DRUGS SEMINAR

8/7/2019 DRUGS SEMINAR

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NEW DRUGSNEW DRUGS

MODERATORMODERATOR-- Dr. ManpreetDr. Manpreet


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CLONIDINECLONIDINE


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CLONIDINECLONIDINE

* centrally acting selective, partial alpha* centrally acting selective, partial alpha

adrenergic agonist (220:1 alpha 2 toadrenergic agonist (220:1 alpha 2 toalpha 1)alpha 1)

* stimulates inhibitory alpha2* stimulates inhibitory alpha2adrenoceptors to reduce central neuraladrenoceptors to reduce central neuraltransmission in spinal neuronstransmission in spinal neurons


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AVAILABILITYAVAILABILITY--

as preservativeas preservative--free Clonidine HClfree Clonidine HCl

150g/ml solution single dose ampoules150g/ml solution single dose ampoules

STORAGESTORAGE--

below 25below 25CC


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MECHANISM OF ACTIONMECHANISM OF ACTION

* produce clinical effects by binding to* produce clinical effects by binding to

alpha 2 receptors.alpha 2 receptors.* 3 subtypes* 3 subtypes

alpha2Aalpha2A-- mediate sedation, analgesia,mediate sedation, analgesia,

sympatholysis.sympatholysis.alpha2Balpha2B-- vasoconstriction and possiblyvasoconstriction and possiblyantishivering effects.antishivering effects.

alpha2Calpha2C-- may be responsible for startlemay be responsible for startleresponse.response.


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PHARMACODYNAMICSPHARMACODYNAMICSCARDIOVASCULAR EFFECTSCARDIOVASCULAR EFFECTS

* decreased BP ( greater fall in systolic)* decreased BP ( greater fall in systolic)

* decreased HR* decreased HRIn chronically treated patientsIn chronically treated patients

-- SVR little affectedSVR little affected-- CO initially decreased, returns toward preCO initially decreased, returns toward pre--drug levelsdrug levels

with time.with time.

RESPIRATORY EFFECTSRESPIRATORY EFFECTS* minimal depressant effect on ventilation* minimal depressant effect on ventilation

* do not potentiate depressant effects of opioids* do not potentiate depressant effects of opioids


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PHARMACOKINETICSPHARMACOKINETICS

ORALORAL -- rapidly absorbedrapidly absorbed

--peak plasma conc.=60peak plasma conc.=60--90min90min--E t1/2 =9E t1/2 =9--12 hrs12 hrs

I.V.I.V. highly lipid soluble & readilyhighly lipid soluble & readily

distributes into extra vascular sitesdistributes into extra vascular sitesincluding CNSincluding CNS


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* Pontine locus ceruleus* Pontine locus ceruleus -- sedationsedation

* Medullary vasomotor response* Medullary vasomotor response peripheralperipheral

vasodilation, decreased BP, HR and CO.vasodilation, decreased BP, HR and CO.* Modification of K+ channels in CNS* Modification of K+ channels in CNS

(hyperpolarization of cell membranes)(hyperpolarization of cell membranes)

--profound decreases in anaestheticprofound decreases in anaestheticrequirements.requirements.

* Neuraxial admn.* Neuraxial admn.-- inhibits spinal substance Pinhibits spinal substance P

release &nociceptive neuron firing d/t noxiousrelease &nociceptive neuron firing d/t noxiousstimulation.stimulation.


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USESUSES

PREANAESTHETIC MEDICATIONPREANAESTHETIC MEDICATIONOral clonidine in preoperative periodOral clonidine in preoperative period--a) blunts reflex tachycardia associated witha) blunts reflex tachycardia associated with

direct laryngoscopy & intubationdirect laryngoscopy & intubation

b) dec. intraoperative lability of BP & HRb) dec. intraoperative lability of BP & HRc) dec. plasma catecholamine concentrationsc) dec. plasma catecholamine concentrationsd) dramatically decrease anaestheticd) dramatically decrease anaesthetic

requirement for inhaled (MAC) & injectedrequirement for inhaled (MAC) & injecteddrugsdrugs


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ANALGESIAANALGESIA

* Preservative* Preservative--free clonidine admn. into thefree clonidine admn. into the epidural orepidural orsubarachnoid spacesubarachnoid space produces doseproduces dose--dependentdependent

analgesiaanalgesia(avoiding side effects of opioids)(avoiding side effects of opioids)

--d/t activation of postsynaptic alpha2 receptors ind/t activation of postsynaptic alpha2 receptors insubstantia gelatinosa of spinal cordsubstantia gelatinosa of spinal cord

--S/E of hypotension, sedation, dryness of mouthS/E of hypotension, sedation, dryness of mouth

* Addition of clonidine 1/kg to lidocaine in* Addition of clonidine 1/kg to lidocaine in TIVATIVAenhances postenhances post--operative analgesiaoperative analgesia

