antihypertensive agents[1].revision

8/13/2019 Antihypertensive Agents[1].Revision

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2006

Antihypertensive agents

Primary MMed (Anaesthesia)


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Classification of antihypertensive agents classify according to

principal regulatory site mechanism of action usage during anaesthesia


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according to site of actionVasomotor centreSympathetic nerve

terminalsSympathetic ganglia of

the heart1receptors of the heart!enin angiotensin

aldosterone system

"receptors of vesselsand vascular smoothmuscle

#idney tu$ules

methyldopa% clonidine% guana$en&% guanfacineguanethidine% guanadrel% reserpine% Mg''

trimethaphan

1$locers (esmolol)angiotensinconverting en&yme inhi$itors

angiotensin ** type 1 receptor $locers(losartan) aldosterone receptor $locers(eplerenone)% receptors of reninreleasing+u,taglomerular cells ($locers)"1$locers (phentolamine)

hydrala&ine% nitrovasodilators%calcium channel $locers% potassiumchannel activatorsdiuretics


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according to mechanism of action

diuretics

sympathoplegicagents

direct vasodilatorsand agents that $locreninangiotensinaldosterone system

deplete the $ody of sodium andreducing $lood volumereduce peripheral resistance%

inhi$iting cardiac function%increasing venous pooling

reduce peripheral vascularresistance and $lood volume


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according to usage during anaesthesia

reducing release ofnoradrenaline vesicles

reducing effects of

noradrenaline-adrenaline

direct vasodilators

".agonists magnesium calcium channel $locers " $locers

$locers calcium channel $locers nitrodilators


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2006

/iuretic agents


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/iuretic agents mechanisms of action

depletion of $ody sodium stores reduction of $lood volume direct vasodilating effects

hypertension control 4ith diuretic$asedpharmacotherapy results in $etter prevention ofheart failure than pressure reduction 4ith otherdrugs


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Mechanism of action depletion of $ody sodium stores and reduction in

$lood volume sodium contri$utes to vascular resistance $y

increasing vessel stiffness and neural reactivity%possi$ly related to increased sodiumcalcium

e,change 4ith a resultant increase in intracellularcalcium initially% reduced $lood volume% reduced cardiac

output% increased peripheral vascular resistance after 89 4ees% cardiac output returns to normal%

peripheral resistance declines


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Mechanism of action direct vasodilating effects

indapamide% a nonthia&ide sulfonamide diuretic has$oth diuretic and vasodilator activity 4ith vasodilatation% cardiac output is

maintained or increased amiloride% inhi$its smooth muscle responses to

contractile stimuli% pro$a$ly though effects ontransmem$rane and intracellular calcium movement

that are independent of its action on sodium e,cretion


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6hia&ide diuretics a'-Clsymport inhi$itors

enhance Ca.'rea$sorptionin the /C6

increase e,cretion of:C2;and phosphate

increase e,cretion of #'and titrata$le acid

e,cretion of Mg.'

inhi$it aCl rea$sorption from/C6 (primary site of action)

and pro,imal convoluted tu$ule(secondary site of action)

from enhanced a'-Ca.'e,change in the $asolateralmem$rane as a result oflo4ering of intracellular a'(due to $locade of a'entry$y thia&ides)

4ea inhi$ition of car$onic

anhydrase due to increased delivery ofa'to distal tu$ule


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Action of thia&ide diuretic agent at /C6

S Symporter

a' a' (;)a'

Cl

7umen *nterstitialspace

Cl ClS

(.)#'#' A6Pase a'

ClS

thia&ide

(a'

Cl

symportinhi$itor) A6P

ase

#'


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6hia&ide diuretics

chemistry

a$sorption

t orally

less lipid solu$le1?@ hoursrenal filtration andtu$ular organic acidsecretory system

$en&othiadia&ine

derivatives 4ith(S2.:.) group

8@@> orally

@1B hoursrenal filtration andtu$ular organic acidsecretory system


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6hia&ide diuretics elimination

degree of protein $inding determines the contri$utionthat filtration maes to tu$ular delivery of thia&ides

sulphonamides are organic acids and are secreted $ythe organic acid secretory system secretion is inhi$ited $y indomethacin and

pro$enecid compete 4ith the secretion of uric acid% uric

acid secretory rate may $e reduced 4ithinitial hyperuricaemia


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Adverse effects of thia&ide diuretics reduce 5C hypotension hyponatraemia hypochloraemia hypoalaemiaD hypomagnesaemia meta$olic alalosis 4eaness% fatiga$ility%

parasthesia

hypercalcaemia hyperuricaemiaD hyperglycaemiaD hypertriglyceridaemiaD hypersensitivity arrhythmiasD

D seen 4ith dosage higher than .@ mg-day


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6hia&ide diuretics impaired glucose tolerance

$y reduced insulin secretion% or $y acting as potassiumchannel opener% counteracts the effect ofsulphonylurea hypoglycaemic agents

may $e related to hypoalaemia as hyperglycaemia ispartially reversi$le 4ith correction of hypoalaemia


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6hia&ide diuretics (drug interactions) Euinidine (prolongation of F6 interval leading to

polymorphic ventricular tachycardia or torsade depointes% due to hypoalaemia) diminish the effects of

anticoagulants% uricosuric agents% sulphonylureas% insulin increase the effects of

anaesthetics% dia&o,ides% digo,in% lithium% loopdiuretics% vitamin /

effect of thia&ide diuretics decreased $y SA*/s% $ile acid seEuestrants (reduce rea$sorption

of thia&ides)% methanamines (alalini&ation of urine) ris of hypoalaemia increased $y

amphotericin G and corticosteroids


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7oop diuretics selective inhi$ition of a'-#'-.Cltransport

system in the luminal mem$rane of the thicascending lim$ of loop of :enle

increase in Mg.'and Ca.'e,cretion inhi$it Ca.'rea$sorption% due to reduction of the

normal lumenpositive potential derived from #'recycling

increase urinary e,cretion of #'and titrata$leacid due to increase delivery of a'to /C6

4ea inhi$itor of car$onic anhydrase activity frusemide increases e,cretion of :C2;and phosphate


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Action of loop diuretic agent at thicascending lim$

SSymporter

#' #'S

a' a' a'Cl

7umen *nterstitialspace

Cl ClS

Ca.'

Mg.'

#'#' A6Pase

#' #'S

a'Cl S

Ca.'

Mg.'

#' A6Pase

frusemide(a'#'.Cl

symportinhi$itor)


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7oop diuretics chemistry

sulphonamide derivative 4ith a car$o,yl group frusemide% $umetanide% torsemide

pheno,yacetic acid derivative

ethacrynic acid


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7oop diuretics

oral a$sorption$ioavaila$ilityonset of action

Vdt% rapidHH>diuretic response israpid follo4ingintravenous in+ection

=?1 7-g=?;1?@ hours;@> meta$olised%8@> unchanged via urineI glomerular filtration

and tu$ular organic acidsecretion

rusemide

sulphonamide derivative8=>% rapidHH>diuretic response israpid follo4ingintravenous in+ection

=?1 7-g=?;; hoursB=> meta$olised%8=> unchanged via urineI glomerular filtration

and tu$ular organic acidsecretion


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7oop diuretics adverse effects ototo,icity

hyperuricaemia hyponatraemia hypoalaemia meta$olic

alalosis ris of cardiac

arrhythmias% especially4ith digo,in

hypomagnesaemia hypocalcaemia

hypercalcaemia mayoccur 4ith severedehydration

hyperglycaemia

increase plasmaconcentration of 7/7cholesterol andtriglycerides% 4hiledecreasing :/7cholesterol

hypersensitivity $one marro4 depression photosensitivity paresthesias gastrointestinal

distur$ances


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7oop diuretics ototo,icity alterations in the electrolyte composition of

endolymph occurs most freEuently 4ith rapid intravenous

administration% less freEuently 4ith oral

administration higher incidence 4ith ethacrynic acid


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7oop diuretics I drug interactions aminoglycosides (augmentation of ototo,icity) oral anticoagulant (increase activity) digo,in (potentiate digo,ininduced arrhythmias) increase plasma concentrations of lithium%

propranolol sulphonylureas (hyperglycaemia) cisplatin (increased ris of diureticinduced

ototo,icity) SA*/s (reduce diuretic response) pro$enecid (reduce transport into tu$ular lumen

and hence diuretic response) thia&ide diuretics (synergism of diuretic activity)


