'It is more blessed to give than to receive.

tPharm acolozïM
f'.1z:5'.

WhiteKnightLove
 Freely you have received; freely give.

A nzin q ' vtr/t?ri,l

*D efinition..
Sevtrecentral(retrosternal)chestpain duetotransientmyocardial
ischem ia catlsed by im balance betw een m yocardialoxygen st
(thro lpply
'
ughthecoronarics)andmyocardialoxygendamand .
ALB...A nginajis a ''sym ptom l'ofa disease known asIsclzem ic H e
Di art
sease(1Hb),Coronary HeartDisease(CHD), orCoronary Arter y
Disease(CAD).

'Yljw es and Causes..

l-stable angina:
' *ltis also know n as exel-tionalangina effortangina-classic angina-typical
-

angina.
*ltis due to '''
atherosclerosis''ofthe coronariesw l-lich causesloss01'-
elasticity,naln-ow ing, and roughness ofthe intil'
na leading to platelet
aggregation (thecondition proceedstounstableangina)and thronlbus
formation (thiscondition isknown asactltemyocardialinfarction) Pain .
isprecipitated by exertion and relieved by rest .

z-v ariantangina: 7
*1tisalso known as Prinzm etal'kangina-vasospastic angina ë f
.

*ltisnotdue to atherosclerosisbutm ay be due to ''stlpersensitivity''of

(.tlreceptors in the corohariesleading to reversible coronary spasm . l3ain
-

isnotprecipitated by excrtion and m ay be precipitated atrestordtlring

sleep.
Jzunstableangina'
.
@1tusually öccursin casesofstable angina com plicated by platelet
aggregation,spasm ofthe coronariés,orrupture ofatherom atousplaquc
into the lun en ofthe coronaries.
*ltisan em argency in w hich pain increaseseven w itl)restanclanti-
anginaldrug therapy,and m ay progressto actlte m yocardialinfarction, it
isknbw n as ''pre-infarction,crescendo anginl,orangina atrest''.
ùRiskFactèrs (Predisposing Factorsl:
1-A ge. 2-SeK. 3-Fam ily histol'
y. 4-O besity. 5-Sm oking.
6 f
Diabetesmellitus. 7-Sedentary life(lackofphysicalexercise).
-

8-Stress. .
f
j)-Hyperlipidemia(high LDL/HDL ratio).
1û-Hypertension.
*p recip itating F actors:
1-Exertion(physicalandmentall'
.2-Heavymeals.3-Coldweather.
WhiteKnightLove
'It is more blessed to give than to receive.

*17.
lJa
sIIOSI'
, S..
' 1-H istory.
2-ECG :perform ed atrestand during exercise (Exercise Tolerance T
$ '''''' > est). '

3-AngiogrAphy (PerctttaneousTransluminalCoronary Angiography)

4-Ergom etrine is used to diagnose variantangina .
.
*hfallagelnellt:
l-correction ofRiskfactors(i'
fpossible) .

z-Avoidance of-precipitating factors.

3--freatm ent.'
A-sllrgicalFrct-///i?cz// .
'

1-PercutaneùusTransltlm inalCoronary A ngioplasty A stentm ay be

i .

mplanted.2-CoronaryArteryBypassGraft(CABG) .
B-D l-ug F/vcrc/clz.'
,

e-l-he aim ofdrug therapy is to restore the balance betw e

tn m yocardial
oxygen stlpply (by V.D.of''normal''coronaries)and myocardialoxygen
demand(byreducingcardiacwork) (
*'
l-
he follow ing m echanis . !
m sm ay be ujed to teduce cardiac w ollk:
1-Blockingcardiac f ll-receptorstodeereasecardiaeproperties
2-Venodilatationtorçducepre-load(venousretuim) . .

3-Al-teriodilatation2+toreduceafter-load(TPR) .

4-lnhibition ofCa intlux into cardiac cellsto decrease calzjae

properties,and into arterioles to induce V .D .
*1n stable aùd unstable angina;antiplateletdrugs133t1stbe given to inlxibit
.

plateletaggregation.
Accordingly
';the anti-anginalJrz/g5'includeL
1-p-Bloekdrs.
2-OrganicNitrates(Nitriteswereusedasantianginaldnlgsbutarenot
com m only used now adaysas they m ay cause'm ethem oglobinem ia-see
later).
2+ . 2+
3-Ca -channelBloclters=ccBs(Ca -Entry Blockels= Ca2llnllux .

lnhibitors=Ua2h-Antagonists).
4-Antiplatelletdnzgs(asaspirin in pediatricdoses=75-150mg.).
s-N icorandil:K +-channelopenerleading to hyperpolarization and
vasodilatation,and also hasnitrate-like action. ltredtlcescardiac w ork
and dilatesponralcoronaries.
6-Trimetazidine(Cal-dioprotective=cytolarotectivel.
'redtlcesmyocardial
oxygen consum ption by inhibiting m yocardialFFA oxidation.
7-Ranolazine:* itincreasesblood flow to the m yocardium by prevention
ofabnonmalopening ofsodium channels leading to reduction of
m yocardialcontractility and reduction in com pression ofintralnural
coronary blood vessels.
WhiteKnightLove

3
 Freely you have received; freely give.

l-n-Blockers.
.
*Allq-blockers-both selectiveandnon-selective-areuseftLlin
prophvlaxlsofstableLpngj/z?rpbeeausethey havethefollowing byneficial
efrects: è
,
l-decreaseheartratc and contractility contractility z-decrease A B P
.

(afterload).3-reducealïxiety.4-reduceexercisetachycardia .

Theseactionslead to decreased cardiacwork and oxygen demands.

wNon-selectivev-i/tlcl-cr,
5'arectpp/rt'
z/z?tWcè//cv/1.
11v,'
?r/c'
???/c
'???g/7Jt'
?becatsse
they lead to ''unopposed al-action''causing m ore vasospaslu .

*cardio-selectivej-blockersareusedwithgreatcaution andarebetter
avoided in variantanginabeeause seleetivîty isnotabsolute .
*In unstab e angina'f
3-blockerswithottt1SA areused.
.

wA dverse ffects and contraindications'

. see A N S,
But
; rem emberthatthey should neverbestopped -$1rJ#t.???/J?.
ç R' .
.

l--f'he doseofj-blockersisadjtlstedaccording totheheartrate, w hich

should notexcee'd 50-60 beats/m inute atrest, and 100-120 beats/m inute
during exercike .

z-p-blockersi
decreaseheartrate-->
.
prolongationofdiastole-->increased
end-diastolicvolume(EDV)andelectiontime-->increasedca1.(jjac Nvork .

and oxygen consum ptîon w hich partially antagonizestheirbenefieîal

effectin angina.This can be corrected by co-adm inistration ofnitrates
(nitratesinèreaseheartrateretlexlyandshortendiastole).

J-.
N'j/rJ/c5'and N itrites . .

*source?synthetiè. '
*chem istly..
O rganic N itrates'
.
l-Nitroglycerin (GlycerylTri-Nitrate=GTN).
z-lsosorbidq D initrate.
J-.
Jz&o-
s'
tlrAjle-l-M ononitrqte.
(N.B.:lnorganicnitratesare inactive).
*pharm acokinetics:
-
A bsol-ption:W ellabsorbed orally and can be given S.L.,I.v .,transdelnual
patch(disc)andointment.
-
D istribution:PassB.B.B .
-
M etabolism '
.l-lsosorbide dinitrate is convel-ted into isosorbide
mononitratà(activemetabolite* hasl00% bioavailability).
z--l-heyareextensivelymetabolizedbyconjugation withglucuronicacid
in theliver;thatiswhy the oraldoseismuch higherthan S.l-.dose.
WhiteKnightLove

4
'It is more blessed to give than to receive.

1Stpassm etabolism can be avoided by giving them S

.L.
,1.V .,oras :1
transderm alpatch. i
.
-Excretionr-f'he con u ated m etabolitesare excreted in uljr . t
nk.y y . .
- .

D rug R p
outes t?/-
. lndjc'
tr///oz7-s- 1
(
A dm inistration f
l
1-NitroglyceIri
n (glyceryl 1-Oral(sustained l-long-tern-lprophylaxl
-
-=s %1
trinitrate= GTN). releasetablets) . ofangina. )
'
1
l
:
1
2-Transderm alpatch z l-ong-ten'
-
n prophylaxis i
l
(disc). ofangina. t
i
l
3-Skin ointnaent. 3-l-ong-term lnrophylaxis )
ofangina j
. I
4-S.L.tablets(pellets) 4-Acutealagina and i
orbuccal(oral)spray . ilrn-
lediate prophlaxis t . i
!
l
5-l-v.infusion. 5-Unstableanginaand i
acutel'nyocartlial i
? ;
infxarction. )
1
2-lsosorbideDinitrate l-oral(sustainedrelease l-Long-terln prophlaxiso'
,
i'l '

tablets). angina. j
1
d
)
a ;
nd im m ediate l
pt
-ophylaxis. p
O .- j
3-lsosorbideMononitrate ral. Lono-tçrmmrophylaxis. j - .

