antihypertensive agents[1].revision
TRANSCRIPT
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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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/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
$lood pressure response continues to increase as doseincreases
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/rugs that alter sympatheticnervous system function
centrally acting sympathoplegic agentsganglion$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 $ind
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Central actingsympathoplegic agents
".receptor agonistsimida&oline receptor agonists
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".receptor agonists
methyldopaclonidine
de,medetomidine
miva&erolguanfacineguana$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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Central acting sympathoplegic agents
renal effects
Methyldopa
reduction in renalvascular resistance
Clonidine
decrease renalvascular resistanceinhi$it the releaseof renin
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Central acting sympathoplegic agents
a$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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Central acting sympathoplegic agents
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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Central acting sympathoplegic agents
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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Central acting sympathoplegic agents
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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Clonidine versus de,medetomidine
$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 $eadministered rapidly
Cl d d d d
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Clonidine versus de,medetomidine
cardiaceffects
renal
effects
othereffects
Clonidine
lo4ers heartrate and cardiacoutputdecrease renal
vascular resistanceinhi$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 $loodpressure
Cl idi d d idi
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Clonidine versus de,medetomidine
orala$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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Clonidine versus de,medetomidine
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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Clonidine versus de,medetomidine
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 $y liver% dose ad+ustment in
cirrhosis t
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*mida&oline receptor agonists
clonidinede,medetomidine
miva&erolrilmenidinemo,onidine
!ilm nidin
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!ilmenidine an o,a&oline% structurally similar to imida&oline
central acting imida&oline receptor agonist central acting antihypertensive agent 4ith no 4ithdra4al
symptoms follo4ing cessation of treatment rapidly a$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
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!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
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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
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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
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2006
Adrenoceptor antagonists
"1adrenoceptor $locing agents
adrenoceptor $locing agents
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2006
Alpha1receptor antagonists
reversi$le antagonists
irreversi$le antagonists
Mechanism of action
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Mechanism of action reversi$le"1receptor antagonists
can dissociate from the receptors phentolamine% tola&oline% pra&osin% la$etalol
duration of action largely dependent on
the rate at 4hich it dissociates from thereceptor the clearance and halflife
Mechanism of action
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Mechanism of action irreversi$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
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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 $ladder andprostate resulting in incontinence
"1receptor antagonists clinical applications
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1 p g pp pheochromocytoma
hypertensiveemergencies chronic hypertension
retention of salt
and 4ater occurs ifadministered4ithout a diuretic
peripheral vasculardisease
treatment of clonidine4ithdra4l syndrome
urinary o$struction
prevention of dermalnecrosis afterinadvertente,travasation of "adrenergic agonist
male se,ual dysfunction direct intracavernous
in+ection of
phentolamine 4ithpapaverine
Classes of "adrenergic antagonists
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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:;
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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
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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
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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
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y pharmacoinetics
lo4 $ioavaila$ility after oral administration crosses GGG t
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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
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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
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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
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pheochromocytoma reduce e,tent of dermal necrosis after
e,travasation of " agonist hypertensive crisis
male se,ual dysfunction
Pra&osin
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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$itor of cyclic nucleotide
phosphodiesterase
Pra&osin
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a$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 $y diseases
that modify the concentration of thisprotein
Pra&osin
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clearance entirely meta$olised t
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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
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adverse effects first dose phenomenon di&&iness palpitation headache lassitude develop antinuclear factor in serum 4hile on pra&osin
therapy
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2006
Geta receptor antagonists
Geta receptor antagonists
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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$ition of peripheral pre+unctional adrenoceptors
reducing sympathetic vasoconstrictor nerve activity
Geta receptor antagonists
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$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
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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
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*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
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*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 $i di
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PropranololD2,yprenolol
Ace$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
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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
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Pharmacoinetic properties
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$ioavaila$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 $ecome saturated
Pharmacoinetic properties
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distri$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
Pharmacoinetic properties
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clearance
t
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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
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eye
reduce intraocular pressure% especially in glaucoma due to decrease aEueous humor production
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*ntrinsic sympathetic activity
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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
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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
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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
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Propranolol
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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
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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 $loodpressure%
4ithdra4al syndrome may involve upregulationorsupersensitivity of adrenoceptors
Propranolol adverse effects
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gastrointestinal effects
diarrhoea% constipation% nausea% vomiting not attri$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$ute to
atherogenesis
Metoprolol