* Intra* Intra--articular administration of clonidine producesarticular administration of clonidine producesanalgesia afteranalgesia after knee arthroscopiesknee arthroscopies


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CHRONICPAINCHRONICPAIN

-- transdermal clonidine shown to decrease paintransdermal clonidine shown to decrease pain

in diabetic neuropathyin diabetic neuropathy-- intractable pain following spinal cord injuryintractable pain following spinal cord injury

-- reported to possess peripheral analgesicreported to possess peripheral analgesic

propertiesproperties


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PROLONGING THE EFFECTS OF REGIONALPROLONGING THE EFFECTS OF REGIONALANAESTHESIAANAESTHESIA

Prolonged duration of sensory & motor blockadeProlonged duration of sensory & motor blockade

in SUBARACHNOID BLOCKin SUBARACHNOID BLOCK* addition of 75* addition of 75--150g, to a solution150g, to a solutioncontaining tetracaine or bupivacaine & placedcontaining tetracaine or bupivacaine & placedin subarachnoid spacein subarachnoid space

* oral clonidine 150* oral clonidine 150--200g admn. 1200g admn. 1--1.5hrs1.5hrsbefore institution of S.A.B has same effectbefore institution of S.A.B has same effect

Increased intensity ofPERIPHERAL NERVEIncreased intensity ofPERIPHERAL NERVEBLOCKSBLOCKS* addition of clonidine to local anaesthetic* addition of clonidine to local anaesthetic


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PROTECTION AGAINST PERIPROTECTION AGAINST PERI--OPERATIVEOPERATIVE

MYOCARDIAL ISCHAEMIAMYOCARDIAL ISCHAEMIA

* decrease in overall mortality (superior to* decrease in overall mortality (superior tobetabeta--blockers)blockers)

* 0.2mg oral or transdermal patch in* 0.2mg oral or transdermal patch inevening before or on morning of surgeryevening before or on morning of surgery

in patients at risk for CAD and continuedin patients at risk for CAD and continued

for 4 days postfor 4 days post--operativelyoperatively


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DIAGNOSIS OF PHEOCHROMOCYTOMADIAGNOSIS OF PHEOCHROMOCYTOMA-- oral 0.3mg decreases plasma conc. in normaloral 0.3mg decreases plasma conc. in normal

patients but not in presence ofpatients but not in presence of

pheochromocytomapheochromocytoma

TREATMENT OF SHIVERINGTREATMENT OF SHIVERING

--75g i.v. clonidine stops shivering (reflects75g i.v. clonidine stops shivering (reflectsability to inhibit central thermoregulatoryability to inhibit central thermoregulatorycontrol)control)

--150g i.v.effective in preventing shivering in150g i.v.effective in preventing shivering in

patients receiving epidural anaesthesiapatients receiving epidural anaesthesia


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OPIOID & ALCOHOL WITHDRAWLOPIOID & ALCOHOL WITHDRAWLSYNDROMESYNDROME

* clonidine 10g/kg i.v. decreases* clonidine 10g/kg i.v. decreasessympathetic NS activity associated withsympathetic NS activity associated withcardiovascular stimulation & attenuatescardiovascular stimulation & attenuates

increase in plasma catecholamineincrease in plasma catecholamineconcentrations when naloxone is admn.concentrations when naloxone is admn.during G.A. to pt. addicted to opioidsduring G.A. to pt. addicted to opioids

*effective in T/t of Alcohol withdrawl*effective in T/t of Alcohol withdrawlsyndrome in pt. not responding to highsyndrome in pt. not responding to highdoses of BZDs or opioidsdoses of BZDs or opioids


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SIDESIDE-- EFFECTSEFFECTS

1) Sedation1) Sedation

2) Xerostomia2) Xerostomia3) Bradycardia (often requires treatment with3) Bradycardia (often requires treatment with

anticholinergic)anticholinergic)

4) Retention of sodium and water4) Retention of sodium and water5) Skin rashes5) Skin rashes

6) Impotence6) Impotence

7) Orthostatic hypotension (rare)7) Orthostatic hypotension (rare)


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DOSAGE GUIDELINES (healthy adults)DOSAGE GUIDELINES (healthy adults)

ORALORAL-- 30g/kg30g/kg

INTRATHECALINTRATHECAL-- 1515--30g added to local anaesthetic agents (max.30g added to local anaesthetic agents (max.1g/kg)1g/kg)

EPIDURALEPIDURAL-- 50g or 1g/kg, whichever is lower (max. 2g/kg)50g or 1g/kg, whichever is lower (max. 2g/kg)

INTRAINTRA--ARTICULARARTICULAR-- 150g or 2g/kg150g or 2g/kg

INTRAVENOUSINTRAVENOUS

*50*50--75g or 1g/kg, whichever is lower slowly 15 minutes75g or 1g/kg, whichever is lower slowly 15 minutesprior to surgeryprior to surgery

*Post operative/ epidural shivering*Post operative/ epidural shivering-- 30g slow i.v.30g slow i.v.