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*ndapamide an indole derivative of

chlorosulphonamide a 4ea acid% 4ith p#a 9?9% differs chemically from

the thia&ides in that it does not possess the thia&idering system and contains only one sulfonamide group

has an antihypertensive action causing a drop insystolic% diastolic and mean $lood pressure%

antihypertensive action is ma,imal at a dose of.?@ mg per day and the diuretic effect is slight%

usually 4ithout clinical manifestation at higher doses% the diuretic effect $ecomes more

prominent


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*ndapamide pharmacoinetics rapidly and completely a$sor$ed after oral

administration pea $lood levels are reached after 1 to . hours? e,tensively meta$olised only @> is found unchanged in the urine t $ound to plasma protein the methylindoline portion of the molecule gives

indapamide its lipophilic character% andindapamideKs lipid solu$ility is @ to 9 times that ofthe thia&ides% it is as a result of this characteristicthat indapamide locali&es in smooth vascular muscle


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*ndapamide I adverse effects giddiness% headaches anore,ia gastric irritation nausea% vomiting constipation and diarrhoea hyperuricaemia hypoalaemia


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Selection of diuretics thia&ide

mild to moderate hypertension threshold amount of $ody sodium depletion may $e

sufficient for antihypertensive efficacy

loop diuretics (frusemide) severe hypertension% 4hen multiple drugs 4ith sodium

retaining properties are used in renal insufficiency% 4hen 3! is L ;=B=ml-min

$lood pressure response continues to increase as doseincreases


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2006

/rugs that alter sympatheticnervous system function

centrally acting sympathoplegic agentsganglion$locing agents

adrenergic neuron $locing agentsalpha and $etaadrenoceptor antagonists


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/rugs that alter sympathetic nervoussystem function classified according to the site of action along

the sympathetic refle, arc centrally acting sympathoplegic agents ganglion$locing agents adrenergic neuron $locing agents alpha and $etaadrenoceptor antagonists

any of the agents 4hen used alone 4ill result insodium retention $y the idneys and increased$lood volume% hence most effective 4hen used

concomitantly 4ith a diuretic


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/rugs that alter sympathetic nervoussystem functioncentrally actingsympathoplegicagentsganglion$locingagents

adrenergic neuron$locing agents

" adrenoceptorantagonists

tend to cause sedation% mentaldepression% distur$ance of sleep%including nightmareinhi$ition of parasympatheticregulation% and profound sympathetic

$locadereducing release of noradrenalinefrom sympathetic nerve endingscausing hypotension that is increased

$y upright posture and after e,erciseeffects depending on the class ofreceptor to 4hich they $ind


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2006

Central actingsympathoplegic agents

".receptor agonistsimida&oline receptor agonists


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2006

".receptor agonists

methyldopaclonidine

de,medetomidine

miva&erolguanfacineguana$en&mo,onidine


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Rostral Ventrolateral

medulla

Nucleus Tractus

Solitarius


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Central acting sympathoplegic agents Ireceptor sites highest density of "methyladrenaline $inding

sites (".receptors) is found in nucleus tractussolitarius (6S) of the medulla

".receptors are coupled to 3o and 3i

3o interacts 4ith mem$rane $ound phospholipase Cand is coupled to voltagegated Ca.'channel% reducingin4ard conductance of Ca.'

activation of 3igated #'channels increases out4ard

conductance of #'% hyperpolarisation of the neuronalcell 3i also supports inhi$ition of adenylyl cyclase


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Central acting sympathoplegic agents Ireceptor sites clonidine also $inds to imida&oline receptorsin the

rostral ventrolateral medulla(!V7M)% 4hich isconsidered the common path4ay for sympatheticvasomotor outflo4

*1($rain) and *.($rain% idney pancreas) *1su$group $inding site for imida&oline drugs 4ith

antihypertensive effects may $e a 3 proteincoupled receptor that utilises the *P;

and /A3 as second messenger system

*1 selectivity0 mo,onidine N rilmenidine N clonidine Nde,medetomidine N miva&erol less sedation and less dry mouth 4ith mo,onidine and

rilmenidine


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Activation of ".responses in the inactive state%

3 protein is notclosely associated4ith the ".

adrenoceptor and is$ound to 3/Pii

".agonist

".receptor

3/P36P

Adenylylcyclase

!.C.proteininase

.C

5n&yme

5n&yme

phosphate

3/P36P

-

cAMPA6P

A6P

A/P.!

3i


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Activation of 3 protein 4hen agonist $inds to the receptor

structure of the receptor changes% and it associates4ith the " su$unit of the 3 proteins

results in reduced affinity of 3 protein for the 3/P%and in the presence of magnesium% is replaced $y 36P

" su$unit then uncouples from the and O su$units andcouples 4ith the effector% resulting in a decrease inthe affinity of the receptor% and the agonist leavesthe receptor site


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Activation of 3 protein duration of $inding of the agonist to the

receptor determines the amount of amplificationof the intracellular response

36Pase on the " su$unit is then activated andhydrolyses 36P to 3/P% releasing an inorganicphosphate

the receptor then returns to the inactive state


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Central acting sympathoplegic agents

cardiaceffects

Methyldopa

varia$le reduction inheart rate cardiacoutput

Clonidine

lo4ers heart rate andcardiac output (morethan methyldopa)modifies $aroreceptor

sensitivityreduction in heartrate% systemicmeta$olism% myocardialcontractility% systemicvascular resistancereduces myocardialo,ygen reEuirements


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renal effects

Methyldopa

reduction in renalvascular resistance

Clonidine

decrease renalvascular resistanceinhi$it the releaseof renin


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a$sorption$ioavaila$ility

distri$ution

Methyldopa

rapide,tensive first passmeta$olism% primarily$y 2sulphate

con+ugation $ygastrointestinalmucosa.@> $ioavaila$ilityenters the $rain via apump that activelytransports aromaticamino acids

Clonidine

rapid and complete asit is lipid solu$le$ioavaila$ility nearly1==> pea plasma

concentration in 8=H= minutes after oraldose.=> $ound to plasmaproteins Vd . 7-glipid solu$le% rapidlyenters the $rainfrom the circulation


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onset ofaction

duration of

action

Methyldopa

slo4 $ecause theactive component ismethylnoradrenaline%ma,imal effect afteroral dose is B8 hoursas effect depends on"methylnoradrenaline%actions persist after

the parent drug hasdisappeared fromcirculation% effectmay persist up to .Bh

Clonidine

onset 4ithin @1=minutes of *M or *Vin+ectionappro,imately @ hours

after intramuscularin+ection and a$out ; hours afterintravenousadministration4ith transdermalpreparation% days


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clearance

Methyldopa

a$out 88> of thedrug that reachessystemic circulation iscleared $y renal

e,cretion% impairedrenal functionreduces renalclearance

Clonidine

@=> e,cretedunchanged in theurine% lo4er thanusual doses may $e

effective in patients4ith renalinsufficiency@=> meta$oli&ed inliverclearance is .Bml-g-min


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t


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Methyldopa indications

mild to moderately severe hypertension duringpregnancy


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Methyldopa I adverse effects sedation

persistent mentallassitude impaired mental

concentration

nightmares mental depression vertigo e,trapyramidal signs

positive Coom$s test (in1=.=> of patientsundergoing therapy N 1.months)

lactation associated

4ith increasedprolactin secretion can occur

$oth in men and4omen

mediated $yinhi$ition action on

dopaminergicmechanisms in thehypothalamus


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Clonidine I other pharmacodynamiceffects 2ther actions

suppression of locus coeruleus sedation and sleep analgesic effects slight reduction of minute ventilation

decrease intraocular pressure alter neuronal activity in the spinal cord treatment

of spasticity $locs adrenalineinduced platelet aggregation

inhi$it secretion of adrenocorticotropic hormone(AC6:) and cortisol inhi$ition of insulin release $y direct effect on

islets of 7angerhans

I:I

ClI

ClI:


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l d d d d


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Clonidine versus de,medetomidine

chemistry

site of

action

Clonidine

.imida&olinederivative

" receptors in the

medullaimida&oline receptors

/e,medetomidine

imida&oline congenerof clonidine% $ut 9,more ".activity thanclonidine

Senantiomer ofmedetomidinemore specific andshorter central acting".agonist effects

full agonist% ". 0 "1 I18==01imida&oline receptors

l d d d d


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$loodpressureeffects

Clonidine

lo4ers $lood pressure$y presynapticmediated reductionof noradrenalinerelease and direct

vagomimetic actionafter intravenousin+ection% $rief rise in$lood pressurefollo4ed $y prolonged

hypotension% due tostimulation of ".adrenoceptors inarterioles

/e,medetomidine

same as concentrationdeclines% asodilatationoccurs due to centraleffect

de,medetomidineshould not $eadministered rapidly

Cl d d d d


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cardiaceffects

renal

effects

othereffects

Clonidine

lo4ers heartrate and cardiacoutputdecrease renal

vascular resistanceinhi$it the release ofreninsignificant analgesiceffects 4hen given

intrathecally

/e,medetomidine

$radycardia andsinus arrest possi$le

same hypnoticeffect a$ruptstopping causes

nervousness%agitation% headaches%rapid rise in $loodpressure

Cl idi d d idi


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orala$sorption

distri$ution

Clonidine

rapid and complete asit is lipid solu$le$ioavaila$ility nearly1==>pea plasma

concentration in 8=H=minutes after oraldose.=> $ound to plasma

proteins Vd . 7-glipid solu$le% rapidlyenters the $rain fromthe circulation

/e,medetomidine

HB> protein $ound0al$umin ' "1glycoproteinVdss 1?;; 7-gp#a ?1

Cl idi d d idi


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clearance

Clonidine

.B ml-g-min@=> e,cretedunchanged in theurine% lo4er than

usual doses may $eeffective in patients4ith renalinsufficiency@=> meta$oli&ed in

liver

/e,medetomidine

dou$le0 9ml-g-min4ith high dosages% Vdis small and clearanceis lo4 due toperipheral

vasoconstrictionundergoeshydro,ylation%methylation andglucuronide

con+ugationH@> e,creted renallyB> e,cretedunchanged in faeces

Cl idi d d t idi


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t


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Miva&erol ".agonist

penetrates the $rain poorly effect mediated via activation of ".receptors

in the spinal cord% in the stellate ganglia% and on

presynaptic terminals in the heart designed to prevent myocardial ischaemia

do4n regulates the sympathetic nervous systemactivity 4hich drives noradrenaline release in the

heart

Mi l


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Miva&erol administration

intravenous $olus follo4ed $y infusion distri$ution

@=> protein $ound

meta$olism t e,creted unchanged $y idney .=.@> undergoes con+ugation in the liver

A li ti i di


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Application in cardiac surgery perioperative use in cardiac surgery

lo4er serum concentrations of catecholamine lo4er incidence of intra and postoperative

hypertension and tachycardia higher cardiac output follo4ing cardiopulmonary

$ypass less postoperative shivering reduction in postoperative o,ygen consumption

S l ti it ti


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Selectivity ratios ".0"1 ".0*1

clonidine .==01 1801

demedetomidine 18==01 ;.01

miva&erol B==01 .1@01

3 f iCl

:2:


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3uanfacine a phenylacetylguanidine derivative highly selective for ".adrenergic receptor lo4ers $lood pressure $y activation of $rainstem

receptors 4ith resultant suppression of

sympathetic activity pharmacoinetics

4ell a$sor$ed after oral administration Vd B8 7-g @=> e,creted unchanged in urine% @=> meta$oli&ed t


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3uanfacine adverse effects

similar to clonidine $ut less severe 4ithdra4al syndrome may occur after a$rupt

discontinuation

Cl

RCRCRRC:

: :.

2:

:

3 $Cl

::


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3uana$en& central acting ".agonist lo4ers $lood pressure $y activation of $rainstem

receptors 4ith resultant suppression ofsympathetic activity

pharmacoinetics 4ell a$sor$ed after oral administration Vd B8 7-g e,tensively meta$oli&ed $y liver% dose ad+ustment in

cirrhosis t


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2006

*mida&oline receptor agonists

clonidinede,medetomidine

miva&erolrilmenidinemo,onidine

!ilm nidin


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!ilmenidine an o,a&oline% structurally similar to imida&oline

central acting imida&oline receptor agonist central acting antihypertensive agent 4ith no 4ithdra4al

symptoms follo4ing cessation of treatment rapidly a$sor$ed after oral administration

pea plasma concentration of 1?@. h 1=> protein $ound clearance

8@> e,creted in urine unchanged the rest undergoes o,alinering hydrolysis t


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Mo,onidine imida&oline compound 4ith selective agonist

activity at imida&oline *1receptors and onlyminor activity at ".adrenoceptors

a$sorption rapid and almost completely after oral administration ma,imum plasma concentration in 1 h

clearance H=H8> e,creted $y the idney% @1> as unchanged

drug t


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Mo,onidine dosing

=?B mg daily should $e reduced if there is renal impairment

fe4 of the adverse effects of clonidine such asdry mouth% sedation% depression% tiredness

Magnesium sulphate


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Magnesium sulphate physiologic calcium channel $locer inhi$its the release of catecholamines from the

adrenal medulla and adrenergic nerve endings has direct vasodilatory effects and

antiarrhythmic properties


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3anglion$locing agents

3anglion $locing agents


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3anglion $locing agents drugs that $loc the nicotinic cholinoceptors on

postganglionic neurons in $oth sympathetic andparasympathetic ganglia

Central

nervoussys

tem

Sympatheticsystem

Parasympatheticsystem

Ach (nic)

Ach (nic)

Ach (nic)

Ach (nic) Adrenal medulla

Salivary glandsAch (mus)

Ach (mus) S4eat glands

A Glood vessels

3anglion $locing agents


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3anglion $locing agents no longer availa$le clinically $ecause of the

to,icities related to their primary action adverse effects from sympathoplegia

e,cessive orthostatic hypotension

se,ual dysfunction adverse effects from parasympathoplegia

constipation urinary retention precipitation of glaucoma $lurred vision dry mouth

6rimethaphan camsylate


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6rimethaphan camsylate rapid onset of hypotensive effect previously used to control hypertensive crisis

acute aortic dissection neurosurgery

precise titration of $lood pressure possi$le dueto the dependence of ganglion $locade on plasma

concentration of agent short halflife

hypotensive effect is mainly due to venouspooling in the capacitance vessels

6rimethaphan camsylate


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6rimethaphan camsylate administration

as an infusion% =?;@ mg-min onset of hypotension 4ithin @ minutes tachyphyla,is occurs after .BB9 hours%

partly due to e,pansion of plasma volume%

sensitivity can $e restored 4ith diuresis adverse effects

paralytic ileus $ladder dysfunction

dry mouth $lurred vision respiratory arrest 4ith N @ mg-min


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2006

Adrenergic neurone $locingagents

guanethidine

guanadrel

reserpine

Adrenergic neurone $locing agents


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Adrenergic neurone $locing agents these drugs lo4er $lood pressure $y

preventing the normal physiologic release ofnoradrenaline from postganglionic sympatheticneurons guanethidine% guanadrel% $ethanidine%

de$risoEuin

3uanethidine : :


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3uanethidine structure

includes a highly $asic nitrogen (guanidine group) thatmaes the drug too polar to enter the central nervoussystem this drug has no central nervous system

effects mechanism of action

depletion of noradrenaline stores $locs e,citationsecretion coupling $y Ca.' local anaesthetic effect

C:.C:.C:.


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Mechanism of action


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Mechanism of action

oradrenergic varicosity ornerve ending at +unctional cleft

a' channel

Ca.'

channel

A

A

Ca.'

AA

a' channel

Ca.'channel

A

3

A

3

3

1? 3uanethidine$locsphysiologicrelease of

noradrenaline

Ca.'

.? 3uanethidinedisplaces A from

vesicles anddepletes store

.

3uanethidine : :


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3uanethidine a$sorption

$ioavaila$ility varia$le ;@=> distri$ution

retention of the drug in nerve endings and uptae intoother sites contri$ute to large volume of distri$utionand long halflife of @ days 4ith constant dosing% the onset of

sympathoplegic is gradual% ma,imum effects

in 1. 4ees clearance

@=> cleared $y the idney

C:.C:.C:.

3uanethidine : :


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3uanethidine dosing

starting dosage is 1=mg-day dosage should not $e changed in intervals shorter than

. 4ees long duration of action% maintenance dose is once a day

contraindication pheochromocytoma

hypertensive crisis $y release ofcatecholamine

C:.C:.C:.