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potency compared 4ith propranolol
eEuipotent at 1adrenoceptors @=1==, less at .adrenoceptors
relative cardioselectivity advantageous in treating hypertensive patients 4ho
suffer from asthma% dia$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 $y metoprolol
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7a$etalol availa$le a racemic mi,ture
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availa$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
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Carvediloli il $ li d $ h li d
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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
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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
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$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
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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
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a nonselective receptor antagonist
has mared class *** antiarrhythmic effects%reflecting potassium channel $locade
5smolollt h t ti l ti t $l
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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$olite 4ith lo4 affinity for receptors
short halflife of 9 minutes useful in controlling supraventricular
arrhythmias% perioperative hypertension% and
myocardial ischaemia in acutely ill patients
Clinical applications di l t neurologic diseases
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cardiovascular system
hypertension ischaemic heart
disease
cardiac arrhythmias hypertrophic
o$structivecardiomyopathy
glaucoma hyperthyroidism
neurologic diseases
migraine tremors
gastrointestinal tract portal hypertension
and $leeding fromoesophageal varices
Hwang NianChih:
Hwang NianChih:
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2006
/irect vasodilators
Calcium channel $locer:ydrala&ine
itric o,ide inducers
Potassium channel openersAngiotensin converting en&yme inhi$itorsAngiotensin receptor $locing agents
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2006
Calcium channel $locers
Calcium channel $locers mechanism of action
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inhi$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)
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Mechanism of action haemodynamic differences among the agents may
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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
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/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 $inding of the drug reduces the freEuency of
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$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.'
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.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
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channel $locers than $ronchiolar% gastrointestinal
and uterine smooth muscle arterioles are more sensitive than veins%
orthostatic hypotension not a common adverseeffect
reducing peripheral resistance in patients 4ithangina reduces left ventricular 4all stress
reduction of coronary arterial tone% prevents focalarterial spasm
dihydropyridines have less effect on myocardiumthan verapamil or diltia&em
Vascular selectivity ratio of vascular potency to cardiac potency
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ratio of vascular potency to cardiac potency high num$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
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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
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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
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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
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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
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/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
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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
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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
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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 $radycardia cardiac arrest
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$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 $epridil prolongs
cardiac actionpotential%
contraindicated inpatients 4ithprolonged F6syndrome
flushing% oedema%di&&iness% nausea% andconstipation
*ndications angina
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angina
only 4ith slo4 release and long acting calcium channel$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
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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
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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
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oral e,tensive $ioavaila$ility protein elimination
agent a$sorption firstpass $ound halflife
verapamil NH=> yes 1=;@> H=> ;8h
nifedipine NH=> no B@9@> H@> .8h
nicardipine 1==> no ;@> NH@> .Bh
isradipine NH=> yes 1@.@> NH@> 9Hh
felodipine 1==> no .=> NHH> 1118h
amlodipine NH=> no 8@H=> H9> ;=@=h
diltia&em NH=> no B=8@> 9=> ;?@h
Verapamil onset of action
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L1?@ minute *V% ;= minutes oral meta$olism and e,cretion
e,tensively meta$olised $y liver% dose reduction inpatients 4ith liver impairment
=> eliminated $y idney 1@> $y gastrointestinal tract
Verapamil indications
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angina% hypertension% arrhythmias (migraine% cardiomyopathy)
usual dosage =?=@=?1@mg-g *V (W=?1mg-g) 9=18=mg every 9 hours
adverse effects hypotension% myocardial depression% constipation%
dependent oedema
ifedipine onset of action
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f @.= min after su$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$olite e,creted in urine
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icardipine onset of action
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.= minutes oral meta$olism and e,cretion
e,tensively meta$olised in liver
icardipine indications
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angina hypertensive emergencies% intra and postoperative
hypertension
usual dosage =?@mg $olus *V% titrate to o$tain desira$le $lood
pressure @1@ mg-hour infusion .=B=mg every 9 hours orally
adverse effects headache% oedema% di&&iness% flushing
icardipine precautions
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p
not compati$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
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Amlodipine indications
h
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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
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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
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angina% hypertension (!aynauds phenomenon)
usual dosage =?@=?1@mg-g *V ;=9=mg every 8 hours
adverse effects hypotension% myocardial depression% constipation%
dependent oedema
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2006
:ydrala&ine
:ydrala&ine a hydra&ine derivative
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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
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:ydrala&ine dosing
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B=.== mg-day the higher dosage 4as selected as the dose at 4hich
there is a small possi$ility of developing the lupuserythematosuslie syndrome
Adverse effects of hydrala&ine headache nausea
lupus erythematosuslie syndrome
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nausea anore,ia palpitations s4eating% flushing
angina or ischaemicarrhythmias as a resultof refle, tachycardia andsympathetic stimulationin patients 4ith ischaemicheart disease
lie syndrome slo4 acetylators
prone to develop thesyndrome (arthralgia%myalgia% sin rashes%
and fever) reversi$le $y
discontinuation ofhydrala&ine
peripheral neuropathy drug fever
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2006
itric o,ide inducers
Sodium nitroprusside
itroglycerin
Mechanism of action $y intracellular release of nitric o,ide
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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
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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=
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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
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of iron% cyanide groups and a nitroso moiety mechanism of action dilates $oth arterioles and veins reducing $oth
peripheral vascular resistance and venous return
result of activation of guanylyl cyclase% either viarelease of nitric o,ide or direct stimulation of theen&yme increasing cyclic 3MP% 4hich rela,es smooth
muscle
C C
C C
C
e.'