* Prepartltions.. t

NitratesarJclassified acèording to dtlration ofaction into:

l-shortactincg nitratesused in acute anginalattacksand fbr im m ediate
pre-exertionalprophylaxis:isosorbide dinitrate and nitroglycerin buccal
spray orS.L.tablets.
z-lwong acting nitratesused in long-ten'n prophylaxisagainstanginal
attacks'
.isösorbide m ononitrate oraltablets,and nitroglycerin oralS.R.
tabletsanjcapsules,transdenualpatchesandointment.
'T harm acodvnam ics:
-
M echanism ofaction.
.
N itratesare reduced by stllthydryl-containing glutathione -s-transferasç
lntonitricoxide(NO).NitricOxidestimtllatesguanylylcyclaseand
5
WhiteKnightLove
 Freely you have received; freely give.

increasessynthesis ofC-G M P w hich in turn leadsto sm ooth m tlscle

relaxation,pal-ticttlarly blood vesseland m ainly veîns, and inhibition of
plateletaggregation.
-
pharm acolo icalaction.u
..

I-CV S:
1-N itrate ' are m ainly venodilators m ore than aj-teriodilators.
'Fz-v enodilatation decreasesvenous return tpre-load)which decreases
.

end-diastolicvolume(EDV).Thisleaclstoreduction tafCO13and
consequently eardiac w ork and m yocardialoxygen dem ands are
decreased.Reduction ofCOP decreasessystolicBP .

3-v enodilatation causesposturalhypotension .

*4-Arteri4dilatationdecreasesTI3R (after-load)whichleadsto
reduction ofcardiac w ork and m yocardialoxygen clem ands Redtlction o'
. f
TPR decreasesdiastolic BP (they decreasesystolic BP moretllan
.

diastolic,w/@.
?).
s-lleduction ofA BP causesreflex sym pathetic stim ulation eausing
increasedheartrate(reflextachycardia)andmyocardialcontractility,
w hich înereases cardiac w ol-k and m yocardialoxygen dem ands .

Tachycardia also shortensdiastole and decreasescoronary perftsiol)

(lslling ofthecoronariesoccursduring diastole).
T0 correctthese unw anted effectsofnîtratesthey are com bined w ith j
Q'-
blockers(orverapamil).
*6-V D ofnorm alepicardialcoronary vessels leadsto openipig of
collateralsj
'and re-distributesblood into the ischem ic areas ?
.

(Rememberthatatheroscleroticvesselscan notbe dilated).

7-V .D .ofcutaneousblood vessels causesflushing,
nï'
hebeneflcialactionsofnitratesï??angina.
8-V.D.ofmeningealbloodvesselscauses''throbbing''(pulsating)
headache.
ll-A ction on platelets'
.N itratesinhibitplateletaggregation by increasing
plateletCtyG M P.
111-Othersm ooth m uscle fibres:nitratescause sm ooth m tlscle relaxation
ofbronchi,GIT,uterus,and tlreters.
lv -M ethem oglobinem ia:nitrites -and to alessextentnitrates-oxidize
ferrous iron ofhem oglobin into ferric iron.This isespecially dangerous
in l11D asitcausesm ore hypoxia.H ow ever, 'm ethem oglobinenèia is
usefulin treatm entofcyanidepoisoning.

nlherapqutic tlses..
l-Anqinlp'ectoris'
.nitratesaretlsefulin a11typesofangina(stable,
variant,andunstable)and allconditionsofangina(acuteattacks,
immediateprophylaxis,andlong-tenn prophylaxis).

6
WhiteKnightLove
'It is more blessed to give than to receive.

The'aim oftherapy w ith nitrates in stable and angina isto reduce cardiac
w ork and m yocardialoxygen dem ands alld notto dilate the coronaries
,
w hereasthe aim ofthe aim oftherapy in variantangina isto dilate the
eoronaries.They are given S.L.orby btlccalspray in acute attaeks and
im m ediateprophylaxis, and are given orally, as skin ointnaellt,and as
transderm alpatch forlong-ternnprophylaxis N itroglycerin is given by IV
.
intwusion in tllt
kstable angina
.

z-l-leartfailure:they reduce pre-load lnainly and after-loaclto a lesser

-

extent.Theyareeffectiveinactlteheartfailttre(nitroglycerinisgivenby
IV infusion)aswellasinchronicheartfailure(oralSR tablets)
R eduction ofpre-load in patients w ith heartfailure im .
provesm yocardial
contractility and increases COP, butin patientsw ithoutheartf'ailure CO P
is reduced due to reduction ofvenousreturn and ED V .
3-Em ergency,hypertension:nitroglycerin IV infusion is used
4-A ctlte m yocardialinfarction:nitroglyccrin IV infusion decreases
.
cardiacw ork,dilatesthe coronaries, and decreasespulm onary congestion
and reduce the size ofinfarction. ,
s-Nitritesasamylnitrite(inhalation)andsodium nitrite(1V)areusedin
cyanide poisoning becatlse they catlse m ethem oglobinem ia.
6--freatm entofacute bronchialasthm aand intestinal, biliary,ol
krenal
'
colics(notcommonlyused). i
t

M dverseelfects..
l-lteflex tachycardia (dangerousin anginalpatientsand avoided by
addingp-blockersorverapamil).
z-posturalhypot
J
ension and dizziness,and m ay cause syncopalattacks
-

(nitratesyncope).Thiscanbepreventedby askingthepatienttotal
teS.L.
pillsw hen jitting -notin the standing position-and to getrid ofthe pill
afterrelief fpain eitherby sw allow ing or spitting .

3--fhrobbin (pulsating)headache and tlushing.

4-M ethem oglobinem ia and cyanosisespecially w ith nitrites.
.

s-A llergic reactionsas skin rash.

6-GIT disturbances.
7-N itrateTolqrance:itisdueto depletion oftissue SH grotlp reqtlired for
de-nitration ofnitrates.Itisprevented by allow ance of ''nitrate-free''
intervalsof$-10 hoursorby altecnative usewith otheranti-anginaldrugs
asCCBSand j-blockers.
8-* N itrate dependence.
9-* Carcinogenicity:nitrates are converted into carcinogenic
nitrosam ines.
10-* Elevation of1CT (intra-cranialtension)andIOP.
WhiteKnightLove
 Freely you have received; freely give.

*D rttg ./c/t.
?#wc//t?/,?,$-.'
.

l-Nitrates+j-blockers= benet-
icialcombination .

z-Nitrates+ Verapannil= beneficialcom bination .

3-N itrates+ N ifcdipine = tm favorable com bination .

4-Nitrates+ Sildenafil(Viagra(1î)))=very dangelouscomj;jua(j.oj4j.ijg(.)au se

. .
.

sildenafilcatlses V D .,hypotension, and reflex tachycardia through

.

inhibition ofphosphodiesterase 5 leading to increased i

G M P Th ntracellularc-
- ey aregiven atleast6-hoursapart . . l
(Al1arephal-macodynamicinteractions) #
)

3-calcium ChannelBlockers (CCBS) .

.

*source:synthetic .

Azchetnistly..they areclassified chem ically into:

l-phenylalkylam ines as Verapam il .

z-Benzothiazepines asD iltiazeln .

3
Ni
-DihydroljyridinesasNi.fedi
trendipine,and lsradipine
pine,Alnlodipina,Ai
.
r
jp/t
nl-j
-
/l
p//'
?c,Nicart/ipine,
*pharm acokinetics:
l-Absop tiontw ellabsorbed orally, and can be gr
iven parenterally
z-Distribution:highly botlnd toplasmaproteins(especially verapa.mil)
and displacedtherdrugsfrom plasmaproteinsasdigitalis, antlpass
B .B.B .
3-Fate'm etabol
.
j ized
' by the liverespecially verapam ilw hich is
extensively lnetabolized and itsoralbioavailability (OBA)isabotlt2524,
w hereasnifedipine has OBA ofabottt50-700A M etabolites are excreted
.

in urine. '
*pharm acodvnam ics .
.

-
sfechanisln tp/-tzc/ïtnrl.
'
CCB Sblock voltage-gttted Caa+channelsand inhibitCa2+ influx into
cardiac and s11100th m usclesespecially arterioles They actfrom the inner
.

side ofthe cellm em brane.

ltshould be noted thatCCB Shave no effecton skeletalm usclesbecatlsc
.

they do notdepend on Ca2h intlux to induee nlttse)e eoyju-aotiolaJnut

.

depend on release ofthe stored Ca2'+ from the sarcoplasm ic reticul

I um
t .
-
pharm acologicalactions..
A -CVS'
.
l-H eal4:verapam ilhasm arked effecton the heal'
tm ore than on arterioles
leading to:bradycardia(-vechronotropic)- decreased AV conduction (-

8
WhiteKnightLove
'It is more blessed to give than to receive.

vedromotropic)- decreasedcontractility(-veinotropic)--decreased
excitability -breduction in CO P .- reduction in m yocardialoxygen needs .

(Theactionsofverapamilontheheartaresirllilarto f?l-blockers .

Verapamilm ay also block q-receptors).

'

z-B lood V essels:

:
Dihydl-opyridinesasnifedipil'
lerelax slmooth l'
nusclesofarterioleslrainly
leading to V .D .ofnorm alcoronariesand otller arterioles N ifedipinc
.

causesreduction ofTPR and A BP, w ith conseqtlentreflex sympathetic

ytim ulation ofthe heart'leading to retlex tachycardia and increasecl
m yocardialcontractîlity H eadache,dizziness,and flushing also ocetlr
.

follow ing V .D .
N .B .D iltiazel'
n hasbalanced action on 1)tlth heartand arterioles .