3uanethidine


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3uanethidine pharmacodynamic effects

early in the course of therapy hypotensive effects is associated 4ith

reduced cardiac output% due to $radycardiaand rela,ation of capacitance vessels%

4ithout consistent change in peripheralresistance

4ith chronic therapy% peripheral resistance decreases

sodium and 4ater retention may $e mared duringguanethidine therapy

3uanethidine I adverse effects


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3uanethidine adverse effects postural hypotension

and hypotensionfollo4ing e,ercise severe reduction in

$lood pressure if

dosages aree,cessively high% orincreased too rapidly

upregulation of post

synaptic receptorsafter longtermtherapy

delayed or retrograde

e+aculation (into the$ladder) in men diarrhoea

due to

parasympatheticpredominance

3uanethidine I drug interaction


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3uanethidine drug interaction drugs that $loc the catecholamine uptae

process or displace amines from nerve terminals$loc the effects of guanethidine cocaine% amphetamine% tricyclic antidepressants%

phenothia&ines% pheno,y$en&amine

concomitant 6CA administration reducesantihypertensive effect of guanethidine if dosageof guanethidine is increased for antihypertensiveeffect and 6CA is then stopped% severe

hypotension or cardiovascular collapse fromunopposed action of guanethidine may result

3uanethidine


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3uanethidine drug interaction

guanethidine increases sensitivity to hypertensiveeffects of e,ogenously administered sympathomimeticagents% from inhi$ition in neuronal uptae of suchamines

phenylpropanolamine% in commercial preparations forrhinitis% can produce hypertension in patients taingguanethidine

/rug interactions


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/rug interactions

a' channel

Ca.'

channel

A

A

3

.? 6yramine%amphetamine% andreserpine release3uanethidine from

vesicles

Ca.'

1? Cocaine% tricyclicantidepressants $locmem$rane transport of3uanethedine1

3 .

A

3uanadrel


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3uanadrel guanidinecontaining adrenergic neuron $locing

agent act in the same 4ay as guanethidine difference $et4een . compounds

9@> $ioavaila$ility

t


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!eserpine an alaloid e,tracted from the roots of

!au4olfia serpentina% for treating mild tomoderate hypertension

mechanism of action irreversi$ly $locs uptae of $iogenic amines into

vesicles% pro$a$ly $y interfering 4ithan uptaemechanismthat depends on Mg.'and A6P resulting indepletion of noradrenaline% dopamine% and serotoninin$oth central and peripheral neurons

chromaffin granules of the adrenal medulla are alsodepleted of catecholamines

!eserpine


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!eserpine readily enters the $rain entirely meta$olised% $ut prolonged effects due

to irreversi$le inactivation of the carriers incatecholamine storage granules

central effects sympathetic refle,es remain largely intact% $lood

pressure is reduced in supine as 4ell as in standingpatients% and postural hypotension is mild

depletion of cere$ral amine stores causes sedation%

mental depression% and e,trapyramidal effects

!eserpine


93/276

!eserpine peripheral effects

depletion of peripheral amines pro$a$ly accounts formuch of the antihypertensive effect of reserpine contraindication

mental depression

gastric ulceration

Adverse effects of reserpine


94/276

Adverse effects of reserpine postural hypotension

less 4ith lo4 doses sedation lassitude

nightmares severe mental

depression 4ith highdosages

e,trapyramidal

effects resem$lingParinsons disease dopamine depletion

in the corpusstriatum

mild diarrhoea%gastrointestinal

cramps% increase gastric acid

secretion

Sympathetic

1 uptae 1% inhi$ited $y cocaine%amphetamine tricyclic


95/276

AA

A

A

A

A

".!

MA2

6yrosine

6yrosine

/2PA

/A"!

! response

response

ormetanephrineC2M6

5ffector cell

Sympatheticnerve ending

euroeffector+unction

1

amphetamine% tricyclicantidepressants

reserpine

metyrosine

tyramineephedrineamphetamine

'

Ca.'

Ca.'

.

. uptae .

A


96/276

2006

Adrenoceptor antagonists

"1adrenoceptor $locing agents

adrenoceptor $locing agents


97/276

2006

Alpha1receptor antagonists

reversi$le antagonists

irreversi$le antagonists

Mechanism of action


98/276

Mechanism of action reversi$le"1receptor antagonists

can dissociate from the receptors phentolamine% tola&oline% pra&osin% la$etalol

duration of action largely dependent on

the rate at 4hich it dissociates from thereceptor the clearance and halflife

Mechanism of action


99/276

Mechanism of action irreversi$le"1receptor antagonists

covalently $ind to the receptors and do not dissociatefrom the receptors (e?g? pheno,y$en&amine)

effects of the drug may persist long after the drughas $een cleared from the plasma

restoration of tissue responsiveness after e,tensive"receptor $locade (e?g? $y pheno,y$en&amine) isdependent on the synthesis of ne4 receptors% 4hichmay tae several days

5ffects of "1receptor antagonism


100/276

1 p g cardiovascular system

postural hypotension and refle, tachycardia postural hypotension due to $locade of "1

receptors in venous smooth muscle

compensatory increase in $lood volume 4ith chronicuse eye myosis nasal mucosa congestion and stuffiness

inhi$ition of contraction of the trigone andsphincter muscles in the $ase of $ladder andprostate resulting in incontinence

"1receptor antagonists clinical applications


101/276

1 p g pp pheochromocytoma

hypertensiveemergencies chronic hypertension

retention of salt

and 4ater occurs ifadministered4ithout a diuretic

peripheral vasculardisease

treatment of clonidine4ithdra4l syndrome

urinary o$struction

prevention of dermalnecrosis afterinadvertente,travasation of "adrenergic agonist

male se,ual dysfunction direct intracavernous

in+ection of

phentolamine 4ithpapaverine

Classes of "adrenergic antagonists


102/276

lasses of " adrenerg c antagon sts alylating agent

pheno,y$en&amine imida&olines

phentolamine

tola&oline pipera&inyl Euina&olines

pra&osin

tera&osin do,a&osin trima&osin

indoles yohim$ine indoramin

ergot derivatives

ergotamine dihydroergotamine

Pheno,y$en&amine h l l l mi

I2C:.C:

C:;


103/276

a haloalylamine mechanisms of action

$locs $oth "1and ".adrenergic receptors forms a reactive ethyleneimonium intermediate that

covalently $inds to " receptors% resulting inirreversi$le $locade

long duration of action% 1BB9 hours slight selectivity for "1receptors% less so than

pra&osin inhi$its reuptae of released noradrenaline$y presynaptic

noradrenergic nerve terminals also $locs histamine (:1)% acetylcholine% and serotonin receptors

C:.C:.Cl

IC:.

Pheno,y$en&amine


104/276

y structure activity

the molecular configuration directly responsi$le forthe $locade is pro$a$ly a highly reactive car$oniumion formed upon cleavage of the ;mem$ered ring ofthe ethyleneimonium intermediate% giving rise to

relative specificity of action

I2C:.C:

IC:.

C:.

C:.

Active ethyleneimonium intermediate

Pheno,y$en&amine


105/276

y effects

$locs catecholamine induced vasoconstriction causes significant fall in $lood pressure 4hen the

sympathetic tone is high e?g? as a result of uprightposture or $ecause of hypovolaemia

cardiac output may increase $ecause of refle, effectsand $ecause of some $locade of presynaptic ".receptors in cardiac sympathetic nerves

indications pheochromocytoma $enign prostatic o$struction

Pheno,y$en&amine


106/276

y pharmacoinetics

lo4 $ioavaila$ility after oral administration crosses GGG t


107/276

imida&oline derivative mechanisms of action

competitive a receptor antagonist 4ith similar affinityfor "1and ".receptors

causing a reduction in peripheral resistance $locs serotonin receptors $locs #'channels agonist at muscarinic and :1and :.histamine

receptors

C:.I

2:

:

Phentolamine tachycardia


108/276

y from . causes

$arorefle, mechanism antagonism of presynaptic .receptors lead to

enhanced release of noradrenaline from sympatheticnerves% noradrenaline then acts via un$loced

adrenoceptors

Phentolamine


109/276

formulation oral phentolamine mesylate is rapidly a$sor$ed and

eliminated pea plasma concentrations are achieved in;=8= min% and the halflife appro,imates @ h

*V $olus or infusion

adverse effects cardiac stimulation0 tachycardia% arrhythmias%

myocardial ischaemia gastrointestinal stimulation0 diarrhoea and increased

gastric acid production

Phentolamine indications


110/276

pheochromocytoma reduce e,tent of dermal necrosis after

e,travasation of " agonist hypertensive crisis

male se,ual dysfunction

Pra&osin


111/276

pipera&inyl Euina&oline

selectivity for "10".receptor is 1===01 $lood pressure is reduced more in the upright than in the

supine position receptor selectivity allo4s noradrenaline to e,ert

unopposed negative feed$ac (on presynaptic ".receptor)on its o4n release may partially e,plain the a$sence of refle,

tachycardia 4ith pra&osin (cf phentolamine and

pheno,y$en&amine) potent inhi$itor of cyclic nucleotide

phosphodiesterase

Pra&osin


112/276

a$sorption a$sor$s 4ell @==> $ioavaila$ility after oral administration pea concentrations reached 4ithin 1; hours after

oral dose

distri$ution H@> tightly $ound to "1acid glycoprotein

free fraction su$+ect to change $y diseases

that modify the concentration of thisprotein

Pra&osin


113/276

clearance entirely meta$olised t


114/276

dosing initiated 4ith 1 mg ; times daily% starting at $edtime

reduces the precipitous drop in standing$lood pressure after the first dose isa$sor$ed