'2
SP mechanism of action
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Glood vessel Vascular smooth muscle cell
SP
C
2X
S5!
2X
Ca.' Ca.'
Ca.'
Ca.
'c3MP
36P3C
'
c3MPdependent protein inase
'
Myosin light chain Myosin light chain P2B
Vasodilatation P2B
C3!P
SP meta$olism . stages
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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
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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 $y the idney
ate of C thiosulphate thiocyanate
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8==> to thiocyanate rate limiting factor is availa$ility of endogenous
thiosulphate (sulphurdonor)
methaemoglo$in cyanmethaemoglo$in hydro,yco$alamin cyanoco$alamin cytochrome iron to,icity
C meta$olism7iver
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CyanMet:$
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
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@= 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$in aree,hausted
SP adverse effects type ** lactic acidosis
tissue hypo,ia from thiocyanate accumulation
4eaness
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tissue hypo,ia from
cytochrome o,idaseinhi$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 $y thethyroid
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Management of cyanide poisoning prophyla,is or treatment of cyanide poisoning
during nitroprusside infusion
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during nitroprusside infusion administration of sodium thiosulphate1@= mg-g
(intravenously over 1@ min) as a sulphur donor%facilitates meta$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 $y glutathione Stransferase% releasing
free nitrite ion in smooth muscle cell
:.C22.
:C22.
:.C22.
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free nitrite ion in smooth muscle cell a different en&ymatic reactionreleases nitric o,ide
2X nitric o,ide or (Snitrosothiol derivative) causes
activation of guanylyl cyclase production of prostaglandin 5 or prostacyclin (P3*.)
and mem$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
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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:
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unchanged nitrate compounds have t
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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
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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
Pharmacodynamic effects vascular smooth muscle
4ith effective $lood concentration
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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)
Pharmacodynamic effects vascular smooth muscle
compensatory responses evoed $y $aroreceptors and
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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
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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$in (containing ferrous
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nitrite ion reacts 4ith haemoglo$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
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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
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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
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6olerance (tachyphyla,is)causes decreased tissue
remedy sulphydryl generating
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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
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Adverse effects of nitrates e,tension of therapeutic vasodilatation
orthostatic hypotension
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orthostatic hypotension tachycardia thro$$ing headache
MCF the follo4ing agents have actions 4hich involve
nitric o,ide
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nitric o,ide acetylcholine 6 nitrates 6 nitroprusside 6 nicorandil 6
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2006
Potassium channel openers
mino,idil
dia&o,ide
pinacidil
Mino,idil mechanism of action
meta$olite mino,idil sulphate opens potassium
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p p p
channelsin smooth muscle mem$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 $y gastrointestinal tract
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y g meta$olism
primarily $y con+ugation in the liver mino,idil glucuronide and mino,idil sulphate
t
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y p p start on @1= mg-day in t4o doses% may $e increased
to 9= mg-day
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/ia&o,ide indication
hypertensive emergencies
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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 $ut lacs
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y
diuretic activity distri$ution
$inds e,tensively to serum al$umin and vascular tissue meta$olism
$oth meta$olised and e,creted unchanged t
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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
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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
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opening potassium channels in $eta cell mem$rane particularly in patients 4ith renal insufficiency
salt and 4ater retention
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