> B-cell -> IgE -> fix on mast cells. Repeat exposure: mast cell degranulation -> histamine etc.
- Histamine release
- Vasodilation, capillary leak, hypotension, bronchospasm
Anticoagulation when given in excess
- Weak intrinsic anticoagulant effect in high doses
- Inhibition of formation and activity of thromboplastin
Warfarin
- Coumarin derivative
- Racemic mixture - S-warfarin has 5x potency of R-isomer
- Dosing - titrated to INR
=> Measure of extrinsic and common pathways - Onset 8-12hrs after loading dose
- Peak effect up to 72hrs
- Duration 3-5 days
MoA
- Vitamin K antagonist
- Inhibits vit K epoxide reductase -> blocks conversion of oxidised vit K to reduced vit K -> ↓synthesis of vit K dependent coagulation factors (factor II, VII, IX, X, protein C + S)
PK
- A - 100% PO bioavailability
- D - appears in blood 1hr post dose, peak 4-12hrs post dose. Peak effect up to 72 hrs - peak effect is reflective of the half-life of the clotting factors formed prior to warfarin admin (inhibits new synthesis but no action on circulating factors). Vit K stores in body delay effect. Duration of action 3-5 days - time for new factors to be syntehsised, withdraw 5-7 days pre-op. >95% protein bound, can be displaced by other drugs -> toxicity
- M - complete hepatic metabolism. Low hepatic extraction ratio
- E - renal excretion, long T1/2 40hrs
Effects
- Anticoagulation
=> Initially prothrombotic - hence use bridging clexane for 4-5days
- Bleeding
- Hypersensitivity
- GIT upset
- Teratogenic + crosses placenta
Reversal
- Time - waiting for production of new coagulation factors. T1/2 B 40hrs -> offset in 5 days. Duration increase in vit K deficient. Duration decrease with CYP inducer (e.g barbiturates)
- Vit K - replenish substrate -> regnerate clotting factors
- FFP - contains all clotting factors
- Prothrombinex - contains F II, IX, X
Drug interactions
- Competition for plasma protein binding sites (e.g NSAIDs) -> ↑effect
- Liver enzyme inhibition -> ↑effect
- Liver enzyme induction -> ↓effect
- Interference with plt function, e.g SSRI deplete platelet serotonin ↓plt aggregation
- Injury to GIT mucosa, e.g NSAIDs
- Altered gut vit K availability
- Interference with metabolism, inhibition/ activation of CYP enzymes
- Interruption of vit K cycle, e.g NAPQI
- Inhibition of synthesis of clotting factors
Factor Xa inhibitors
E.g rivaroxaban, apixaban
- Bind and inhibit factor Xa directly without a requirement for ATIII
- Advantage is small size and ability to inactivate circulating, as well as bound forms of factor Xa
MoA
- Direct Xa inhibition
- Rapid activity and reversibly (with specific monoclonal Ab, cost +++)
=> Prolongation of coagulation time by 2-3hrs after ingestion, with ↑in PT and APTT ~20%
- Prevent conversion of prothrombin to thrombin
Monitoring
- PT - sensitive and readily available
- Anti-Xa
Cessation
- Prior to surgery
=> 48hrs if normal renal function
=> 72hrs if eGFR<50 or >70yrs
=> 4days if GFR<30 or liver disease
- Neuraxial
=> As for surgery
=> Wait at least 6hrs post after block or epidural catheter removal
Rivaroxaban
- A - 90% PO bioavailability
- D - high protein binding, difficult to remove with dialysis, peak effect 2-3hrs
- M - hepatic CYP3A4 metabolism with no active metabolites
- E - renal and hepatic excretion. T1/2 5-13hrs
Apixaban
- A - 50-80% PO bioavailbiltiy
- D - high protein binding, difficult to remove with dialysis, peak effect 2-3hrs
- M - hepatic CYP3A4 metabolism with no active metabolites
- E- renal + hepatic excretion. T1/2 12hrs. Dose reduced in elderly and underweight.
Direct thrombin inhibitors/ Dabigatran
- Prodrug - dabigatran etexilate
MoA
- Direct thrombin (IIa) inhibitor - inhibits conversion of fibrinogen to fibrin
- Prevents thrombus formation
- Also inhibits - free thrombin, fibrin-bound thrombin, thrombin-induced platelet aggregation
PK
- A - 6.5% bioavailability of prodrug, oral bioavailability 80-100%, peak Cp within 0.5-2hrs
- D - low protein binding 35%, removed with HD
- M - rapidly and completely hydrolysed and activated by liver and plasma esterases to dabigatran. Metabolised by glucuronide conjugation.