Pra&osin


115/276

adverse effects first dose phenomenon di&&iness palpitation headache lassitude develop antinuclear factor in serum 4hile on pra&osin

therapy


116/276

2006

Geta receptor antagonists



117/276

mechanism of antihypertensive action

decrease in cardiac output negative inotropic and chronotropic effects adrenoceptor $locade at atrioventricular

node

inhi$ition of 1mediated renin production anddepression of the reninangiotensinaldosteronesystem

inhi$ition of peripheral pre+unctional adrenoceptors

reducing sympathetic vasoconstrictor nerve activity



118/276

$y opposing .mediated vasodilatation% may

result in an initial rise in peripheral vascularresistance from unopposed " receptormediatedeffects

distinguishing properties reversi$le - irreversi$le $inding to receptors full antagonists - partial agonists (intrinsic

sympathomimetic activity% *SA) relative affinity for 1and .receptors

pharmacoinetic characteristics local anaesthetic mem$ranesta$ilising effects (MSA)

Geta receptor antagoniststypes


119/276

pure antagonists

occupancy of a $eta receptor causes no activation ofthe receptor partial agonists (intrinsic sympathetic activity)

cause partial activation of the receptor% $ut less than

that caused $y full agonists adrenaline andisoprenaline inverse agonists

have the a$ility to inactivate active state receptors propranolol N $ucidolol and carvedilol in

producing negative chronotropic andinotropic effects

Selective 1receptor antagonists


120/276

*SA MSA lipid elimination $ioavaila$ility protein

solu$ility t(*V) @@>

atenolol no no lo4 8H B=> L@>

$isoprolol no no lo4 H1. 9=>

ace$utolol yes yes lo4 ;B @=> .=>

celiprolol yes (.) no B@ =>

$eta,olol no slight lo4 1B.. H=>

metoprolol no yes mod ;B @=>1=>

onselective receptor antagonists


121/276

*SA MSA lipid elimination $ioavaila$ility protein

solu$ility t H=>timolol no no mod B@ @=> 1=>o,prenolol yes yes 9=>la$etalolD no yes mod @ ;=> @=>

carvedilolD no 1= .@;@> @>

pindolol yes slight mod ;B H=> B@>carteolol yes no lo4 8 9@>nadolol no no lo4 1B.B ;;> 1@>D "1antagonism as 4ell (vasodilatory effect)

7ipophilic receptor antagonistsP l lD 3 ll li hili hi h i $i di


122/276

PropranololD2,yprenolol

Ace$utolol

MetoprololD6imolol7a$etalolD"

Carvedilol"

GisoprololGeta,olol

Pindolol

5smolol

3enerally% lipophilic% high protein $inding(e,cept ace$utolol% metoprolol and timolol)%

high CS penetration% lo4 $ioavaila$ility%larger Vd of N.7-g (e,cept o,yprenolol1?.7-g)% short t)? Meta$olised $y liver% appro,? @=> renale,cretion? t


123/276

Atenolol

CarteololadololPindololCeliprolol T

3enerally hydrophilic% lo4 protein $inding% lo4

CS penetration% high $ioavaila$ility @=H=>(e,cept nadolol .=>)% smaller Vd of =?.7-g% longer t


124/276

Pharmacoinetic properties


125/276

$ioavaila$ility

first pass effect% e,tensive for most% 4ith lo4$ioavaila$ility e,cept for $eta,olol% pen$utolol% pindolol%

and sotalol

interindividual varia$ility hepatic e,traction mechanism may $ecome saturated



126/276

distri$ution

rapidly distri$uted and have large volumes ofdistri$ution

propranolol and pen$utolol are Euite lipophilic andreadily cross the $lood $rain $arrier

if highly protein $ound% are not cleared significantly$y haemodialysis



127/276

clearance

t


128/276

respiratory tract

$ronchoconstriction 4ith increased air4ay resistance use of selective 1receptor antagonists may

$e prefera$le 4hen .receptor $locade isundesira$le

e?g? esmolol% ace$utolol% metoprolol%$isoprolol% celiprolol% atenolol% $eta,olol

as specific 1receptor antagonist 4ithout .

activity is currently unavaila$le% thereforethese drugs should generally $e avoided inpatients 4ith asthma

2ther effects


129/276

eye

reduce intraocular pressure% especially in glaucoma due to decrease aEueous humor production


130/276

*ntrinsic sympathetic activity


131/276

drugs 4ith retention of *SA (partial agonists)

may $e useful for patients 4ho developsymptomatic $radycardia or $ronchoconstriction4ith nonselective $eta receptor antagonists ace$utolol celiprolol carteolol o,prenolol

pindolol

Mem$rane sta$ilising action


132/276

result from typical local anaesthetic $locade of

sodium channels can $e demonstrated in neurons% heart muscle% and

seletal muscle mem$rane ace$utolol% $eta,olol% la$etalol% metoprolol% pindolol%

propranolol% o,prenolol these drugs should not $e applied topically to the eye%

as local anaesthesia of cornea is undesira$le

Propranolol p t t p 1 nd . d n pt s $l in d


133/276

prototype 1 and . adrenoceptors $locing drug receptor activity

negligi$le effects at " and muscarinic receptors may $loc some serotonin receptors in the $rain no detecta$le partial agonist action at receptors

for treatment of mild to moderate hypertension%

4ithout postural hypotension in severe hypertension% propranolol is useful in

preventing refle, tachycardia that often resultsfrom treatment 4ith direct vasodilators


134/276


135/276

Propranolol


136/276

dosage

usually start 4ith 9= mg-day in divided doses dosage range from 9=B9= mg-day resting $radycardia and a reduction in heart rate

during e,ercise are indicators of $eta$locing effect

Propranolol adverse effects


137/276

result of $locade in heart% vessels and

$ronchial tree occur in patients 4ith reduced myocardial reserve%asthma% peripheral insufficiency% and dia$etes

discontinuing propranolol after prolonged use canprecipitate 4ithdra4al syndrome nervousness% tachycardia% increased

intensity of angina% increased of $loodpressure%

4ithdra4al syndrome may involve upregulationorsupersensitivity of adrenoceptors

Propranolol adverse effects


138/276

gastrointestinal effects

diarrhoea% constipation% nausea% vomiting not attri$uted to $eta receptor $locade effects similar to those caused $y methyldopa

and clonidine

insomnia% lassitude% mental depression% nightmares meta$olism

increased plasma triglycerides% decreased :/7cholesterol% 4hich theoretically can contri$ute to

atherogenesis

Metoprolol


139/276

potency compared 4ith propranolol

eEuipotent at 1adrenoceptors @=1==, less at .adrenoceptors

relative cardioselectivity advantageous in treating hypertensive patients 4ho

suffer from asthma% dia$etes or peripheral vasculardisease% since .receptor activity is important in theliver (for glycogenolysis) and $lood vessels(vasodilatation)

Dcardioselectivity is not complete% asthma may still $ee,acer$ated $y metoprolol


140/276

7a$etalol availa$le a racemic mi,ture


141/276

availa$le a racemic mi,ture molecule has . centres of asymmetry0 . pairs of chiral

isomers (B isomeric compounds) !! isomer is a potent nonselective $locer

potency is less than that of propranolol has some intrinsic sympathomimetic activity at

.receptor (may contri$ute to vasodilatation) S! isomer is a potent "1$locer

potency is less than that of phentolamine SS has some "1$locing effect

!S isomer devoid of " and $locing effects 0" antagonism after oral dosing

varies from ;01 to 1=01


142/276

Carvediloli il $ li d $ h li d


143/276

primarily meta$olised $y the liver% undergoes

e,tensive firstpass meta$olism L.> of given dose e,creted unchanged in the urine ; active meta$olites $ut none of these appears to have

$eta$locing activity

other effects calcium channel $locing activity antio,idant properties

inhi$its generation of o,ygen free radicals

and prevents lo4density lipoproteino,idation% 4hich in turn% reduces the uptaeof 7/7 into the coronary vasculature

Carvedilol I adverse effectsl h i i i f i


144/276

postural hypotension

di&&iness fatigue diarrhoea (.?.>)

$radycardia (.?1>)

urinary tract infection

(1?9>) insomnia (1?8>) pharyngitis (1?@>)

oedema (1?B>) dyspnoea (1?B>)