3-
h ABP:a1lCCBscatlsehypotension (notrelated toposttlre, ),
t?/7t,
'.
?).Tl'
le
ypotensive action ofverapanAilis m ainly due to reduction in CO P, but
nifedipine -auseshypotension l'nainly due to V D .and reduction 01-TIAlt
. .
B- 514-100th '
nuscle t'
ibres:CC BSrelax slmooth lmuscles ofthe tlterus
bronchi, G IT,and ttreters. ,

*l-herapeutic 1/-
çc,s' '
.
.
.
l-A ngina pectoris'Prophylaxis ofal1types ofangina. Verapam ilis
.

usually used i% stableanginaasitrecltlcescardiacwork allclnlyocarclial

oxygen requjirem çnts.N ifedipine isusually used in variantalld unstable
angina,due to its potentvasodilator eftkct.
z-H ypertension:al1CCBS are usefulin treatm entofhypertension .

3-A rrhythm ias:verapam iland diltiazem are used in supraventricular

17
an-hythm ia and are classi'
fied asclass IV antiarrhythm ic dl-ugs t.

D ihydropyridinesare contl-aindicated in tachyarrhythnnias as they lead to

reflex cardiac stim ttlation).
4-l-lypertrophic obstructive cal-diom yopathy.
S-PV D Sas Raynaud's disease.
6-prophylaxis ofm igraine headache.
7--rocolyticsin prem ature labor.
8-N im odipine isused to preventcerebralvasospasm after subarachnoid
'
helnon-hage. , ' tj
t

*Wdverseetfects..
A-commonWlvcr-s'cetfects:
l-llypotension.
z-constipation(morewithverapamil).
3-l-leadache,flushing,andankleedema(duetoV.D.,sotheyaremore
mktrkedwitl)dihydropyridinesasnifedipine).
B-speciflcaï
lverseetf
.
'ectsofverapamil.
9
WhiteKnightLove
 Freely you have received; freely give.

l-Bradycartia.
z-lkeduction'ofAV conduction .

3-Decreasesl'nyocardialcontractility .

C-S ccilc ?tl/tyns'f?etfectstn/rn/ - */è.a(l'

.. pine-u
.
1-lketlex ta hycardia .

2-''C/oronarv Stealf,-'l'
lt'
.
:
-l.
ttllllel:llll''.nifedipine dilatesl'
. lol-l
'nalcoronaries
and notatherosclerotic vessels so the nonuall'nyocal-ditlm ''steals''tlle
blood fronqthe iqchelric nayocardiuln .

*contraintlications:
l-lrlypotension.
z-vcrapalniliscontraindicated in:Bradycardl
'a-hhlblock - Collgestive
heartfailtlre.
3-N ifedipine is contraindicated in tachyarrhythl-nias .

*D l'
.uç interactions .
.

A -pharm qcokinetic interactionss '

l-CCBS especially verapam ildisplace digitalis froln plasm a proteins .

Z-CCBS especially verapam ilclecrease renalexcretion ofdigitalis

(digoxin). -
B-pharm acodynam ic interaction:
l-verapamil+ fs-blockers= severebradycardia,AV block, and
dim inished contraetility and m ay cause cardiac arrest .

z-verapam il+ Nitrates= benet-icialcombination (verapam ilpreyents

.
retlex tachycgrdia caused by nitrates).
,
* '
* )
3-Nifedipine+ p-blockers= beneficialcombination (p-blockersprevent
ref-
lex tachycardiaindtlcedc by nifedipine).
4-N ifedipine + N itrates = severe hypotcnsion and reflex tachycartlia .

4-A ntlp
' latelet rugs..
They inhibitplateletaggregation and are used in stable and llnstable
angina.Thejinclude:
l-xdypjr/zk-lpediat
ricdose=75-150mg./day)andDazoxiben.Theyinhibit
TXA :synthesis.
l-D ipvridamole'
.inhibitsphosphodiesterase-->'yC-AM P in platelets,
blood ve'
ssels,and hea14 -->inhibition ofplateletaggregation,V .D .,and
myocardialstimtllation (also reflexlyduetohypotension).ltisused in
stable angina and in throm bo-em bolic diseases.
?-Tick/pidine and Clovidopwel:inhibitA Dp-dependentplatelet
aggregation:
4-sulphinpyrazone' .inhibitsCO X .
5-PG 1aanalogues asEpoprostenolu
WhiteKnightLove
'It is more blessed to give than to receive.

H vpqrtqnsiqn
*D efl-nition..
Elevation ofA BP k 140/90 m m llg, m easured atleast2 tim es on 2.
differentoccasions.
*llnvpes and Cc-
/z/xcw (Etiolop )).. .
1-prlm ary hypertensioll= tdiopathic = Essentialhypertension'
-
' . opeul
's iî)
over90% ofpatients,ln these patientsthere isno cause torhypkj
.
z zl-tension.
-secondary 'hypertension:hypel-tension is caused by:
-

A -D iseases;renalim pail-rnent-rçnalartery stenosis C ushing syndrom e-

-

Pheochrom ocyton-ta-Conn'sdisease.
B -Dlalgs:synnpathom im eticsasadrenaline, noradrenaline,ephedrille,
phenylephrine(nnainly by alpha 1stimulation)
Col-tisoland oralcontraceptivepills(dueto saltand watcrretention) .
R em em ber ''
$cl
-teese reaction''and ''rebound hypertension''due to sk'
ldden
clonidine w lthdraw al.

A ntihvnqttqnsive D rJze>'.- .
.

AB P is controlled by:
-

1-Cardic outptlt(COP),which isdependenton m yocardialcontractility,

. heartraté,venous return and blood volum e.
2-Total eri heralresistance(TPR),alsoknown as''
- systemicvasctllar
resistance''('
SVR),which isdependenton thetone ofperipheral
arterioles.
3-CO P and TPR are controlled by the sym pathetic nervoussysteh'
lancl
therenin-angiotensin-aldostel-onesystem (RA AS).
4-The intlux ofCa2+into the cardiac and sm ooth m usclesofal-terioles
cells-through voltage gated C a2+ channels-incleases cop and crPR ,
.
.
rejpectively.
WhiteKnightLove
 Freely you have received; freely give.

A ccordingly;antihypertensive drugs incltlde' .

j.-llenilt-zzjIlkxlotensltl-A ldostel-tlne X1?.

ç/t.!???antazonists: ..

A -Angiotensin Converting Enzyme lnhibitors(ACE inllibitors)as

Captopril, '
B-Angiotensin ReceptorBlockers(ARBs)asLosartan.
C-lnhibitors ofrenin release'alpha 2 agonists as clonidine, and beta
.

antagonists ajpropranolol .

D -R enin inhibitorsas aliskiren .

l-swnpathetic D eprzd- swzzzz/-s'(Sylnpathol ytics, kslyvs/ac-

////tp/-
- v/gjtr/ck
y?.
'
a-centralsvmpatholvtics /pc/?,/Jc'c a-J 6>z:?#?/,
s'/-
.
&(asClonidine and alpha-
,

m ethyldopaland Im idazoline 1 tpj.o/?/x/.

, 5'(asrilmenidineandmoyonidine).
,

b-CompetitiveganglionA/tpc/ccrx(theyareobsoleteexceptTrime ;taphan) .

c-Adrenergicnellrondepressants(andrenergicneuron blockers,
antiadrenergic drugsl:Guanetllidilne-lteserpinetrarely used).
d-Adlvnoceptortr //?/t:
?et?z7js'/-ç'q-blockers(asPropranololl- selectiveqz-
.
- .

blockers(asPrazosin)-drugsthatblock (3andcz-receptorstasLabetalol) .

3- Calcilzza channelblockers (asVerapamil,Diltiazem,and

. -

Nif-
edipinelh
4-D itlretics:Tlaiazidediuretics(asHydrochlorothiazidel-Loop
diuretics(asFruseluide)- K.'-sparing ditlretics(Spironolactone-
Amiloride-Triamterene).
5-Vasodiltltors:
A -Arteriodilators.
.
Comm on aclibn:they causeV .D.ofal-terioles- JTPR-->tABP.
Com m on A dverse effects'
.hypotension causesrellex sym pathetic
stim ulation leading to: ,
1-Increased myocardialcontractility and heal'trate (reflex tachycardia).
2-Increased renin-angiotensin system w hich stim tllatesaldosteronc
-
j- w. ' t
synthesis and release causing N a and waterrctention.
ThatisWhy they should becombined with p-blockersand loop diuretics.
3-H eadache gnd flushing.
Examplesinctude:Hydralazine- M inoxidil-Diazoyide-Fenoldopanx

B-VenodilatorsasNitt-ates(seeAnginaPectoris).
. . d D ila1()l--b.).
)ns'hkfixed,Balanced,t?.r Col31I/ù<-
C-Arteriopc/'?otW/tr?/t' - . '
They clilateboth arteriesandveins,assodium nitroprusside.,ACE
i
inhibitors,ARB S,and selective al-blockersare also m ixed dilatörs.
WhiteKnightLove
'It is more blessed to give than to receive.