- E - renal elimination. T1/2 12-17hrs. Reduced Cl in elderly and renal failure
Effects
- Anticoagulant
- Inhibits platelet aggregation
- Haemorrhage
- Allergy
- Gastritis
Monitoring
- ECT (sensitive by not readily available)
- TT (sensitive but not readily available)
- APTT (>2.5x control -> ↑risk of bleeding)
Cessation prior to surgery
- Cease for at least 72hrs
- Longer if renal impairment
- Consider bridging therapy with with either enoxaparin or UFH for pt with mod-high risk form thromboembolic events
Central neuraxial blocks
- Generally, avoid performing
- Otherwise, as for prior surgery
- Next dose -> wait for at least 2hrs after block or epidural catheter removal
Reversal - monoclonal Ab (idaracizumab)
Anti-platelets
- COX-1 inhibitor - aspirin
- Platelet phosphodiesterase inhibitors - dipyridamole
- P2Y12 receptor antagonist - clopidogrel, ticagrelor
- Glycoprotein IIb/IIIa receptor antagonist - tirofiban
- Miscellaneous - dextrans, epoprostenol (Prostacyclin or PGI2)
Clopidogrel
- P2Y12 receptor antagonist
- Thienopyridine
- Pro-drug
- Dose 300mg load and 75mg/day
MoA
- Purinergic receptor antagonists
- ADP released from damaged cells binds P2Y12 receptor - sustained platelet aggregation requires coactivation of PGY1 and PGY12 receptors
- P2Y12 is a GiPCR - inhibit adenyl cyclase and potentiates dense granule secretion, procoagulant activity, and platelet aggregation. Without continued P2Y12 activation, aggregated platelets disaggregate
- Selectively inhibits PGY12 on platelet surface without direct effect on AA metabolism
- Forms covalent disulphide bond with receptor rendering it unresponsive to ADP
- Binding is irreversible so platelets affected for lifespan
PK
- A - 50% absorbed rapidly
- D - highly protein bound >95%, inhibition of plt 2hrs post ingestion
- M - metabolised into active 2-oxo-clopidogrel via CYP2C19 (15%). Genetic polymorphism mean poor metabolisers have reduced effect. Intermediate metabolisers have some effect but some resistance (30%). Metabolised by esterases to produce an inactive carboxylic acid derivative (85%)
- E- renal + hepatically cleared. T1/2 parent 30mins, T1/2 active metabolite 7hrs.
Adverse effects
- Bleeding
- Thrombocytopenia
- Neutropenia - bone marrow suppression
- Hepatic dysfunction
- Rash
Ticagrelor
- P2Y12 receptor antagonist
- ADP analogue
MoA
- Selective non-competitive reversible PGY12 inhibitor
- Binding site different from ADP, making it an allosteric antagonist
=> Rate of recovery of anti-platelet effects faster than clopidogrel (still w/h for 5/7)
PK
- A - 35% PO bioavailability, rapid absorption, peak Cp at 1.5hrs
- M - CYP3A4 -> major metabolite is as active as ticagrelor
- E - T1/2 8-12hrs
Adverse effects
- Adenosine mediated
=> Dyspnoea
=> Ventricular pauses
Glycoprotein IIb/IIIa receptor antagonists
Tirofiabn
- Non-peptide peptidomimetic
- Uses - short term IV infusion in pt with ACS
MoA
- Reversible inhibition of platelet GP IIb/IIIa receptors
- Only effective as long as Cp high enough to outcompete fibrinogen for receptors
PK
- D - 65% protein bound
- M - limited metabolism
- E - 2/3 renal, 1/3 hepatic
Side effects
- Bleeding
- Allergic reaction
- Thrombocytopenia
- Delay surgery 4hrs after infusion has been ceased
Platelet phosphodiesterase inhibitor
Dipyridamole
- Pyrimido-pyrimidine derivative
- Use - secondary prevention post stroke
MoA
- Inhibition of uptake of adenosine into platelets -> ↓platelet adhesion to damaged wall vessels
- Inhibition of platelet phosphodiesterase (high doses) -> ↑platelet cAMP -> ↓platelet adhesion and aggregation
PK
- Highly protein bound
- Hepatic metabolism - conjugated to glucuronide and excreted in bile
- T1/2 10hrs
- TTPE 75mins
Effects
- Vasodilator and anti-platelet properties
- Potentiates effects of prostacyclin
- Potent coronary vasodilator
Other anti-platelets
Dextrans
- Inhibit vWF
- Bind to platelets, RBC, vascular endothelium and reduce platelet adhesion and RBC aggregation
- Dilution effect on clotting factors
- Interfere with cross-matching
Epoprostenol (prostacyclin or PGI2)
- Platelet ant-aggregation
- Potent vasodilator
=> Hypotension
=> Tachycardia
=> Facial flushing
=> Headache
Ginko biloba
- Herbal anti-platelet
Tranexamic Acid
- Anti-fibrinolytic
- Synthetic derivative of lysine
- Uses - menstrual bleeding, haemophilia, reduce intra-op blood loss
- Dose 15mg/kg
- Clear colourless solution, 1g/10mL
MoA
- Reversibly inhibits lysine-binding sites on plasminogen preventing binding to fibrin. At very high concentrations may non-competitively inhibit plasmin
- Inhibits activation of plasminogen to plasmin. Plasmin activation and subsequent fibrin degradation inhibited as tissue plasminogen activator (tPA) and plasminogen can no longer co-localise on the surface of fibrin
- Prevents fibrinolysis
PK
- A - 50% PO bioavailability
- D - no albumin binding, 3% plasma protein bound
- M/E - majority excreted in urine, 90% eliminated at 24hrs
Adverse effects
- Prolonged infusion associated with seizure (due to crossing BBB and antagonising GABA and glycine receptors)
- ↑seizure risk in cardiac surgery using large bolus doses
Contraindications
- Active intravascular clotting
- SAH - may ↑cerebral ischaemic complications
- Hypersensitivity
- Caution if at risk of thrombotic complications
