CRIT5003 – MODULE 3.3.A
Andrew Couch
ANTIHYPERTENSIVE OVERVIEW AND CLASSIFICATION CONTROL OF BLOOD PRESSURE: PRESSURE : Components o !"scu#"r s$stem: Aort" – e#"st%c& stor"'e o ener'$ (potent%"# %n s$sto#e) *%net%c %n d%"sto#e+ Arter%es – #ow res%st"nce) some stor"'e o ener'$ Arter%o#es – " m",or contr%-utor to TR) contro# /ow o -#ood to p"rt%cu#"r or'"ns "t "n$ '%en t%me C"p%##"r%es – th%n w"##ed& e1ch"n'e o w"ter "nd su-st"nces& s#ow r"te o /ow !e%ns – h%'h c"p"c%t"nce& #ow res%st"nce
Role of Arterioles: 2 2 2
moo mooth th musc# musc#e e r%c r%ch h – ton%c ton%c cont contr"c r"ct% t%on on Res%st" es%st"nce nce %s pro propor port%o t%on"# n"# to to the r"d%u r"d%us s 4 ( thus thus " sm"## sm"## ch"n' ch"n'e e %n r"d%us r"d%us 6 s%'n%7c"nt ch"n'e to res%st"nce – 8"'en2o%seu##e9s L"w+ moo mooth th mus musc# c#e e tone tone:: cont contro ro## ##ed ed -$ -$ -$: -$: D%rect %nner"t%on – nere end%n's th"t w%## "ct%"te "#ph" (contr"ct%on+ o "nd ;< receptors (d%#"t"t%on+ o C%rcu#"t%n' hormones ("n'%otens%n II) "dren"#%ne) "sopress%n+ Autore'u#"t%on o /ow (met"-o#%c = m$o'en%c "ct%%t$+ o
ressure (drop> (drop> ch"n'e+ 6 /ow 1 res%st"nce: Remember: (ohm’s law)
Under ideal laminar ow !ondi"ions# ow !ondi"ions# in whi!h $as!%lar resis"an!e is inde&enden" o' ow and &ress%re# "he rela"ionshi& be"ween &ress%re# ow and resis"an!e !an be be de&i!"ed as shown in the gure to the right Be!a%se ow and resis"an!e are re!i&ro!all rela"ed# an in!rease in resis"an!e de!reases 'low a" an *i$en +P ,lso# a" an *i$en ow alon* a blood $essel or a!ross a hear" $al$e# an in!rease in resis"an!e in!reases "he +P Chan*es in resis"an!e are "he &rimar means b whi!h blood ow is re*%la"ed wi"hin or*ans be!a%se !on"rol me!hanisms in "he bod *enerall main"ain ar"erial and $eno%s blood &ress%res wi"hin a narrow ran*e -owe$er# !han*es in &er'%sion &ress%re# when "he o!!%r# o!!%r# will a.e!" ow ow
CRIT5003 – MODULE 3.3.A
Andrew Couch
The abo$e rela"ionshi& also indi!a"es "ha" "here is a linear and &ro&or"iona"e rela"ionshi& be"ween ow and &er'%sion &ress%re This linear rela"ionshi&# howe$er# is no" 'ollowed when &a"holo*i!al !ondi"ions lead "o "%rb%len" ow# be!a%se "%rb%len!e de!reases "he ow a" an *i$en &er'%sion &ress%re F%r"hermore# "he &%lsa"ile na"%re o' ow in lar*e ar"eries also al"ers "his rela"ionshi& so "ha" *rea"er &ress%res are re/%ired 'or a *i$en ow 0n o"her words# &%lsa"ili"# li1e "%rb%len!e# in!reases resis"an!e "o ow
As dep%cted "-oe) the "scu#"r tree %s d%%ded %nto se'ments) "nd /ow %s e?u"# %n e"ch se'ment. The res%st"nce %n e"ch se'ment determ%nes the pressure drop. Thus % we %ncre"se "rter%o#"r res%st"nce) we shou#d note "n %ncre"se %n "rter%"# pressure) "nd " decre"se %n c"p%##"r$ pressure. Thus res%st"nce %n the "rter%o#es %s er$ %mport"nt. It determ%nes: 2 2 2
Arter%"# -#ood pressure D%@erent%"# /ow to or'"ns C"p%##"r$ pressure %n e"ch or'"n (e' *%dne$s – BR+ There'ore in!reasin* "he !a&illar &ress%re in "he 1idnes in!reases o 2FR
CONTROL OF BLOOD PRESSURE CENTR,L CONTROL: ensor: ;"roreceptor (c"rot%d -od$ "nd "ort%c -od$ w"## stretch+ E@ector: !"somotor Centre (!MC+ – &or"ion o' med%lla oblon*a"a "ha" re*%la"es BP 2
2
$mp"thet%c o $stem%c res%st"nce 8R> contr"ct%#%t$ o !enous return o o Ren%n secret%on (%" ; receptors on ce##s %n *%dne$+ "r"s$mp"thet%c
CRIT5003 – MODULE 3.3.A
Andrew Couch
CRIT5003 – MODULE 3.3.A
Andrew Couch