* H.T. Crisis* H.T. Crisis--150150--300g slow i.v. over 10 min (max. 3g/kg)300g slow i.v. over 10 min (max. 3g/kg)

CONTINUOUS EPIDURAL INFUSIONCONTINUOUS EPIDURAL INFUSIONstarting dosestarting dose--30g/h, titrated according to response30g/h, titrated according to response


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CONTRAINDICATIONSCONTRAINDICATIONS

* Known hypersensitivity* Known hypersensitivity

* Brady* Brady--arrythmias or heart blockarrythmias or heart block* Cardiovascular/ haemodynamic instability* Cardiovascular/ haemodynamic instability

* Patients on anticoagulant therapy or with* Patients on anticoagulant therapy or with

bleeding diathesisbleeding diathesis* Local infection at site of epidural injection* Local infection at site of epidural injection

* Obstetric patients (category C)* Obstetric patients (category C)

* Lactating patients* Lactating patients


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DEXMEDETOMIDINEDEXMEDETOMIDINE


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MedetomidineMedetomidine4(5)4(5)--11--22--33--dimethyl phenyl [ethyl] imidazoledimethyl phenyl [ethyl] imidazole--prototype of novel superselective alpha2 agonistsprototype of novel superselective alpha2 agonists--highly selective, specific, potent alpha2highly selective, specific, potent alpha2--adrenergic agonistadrenergic agonist

(1,620:1 alpha2 to 1)(1,620:1 alpha2 to 1)

DexmedetomidineDexmedetomidine--

--DD--enantiomer of this racemateenantiomer of this racemate--full agonist at alpha2C and partial at alpha2A and 2B receptorsfull agonist at alpha2C and partial at alpha2A and 2B receptors

AtipamazoleAtipamazole a specific & selective alpha2 receptor antagonist,a specific & selective alpha2 receptor antagonist,rapidly & effectively reverses sedative and cardiovascularrapidly & effectively reverses sedative and cardiovascular

effects of i.v. dexmedetomidineeffects of i.v. dexmedetomidine


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MECHANISM OF ACTIONMECHANISM OF ACTION-- similar to clonidinesimilar to clonidine

PHARMACOKINETICSPHARMACOKINETICSProfileProfile-- more favourable for perioperative usemore favourable for perioperative use--Et1/2: 2Et1/2: 2--3 hrs3 hrs

(clonidine:6(clonidine:6--10hrs)10hrs)--Highly protein bound >90%Highly protein bound >90%

(clonidine:20(clonidine:20--40%)40%)--Extensive hepatic metabolismExtensive hepatic metabolism--Weak inhibitory effects on cytochrome p450 enzyme systemsWeak inhibitory effects on cytochrome p450 enzyme systems

that might manifest as increased plasma conc. of opioidsthat might manifest as increased plasma conc. of opioidsadministered during anaesthesiaadministered during anaesthesia

PHARMACODYNAMICSPHARMACODYNAMICS--similar to clonidinesimilar to clonidine


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USESUSES

PREPRE--ANAESTHETIC MEDICATIONANAESTHETIC MEDICATION

--attenuates hemodynamic responses toattenuates hemodynamic responses totracheal intubationtracheal intubation

--decreases plasma catecholamine conc.decreases plasma catecholamine conc.during anaesthesiaduring anaesthesia

--decreases perioperative requirements fordecreases perioperative requirements for

inhaled anaesthetics & opioidsinhaled anaesthetics & opioids


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ANALGESIAANALGESIA

High doses (loading 1g/kg followed by 5High doses (loading 1g/kg followed by 5--10g/kg/hr) produces total i.v. anaesthesia10g/kg/hr) produces total i.v. anaesthesiawithout associated depression of ventilationwithout associated depression of ventilation

ororCan be added to lignocaine in dose 0.5g/kgCan be added to lignocaine in dose 0.5g/kg

-- potential anaesthetic technique forpotential anaesthetic technique for

patients with difficult upper airwaypatients with difficult upper airway


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ATTENUATION OF EMERGENCE SYNDROMEATTENUATION OF EMERGENCE SYNDROME

--hyperdynamic state seen after emergence fromhyperdynamic state seen after emergence from

general anaesthesiageneral anaesthesia-- improve performance of several cognitiveimprove performance of several cognitivetasks which rely on the prefrontal cortex( PFC)tasks which rely on the prefrontal cortex( PFC)