GENERAL R ULES:
l-A rteriodilatorscause throbbing headache tlushing,reflex tachycardia
,
and saltand w aterretention .
,
2-A rteriodilatorsareusef'
ulin treatm entofhypertensio
n and heartliailure
asthey decrease TPR = After-load. .

3-Venodilatgrscausepost -uralhypotension and m ay t)esyncopt/Iwllich is

particularly dangerousin old patients .

4-D l-tlgs thatare given orally are tlsed in chronic pati

blockers,CCBS,A CE inhibitors ents(Thiazides,f)-
M inoxidil),drugsthataregiven
,
parenterallvonly(1V,IV infïlsion,1M )areused inemergency
hypertensiun only (Na nitropl-usside, D iazoxide,Trim etaphan
Fenoldopam).Drtlgsthatcan be given both orally and parenter,ally are
tlsefulin both chronicand em ergency eonditions(loop diureticsas
Frusem ide, lïnalaprilat, Hydralazine).

A rteriodilators:
l-H vdralazine..
*source.synthetic.
.

*pharm acokinetics:
l-Absorbedotullyandmaybegivenparenterally .

z-M etabolizedin theliverbyacetylationtconjtlgation withacetate)which

isgenetically determ ined;ie.peopleareeitherfttst(rapid)acetylatorsor
.

slow acetylators.Slow acetylatorsare liableto idiosyncracy in the form

ofperipheralnetlritis(prevented andtreatedbypyridoxine= B(
y)?jntl
reversibleiatrogenicsystemicluptlserythematosus(SLE) O n the other
.

hand,in fastacetylatorshydralazine show s lessantihypertensive action .

Oralbioavailalilityislow (25%).
3-M etabolitesare excreted in urine.
*pharm acodpnam ics:
-
M echanism ofaction:Directarteriodilatation (mayactbyNO release).
.

-
pharm acoloricalc?c/D ??5'.'
I-V.D.ofarterioles-->t TPR=SVR (after-load)- tABP (* potènt).
z-lteflexsympatheticstimulation -->retlextachycardia(add Il-bljtockeror
'
. .
verapamil),and icreased renin-aùgiotensin-aldosteroneactivity s->Naj-and
waterretention (addloop diureticasfrusemide).
*lherapeutic uses..
1-Hypertension:severe chronichypertension,given orally taddj-blocker
.

andloopdiuretics)andemergencyhypel-tension,given 1V.
2-Chronic heartfailure,given orally.
WhiteKnightLove

t 13
 Freely you have received; freely give.

'

*Advel-secj
//
'c
-c?s'.' . *c-'ontraintlit-
iatitlla-v .
'

Con'
tmongttvcns'cetïects:
l-Reflex tachyeardia .
l-Tachyan-llythnnias .
2-Anginalpains. 2-Angina pectoris .
3-Saltand w aterretention .

4-I-leadache,flushing, and sw eating.

S eci247adverse e èc/x es cc/'4;
///?in slow :?cc/J?/t:?/o/:s') '
.

5-Peripheralneuritis, treatedbypyridoxine(vitamin B6).

6-latrogenicreversiblesystemic-lupuserythematostls(SLE) .

J- inoxidl'l'
'
*soul'
-ce.
-synthetic .
zyPharm acok
'.inetics .
.

l-Givenorally only(given ashairlotionin treatmentofalopecia) .

z-M inoxidilisaprodrugconvertedbyconjungationwithstllphatçinthe
liverinto active m inoxidilsulphate.
*pharm acodvnam ics .
.

-
M echanism ofaction.
' . -
M inoxidilis a K j--channelopener -->efflux ofK -j
.and hyperpolarization
.

of sm ooth m us
i
cle ofarterioles-->V D .ofarterioles..
-
pharm acologicalactions .
.

I-V.D.ofal-terioles- JTPR (after-load)- tABP (* potentandlong

acting).
z-lkeflex sympatheticstimulation-->ref'lextachycardia(addj-blockeror
verapamil)and increased renin-angiotensin-aldosteroneactivity)-...Na'
andwaterretention (addloopdiureticsasfrusemide). 4
*lherapetltic uses.. î
l-llypertension:chroniçhypertension reyistantto hydralazine (itdd f3-
blockersand loop diuretics),given orally.
z--
freatm entofalopecia orbaldness,given topically as hairlotion.
'bz
qdverseelfects: *contraindièations.
'
.
Commonadverseelfects:
1-Reflex tachycardia. 1-Tachyarrhytllm ias.
2-A nginal ains. 2-A ngina pectoris.
3-Saltand Syaterretention.
4-Headachaand tlushing.
Specitlcadverseelfect:
5-Hypelrichosis(specificadverseeffect).
WhiteKnightLove

14
'It is more blessed to give than to receive.

3-D iazoxide '

.... . .. . * .

*sotlrce..synthetic.
*chem istlw :related to thiazides .

epharm acokinetics:
l-Absorbedorallyandalsogivenparenterally(1V injectionand inftlsiolè) .

z-l-liglaly bJunc1t
oplaslnaproteins.
3-partly l'nctabolized by the liverand partly excreted unchanged in tkl-ilae
(byactivetransportasthiazidesandinterfereswithuricacidsecretion
leading to hypelalricel-nia).
*p harm acodvnanlics:
/
lz
-.
.
/r
cc/ct?/kj-s
-z/cofaction.
.
A s m inoxidil;diazoxide isa K'V-channelopenerlcading to
hyperpolarization and V D .ofarterioles..

-
pharmacolobicalactions..
I-V.D.ofarterioles. --ytTPR (after-load).--ytABP (* potent-rapidonset-
longduration).
z-Reflex sympatheticstimtllation -->retlextachycardia(addjhblocltersor
.-

verapal-nil)and increased relniln-alpgiotellsilA-ctlt'

lostcl-olAe activity s.
yNa'
andwaterretention (add loop diureticsasfrusemide).
3-lnhibition ofinsulin release from pancreas due to opening of1Q6-
channelsinB-cellsofpancreas(asthiazides)leading tohyperglyccrnift.
4-Hypenlricem
1 ia .

*lherapetttic uses..
1-Emergencyhyperternsion(given 1V).
2-Treatmentofinsulinoma(givenorally).
ez
qdverseeyects: ' -
bcontl-tlilqclictltitllî-
s.
'
Colnmon adverse c/-
/èclç.
1-Reflex tachycardia. 1-Tachyarrhythm ias.
2-A nginalpains. ' 2-Anginapectoris.
3-Saltandwaterretention (in contrastto thiazides).
4-H eadache and tlushing.
Specificadversect/'c
'c/A'.
'
H YPerglycem,ia-Hypelrricem ia-H ypoltalem ia - Hypersensitivity
reactions(asthiazides).

4-F enoldopam :
* Selective D l-agonist-->V .D .ofarterioles.
. G iven by IV infusion. '
* U sed in em ergency hypertension.
* A dverse effects'
:Retlex tachycardia-l-leadache - F'lushing - Elevation
ofIOP. #
WhiteKnightLove
 Freely you have received; freely give.

*zlrteriqvenodilators (7#'
/xçJ Va-îodilqtors) .
.

' Sodiuln A //rtlprl/x5'/lc '

.

*sol,
fl-cezLjypthetic.
.

nbpllal-lnac'ok-ile
letic-
g
'
.

1-Given by IV infusion (should neverbegiven orally asitismctpbolized

intoeyanicle).
z-M etabolized in RBC Sand endothelium ofblood vesselsinto cyanide
.
(toxicn-
tetabolite)whichisrapidl
.
ymetabolizedbyrhodanaseenzLymein
theliverintothiocyanate(toxicmetabolite)which isexcretedinurine .

*pharm acodvnam i ics

.
.

-
A.
./t?t:
?/'
?t7?z?/A'?7Jof4?t?pb/J.
'
Releasesnitricoxide(NO)-->activation ofguanylylcyclase-
IC-GM P-/V .D.ofboth al-teriolesand veinsand inhibition ofplatclct
aggregation.
-
pharlnacologicalactionn'
l-Arteriodilatation -->t TPR (after-load)and ABP .

z-venodilatation -->tPre-load.
3-Retlex sym patlaetic stim ulation -->Tachycardia .

4-lnhibitsplateletaggregation.
(N.B.:NitroprussideinnormalindividualscausesslightredtlctionofC.OP
due to decrease in venotlsretuna, butin patientsw ith hcartfailttre it
increasesCt')P duetoreductiolain after-loadand ABP) .

*Therapeutic z/xc-
$'..
1-Em ergency hypel-tension.
' 2-Acute heartfailure.
3-Co
'ntrolled hypotension during plastic and neurostlrgery (Trimetaphan
v .
''. %.'' *. u

andHalothanemay bealso used).