RE!S!ON: Arterial Barore"e#tors: lo!a"ion and s"im%l%s3res&onse The sin*le mos" im&or"an" ree4 "ha" main"ains ar"erial blood &ress%re in "he shor" "erm
Stret"h re"e#tors Loc"t%on: Caro"id Sin%s (" swe##%n' "t the or%'%n o the %ntern"# c"rot%d "rter$+ 2 cont"%ns " re#"t%e#$ h%'h de'ree o e#"st%c t%ssue "nd #ess smooth musc#e (c"rot%d s%nus w%## stretch more th"n other esse#s+ 2 %nner"ted -$ " -r"nch o the '#ossoph"r$n'e"# nere (Ith+ ,or"i! ,r!h – "ort%c -"roreceptors 2 %nner"ted -$ "'"# nere (th+ ;"roreceptors "re st%mu#"ted -$ -oth the r"te o ch"n'e o pressure (%n pu#s"t%#e pressure the pressue %ncre"ses r"p%d#$ dur%n' the s$sto#%c ph"se+) "nd the me"n "rter%"# pressure. Re'er "o &i! below:
The -"roreceptors wor* -$: A decre"sed "rter%"# pressure resu#ts %n DECREAED -"roreceptor 7r%n' r"te wh%ch resu#ts %n: + Incre"sed s$mp"thet%c "somotor "ct%%t$ <+ Incre"sed s$mp"thet%c c"rd%"c "ct%%t$ 3+ Decre"sed "'"# c"rd%"c "ct%%t$ NB: The barore!e&"or ree4 !han*es in ar"erial &ress%re are PREDO50N,TEL6 se!ondar "o total #eri#heral resistan"e "s opposed to c"rd%"c output ch"n'es.
CRIT5003 – MODULE 3.3.A
Andrew Couch
REN,L CONTROL:
Renin Ren%n re#e"se %s st%mu#"ted -$ < mech"n%sms: . $mp"thet%c -et"2 "drener'%c receptor st%mu#"t%on %n "pp"r"tus <. Decre"sed ren"# "rter%o#e pressure
Angiotensin II For*s -$ three mech"n%sms: . !"scu#"r smooth musc#e "soconstr%ct%on <. Incre"sed "#dosterone secret%ons 3. Incre"ses s$mp"thet%c nere end%n' noradrenaline ,ldos"erone
Na7 and -89 re"en"ion
Su$$ar%:
Red in!reased P%r&le de!reased
&'PERTENS!ON: Essent%"# (pr%m"r$+ 8$pertens%on (G02H5+ econd"r$ 8$pertens%on (52<0+
CRIT5003 – MODULE 3.3.A
2 2 2 2 2 2
Andrew Couch
Ren"# "rter$ stenos%s Chron%c *%dne$ d%se"se r%m"r$ h$per"#dosteron%sm (Conn9s – adrenal adenoma; -%#"ter"# %d%op"th%c "dren"# h$perp#"s%"& con'en%t"# "dren"# h$perp#"s%"+ OA Th$ro%d d%se"se h"eochromoc$tom"
Pathogenesis of HTN Resett%n' o -"roreceptor "nd ren%n response to m"%nt"%n " h%'her -#ood pressure Fhen we %n%t%"##$ commence p"t%ents on "nt%2h$pertens%e ther"p$) there %s 'ener"##$ " counter"ct%on -$ compens"tor$ receptors -$ -"roreceptors "nd the ren%n s$stem: Com&ensa"or Rea!"ion: 3
"J> 8<0 retent%on Fe see th%s w%th s$mp"tho#$t%cs (OT ;2;#oc*ers thou'h+ o A#so seen w%th "sod%#"tors e' CC;s ("m#od%p%ne+ o er%pher"# oedem" 3 T"ch$c"rd%" oted w%th "#ph"2 -#oc*ers "nd d%rect"sod%#"tors o E' pr"Kos%n "nd "m#od%p%ne
ACE Inh%-%tors) A
VASCULAR SMOOTH MUSCLE Remem-er "scu#"r smooth musc#e %s under ton%c contr"ct%on. Th%s contr"ct%on occurs %" "ct%n "nd m$os%n coup#%n' "s %n s*e#et"# musc#e ( althogh it is not o!ganise" into #an"s$ . Th%s contr"ct%on %s " resu#t o %ncre"sed %ntr"ce##u#"r C"
2
8umor"# (nor"dren"#%ne) "n'%otens%n II) "sopress%on etc+ Mech"n%c"# (m$o'en%c response+ o li1el L3"&e !a87 media"ed E#ectr%c"# (d%rect %nner"t%on+
!ACULAR MOOT8 MUCLE (!M+ IER!ATIO BACTOR (s"im%la"or ? inhibi"or):
CRIT5003 – MODULE 3.3.A
@S5 !on"ra!"ion "he 'ollowin* 3
3 3
3 3
Andrew Couch
*enerall wor1s b me!hanism:
S"im%la"ion o' L3"&e $ol"a*e *a"ed Ca87 !hannels res%l"s in in!reased 0C Ca87 ions This is '%r"her !on"rib%"ed "o b release o' Ca87 ions 'rom SR Ca77 "hen binds !almod%lin whi!h in"era!"s wi"h $%osin light "hain (inase )*LC+, Calmod%lin is a !al!i%m3bindin* messen*er &ro"ein e4&ressed in all o e%1aro"i! !ells -ith "onsu$#tion of an ATP $ole"ule. this #hos#hor%lates *%osin light "hain Th%s resu#ts %n "ct%n2m$os%n %nter"ct%on "nd su-se?uent contr"ct%on o !M.