--thus, value in disorders associated withthus, value in disorders associated withenhanced startle responses and sensorimotorenhanced startle responses and sensorimotorgating deficitsgating deficits

eg. schizophreniaeg. schizophreniaattention deficit hyperactivity disorderattention deficit hyperactivity disorder

postpost--traumatic stress disordertraumatic stress disorder


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SHIVERINGSHIVERING

-- useful in treatmentuseful in treatment

POSTPOST--OPERATIVE SEDATIONOPERATIVE SEDATION

--infusion (200infusion (200--700g/kg/hr) is useful for700g/kg/hr) is useful for

postoperative critical care patients in ICU,postoperative critical care patients in ICU,especially when mechanical ventilation viaespecially when mechanical ventilation viatracheal tube is necessarytracheal tube is necessary

--in contrast to BZD and other sedatives,in contrast to BZD and other sedatives,dexmedetomidine treated patients aredexmedetomidine treated patients areadeqately sedated yet, rousable andadeqately sedated yet, rousable andresponsiveresponsive


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LEVOSIMENDANLEVOSIMENDAN


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PERIOPERATIVE CARDIAC DYSFUNCTIONPERIOPERATIVE CARDIAC DYSFUNCTION

During anaesthesiaDuring anaesthesia--

VasodilatationVasodilatation

Volume shifts, blood lossVolume shifts, blood loss

PainPain

HypothermiaHypothermia

Increased myocardial workIncreased myocardial work Release of inflammatory mediatorsRelease of inflammatory mediators

Sympathetic NS activationSympathetic NS activation

Patient profilePatient profile-- prepre--existing CADexisting CAD

PREDISPOSE TO MYOCARDIAL ISCHAEMIAPREDISPOSE TO MYOCARDIAL ISCHAEMIA


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MANAGEMENT OF PERIOPERATIVEMANAGEMENT OF PERIOPERATIVECARDIAC FAILURECARDIAC FAILURE

* Afterload reduction* Afterload reduction-- vasodilatorsvasodilators

* maintenance of coronary perfusion* maintenance of coronary perfusion-- adequateadequate

MAP

(fluids, vasoconstrictors)MAP

(fluids, vasoconstrictors)

*augmentation of cardiac contractility*augmentation of cardiac contractility-- infusion ofinfusion ofinotropic drugsinotropic drugs


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HOWEVERHOWEVER

Short term infusion of inotropic drugsShort term infusion of inotropic drugs

--not associated with improved long termnot associated with improved long termprognosisprognosis

-- long term use associated with arrhythmias,long term use associated with arrhythmias,sudden death, increased mortalitysudden death, increased mortality

-- most increase cardiac contractility bymost increase cardiac contractility byincreasing cAMP levelsincreasing cAMP levels

* intracellular calcium overload* intracellular calcium overload

* increased myocardial O2 consumption* increased myocardial O2 consumption* myocardial cell death (apoptosis)* myocardial cell death (apoptosis)


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LEVOSIMENDANLEVOSIMENDAN

** novel cardioprotective inotropenovel cardioprotective inotrope

*(R)*(R)--[[4[[4--(1,4,5,6(1,4,5,6--tetrahydrotetrahydro--44--methylmethyl--66--oxooxo--33--pyridazinyl)pyridazinyl)--phenyl]hydrazono]propanedinitrilephenyl]hydrazono]propanedinitrile


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*active enantiomer of*active enantiomer ofsimendansimendan

*clear yellow liquid for intravenous infusion*clear yellow liquid for intravenous infusion

*Pharmacokinetics*Pharmacokinetics

clinical effects prolonged due to activeclinical effects prolonged due to activemetabolitemetabolite OROR--18961896

Half lifeHalf life--80hrs80hrs

Potentiates hemodynamics after cessation ofPotentiates hemodynamics after cessation ofparent drugparent drug

*Dosing as indicated by clinical experience*Dosing as indicated by clinical experience--

Loading dose of 6Loading dose of 6--24g/kg followed by24g/kg followed by

infusion of < 0.4g/kg/hinfusion of < 0.4g/kg/h


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ISCHAEMICPREISCHAEMICPRE--CONDITIONINGCONDITIONING

adaptive cellular response to ischaemia which protects the cell from furtheradaptive cellular response to ischaemia which protects the cell from furtherischaemic insult, slows the rate of cell death and preserves organ functionischaemic insult, slows the rate of cell death and preserves organ function

*Levosimendan mimics ischaemic preconditioning*Levosimendan mimics ischaemic preconditioning--protection to heart during ischaemiaprotection to heart during ischaemia--reparfusion statesreparfusion states

--improve haemodynamic state in heartimprove haemodynamic state in heartfailurefailure

*augments myocardial contractility without increasing myosin*augments myocardial contractility without increasing myosinATPase activity or oxygen consumptionATPase activity or oxygen consumption


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MECHANISM OF ACTIONMECHANISM OF ACTION

1)Enhances myocardial contractility by1)Enhances myocardial contractility by

sensitising myofilaments to intracellular calciumsensitising myofilaments to intracellular calcium--binds to troponin C, stabilises calciumbinds to troponin C, stabilises calcium--boundboundconformation and prolongs the systolicconformation and prolongs the systolic

actinactin--myosin interactionmyosin interaction


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2)Role of KATP channel activation2)Role of KATP channel activation