4-Acutedissectipgaorticaneurysm (combinedwithfs-blockel-s).
*Xdversee(
'(ects:
1-Severe hypotension,reflex tachycardia and arrhythm ia,and angina
pains are obyerved with overdose.
2-A ccum tllation ofcyanide occurs in hepatic insufficiency and m ay
causedeath (ltisprevented and treated by thiosulphateor
hydroxocobalamin).
3-A cctlm ulation ofthiocyanate occurs in renalim pairm entand leadsto
disorientation,w ealtness,psychosis,and convulsions.Itistreated by
hem odialysist
4-Rebotlnd hypertension ifstopped suddenly., *

16
WhiteKnightLove
'It is more blessed to give than to receive.

Precalttion-vt'
#/z'//cj
F t'1'
, 1.
'rinf/.
/.
5.///7ofi
Witl-opl'-l.
. ts--b-ide.
'
1-Should be fkeshly prepared.
2-
i Shotlld be covered w ith foil-paper to avoid m etabolism by sun light -

nto cyanîde.
3-D ose should be adjtlstedin liverand/orrenalinapail -naentto avoid
accum ulatiqnfofcyanide and/orthiocyanate.
4-M onitorA B P and heartrate .

5-Neverstop'infusion suddenly to avoid rebotlnd hypcl-tension.

R
A enin-A nzioteils
%in-A ldostel-tlneSvstem (RAAS)fzzz/let?/:
.

zfs'/.
s'..
,
sytqdptvpsip Cppyvvtinu Engvm elphibitqrs(A CE inhibitors):
- .

*sollrce.synt;
hetic.
.

*chemistrv:sonneeontain SH group(ascaptopril)wlnereasothersdonot
contain SH group.
*pharm acokinetics:
*A
*Dibs
storption:
ribution:wpas
ellsabs
plaor
cebed
ntalorally (enalaprilatisgiven 1V).
banierand areteratogenic (renal
hypoplasia).
*Fate:
Captopril.is an active drug and is m etabolized by the liver .

fisinopril:is an active drug butis notm etabolized, itis exereted

unchanged in urine,
E nalapril,Perindopril, .J
?tw??/prj/.
'areinactivedrttgs(prodrugs)which are
m etabolized by the liverinto activem etabolites, then the active
m etabolitesare excreted in urine.
*pharm acodvnam ics. .

*hfechanism o/'/c/jozu,inhibitACE leading to inhibition ofAT-l1 .

synthesis.A CE is identicalto kininase 11enzym e, so A CE inhibitors also

lead io inhibition ofdegradation ofbradykinin'and accordingly
bradykinin acc 'um ulation occurs.
*pharmacolo icalactions .
.

A-Actions tr/z/g inhibition ta/'/1T-11 Jo

'rr/vtp/ïtnz?,'
l-A rteriövelaj
odilafatiola.
'V . D.ofboth arteriolesand veins--xt'
-
f-lltt
(afterload)and venousreturn(preload)--.tABP.
2-tAldosteronesynthesisand release -->sodium and waterexcretion-
thusdecreas'i
ù
ng blood voltlme-and potassium retention (hyperkalem ia).
3-tSympatheticactivity(ttransmissioninsympathetic
ganglia- treleaseofnoradrenalinefrom adrenergicneurons,andalso J
releaseofcatecholaminesfrom adrenalmedulla).
B-Action Jz/cto tpccr/zzzl//tp//tnz?ofbradvkinin:
l-v asodilatation due to nitric oxide release and synthesis ofvasodilator
17
WhiteKnightLove
 Freely you have received; freely give.

prostaglandins(PGE andPG1).
2-Drypersistentcotlgh (duetoinflalulmatoryreactioninthelungs).
*lnherapellticl?/-çc-
ç(indications).
'
l-l-lypertension (dr-ugsofchoice in hypel-tension lvithD .M .).ACE
inhibitorsareused in chronic hypertension (glven orally)and ellalapl-ilat
(activenaetaboliteofenalapril)isgiven IV in emcrgencyhypertension.
z-H eal4 failure:A CE inhibitors rcduce preload, afterload,and blood
volulne.They are notdirectpositive inotropics .

3-A ftel-m yocardialinfarction to l-edttce post-infarction l-em odeling .

4-D iabetic nephropathy'.A CE inhibitorsare given in doses low erthan

those used in hypertension and heartfailtlre to decrease proteintlrea and
fo stabilizerenalftm ctionsin diabetic atients .

WAth.'el-se ef'ects dûtl

k?zk/rc///?l/'y.////s.s'
1-severe posttlralhypotension after 1-l-lypotension.
the firstdose ''firstdose
hypotension''
2-Dry persistentcough. z-Bronchialasthm a .

3-llypersensitivity' .angioedem a 3-A llergy.

especially in SH containing drugs .

4--feratogenicity. 4-pregnancy.
s-l-lyperkalem ia. s-W ith potassittm sparing diuretics .

6-proteinure/.
7N eutropenia/
8-lm paired taste sensation
(dysgeusia).i
g-A cute renalfailure in case of 6'-B ilateralrenalartery stenosis.
bilateralrenalarte stenosis. -

*D rug interàctions:
A -pharm acokinetic interaction. .Antacidsdecrease oralabsol-ption and
oralbioavailability ofA CE inhibitors.
B-phannacodynam ic interactions' .
1-W ith potassium losing ditlreticsas thiazidesand loop diuretics:
synergism and avoid hypokalem ia.
z-'W itlnpotassiul'
n sparing ditlretics as spironolactone,triam terene,and
anailoridè'.severedangel-oushyperkalem ia lmay occur.
- ï
3-N SAID S a7aspirin'
.
.antagonize th' e antihypertensive action ofA1 CE
inhibitorsasthey reduce synthesisofvasodilatorPG s,and m ay cause salt
&nd w aterretention.

18
WhiteKnightLove
'It is more blessed to give than to receive.

Angiotensin11(AT1I) JlL--'f lnhibitor% -

l-stim ulatesspecit'ic A va
1-1receptors . l.
-lnhibitsA CE leading to I:nl-
lW-Wtion ofl
lbl
A T 11synthesis.A lso inhibits
inactivation(degradation)()13bradykinin.
z-v el-y potentV -C ,ofboth arteriesand
veins leading to increased'preload
. Z-V D .ofbotlzveins and arterîes leading
.

(venousreturn),COP,afterloaclI-l-PRI, todecreased:preload, afterload,CO P

and A BP. TPR, and A BP. ,

3-stil-nulation ofaldosterone synthesis 3 lkeduction ofaldosterone synthesisand

-

and reltease fronaadrenalcortex leading release leading to exeretion ofN a':11(1

'
to N a and w aterretention and increased
. w aterin urine which decl-easesblood
blood volum e, anclexcretion ofK + . voltlm e,and hyperkalenxia .

4-sympatheticsdim ulàtion by: 4 t Sytupatlt

-
eticactivity.
-
stim ulation ofsym pathetic ganglia and
release ofnoradrenaline from adrenergic
neu ro ns. t
l
- jtim ulation ofreleaseof
catecholam ines from adrenalm edulla.

.
s--rrophic changesandfem odeling of s-preventsrem odeling afteêmyocardial
cardiacluyocytesfbllowing myocardial infarction (cardioprotective) .

infarction(mitogenicaction).
6-A ctions on theki
, dney: U-lncrease renin release. 1
1
-
N egative feed-b@ck inhibition on rcnin
,

release.
-
V .C .ofrenalblood vessels.
-
* lncreases sodium and w ater
reabsol-
ption from proxim alconvoluted
tubules. '

'

v-used to elevatr
'ABlain severe 'F-uses:treatmentot-hypertension tdrug
hYPotension especially dueto overdose ofchoicein diabetes-hhypertension)-
..ofalpha blockers,given by IV infusion treatm entofheartf-
ailtll'
e-
'

(PCPtide)- Cal-dioprotectiveaftermyocardial
infarction - redtlce sproteintlrea catlsetl
by diabetic nephropathy.

19
WhiteKnightLove
 Freely you have received; freely give.

I)-Anziotensin ReceptorBlockerj(ARBs):
*Exaillple-
z:Loszàl'tan-'valsal-taln-cktncle>tAl-tttla-Tellaaesal-tal
- n.
thjx
lechanism t?/'
c?c//o??.
'connpetitiveantagonistswith ATll(-,11A T-1
.

receptors.
nzpharlnacolooietllt7c/jf'
. )??A'.'
The actions ()f A RBS are identicalto those ofA CE inhibîtors excel
- pt
accunnulation ofbradykinin becatlse they do notinhibitdegradation of'
bradykinin (thay do notinhibitA CE whicla1salso kno' wn askilainase 1l) .

l-A rteriovenodilatation:V D.ofbotharteriolesandveins--/JTPR

.

(afterload)andvenotlsreturn(preloadl--ytABP.
2-t Aldostth-onesynthesisand release -->sodièllm and Nvaterexcretion-
thusdecreasing blood volufj-le-and potassitllm retention thyperkalen-tia) .

3-. )Syl- npathetic activity (ttranslzlission in syl-

npathetic
ganglia--yt x.releaseofnoradrenaline fron:adrenergicnetrrons, and also t.
.

releaseofcatecholam inesfrom adrenalm edulla), *

*lndications:
The therapeutic uses Ot-A RBS are the sam e as A CE'inhibitol's:
l-l-lypel-tension.
z-l-
leartfailure.
3-To protects the heartafterm yocardialinfarction .

4-D iabetic nephropathy.