Carvedilol contraindications$ hi l th


145/276

$ronchial asthma

severe $radycardia decompensated U:A functional class *V heart

failure reEuiring intravenous inotropic support

sic sinus syndrome (unless a permanentpacemaer is in place) second or thirddegree atrioventricular $loc cardiogenic shoc severe liver impairment no4n hypersensitivity

Gisoprololt i $ t i it


146/276

possesses an asymmetric car$onatom in its

structure% and is provided as a racemic mi,ture Senantiomer is responsi$le for most of the $locing

activity

Sotaloll ti t t i t


147/276

a nonselective receptor antagonist

has mared class *** antiarrhythmic effects%reflecting potassium channel $locade

5smolollt h t ti l ti t $l


148/276

ultrashort acting selective 1receptor $locer

B=01 affinity for 1receptor cardioselectivity $enefits asthmatic patients structure contains ester linage

esterases in red $lood cells rapidly meta$olise esmololto a meta$olite 4ith lo4 affinity for receptors

short halflife of 9 minutes useful in controlling supraventricular

arrhythmias% perioperative hypertension% and

myocardial ischaemia in acutely ill patients

Clinical applications di l t neurologic diseases


149/276

cardiovascular system

hypertension ischaemic heart

disease

cardiac arrhythmias hypertrophic

o$structivecardiomyopathy

glaucoma hyperthyroidism

neurologic diseases

migraine tremors

gastrointestinal tract portal hypertension

and $leeding fromoesophageal varices

Hwang NianChih:

Hwang NianChih:


150/276

2006

/irect vasodilators

Calcium channel $locer:ydrala&ine

itric o,ide inducers

Potassium channel openersAngiotensin converting en&yme inhi$itorsAngiotensin receptor $locing agents


151/276

2006

Calcium channel $locers

Calcium channel $locers mechanism of action


152/276

inhi$ition of calcium influ, into arterial smooth muscle

cells% resulting in arteriolar dilatation and lo4ering of$lood pressure classes

phenylalylamines

verapamil dihydropyridine amlodipine% felodipine% isradipine% nicardipine%

nifedipine% nisoldipine $en&othia&epines

diltia&em diphenylpipera&ines (not for treatment of hypertension)


153/276

Mechanism of action haemodynamic differences among the agents may


154/276

haemodynamic differences among the agents may

influence the choice of a particular agent dihydropyridines act preferentially on vascular smooth

muscle% e,erting potent peripheral vasodilatingeffects

verapamil and diltia&em are less specific forperipheral vascular smooth muscle and more active inthe myocardium and cardiac conductive tissues $oth have cardiac depressant effect as 4ell

as inhi$ition of refle, sympathetic activity

Comple, allosteric relationship drugs $inding at the


155/276

/iltia&emVerapamil

ifedipine

drugs $inding at the

dihydropyridine siteappear to increase theaffinity of diltia&emfor the

$en&othia&epine site%and vice versa

Mechanism of action $inding of the drug reduces the freEuency of


156/276

$inding of the drug reduces the freEuency ofchannel opening result in mared decrease intransmem$rane calcium current smooth muscle rela,ation reduction in cardiac contractility decrease in sinus node pacemaer rate

decrease in atrioventricular node conduction velocity channel $loc can $e partially reversed $y

elevating the concentration of calcium drugs that increase the transmem$rane flu, of

calcium% such as sympathomimetics

Site of action Ca.' channelCa.' channel $locere,tracellular Ca.'


157/276

.agonists

Ca.'calmodulin comple,

Calmodulin

A6P

cAMP

Activated myosinlight chain inase

Myosin light chain Myosin lightchain P2B Myosin lightchainA6P

Contraction !ela,ation

P2B

Myosin lightchain inase

Myosin lightchain inase(P2B).

intracellular Ca.'

Ca channel $locer

e,tracellular Ca

5ffect on smooth muscle vascular smooth muscle more sensitive to calcium

h l $l th $ hi l t i t ti l


158/276

channel $locers than $ronchiolar% gastrointestinal

and uterine smooth muscle arterioles are more sensitive than veins%

orthostatic hypotension not a common adverseeffect

reducing peripheral resistance in patients 4ithangina reduces left ventricular 4all stress

reduction of coronary arterial tone% prevents focalarterial spasm

dihydropyridines have less effect on myocardiumthan verapamil or diltia&em

Vascular selectivity ratio of vascular potency to cardiac potency


159/276

ratio of vascular potency to cardiac potency high num$er mean greater vascular% less cardiac potency '' vasodilatation greater than myocardial depression myocardial depression greater than vasodilatation

availa$le data estimated ratio

nicardipine 1?= I amlodipine '' nitrendipine 1B?B I nisoldipine '' isradipine ?B I $epridil felodipine @?B

nifedipine ;?1 verapamil 1?; diltia&em =?;

5ffect on cardiac muscle ischaemia causes mem$rane depolarisation


160/276

ischaemia causes mem$rane depolarisation%

calcium influ, in ischaemic cells is increased elevated intracellular calcium accelerates the activity

of several A6Pconsuming en&ymes% 4hich furtherdepletes the already marginal cellular A6P stores%

maing the heart even more suscepti$le to ischaemicdamage calcium channel $locers reduce this ischaemic damage

$y reducing the incidence of arrhythmias and theultimate si&e of the infarct

5ffects on SA node AV node verapamil and diltia&em


161/276

verapamil and diltia&em

$loc calciumdependent action potential in slo4response cells in the SA node and AV node% resultingin $locing of impulse generation in the nodes

$loc AV node more selectively than do thedihydropyridines

effective in treating supraventricular reentrytachycardia and decreasing ventricular response inatrial fi$rillation or flutter

nifedipine does not affect AV nodal conduction

5ffect on cardiac muscle reduction in cardiac contractility cardiac output


162/276

reduction in cardiac contractility%cardiac output%

and cardiac o,ygen consumption sodium channel $locade $y $epridil% verapamil and diltia&em negligi$le effect $y dihydropyridines

potassium channel $locade $y $epridil results in prolongation of cardiacrepolarisation and a distinct ris of induction ofarrhythmias

5ffect on cardiac muscle nonspecific sympathetic antagonism is most


163/276

nonspecific sympathetic antagonism is most

mared 4ith diltia&em% less 4ith verapamil nifedipine does not appear to have this effect% thus

refle, tachycardia to hypotension occurs freEuently4ith nifedipine and less so 4ith verapamil

!elative cardiovascular effects/rug Vasodilatation Contractility Conduction Automaticity


164/276

/rug Vasodilatation Contractility Conduction Automaticity

Verapamil B B @ @ifedipine @ 1 1 =

icardipine @ 1 1 =

/iltia&em ; . @ B

raned from least prominent (=) to most prominent (@)

2ther vascular effects seletal muscles are not depressed $y calcium


165/276

seletal muscles are not depressed $y calcium

channel $locers $ecause intracellular pools ofcalcium are utilised to support e,citationcontraction coupling

cere$ral vessels

nimodipine has a high affinity for cere$ral $loodvessels% reducing vasospasm after su$arachnoidhaemorrhage

on vascular effects minimally interfere 4ith stimulussecretion


166/276

minimally interfere 4ith stimulus secretion

coupling in glands and nerve endings $ecause ofdifferences $et4een calcium channels indifferent tissues

verapamil inhi$it insulin secretionin humans% $ut

the dosage reEuired are greater than those usedin management of angina may interfere 4ith platelet aggregation in vitro

and prevent or attenuate the development of

atheromatous lesions in animals

on vascular effects verapamil $locs P1= glycoprotein 4hich is


167/276

verapamil $locs P1= glycoprotein4hich is

responsi$le for transport of many foreign drugsout of cancer (and other) cells% this action is not stereospecific increased e,pression of the P1= multidrug

transporter protein is associated 4ith thedevelopment of resistance to chemotherapy in cancercells

verapamil partially reverses the resistance of cancercells to many chemotherapeutic drugs

Adverse effects $radycardia cardiac arrest


168/276

$radycardia

atrioventricular $loc com$ining verapamilor diltia&em 4ith$eta $locer

congestive heartfailure negative inotropic

effecte

myocardial infarction if onset of

hypotension is rapid

cardiac arrest

torsade de pointes $epridil prolongs

cardiac actionpotential%

contraindicated inpatients 4ithprolonged F6syndrome

flushing% oedema%di&&iness% nausea% andconstipation

*ndications angina


169/276

angina

only 4ith slo4 release and long acting calcium channel$locers immediaterelease short acting calcium channel