MITOCHONDRIAL KATP channels (mKATP)MITOCHONDRIAL KATP channels (mKATP)

-- act as guardians of cellular integrity byact as guardians of cellular integrity bystabilising mitochondrial metabolism duringstabilising mitochondrial metabolism duringischaemiaischaemia

-- opening of mitochondrial permeablityopening of mitochondrial permeablitytransition pore (mPTP) in response to ischaemictransition pore (mPTP) in response to ischaemicstress : central mechanism in cell damagestress : central mechanism in cell damage

-- levosimendan activates mKATP channelslevosimendan activates mKATP channels*stabilise mitochondrial metabolism*stabilise mitochondrial metabolism*maintain closure of of mPTP*maintain closure of of mPTP


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SARCOLEMMAL MEMBRANE KATP channelsSARCOLEMMAL MEMBRANE KATP channelsActivationActivation-- potassium ion efflux and membranepotassium ion efflux and membrane

hyperpolarisationhyperpolarisation-- inhibit inward Linhibit inward L--type calcium current,type calcium current,

lower intracellular calcium current,lower intracellular calcium current,

vasodilatationvasodilatation* in arteries, arterioles and veins* in arteries, arterioles and veins

* acts as an vasodilator agent on systemic* acts as an vasodilator agent on systemic

vasculature and microcirculationvasculature and microcirculation

* Key role in maintaining basal tone of coronary* Key role in maintaining basal tone of coronary

vasculaturevasculature


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3) EFFECT ON LUSITROPHY3) EFFECT ON LUSITROPHY

*Diastolic dysfunction*Diastolic dysfunction major component of heartmajor component of heartfailure,present in upto 50% patientsfailure,present in upto 50% patients

*Levosimendan does not appear to worsen*Levosimendan does not appear to worsenlusitrophy due to its stabilising action of thelusitrophy due to its stabilising action of thecalciumcalcium--troponin C complextroponin C complex

(and not increasing the binding affinity of(and not increasing the binding affinity ofcalcium to troponin C)calcium to troponin C)


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4) PHOSPHODIESTERASE INHIBITION4) PHOSPHODIESTERASE INHIBITION

At conc. >0.3MAt conc. >0.3M

-- inhibits PDE III in vitroinhibits PDE III in vitro-- role of cAMP ?role of cAMP ?

-- however,III & IV isoforms not simultaneouslyhowever,III & IV isoforms not simultaneously

inhibited. Thus unlikely to be primaryinhibited. Thus unlikely to be primarymechanism of action.mechanism of action.

-- In clinical practice, plasma levels less thanIn clinical practice, plasma levels less than

100ng/ml recommended.100ng/ml recommended.


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CARDIOVASCULAR EFFECTS OF LEVOSIMENDANCARDIOVASCULAR EFFECTS OF LEVOSIMENDAN

Increase inIncrease in

--HRHR--COCO

--LV stroke volumeLV stroke volume

Decrease inDecrease in

--LV EDPLV EDP

--SVRSVR

AlsoAlso

Increase blood flow to renal medulla & smallIncrease blood flow to renal medulla & smallintestineintestine

Improved gastric mucosal oxygenationImproved gastric mucosal oxygenation


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* Unlike other positive inotropic agents* Unlike other positive inotropic agents

(increase intracellular cAMP)(increase intracellular cAMP)

--not associated with increased incidence ofnot associated with increased incidence ofarrhythmias leading to cardiovasculararrhythmias leading to cardiovascularmortality.mortality.

*ROLE IN ISCHAEMIA*ROLE IN ISCHAEMIA--REPERFUSION INJURYREPERFUSION INJURY(during ischaemia, acidosis decreases calcium(during ischaemia, acidosis decreases calciumsensitivity in the failing heart)sensitivity in the failing heart)

-- levosimendan has potential to preservelevosimendan has potential to preservecontractile functioncontractile function

(unique myofilament action)(unique myofilament action)


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CLINICAL APPLICATIONSCLINICAL APPLICATIONS

1) HEART FAILURE1) HEART FAILURE-- beneficial effect on survivalbeneficial effect on survival

in acute decompensated failure compared toin acute decompensated failure compared todobutamine at 31 and 108 daysdobutamine at 31 and 108 days

2) INOPROTECTION2) INOPROTECTION--

positive inotropy +activation of KATP channelspositive inotropy +activation of KATP channels--cardiogenic shockcardiogenic shock

--evolving myocardial infarctionevolving myocardial infarction

--perioperative ischaemiaperioperative ischaemia--emergence from CPBemergence from CPB

3) Catecholamine resistant SEPSIS3) Catecholamine resistant SEPSIS


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XIMELGATRANXIMELGATRAN

Xi lXi l


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XimelgatranXimelgatran

* first orally available direct thrombin inhibitor* first orally available direct thrombin inhibitor