*
zz
jdverse c//èc/-
. $'andcontraindièations..
AsACE inhibitorsexceptdry cough (they aresafely tlsed in asthluatic
patients).
NLB.u.Saralasin is a peptide A T-1 antagonistw hich isnotused clinically
.

intreatmcntsofhypertensionbecauseitisapal-tialagonist.
C d nhibitors ofrenin release:alpha 2 agonists as clonidine,and beta
antagonists aspropranolol.

ll-lkenin inhibitors asAliskiren.

wlnhibitrenin enzyl'
ne ->inhibition ofangiotensin syntllesis --.
+ V .D .and
tABP.
'lu sed in treafm entofhypertension,given orally either alone
(inonotherapy)
t'
torin combinationwithdiuretics .

l'
l-hey arenotcom m onlytlsed becauseof:-low oralbioavailabilië
ty-'I
-
renin due to lossofnegative feed-bacltinhibition by A T-l1-diarrhea.

20
WhiteKnightLove
'It is more blessed to give than to receive.

eart alyul.e )
*D efîllition..
Itisthe lnability ofthcheartto l-naintain an adeqtlate COP stlfl-iciel'
ltt() .

l'
neettissue oxygen requil-ennents H ealrtfailtlre isregarded to as
.

''ilubalance betw een CO P and tisstte oxygen reqttirttluel-tts''.

'bTvpes t?f/-
fc/z/'/Failllre.
.
A -A ccording to CO P..
1-Low CO P f' ailure:the m otcom m on type ofI21F .

2-l-1igh CO P failure'
.due to hypel-thyroidism , severeanemia,plrgnallcy.
Treatnaentofà
. (
thist'y peofheal'tfailttreisbytreatm entofthecatlke
''''' .
.

B-A ccording to &z?.

çc/.'
l-chronicheartfailure(CHl7). '
z-Acutehea14failure(AHF).
C-According to Sideaffbcted:
l-ltight-sided heartfailure:leads to systèm ic congestion .

z-Left-sided heartfailure:leadsto pulm onary congestion .

3-combineqheartfailure'
.leadstobothsystemicandpttlmonary
congestion.

Com'pensatoly At/tv
yc/csnjçzn-çin f/t:
- ?cr
pr/Failure:
They try to increase CO P butw illeventually failand heartfailtlre
becom es ''nAanifest''or ''decol-npensated''
The com pensatory m echanism s include:
J-lncrease in cardiac sizeby hypertrophy and dilatation (cardiomegaly).
.

z-lletlex symgatheticstimulation:1ow COP -->low ABP(exceptin

hypertensivefheal'tfailure)--,1-Tachycardiaand increaseclmyocardial
contractility.2-V,C.ofboth arteriesand veins(safter-load and pre-load).
3-lncreased renin-angiotensin activity - V .C.of% both arteriesandlveins,
and increased aldosterone synthesis and release --ysoditlm and w a'ter
retention- edem a and increased blood volum e .
i ,

A im 'ofTreatm entin l-leal4 Failure D rugs Useçl

1-lncrease nbyocardialcontractility to 1-Positive inotropic drtlgs
increase COP. (myocardialstimulants).
Z-V .D .ofboth veins and arteriesto reduce 2-V asodilators:Venodilators-
pre-load and after-load. Arteriodilators-M ixed dilators.
3-D ecrease blood volum e and edem a. 3-D iuretics.
WhiteKnightLove
 Freely you have received; freely give.

I-p
-osi
i tivc Inotropic . rttzs t'
.
lt/tcc'g -tï
cialk
l V//'
7?,
?2,
//t???/-
- ç)
*7o ncrease l'nyocal-clialcontractility itis essentialto increase fi-eq C'ft2'
inside cardiac cells : ,
Calciun-lbinds.totheinhlh
.
'itory(tropollin)ttptl
facilitatessliding ofthecontractileproteins(actin and m yosin)leading to .

nnyocardialcontraction(positiveinotl-opiicaction) .

wM echanism s to increase ti-ee Ca2+ incltlde

. .
.

A -lncreasing intracellular C-A M P by:

1-Stil- nulation ofjl-receptorsbyl7opalnilte f-')t?/??f/tp?J??'??c,and
,
Prenalterol--->activation ofadenylylcyclase --+-rsynthesisofC-AM P.
2 .

lnhibition ofphosphodiesterases(PDE)by Nfethylxanthines(as

-

Aminophvlljne)andBipvridines(asAmrinoneandM ilrinone) .

B -l17CI-easing intrace:ularNa*by inhibition ofNa'/1Q'A' fpaseby

CardiacGlvcosides(Digitalispreparations) .

1
*
-C/rV/
Wc GIjICOSI
'
CXv
%(X /'
G
>/
. '
/J/X Iï
'l'(-
?
;)6ll'
.
-t1tl
'
Ol1g
b'
)
,=
,
.

sollrce..Plantorigin (Digitalispurpurea, Digitalis lanata

p

Strophanthus). n
'
Ychem istly :each m oleculeiscomposed of:
1-N on-sugxrl
part(aglycone)fornaedofasteroidnucleus;itisrespolpsible
forthe phannacodynam ic properties .

2-Sugarpart(glyeone)which isresponsibleforthe clegreeo(3lipid

solubility and accordingly the phannacokinetic propel-ties .

(Bothpartsofthenaoleculeareboundbyanetherlink) .

*pharm acokinetics:
The pharm acokinetic propel-tiesvary aceorcling to the type ofdigitalisas
fbllow s: L
Pharm acokinetics D i itoxin D iooxin & ?/t'
,//p:7/?7 1
,
l-Lipid Soltlbility'
. H igh. M oderate . W atersoltlble, 1
2-OralA bsorption'
. A lm ostcom plete. M oderate. Notabsorbed. ,
l
3-Oral 90 % 75% Zero )
bi j
oavailability'. l
4 j
-
Route of O rally only. Orally alld 1V . IV only. l
adl-ninistration: l
'
s-plasl'
naprotein 1-lighly'bound(95%). Moderate(25t4,). Allnostunbound. j
l
binding.
. '
h-passageacross M arked . Less. Cannotpass. l
!
BBB : p
t
7-lzate.
'
M ainly m etabolized M ainly excreted Excreted tlnchanged i
b j !
yHM E (80$$), tlnchangedinurine in urine(avoicledin E
avoidedinliver (80%), avoidedin l-enalil'npairnnent). l
l
ilm airm ent. renalilnpainnent. u
..
WhiteKnightLove

22
'It is more blessed to give than to receive.

8-Elim ination tl/2 7 days . A bout l.5 day. A bout 1 day.

and D uration: Long . M oderate. Sllol-t
g-cum ulation M ostctlm ulative . M oderate. Least.cum ulative
.
(especiallyin
. cardiac and skeletal
musclesl.
'
* lo-choice: ln CH F w ith renqtl Drug ofchoice in
insufficienc C1'l17and A HF .

NLB...cligoxin shouldneverbeinjected IM ê1S it1-1-1:1y CêlIISe S0VC1*e 17ê1irl,.

irritation,and
4t
even m uscle necrosis.
*pharm acodvnam ics:
-
M echanism tp/c?c/jt7
?/?.'
Cardiac glycosidespartially inhibitm embrane-bound Na1/lC ATpase
(Na+pump)incardiaccells-->increase in intracetlllarN a'-->increase in
intracellulalCa2-hby: -

1-tCa2+m a-1'exchange .

z-llteleaseofCa2+from sarcoplasm ie reticulul'n .

3-Opening ofvoltage-gated Ca2+channels .
Elevation offree Ca( @r
-1
.increases m yocardialcontractility
Vtvv j/,
/?/?tlr/t'
??7/note.
. . .
Cardiacglycosi*des'''andpotassitlm (andto alessextentm agnesium)
com peteforNa /IQ A-l-pase,thatiswl3y hypokalem iaisthemost
'

im portantpredisposing factor fordigitalistoxicity.

- -

(K i-andM g::!-i-activatebutdigitalisand Ca(1!.1-inhibittheenzyme)

. .
.

'

-
pharnlacologicalactiohs .
.

l-positive lnotropic action especially in leftventricularsystolic

dysfunction. .

z-lncreased CO P in patients w ith congestive heartfailurea (butithasno

- - -

effectorm a#.even decreaseCO P in nol-m alindividualsdueto

bradycardia).
3-lncrèased m echanicalefficiency ofthe heartas digitalis increases
contractility (workdone)withoutmarkedincreaseinoxygen
consumption(energyconsumed). ; .

4-ltedtlction ofcardiac sizeto nonual,and reductlon ofED V , ESV ,and

venouspressute.
s-lleartrate:y
lDigitalisdeckeasesSAN autom atiçity;ithasnegative chronotropic -

action leading to decrease in heartrate.Rem emberthatbeforediéitalis

there is com pe
jnsat
'oly tachycardia .

wlkeduction in heartrate isdue to:

WhiteKnightLove

23
 Freely you have received; freely give.

'

1-Vagalaction digitalis stim ulates vagalC I.C.both directly and reflexly

.
.
.

through stimyl
1 ation ofbaroreeeptors, and sensitizesSA N to
acetylcholine.This vagalaction is the m echanism ofbradycardia in th
beginning oftr e
eatmentby digitalis(early digitalization).
z-Dil-e(ï
'taction(extra-vagalactionl'digitalisdecreases SAN autom
. l aticity
directly and decreases sensitivity of SAN to catecllolam i
nes(anti-
adrenergicaction).Thisactionoccursafterfulldigitalization ( .