$locers can increase the ris of myocardial

infarction% therefore are contraindicated in nonF infarction% diltia&em can reduce freEuency of

postinfarct angina

hypertension $ut can 4orsen heart failure $ecause of negative

inotropic effect

*ndications supraventricular tachyarrhythmias


170/276

supraventricular tachyarrhythmias

verapamil and diltia&em caution in digitalised patient% verapamil may increase

plasma digo,in concentrations throughpharmacoinetic interaction% (less consistent 4ith

diltia&em and nifedipine) hypertrophic cardiomyopathy migraine !aynauds phenomenon atherosclerosis

Contraindications vasodilator treatment in presence of heart failure

all calcium channel $locers can 4orsen heart failure as


171/276

all calcium channel $locers can 4orsen heart failure as

a result of negative inotropic effect verapamil or diltia&em in com$ination 4ith

$locer $epridil in the presence of arrhythmias

$epridil prolongs cardiac action potential

promptrelease% short acting nifedipine in thepresence of myocardial infarction

due to rapid onset of hypotension 4ith this formulationand resulting sympathetic response

Pharmacoinetics


172/276

oral e,tensive $ioavaila$ility protein elimination

agent a$sorption firstpass $ound halflife

verapamil NH=> yes 1=;@> H=> ;8h

nifedipine NH=> no B@9@> H@> .8h

nicardipine 1==> no ;@> NH@> .Bh

isradipine NH=> yes 1@.@> NH@> 9Hh

felodipine 1==> no .=> NHH> 1118h

amlodipine NH=> no 8@H=> H9> ;=@=h

diltia&em NH=> no B=8@> 9=> ;?@h

Verapamil onset of action


173/276

L1?@ minute *V% ;= minutes oral meta$olism and e,cretion

e,tensively meta$olised $y liver% dose reduction inpatients 4ith liver impairment

=> eliminated $y idney 1@> $y gastrointestinal tract

Verapamil indications


174/276

angina% hypertension% arrhythmias (migraine% cardiomyopathy)

usual dosage =?=@=?1@mg-g *V (W=?1mg-g) 9=18=mg every 9 hours

adverse effects hypotension% myocardial depression% constipation%

dependent oedema

ifedipine onset of action


175/276

f @.= min after su$lingual or oral route% less than 1

minute after intravenous administration meta$olism and e,cretion

meta$olised to an acid lactate 9=> of the drug and meta$olite e,creted in urine


176/276

icardipine onset of action


177/276

.= minutes oral meta$olism and e,cretion

e,tensively meta$olised in liver

icardipine indications


178/276

angina hypertensive emergencies% intra and postoperative

hypertension

usual dosage =?@mg $olus *V% titrate to o$tain desira$le $lood

pressure @1@ mg-hour infusion .=B=mg every 9 hours orally

adverse effects headache% oedema% di&&iness% flushing

icardipine precautions


179/276

p

not compati$le 4ith sodium $icar$onate solution or:artmann solution patients 4ith renal or liver impairment% hypotension

and glaucoma

contraindication intracranial haemorrhage increased intracranial pressure pregnant or nursing 4oman


180/276

Amlodipine indications

h


181/276

angina% hypertension usual dosage

@1=mg once daily adverse effects

headache% oedema% fatigue% nausea% flushing% di&&iness contraindications

no4n hypersensitivity to dihydropyridines% pregnancy%lactation

/iltia&em onset of action


182/276

L; minute *V% N;= minutes oral meta$olism and e,cretion

e,tensively deacylated drug and meta$olites e,creted $y gastrointestinal

tract

/iltia&em indications


183/276

angina% hypertension (!aynauds phenomenon)

usual dosage =?@=?1@mg-g *V ;=9=mg every 8 hours

adverse effects hypotension% myocardial depression% constipation%

dependent oedema


184/276

2006

:ydrala&ine

:ydrala&ine a hydra&ine derivative


185/276

dilates arterioles $ut not veins mechanism of action

interfering 4ith the storage of catecholamines displaces catecholamines from secretory

vesicles displaces vesicular Ca'' these effects occur 4ithin seconds

independent of endothelium and is not related to

guanylate cyclase activation a$sorption

4ell a$sor$ed orally


186/276

:ydrala&ine dosing


187/276

B=.== mg-day the higher dosage 4as selected as the dose at 4hich

there is a small possi$ility of developing the lupuserythematosuslie syndrome

Adverse effects of hydrala&ine headache nausea

lupus erythematosuslie syndrome


188/276

nausea anore,ia palpitations s4eating% flushing

angina or ischaemicarrhythmias as a resultof refle, tachycardia andsympathetic stimulationin patients 4ith ischaemicheart disease

lie syndrome slo4 acetylators

prone to develop thesyndrome (arthralgia%myalgia% sin rashes%

and fever) reversi$le $y

discontinuation ofhydrala&ine

peripheral neuropathy drug fever


189/276

2006

itric o,ide inducers

Sodium nitroprusside

itroglycerin

Mechanism of action $y intracellular release of nitric o,ide


190/276

nitric o,ide $inds to the haem comple, ofguanylate cyclase the resulting nitrosylhaem activates this en&yme

4ith increased production of c3MP and activation

of c3MPdependent protein inase this is follo4ed $y phosphorylation of target

proteins and dephosphorylation of myosin lightchain

$iological activity of nitric o,ide is rapidlyterminated due to avid $inding to :$

Mechanism ofaction of

itrates 5ndothelial cells

2X or Snit s thi l


191/276

action of

nitrovasodilatorsnitrosothiol

derivative

3uanylyl cyclaseActivated guanylyl cyclase

36P c3MP

Activated myosinlight chain inase

Myosin light chain Myosin light chain P2B Myosin light chain

A6P

Contraction !ela,ation

'

'

c3MPdependent protein inase

P2B

calcitonin gene

related peptide

Ca''dependent #'channels '

itric o,ide 1H9=


192/276

endothelium dependent vascular rela,ationdemonstrated and endothelial derived rela,ationfactor (5/!) proposed

1H98

urchgott and *gnarro independently proposed 2X as5/!

1H9 production of 2X $y endothelium 4as confirmed $y

Palmer et al?

Sodium nitroprusside a nitrovasodilator having a structure a comple,

2


193/276

of iron% cyanide groups and a nitroso moiety mechanism of action dilates $oth arterioles and veins reducing $oth

peripheral vascular resistance and venous return

result of activation of guanylyl cyclase% either viarelease of nitric o,ide or direct stimulation of theen&yme increasing cyclic 3MP% 4hich rela,es smooth

muscle

C C

C C

C

e.'

'2

SP mechanism of action


194/276

Glood vessel Vascular smooth muscle cell

SP

C

2X

S5!

2X

Ca.' Ca.'

Ca.'

Ca.

'c3MP

36P3C

'

c3MPdependent protein inase

'

Myosin light chain Myosin light chain P2B

Vasodilatation P2B

C3!P

SP meta$olism . stages


195/276

nonen&ymatic and en&ymatic nonen&ymatic path4ay

in the $lood% nitroprusside is rapidly meta$olised $yuptae into red $lood cells

an electron is transferred from the (ferrous) e''of:$2.forming methaemoglo$in 4ith (ferric) e'''

the resulting nitroprusside molecule is unsta$le andreleases all @ C 1mg SP releases =?BBmg C

SP meta$olism en&ymatic path4ay


196/276

cyanide in turn is meta$olised $y the mitochondrialen&yme rhodanase% in the presence of thiosulphate(sulphur donor)% to thiocyanate

thiocyanate is distri$uted in e,tracellular fluid andslo4ly eliminated $y the idney

ate of C thiosulphate thiocyanate


197/276

8==> to thiocyanate rate limiting factor is availa$ility of endogenous

thiosulphate (sulphurdonor)

methaemoglo$in cyanmethaemoglo$in hydro,yco$alamin cyanoco$alamin cytochrome iron to,icity

C meta$olism7iver


198/276

CyanMet:$

Met:$

Cyanide pool

Met:$

2,y:$ 6hiosulphate

6hiocyanate

6hiocyanate

SP 2X

CC

CC

CC

C

Cytochrome

o,idase (C2)

CC2

C2 6hiocyanateo,idase

!hodanase

!enale,cretion

SP meta$olism most normal adults can meta$olise appro,imately

@= mg of SP 4ith e,isting sulphur stores


199/276

@= mg of SP 4ith e,isting sulphur stores factors reducing these stores

malnutrition surgery

diuretics cyanide radicals may accumulate and produceclinical to,icity 4hen infusions e,ceed .Qg-g-min% or

4hen suphur donors and methaemoglo$in aree,hausted

SP adverse effects type ** lactic acidosis

tissue hypo,ia from thiocyanate accumulation

4eaness


200/276

tissue hypo,ia from

cytochrome o,idaseinhi$ition increase in the mi,ed

venous P2. arrhythmias e,cessive hypotension death methaemoglo$inaemia

methaemoglo$in has lo4affinity for o,ygen%leading to tissue hypo,iaand death

4eaness%disorientation%psychosis% musclespasms% convulsions4ith serum

concentration greaterthan 1=mg-dl

delayed hypothyroidism thiocyanate inhi$ition

of iodide uptae $y thethyroid


201/276

Management of cyanide poisoning prophyla,is or treatment of cyanide poisoning

during nitroprusside infusion


202/276

during nitroprusside infusion administration of sodium thiosulphate1@= mg-g

(intravenously over 1@ min) as a sulphur donor%facilitates meta$olism of cyanide

hydro,oco$alamin@1= mg (intravenously) com$ines

4ith cyanide to form the nonto,ic cyanoco$alamin sodium nitrite @ mg-g (in ;B min)% reduces :$2.to

methaemoglo$in% 4hich 4ill compete 4ith cytochromeo,idase for C

itroglycerin I mechanism of action denitrated $y glutathione Stransferase% releasing

free nitrite ion in smooth muscle cell

:.C22.