* uncharged lipophilic drug with little intrinsic* uncharged lipophilic drug with little intrinsicactivity against thrombinactivity against thrombin

*PRODRUG of MELGATRAN,*PRODRUG of MELGATRAN, an active sitean active site--directed thrombin inhibitordirected thrombin inhibitor

** DoseDose

XimelagatranXimelagatran-- 20mg oral BD20mg oral BDMelagatranMelagatran-- 3mg sc BD3mg sc BD


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PHARMACOKINETICSPHARMACOKINETICS

* Well absorbed from GI tract* Well absorbed from GI tract* Bioavailability approx. 20%* Bioavailability approx. 20%

* Rapid biotransformation to melagatran via* Rapid biotransformation to melagatran via

two intermediate metabolitestwo intermediate metabolites-- H338/57H338/57H415/04H415/04

*Melagatran levels peak in blood in 2hrs*Melagatran levels peak in blood in 2hrs

Half life 3Half life 3--4 hr (healthy volunteers)4 hr (healthy volunteers)

44--5 hr (patients)5 hr (patients)

Therefore twice daily dosing requiredTherefore twice daily dosing required


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* To* To--date, no foods or drugs documented todate, no foods or drugs documented toinfluence absorptioninfluence absorption

* Does not inhibit cytochrome p450 enzymes,* Does not inhibit cytochrome p450 enzymes,

thus low potential for drug interactionsthus low potential for drug interactions

* Melagatran eliminated via kidneys* Melagatran eliminated via kidneys-- dosedoseadjustments needed inadjustments needed in severe renalsevere renal

insufficiency (creatinine clearance


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PRINCIPAL ADVANTAGE OVER VITAMIN KPRINCIPAL ADVANTAGE OVER VITAMIN KANTAGONISTSANTAGONISTS

-- based on pharmacological profilebased on pharmacological profile-- absorbed orallyabsorbed orally

-- longer half lifelonger half life

-- predictable anticoagulant responsepredictable anticoagulant response-- clearance not affected by liver or mildclearance not affected by liver or mild--moderate renal diseasemoderate renal disease

--no coagulation monitoring necessaryno coagulation monitoring necessary(except in severe renal disease )(except in severe renal disease )

SS CC


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SIDESIDE--EFFECTEFFECT

* Elevation of liver transaminases* Elevation of liver transaminases

--Typically, changes in liver enzymes occurTypically, changes in liver enzymes occurafter 6 weeks to 4 months of therapyafter 6 weeks to 4 months of therapy

--Usually asymptomatic and reversible, even ifUsually asymptomatic and reversible, even if

medication is continuedmedication is continued--Although increase appears benign, long termAlthough increase appears benign, long termconsequences yet to be determinedconsequences yet to be determined

--L.F.TS need to be determinedL.F.TS need to be determined

USESUSES


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USESUSES

* Thromboprophylaxis* Thromboprophylaxis after hip or kneeafter hip or knee

arthroplastyarthroplasty--found to be more effective than enoxaparinfound to be more effective than enoxaparinand warfarin in separate studiesand warfarin in separate studies

* Acute treatment of venous thromboembolism* Acute treatment of venous thromboembolism

--found to be as effective as conventionalfound to be as effective as conventional

anticoagulation in phase III trialsanticoagulation in phase III trials--significantly reduced risk of recurrentsignificantly reduced risk of recurrentthrombosis without increasing risk of majorthrombosis without increasing risk of majorbleedingbleeding

*P ti f th b b li t i*P ti f th b b li t i


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*Prevention of thromboembolic events in*Prevention of thromboembolic events inpatients with nonvalvular atrial fibrillationpatients with nonvalvular atrial fibrillation

--unmonitored fixed dose ximelgatran asunmonitored fixed dose ximelgatran aseffective & safe as doseeffective & safe as dose--adjusted warfarinadjusted warfarin

*Prevention of recurrent ischaemia in patients*Prevention of recurrent ischaemia in patientswith recent MI (ST elevation or non STwith recent MI (ST elevation or non STelevation)elevation)

--found effectivefound effective

--phase III trial under considerationphase III trial under consideration


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ROLEOFNITROUSOXIDEINRECENTROLEOFNITROUSOXIDEINRECENTANAESTHESIA PRACTICEANAESTHESIA PRACTICE

NITROUS OXIDENITROUS OXIDE


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NITROUS OXIDENITROUS OXIDE

An inorganic anaesthetic gasAn inorganic anaesthetic gas Discovered by Joseph Priestley in 1772Discovered by Joseph Priestley in 1772

Sir Humphrey DavySir Humphrey Davy recognized its painrecognized its pain

relieving featurerelieving feature 11ststpublic demonstrationpublic demonstration--1845 by Horace Wells1845 by Horace Wells

(failed)(failed)