Vtwv im portantnotes: .
l--l-heearliestobjeetivemanifestationofdigitalist'oxicityis
''BRA DY CA RD IA f60 beats/m inute.
z-Atropine can antagonize digitalis induced bradycardia ifgiven in etu-ly
-

digitalization buteannotantagonize itil'lfully digitalized

patients.
6-Refractor Period R .P.:
l RP IqtzalAction D irectAction N
etc//RJ
'C/
Atl-ial.
-
Shortens. Prolongs. Shortening .
2-A V: Prolongs . Prolongs. Prolongation
3-Ventriculan. N ö effkct . Shol-tens. Shol-tening . .

7-Conductivit : ,

Site Va alAction D irec'tA t//jt-

l Att.ial..
-
Accelcrates
.
kp? N(?t.
/t-
//èc.
/
. Slow s. A ccelerates
2-A P'? Slow s . Slow s. Slows= negat. ive dl-ol-notl'opic
J-Ventricular: N o effect. A ccelerates. A ccelerates .
. !

8-A utom aticity:in therapeutic levels, digitalishasno effectbutin

digitàlistoxicity there is increased ventriculatautom aticity leading to the
appearanceofectopic pace-m akers(ectopicfoci)and ventricular
al-rhythm ias.: '
Vervïzp/ptnr/c-/r)/note.
.
D igitalisistlsefulin treatlnentofsupra-ventrieulararrhythl-niasbutis
contl-aindicatj
ed in'ventricttlaral-l-hytlAlrias.
.

g-Excitability:
-
1n therapeuiiclevelsdigitalisincreasesexcitability dueto increased
intra-cellularN a+ w hich causespartialdepolarizatîon .
-
1n easesofdigitalis toxicity;excitability m ay be reduced due to
'
-
inactivation offastN ar n-channels .
.

IO-A BP:
-D igitalis''norm alizes''A B P ifitw as low asitincteases CO P H ow ever; .

itmayincreaseABP in caseoftoxicitybyV.C.(directaction anç

tlby
stimtllation ofVM C). :
i
i
l
24
WhiteKnightLove
'It is more blessed to give than to receive.

-D igitaliscanibe used in patientssuffel-ing frorn laylnzrtensive heart

failtlre.

1l-D ittretic A ction:

D igitalishasa diuretîc action only in cases ofcongestive lleartfailtlre by
' the follow'ing nnechanisrns:
1-lncreasesCO P -.->trenalblood tl()w (RB17)--y) GFR and ditlresis
z-lncreases CO P dccreasesrenalischem ia and accordingl .
@ y decl-eases
renin release-->tangiotensin 11o taldosterone synthesisand release --
t sodium andwaterretention and diuresis .
w
3-* Directaction on renaltubules--ytsoditlm and water
reabsorption- diuresis ,

4-* Com petition with aldosterone--.tsodiuln andw ater

reabsol-
ption- diuresis .

1z-Blood V olullne:
D iuretic action ofdigitalisin lleartfailure decreasesblood volulace.

l3-coronal'y kessels' .

--fherapeutic,leve'lsofdigitalis have no effeeton coronary circulation aj-tt

i l .

tcan be usedfîn patientsw ith angina and heartfailure .

-1n digitalistoxicity coronal-y vasospasl'
n nnay occtlr.

14-E.C .G .
llarolongation
t!
ofP-R interval:due to delay in A V conduction.
wshortQRS and Q-T segmentdueto strong shortsystoleandlupid
repolarization.
*Depressed $-T segment(especially in case 01'
-toxicity) .

lls-latorinverted T-w ave.

*Bradyeardia.
wventriculararrhythm ias(extrasystole-pulstlsBigemintlsorTlwigem inus-
V entriculartachycardia-V entrictllar Fibrillation=v .lc.).

Therapetttje zf-
&c-$'.
'
--

l-c ollgestive:hea14 failurq, especially leftventricularsystolic dysftlnction,

D igitoxin and digoxin can be usqd in CH F w hereas digoxin and otlabain
canbeusedinAHF (acuteL.V.F.).
Signsofiluprovement:theartrate-tcardiacsize-trespiratoryrate
(dyspneal-tedemaand bodyweight-tlurineotltput
z-AtrialFibrillation(A.F.I:digitalisisusefulinA.f
.,'.withorwithotlt
heartfailure lthasthe follow ing advantages'
.
WhiteKnightLove

25
 Freely you have received; freely give.

3 A tl-ialFlqtj
-
ter:cl'
igitalis protectsthe ventricles by reducilèg A V.

conduction butitm ay convertatrialflutter into A .F.

A fterstopping digitalisone ofthe follow ing m ay occur:
-
N orlmalsinusrhytlal'n isrestored and the patientiscured.
- A .F.persists.
-
Tl'1e condition reverses into atriàltlutter
.

lfA .F.persistsoratrialf.1utterrecurs;Quinidipeisgiven to restorex

norm alsinusrhythl'n.Itshotlld be noted thatquinicline shotlld nevertae
given before digitalisbecause quinidine n- lay increase AV conduetion cltle
.

to atropine-like action leading to ventrictllar arrhythm ia w hicl)nlay be

fatal.ln addition;quinidine should neverbe given w ith digitalisto avoid
.
seriousdrug interactions(seelater). )
:
4-paroxvsm ah1AtrialTachvcardia(PATI:digitalisdecreasesSAN
autom aticity and AV conductivity.
N.B.PAT isalso treated by f'
J-blockers,verapamil,and Ma-agonistsas
edrophonium ,m ethacholine,and neostigm ine .

*WdverseelfectstTbxjc//vl.'
1-CV S:Bradycardia - PartialA V block - V entricularal-rhythm ias
(extrasystoll-pulsusbigeminusortrigemintls-ventriculartctchycardia-
V.F.).
2-G 1T:aporexia,nausea,vom iting,colics,and diarrhea.N ausea is lriainly
due to centralstim tllation ofCTZ and lessprobably due tt)localG l'r
in-itation.
3-CN S:headache,drow siness,confïlsion,halltlcinations,and convtllsions
(rarebutindicàtesserioustoxicity).
4-Eye: bltlrring ofvisison,disturbance ofgreen and yellow vision
(chromatopsiâ),amblyopia,ordiplopia.
S Gynecom astia:m ay be dueto steroid strtlcture.
WhiteKnightLove
'It is more blessed to give than to receive.

*contraindications?
1-Bradycardja.
2-PartialA ' V block.
3-V entrictllttran-hythnaias.
4-l-lypertrophicobstrtlctivecardiol-
nyopathy(treatedbyj-blockersol-
CCBs).
5-Constrictive pericarditis .

6-Severe valve stenosis .

7-* D igoxin iseontraindicated in renaldisease .

8-* D igitoxi'
n iscontrainclicated in liverdisease
' .
,

*D rllg.j/k/c/' -/zt?/jt?zz.t.)
A -#/.
?//-/??y/:'o/c'//'
?c//& interactions:
l-A bsorption:
-
Drtlkysthatdecrease digitalisabsorotion:
'
.

Antaeids(M g.andAl.salts),Antiemetics(metoclopram ide)

Ant
A idian-healdrugs(kaolinandpectin), Antibiotics(neomyc,in),and
ntihyperlipidemicdntgs(choldstyramine) .
-
D p-tl>/.s thatincrease digitalisabsorption:
Antim uscarinic dnlgs as atropine and pl-opantheline They rnay lead to
.

digitalistoxicity.

z-Distribtltiq
sn:
M any drugsdisplacc digitalis from plasm a proteilksand m ay lead to
digitalistoxicity', aspropranolol,N SA tD Sas aspirin, CC BS asverapam il
and n'ifedipine, am iodarone,stllphonam ides, and qtlinidine.

3-M etabolism :
-
HM E inducers asrifam picin,nicotine, phenytoin,and phenobarbitone
decrease bioqvailability ofdigitalis
'
.
' .
-
H M E inhibitprsas contraceptivesand erythrom ycin increase
.
bioavailabill1tytand m ay induce digitalis toxicity.

4-Excretion:
.
Qtlinidine,amiodarone,and CCBSespecially verapam ildecreaser
Lenal
clearance ofdigoxin and m ay cause toxicity .
)
N B Qtlinidineinducesdigitalistoxicity by displacingdigitalisfrom
plasm a proteinsand decreasing its renalexcretion.
l

B-pharmacodvnam ic /?7/c?v7&/jf??:.s-.
l-loY-losing ditlretics as thiazides and loop diureticscause hypokalennia
and hypom agnesem ia w hich predispose to digitalis toxicity.
2-K ''
-spaling ditlretics causehypel- kalem ia w hich antagonizesdigitalis .

27
WhiteKnightLove
 Freely you have received; freely give.

3-j-blockersandverapal-
nilantagonizeinotropicactionofdigitalisbtlt
augm entbradycardia and A V block.
4-sympathonnil-neticsactingasf
3l-agonistsasadrenalineandisoprt
pllttline
nlay lead to ventriculararrhythl-
nia .
2''
5-Ca saltsinelease the actîon ofdigitalis and m ay lead to toxicity
-

6-Thyroxin (may leadtoventriculararrhythmias) .