M$os%n L%'ht Ch"%n hosph"t"se (MLC+ resu#ts %n dephosphor$#"t%on o MLC "nd hence re#"1"t%on
Fhen ot"ss%um ch"nne#s open) h$perpo#"r%K"t%on o the ce## occurs. Th%s resu#ts %n decre"sed C"
CRIT5003 – MODULE 3.3.A
Andrew Couch
IMPORTANT( REMEM;ER th"t %n smooth musc#e ce##s) "n ICREAE %n cAM 6 DECREAED "sod%#"t%on "nd %ce ers". (;< "< respect%e#$+ T8I I T8E OOITE to C"rd%"c contr"ct%#e "nd nod"# ce##s) where "n ICREAE %n 0n re'eren!e cAM resu#ts"o %n "he ICREAED abo$e dia*ram: contr"ct%on) %ncre"sed 8R respect%e#$ Al%ha&'( Remember al&ha38 re!e&"ors are !lassi!all lo!a"ed on $as!%lar &re3A %n!"ional "erminals where is 0N-0B0TS "he '%r"her release o' noradrenaline in a 'orm o' ne*a"i$e 'eedba!1 -owe$er# "here are a 'ew &os"3sna&"i! ,38 re!e&"ors# whi!h wor1 as 'ollows: !%" "n inhi#ito!) 2prote%n decre"sed cAM %n"se "here'ore in!reases !on"ra!"ion
%ncre"sed M$os%n L%'ht Ch"%n
Al%ha&*( orep%nephr%ne re#e"sed rom s$mp"thet%c nere term%n"#s "ct on ") wh%ch "re coup#ed to ? receptors (coup#ed to LC+& th%s resu#ts %n re#e"se o IC C"
A#so wor*s to decre"se the %nh%-%tor$ enK$me +)osin light ,hain %hos%hatase -MLCP$
.eta&'( C%rcu#"t%n' ep%nephr%ne rom "dren"# medu##" (or e1o'enous+ "cts on ;2< receptors %n the -#ood esse#s ("nd -ronch%"# smooth musc#e+ #e"d%n' to reduced %nw"rd C" "ct%n %nter"ct%on "sod%#"t"t%on.
Remember "ha" bo"h B3 and B38 re!e&"ors are !o%&led "o 2 s"im%la"or PCR and "h%s bo"h a!"i$a"e adenll !!lase "o in!rease &rod%!"ion o' !,5P 'rom ,TP -O
CRIT5003 – MODULE 3.3.A
Andrew Couch
in!reased mosina!"in in"era!"ion; B8 howe$er res%l"s in de!reased 0C Ca87 and de!reased mosina!"in in"era!"ion FURT-ER RE@0S0ON:
*us"arini" / )si$ilar to al#ha /, 0 1 e2o"rine glan3s 3
21PCR (Th%s asso!ia"ed wi"h PLC# 0P# D,2 e"!)