Reintroduced by Edmund AndrewsReintroduced by Edmund Andrews


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Sli htl t t t d dSli htl t t t d d


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Slightly sweet taste and odourSlightly sweet taste and odour

NonNon--irritating to airwayirritating to airway

Mucous glands not stimulatedMucous glands not stimulated Low solubility coefficientsLow solubility coefficients

-- rapid rise in alveolar blood and brain partialrapid rise in alveolar blood and brain partial

pressures on inductionpressures on induction--similarly, washout and therefore emergencesimilarly, washout and therefore emergenceare rapidare rapid

Oil/gasOil/gas--1.41.4Blood/gasBlood/gas--0.470.47

Water/gasWater/gas--0.440.44

ANALGESIC POTENCYANALGESIC POTENCY


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ANALGESIC POTENCYANALGESIC POTENCY

Analgesia in dose dependent mannerAnalgesia in dose dependent manner

50% N50% N22O approx. equivalent to 10mg of morphineO approx. equivalent to 10mg of morphine

--Alters sensory thresholds associated with touch,Alters sensory thresholds associated with touch,temperature, light and soundtemperature, light and sound

--Noxious stimuli eg. cutaneous and ischaemic painNoxious stimuli eg. cutaneous and ischaemic pain

obtundedobtunded Induction of anaesthesia not possible but an excellentInduction of anaesthesia not possible but an excellent

carrier of other agentscarrier of other agents

Its addition can substantially reduce the amont ofIts addition can substantially reduce the amont ofvolatile agentvolatile agent( Second gas effect)( Second gas effect)

Because of rapid rise in alveolar conc., surgicalBecause of rapid rise in alveolar conc., surgicalanaesthesia achieved more rapidlyanaesthesia achieved more rapidly

(Concentration effect)(

Concentration effect)

CARDIOVASCULAR SYSTEMCARDIOVASCULAR SYSTEM


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CARDIOVASCULAR SYSTEMCARDIOVASCULAR SYSTEM

Effect may be depressant or stimulantEffect may be depressant or stimulant

Depends on anaesthetic with which it is usedDepends on anaesthetic with which it is usedand CVS status of patientand CVS status of patient

Direct myocardial depressantDirect myocardial depressant

However in 1However in 1ststhour of anaesthesiahour of anaesthesia MAP elevated, HR, SV slightly increasedMAP elevated, HR, SV slightly increased

--related to CNS excitation (incompleterelated to CNS excitation (incomplete

anaesthesia) or increase in PaCO2anaesthesia) or increase in PaCO2 Even in patients with CAD, it decreases LVEven in patients with CAD, it decreases LVPressure product (main determinant ofPressure product (main determinant of

myocardial O2 demand)myocardial O2 demand)

RESPIRATORY SYSTEMRESPIRATORY SYSTEM


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RESPIRATORY SYSTEMRESPIRATORY SYSTEM

Small fall in TV, increases WOBSmall fall in TV, increases WOB

DisadvantagesDisadvantages--

--100% O2 cannot be provided100% O2 cannot be provided--Increases PVRIncreases PVR

--Depresses hypoxic pulmonary vasoconstrictionDepresses hypoxic pulmonary vasoconstriction

--Can diffuse into air containing cavities like a lung bulla

Can diffuse into air containing cavities like a lung bullaincreasing its size, can lead to pneumothoraxincreasing its size, can lead to pneumothorax

--Diffusion hypoxiaDiffusion hypoxia

BUT interesting factBUT interesting fact

Decreases respiratory depression during emergence fromDecreases respiratory depression during emergence fromanaesthesia with sevoflurane/N2O (Miller 6anaesthesia with sevoflurane/N2O (Miller 6thth edition)edition)

DIFFUSION OF N2O INTO CLOSED GAS SPACESDIFFUSION OF N2O INTO CLOSED GAS SPACES


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DIFFUSION OF N2O INTO CLOSED GAS SPACESDIFFUSION OF N2O INTO CLOSED GAS SPACES

Rate of diffusion 35 times faster than nitrogenRate of diffusion 35 times faster than nitrogen

Rapid increase in volume and size of gas cavitiesRapid increase in volume and size of gas cavities

SIGNIFICANCESIGNIFICANCE--

Pulmonary bullaPulmonary bulla-- PneumothoraxPneumothorax

Middle ear surgeriesMiddle ear surgeries-- displacement of graft indisplacement of graft in

tympanoplasty, disorientation of stapestympanoplasty, disorientation of stapes Intraocular gas bubble (SF6) in eye surgeriesIntraocular gas bubble (SF6) in eye surgeries

Posterior fossa craniotomiesPosterior fossa craniotomies

LaparoscopyLaparoscopy Tracheal tube cuff and balloon tipped cathetersTracheal tube cuff and balloon tipped catheters

( Swan ganz)( Swan ganz)

All surgeries with risk of venous air embolismAll surgeries with risk of venous air embolism