*D izitalis Toxioitv.'
,

*cardiacglycosideshavelow therapeuticindex (narrow safety margin)

é'l-he earliestn'
lanifestationsoftoxicity:nausea and von-liting .
b , and
radycardia below 60 beats/m inute. O therm anifestations oftoxicity:see
before.
*Digitalistoxieityisusually chronic(digitalisisacunnulativedrug)and
rarely acute due to high loading dose especially in old age .

*FzactorsyprctWx/-ltzs-/pv
-
. s t
o tWq?/tp/l.
a î-toxlcitv:
l-llypokalem ia and hypom agnesem ia due to conc
urrentuse of-tlliazides
orloop diuretics w ith cligitalisin treatm entofheartfail
z llypercalcem ia.
-
tlre.
3-sym pathom im etics:J
.
31agonistsasadrenalineandisoprenalinc, .

4-HM E inhibitors(seebefore).
s-Drugsthatzisplacedigitalisfi'om plasm aproteins(seebeforel
6-Drugsthatteducerenalclearance ofdigoxin (see before) ,
i .
7-A cidosis,llypoxia,and ischem ia'decrease activity ofxN a#.
. /K -1
.A r.
l.
,Pase
and increase the effectofdigitalis,
8-llypothyroldism decreaseselimination ofdigitalis .

9-O ld age:dim inished liverand kidney functionsreduce elim ination of

digitalis.
lo-l-lepatic insufficiency reduces m etabolism ofdigitoxin and renal
im painrentreduce renalexcretion ofdigoxin .

1l-Thyroxin.

*precautions with lfgj/tp/j-çtherapv = # /-cvt

. ???/j/???ofdizitalistoxicitjl.
- --- -

l-A void and correctpredisposing factors especially hypokalem ia and

m onitorjerum potassitlm .
z-M onitoringplasmalevelofdigoxin (therapeuticlekel' .0.5-2ng./1nL.)
and digitoxin (therapeuticlevel:10-25 ng./m L).
3-Adjtlstthedoseino1d age(accordi .ngtorenalfunction).
4-Avoid loading dosem ethod in old age,and besure thatthepàtientllas
notreceived digoxin in the previous2 w eeks.
s-check forearly signs oftoxicity'
.bradycardia below 60 beats/m intlte,
and natlsea and vom iting.
WhiteKnightLove
'It is more blessed to give than to receive.

O ther P ositive Inotropic zDr?,

/gx.' ,

2-B lp
' yrrjlj/ccs'.'
. '

*.
/k/t9't?/?t
r?1??'
,$'??cofaction.
.inhibitPDE type3 --+increasein C-A1
kIP .

nbpharmacolopxicalactions:Positive inotropic action and V D .w hich.

reducespre-loadandafter-load (theyareknownas''lno-dilators'').
*E'xalnple- %.
1rp,-//74/,7c = lnam rinone:given IV for short-terrn treatn-lentofactlte
- ..

healifailure.ltishighly toxic and may cattsetl?rol-

nbocytopenia and
hepatotoxicity.
-
hlilrinone.
.m ore potentand lesstoxic than am rinone.
s-x m inoNhjzll,/*z7&.*
*hfechanism ofaction.
.inhibitsPDE type4 and increasesC-AlklP .

*pharmacoickicalactionsu
'positiveinotropic+V.D.(alsoinodilator)+
bronchodilator+ D iuretic + CN S stilnulant .

*Given slowlyIV in acuteheartfailure(increasesCOP 1'

-
01.3()naintltes) .

4-B é-zqgonists..oopamine-oobutamine--prenalterol
Il-D iureticbv:
l-rhey are the firstline in treatm entofH F.
*'l-hey reduce blood volum e and accordingly decrease venous return
(preload).Thtyalsodecreaseedemaandvisceralcongestion .

*'
l-hiazidesal'cused in ehronic m ild and m oderate l-lF-loop diuretics are
used in chronic severe and resistantH F as w ellas in A LIF.
Potassium sparing diuretics are added to avoid hypokalelmia .

111-Vasodilators:
l-A rteriodilators:ashydralazine and m inoxidil,which decrease system ic
vascularresistance(SVR)= afterload.
z-v enodilators:asnitrates,w hich decrease venotlsreturn = preload.
S-M ixeddilators(Combineddilators,arteriovenodilatorsl:asACE-Is,
A ll-
B s,selective a1 blocltersasprazosin,and soditlm nitroprusside.They
reduceboth preload and afterload. '
1V-B eta-A drenocep tor Antagonists..
The Role ofn-Blockers jz?H eartFailure..
Traditionallvj-blockersarecontraindicatedinsevereheal' tfailure(class
1V)becausetheyhavenegativeinotropicactionanclmay worsentllecase
(especially ifcompensated by sympathetic cardiacstimulation).
Receintlysomep-blockersasBisoprolol,Az /c/flprf'
k/t'
?/,tw?JCalv'edilolare
given in sm alltdoses-w hich m ay be gradtlally increased-in selected cases
'
x
otmoderateHF (class11-111)to protectthe lleartagainstthehanuful
effectofexcest
sive circulating catecholam ineson cardiac cellsw hich
inducesrem oy
deling and apoptosis.
WhiteKnightLove
 Freely you have received; freely give.

'
#ln
reatlnel-
ltof#?'fV/:?//-
$'toxieitv..
l-stop digitalis.
2-ln case ofhypokalem ia.stop K-'-losing diureticsand give IQCI(syrup
.
,
sustained release tablets, orslowliy IV infusickn)l' .,
rctrp/
, in case
. of A
l
-el
lal
ilupairlmentand A V block.
3-1n case ofhypercalcelmia:give Caî!-l.chelating agelltas Edcta 1$/r.
. .
.
.
.
,

4-To treatA V block use atropine .

5-To treatventrictllararrhythl-niag'IkritllA V 1110c1.:. Plècnvtoilu

.

bl To treatvtntricular arrllythm ias I'VitholttA V block:Lidpcain: ,j)--

- w
ockers,orD isopyram ide.
.

6-Digoxin antibodies(Fabfraglùents)aregiven .

7-cholestyram ineto decrease oralabsollation ofdigitoxin (i11aeute

toxicity).
8-oxygen inhalation in case ofcardiac îschem ia w hich predisposesto
ventriculararrhythm ias .

Jzp/'-pimportant#?(?/c.'
Quinidineiscontraindicated in treatm entofarrhythluiasdueto digitalis
toxl
ktiity lkvhy.
?l.
A'
fc///oJ.
s'ofdigitalization.
.
l-l-oading Jtuc m ethod:a large dose isgiven to reach the steady state
concentratiop (Css)in ashortperiodoftime.Itmay leadtotoxicity
'especially in (?ld age.ltis follow ed by a stualldaily dose to naaintain C
(maintenanc4
etdose) .
ss
z-N on-loadinbrdose ??J/?//?tpJ.'the sm allm aintenance dose isgiven daily
.

and Cssisreached after4-5 half-lives;w hich eqtlalsabout 1w eek'for

digoxin (4or5x 1.5)andabout1month fordigitoxin (4 or5x 7).
t

29
WhiteKnightLove
'It is more blessed to give than to receive.

ClassiflcatiolîofAnti-ajrrhvthm ic D rttgs
-

l-class 1.-theyareNai-channelblockersandaresubdivicled into:

Class 1-A :they areNaf-channelblockersofm oclerateefficacy and can
a1so block l/tchannels.
Exal-nples:Quinidine-procaintplAaitle-Disopyl
-Cll'
laitle
.

*'
They have atropine-like action
.

louinidineisusedin a1ltypesofarrhythnniasexceptdueto cligitalis

toxicity(seedigitalis).
*Digitalisshould begiven beforeQ uinidinein atl'ialfltltterand
'
fibrillation (see digitalis).
C lass l-B:the i
y areweak Na-
f-channelblockersand also open 1t'
'-
channels.
Exam ples:Lidocaine-phenytoin .

@Lidocaine and phenytoin are very effective in ventricularaln'

iaythlni
(see digitalis) .
as
ltxidocaine isalso a localanaesthetic alïd should be given IV as
antiarrhythm ic because itundergoes allnostcolzlplcte firstpass ef-fectin
the liver.
*phenytoin isalso anti-vpileptic .

Class l-C :they areverypotentN a'

b-channelblockersand have no effect
+
on K -channels.
Exam ples:Encainide-Flecainide-pl-opaf'ellone.
l

Cla-v 11.
.theyarej-blockers(seeANS) .

'

Class 111..theyarelc -channelblockers .

Exam ples-
.A ll
uiodarone-sotalol-Bl-etylitlnA.
.

*Amiodaronehasalso class1action (Naj--chaùnelblockerla class 11

action(j-bloclteraction),classIV action(Ca'i
'-channelblocker),and also
cz-blockeraction.ltisanti-an-hythm ic,anti-anginal,and anti-hypertensive
butisvery toxlc.
lsotalolisal#
so p-blocker.
*Bretylium is also adrenergic neuron blockerthatinhibits noraclrenaline
release asguartethidine.

C lass V1tca-h-channelblockers(CCBs):verapamilanddiltiazem are

'
.

usedbutdihydropyridinesasnifedipinearecontraindicated(theycause
hypotension and reflex tachycardiabecatlsethey arepotentvasodilators).
WhiteKnightLove