:C22.

:.C22.


203/276

free nitrite ion in smooth muscle cell a different en&ymatic reactionreleases nitric o,ide

2X nitric o,ide or (Snitrosothiol derivative) causes

activation of guanylyl cyclase production of prostaglandin 5 or prostacyclin (P3*.)

and mem$rane hyperpolarisation may $e involved calcitonin generelated peptide% 4idely distri$uted

in cardiovascular tissues and release is regulated $y2 and c3MP% causes vasodilatation

Pharmacoinetics of nitroglycerin a$sorption


204/276

lo4 $ioavaila$ility (1=.=>) $y oral route% due to highcapacity hepatic organic nitrate reductase thatremoves nitrate groups in a step4ise fashion fromthe parent molecule until the drug is inactivated

su$lingual% $uccal% and transdermal route avoids firstpass effect% preferred for

achieving therapeutic $lood concentrationrapidly

total dose $y this route is small and effectis of short duration

Pharmacoinetics of nitroglycerin meta$olism

unchanged nitrate compounds have t< of .9 minutes

Hwang Nian

Chih:

Hwang Nian

Chih:

Hwang NianChih:

Hwang NianChih:

Hwang Nian

Chih:

Hwang Nian

Chih:


205/276

unchanged nitrate compounds have t


206/276

e,creted primarily as glucuronide derivatives of thedenitrated meta$olites via idney

Pharmacodynamic effects vascular smooth muscle

all segments of the vascular system from aorta through


207/276

all segments of the vascular system from aorta throughlarge veins rela, in response to nitroglycerin veins respond at lo4est concentrations%

arteries at slightly higher concentrations%concentration of IS: receptors greater inveins

arterioles and precapillary sphincters aredilated less than the large vessels% partly

$ecause of refle, response and partly $ecausedifferent vessels vary in their a$ility to releasenitric o,ide


4ith effective $lood concentration


208/276

4ith effective $lood concentration venous capacitance increases 4ith reduction

in ventricular preload pulmonary vascular pressures and heart si&e

are significantly reduced (ma,imum effect @mg-g-min)

dilatation of aorta% temporal artery%

meningeal artery (headache)


compensatory responses evoed $y $aroreceptors and


209/276

compensatory responses evoed $y $aroreceptors and

hormonal mechanisms responding to decrease $loodpressure

in normal su$+ects% nitroglycerin transiently increasestotal coronary $lood flo4

in patients 4ith coronary artery disease% no increasein total coronary $lood flo4 relief of angina pro$a$ly the result of

decreased myocardial o,ygen consumption

secondary to reduction in preload and $loodpressure

Pharmacodynamic effects other smooth muscle organs

rela,ation of smooth muscle of $ronchi


210/276

rela,ation of smooth muscle of $ronchi%gastrointestinal tract and genitourinary tract rela,ation of the uterus 4ith $olus doses of

nitroglycerin @= Qg

platelets nitric o,ide released from nitroglycerin stimulates

guanylyl cyclase in platelets increase in c3MP and decrease in calcium entry

responsi$le for decrease in platelet aggregation

Pharmacodynamic effects other effects

nitrite ion reacts 4ith haemoglo$in (containing ferrous


211/276

nitrite ion reacts 4ith haemoglo$in (containing ferrousiron) to produce methaemoglo$in (containing ferric iron) methaemoglo$in has lo4 affinity for o,ygen%

large amounts of nitrite can result in

pseudocyanosis% tissue hypo,ia and death in an adult% the plasma concentration of

nitrites even from large amounts of organicand inorganic nitrates 4ill not cause

significant methaemoglo$inaemia% ho4ever inan infant% to,icity may result

Methaemoglo$inaemia and Cpoisoning cyanide poisoning results from comple,ing of

cytochrome iron $y the C


212/276

cytochrome iron $y the C methaemoglo$in has very high affinity for C%

thus administration of sodium nitrite (a2.)soon after cyanide e,posure 4ill regenerate

active cytochrome the cyanhaemoglo$in produced can $e further

deto,ified $y intravenous administration of sodiumthiosulphate (a.S.2;)% resulting in the formation of

thiocyanate ion (SC)% a less to,ic ion that is readilye,creted

Methaemoglo$inaemia methaemoglo$inaemia% if e,cessive% can $e

treated $y giving methylene $lue intravenously


213/276

treated $y giving methylene $lue intravenously action of methylene $lue depends on the availa$ility of

reduced nicotinamide adenine nucleotide phosphate(A/P:) 4ithin the red $lood cells


214/276

6olerance (tachyphyla,is)causes decreased tissue

remedy sulphydryl generating


215/276

sulphydryl groups diminished release of 2from nitroglycerin

decreased activation ofguanylyl cyclase

decreased release ofendogenous C3!P

sympathetic compensation

agent may $e partially

reversed 4ith thiolcontaining compounds

lie acetylcysteine may $e partially

reversed $y acetylcysteine or

captopril inducedrelease of C3!P


216/276

Adverse effects of nitrates e,tension of therapeutic vasodilatation

orthostatic hypotension


217/276

orthostatic hypotension tachycardia thro$$ing headache

MCF the follo4ing agents have actions 4hich involve

nitric o,ide


218/276

nitric o,ide acetylcholine 6 nitrates 6 nitroprusside 6 nicorandil 6


219/276

2006

Potassium channel openers

mino,idil

dia&o,ide

pinacidil

Mino,idil mechanism of action

meta$olite mino,idil sulphate opens potassium


220/276

p p p

channelsin smooth muscle mem$rane involves A6P sensitive #'channel

this action sta$ilises the mem$rane at its restingpotentialand maes contraction less liely

dilates arterioles $ut not veins indication

replaces hydrala&ine 4hen ma,imal doses of the latterare not effective

in patients 4ith renal failure and hypertension% 4ho donot respond 4ell to hydrala&ine

Pharmacoinetics a$sorption

4ell a$sor$ed $y gastrointestinal tract


221/276

y g meta$olism

primarily $y con+ugation in the liver mino,idil glucuronide and mino,idil sulphate

t


222/276

y p p start on @1= mg-day in t4o doses% may $e increased

to 9= mg-day


223/276

/ia&o,ide indication

hypertensive emergencies


224/276

yp g hypoglycaemia secondary to insulinoma

mechanism of action prevents smooth muscle contraction $y opening

potassium channelsand sta$ili&ing the mem$rane

potential at the resting level involves A6P sensitive #'channel

Pharmacoinetics chemistry

similar chemically to thia&ide diuretics $ut lacs


225/276

y

diuretic activity distri$ution

$inds e,tensively to serum al$umin and vascular tissue meta$olism

$oth meta$olised and e,creted unchanged t


226/276

e,cessive hypotension can $e avoided $ystarting 4ith @=1@= mg

if necessary% doses of 1@= mg may $erepeated every @ minutes to achieve $loodpressure control

intravenous infusion at rates of 1@;= mg-min

Adverse effects of dia&o,ide hypotension

occurs after smaller doses in patients 4ith chronic


227/276

renal failure% due to reduced protein $inding capacity greater if pretreated 4ith $locers to prevent

refle, tachycardia and associated increase in cardiacoutput

can result in stroe and myocardial infarction refle, sympathetic response

angina% ischaemia% cardiac failure

Adverse effects of dia&o,ide hyperglycaemia

inhi$its insulin release from pancreas% pro$a$ly $y


228/276

opening potassium channels in $eta cell mem$rane particularly in patients 4ith renal insufficiency

salt and 4ater retention

8/13/2019 Antihyperten

antihypertensive agents[1].revision

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