*us"arini" 4 )si$ilar to al#ha 4, 0 inhi5itor% "ar3ia" tissue 6 6
2i PCR (Th%s inhibi"s adenll !!lase# and red%!es !,5P &rod%!"ion) Remember "ha" 5%s!arini! 8 re!e&"or a*onism is also asso!ia"ed wi"h a 21PCR# and res%l"s in in!reased e%4 o' Po"assi%m !%rren" > res%l"in* in h&er&olari=a"ion
*us"arini" re"e#tors: 71 0 7i 0 71 0 7i 0 71 )*/ 0 *4 0 *8 0 *9 0 *, Ni"otini" Re"e#tors: )Ligan36gate3 "hannels, U&on in"era!"ion wi"h an a*onis" (e* ,!h# ni!o"ine e"!)# !on'orma"ional !han*e o!!%rs# and "he !hannel o&ens# allowin* &osi"i$el !har*ed ions "o mo$e "hro%*h i" > i" is a non3sele!"i$e !a"ion !hannel The mo$emen" o' !a"ions !a%ses a de&olari=a"ion o' "he &lasma membrane (whi!h res%l"s in an e4!i"a"or &os"sna&"i! &o"en"ial in ne%rons )# b%" also b "he a!"i$a"ion o' $ol"a*e3*a"ed ion !hannels TO SU**AR!SE: @S5 CONTR,CT0ON: 0n!reased Ca87 so%r!e: E4"ra!ell%lar ($ia L3"&e Ca87 !hannel) 8 0n"ra!ell%lar s"ores 'rom Sar!o&lasmi! re"i!%l%m (0P media"ed) @S5 REL,,T0ON: 0nhibi"ion o' 5LCG b in!reased !,5P ($ia B8 re!e&"ors) 0n!reased 5LCP ('rom in!reased !25P 'rom in!reased Ni"ri! O4ide) De!reased 0n"ra!ell%lar Ca87 -&er1alaemia 0n!reased re3%&"a1e in"o SR s"ores ($ia B8 2s "im%la"or e.e!")
CRIT5003 – MODULE 3.3.A
0N @,SCUL,R S5OOT- 5USCLE:
!n"rease3 "A*P )7s, 3 3 3
Be"a 8 (adrenaline) ,8 > (adenosine) 0P (P208) 3 0P &ros"a!!lin re!e&"or
De"rease3 "A*P )7i, 3
,l&ha38 (noradrenaline and adrenaline)
A"ti;ate3 71 )thus in"rease3 !P8, 3
,l&ha3# ,n*io"ensin# @aso&ressin# endo"helin
Andrew Couch
CRIT5003 – MODULE 3.3.A
Andrew Couch
ote th"t the endothe#%um p#"$s "n %mport"nt ro#e %n "scu#"r smooth musc#e tone. Re#"1"t%on "ssoc%"ted w%th endothe#%um der%ed "ctors %s oten "ssoc%"ted w%th J ch"nne# re#"ted h$perpo#"r%K"t%on. 2 2
%tr%c O1%de rost"c$c#%n (I<+
Ch!oni, H)%e!tension is asso,iate" /ith a#no!+al 01 ,hannels
CRIT5003 – MODULE 3.3.A
Andrew Couch
ANTI&HYPERTENSIVE DRU2S CLAIBICATIO:
An'%otens%n re#"ted (ACEI) A
CCBs !an be !onsidered as dire!" $asodila"ors# al"ho%*h "he do also ha$e si*niH!an" e.e!"s on "he hear" In/uence o cho%ce or " p"rt%cu#"r "'ent %s dependent on other comor-%d%t%es:
LVF – ACE>A A A @era&amil in @T !an !a%se @FI)) ;2;#oc*ers DM 2 ACEI> A
S65P,T-OPLE20, 2 2 2 2
Centr"#> "somotor centre (e' "#ph"2< "'on%st+ $mp"thet%c '"n'#%" – e@ect%e -ut o-se#%te dur to s>e A#ph" -#oc*ers (pr"Kos%n+ ;et" -#oc*ers In%t%"# reduct%on %n c"rd%"c output (decre"sed 8R !+ o econd"r$ reduct%on %n "scu#"r res%st"nce (decre"sed ren%n> AII+ o
,N20OTENS0N ,NT,2ON0S5 Ace %nh%-%tors An'%otens%n receptor -#oc*ers
CRIT5003 – MODULE 3.3.A
Andrew Couch
@,SOD0L,TORS: 2 2 2 2
L2t$pe C"
D0URET0CS In%t%"##$ d%uret%cs #e"d to " decre"se %n ECB "nd -#ood o#ume. Th%s o-%ous#$ w%## resu#t %n "n %n%t%"# d%rect e@ect o decre"sed -#ood pressure:
& 3
De,!ease" 3enos !et!n4 ths ,a!"ia, ot%t 0n!reased ss"emi! $as!%lar resis"an!e o B%" "he de!reased !ardia! o%"&%" &re$ails and an red%!"ion in BP o!!%rs
O$er J3K wee1s: 2 2 2
C"rd%"c output norm"#%ses The m%#d decre"se %n -#ood o#ume rem"%ns 8oweer) s)ste+i, 3as,la! !esistan,e "e,!eases to #elo/ %!e& t!eat+ent le3els Th%s !on"in%ed e.e!" o' de!reased BP remains o Mech"n%sm not u##$ understood o Nde!reased ne%ronal a!"i$i"# &ossibl d%e "o de!reased sodi%m le$els