Interesting factsInteresting facts


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Interesting factsInteresting facts--

in event of venous air embolism, N2O favoursin event of venous air embolism, N2O favours

earlier detection of small emboli by dopplerearlier detection of small emboli by doppler increases the sensitivity of endincreases the sensitivity of end--tidal CO2 andtidal CO2 and

pulmonary artery pressure monitoring inpulmonary artery pressure monitoring indetectiondetection

Xenon also expands gas bubbles, though to aXenon also expands gas bubbles, though to asmaller extentsmaller extent

UNIQUE PROPERTYUNIQUE PROPERTY


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UNIQUE PROPERTYUNIQUE PROPERTY

Oxidises and inactivates vitamin B12Oxidises and inactivates vitamin B12

component of certain enzymes likecomponent of certain enzymes like methionine synthetase essential for normalmethionine synthetase essential for normalDNA productionDNA production

Effects on foetusEffects on foetus

--Controversial..Controversial..

--recommended to avoid during first 2 trimestorsrecommended to avoid during first 2 trimestors--however, a retrospective study did nothowever, a retrospective study did notdemonstrate adverse effectsdemonstrate adverse effects

CONTROVERSY OF HEMATOLOGICAL ANDCONTROVERSY OF HEMATOLOGICAL AND


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CONTROVERSY OF HEMATOLOGICAL ANDCONTROVERSY OF HEMATOLOGICAL ANDNEUROLOGICCHANGESNEUROLOGICCHANGES

Studies showStudies show megaloblastic changesmegaloblastic changes after a protractedafter a protracted

use of N2O for as long as 24hrs and agranulocytosisuse of N2O for as long as 24hrs and agranulocytosisafter 4daysafter 4days

ButBut

--These changes are readily reversible onThese changes are readily reversible on

discontinuationdiscontinuation--Folinic acid 30 mg before N2O administration canFolinic acid 30 mg before N2O administration canprevent themprevent them

--Studies show that the use of N2O does not alter theStudies show that the use of N2O does not alter the

viability of bone marrowviability of bone marrow The much talked aboutThe much talked aboutsubacute combinedsubacute combined

degeneration of spinal cord,degeneration of spinal cord, develops only afterdevelops only afterseveral months of everyday exposureseveral months of everyday exposure

ThusThus


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ThusThus

For routine use as carrier agentFor routine use as carrier agent

--regarded nontoxicregarded nontoxic Use in excess of 6 hoursUse in excess of 6 hours--

--neurological & hematological defects mayneurological & hematological defects may

occuroccur Concern in operating room personnel ??Concern in operating room personnel ??

--scavenging systems, closed circuitsscavenging systems, closed circuits

LOW FLOW TECHNIQUE AND N2OLOW FLOW TECHNIQUE AND N2O


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LOW FLOW TECHNIQUE AND N2OLOW FLOW TECHNIQUE AND N2O

N2O insoluble as compared to O2N2O insoluble as compared to O2--once reaches equilibrium with FRC andonce reaches equilibrium with FRC andtissue, its uptake is reducedtissue, its uptake is reduced

O2 is continuously removed and insoluble N2OO2 is continuously removed and insoluble N2Ouptake is minimaluptake is minimal

The gas returning to circuit has more N2O, lessThe gas returning to circuit has more N2O, less

O2 with time due to concentration effectO2 with time due to concentration effectHYPOXIC MIXTUREHYPOXIC MIXTURE

ROLE IN NAUSEA AND VOMITINGROLE IN NAUSEA AND VOMITING


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ROLE IN NAUSEA AND VOMITINGROLE IN NAUSEA AND VOMITING

Thought to be a major concern in etiologyThought to be a major concern in etiology Several studies demonstrate no increase inSeveral studies demonstrate no increase in

incidence ofPONVincidence ofPONV

Continues to be used in ambulatoryContinues to be used in ambulatoryanaesthesiaanaesthesia

REFERENCESREFERENCES


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REFERENCESREFERENCES

P

harmacology andP

hysiology in AnaestheticP

harmacology andP

hysiology in AnaestheticPracticePractice-- Robert K. Stoelting, 4th editionRobert K. Stoelting, 4th edition

MillerMillers textbook of anaesthesia 6s textbook of anaesthesia 6thth editionedition

International Practice of anaesthesiaInternational Practice of anaesthesia CedricCedric

Prys Roberts 10Prys Roberts 10thth editionedition Wylie and Churchill Davidson textbook ofWylie and Churchill Davidson textbook of

anaesthesiaanaesthesia-- 77thth editionedition

ISACON MysoreISACON Mysore

20062006 Inoprotection: the perioperative role ofInoprotection: the perioperative role of

levosimendan, Anaesthesia and Intensivelevosimendan, Anaesthesia and IntensiveCare,35,No.6,December2007Care,35,No.6,December2007


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THANKYOUTHANKYOU

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