Sympatholytics

(Adrenergic antagonists)
Lecture 8
Drugs counteracting the sympathetic effects.
 Classification of blockers
• Receptors of sympathetic system: alpha &
beta.
• Sympatholytics are divided into:
1- Alpha blockers.
2- Beta blockers.
 Alpha blockers
• Alpha blockers are further classified into:
A) Nonselective alpha blockers (acting on both alpha 1 and alpha 2):
Phentolamine
Phenoxy-benzamine.
B) Alpha 1 blockers (alpha 1 kanet mwgoda fl smooth muscles)
Prazosin
Terazosin
Doxazosin.
C) Alpha 2 blockers ( alpha 2 was found presynaptically and centrally) (note: alpha
2 blockers are of a therapeutic value awi ya3ny)
Yohimbine.
Tolazoline.
 α- Blockers.
• Effects of α1 blockers on :

1- CVS (heart , blood vessels and blood pressure)

a) Heart:
fe beta1 receptors asln! Yb2a blocking alpha l mfrood myb2ash lee effect on the heart.
B) Blood vessels.
Feha alpha1 (bt3ml Vasoconstriction) w beta2 (bt3ml vasodilation)
Blocking alpha1 will lead to unopposed beta2 effect (ya3ny l balance l kan bein alpha1 w beta2 da3
w beta2 effect ba2a predominating) leading to vasodilation and decrease in blood pressure awii.

• W 3shan howa decrease gamed ….Baroreceptors sensed this decrease in blood pressure fa t7awl
tincrease blood pressure ,how?
-activate the CAC (cardiac activaing center: yzwd sympathetic lel heart) and VMC (vasomotor center:
yzwd sympathetic tone lel blood vessels)
*Activation of CAC lead to increase in heart rate.
* Activation of VMC l mafrood tincrease blood pressure bs ana already using alpha1 blockers therefore
no vasoconstriction.
• Yb2a although blocking alpha1 had no effect on the heart directly, bs l reflex tachycardia l
3mlto l baroreceptors 3shan l decrease l gamed l l alpha1 blocker 3amlo fl blood vessels lead
to increase in heart rate and cardiac output.
• Conclusion: alpha1 on CVS: Vasodialtion gamed….reflex tachycarida mn l baroreceptors
zawdly l heart rate and cardiac output.
• Effect of α1 & α2 blocker on CVS:
alpha2 is present presyaptically and centrally.
A) Presynaptic alpha2 is Gi ya3ny inhibitory…y3ny decreases release of noreadrenaline.
Yb2a lw I blocked this receptor l by3mly inhibition release of noreadrenaline 7yzeed .
B) Centrally…same as presynaptic ones, they lead to peripheral decrease in noreadrenaline…
y3ny lw blocked brdo 7y3mlo increase in release of noreadrenaline.
• Therefore nonselective alpha blocker, lama it blocked alpha2 , it increased release of
noreadrenaline ( sympathetic neurotransmitter) therefore:
a) Heart: noreadrenaline zad, msh odamo fl heart ghier beta1 w heya msh blocked ahl f yact
3leiha w y increase heart rate.
B) Blood vessels: noradrenaline zad, howa odamo two receptors fl blood vessels, alpha1 and
beta2…drug is blocking the alpha1….msh odamo gheir beta2 Vasodilation (unopposed beta2
effect) decrease in blood pressure Baroreceptor activation of CAC and VMC….VMC zy
2eltha 3shan ana blocking alpha1, CAC yfurther increase sympathetic tone lel heart (reflex
tachycardia).
• Yb2a l far2 fl nonselective, en l heart rate zad not only due to reflex tachycarida mn l
baroreceptors, but also from the increase in noradrenaline release due to blocking alpha2.
(ya3ny 3ndy two causes for tachycarida fl nonselective,w only one fl selective alpha1)
 Therapeutic uses and side effects of alpha
blockers.
• Uses:
1) Hypertension (due to the unopposed beta2 effect l 3mlt vasodilation gamed)
due to blocking l alpha1.
Note: We do not use alpha1 blockers m3 nfsohom keda for hypertension….due to the reflexes
l bt3mlhaly l baroreceptors (reflex tachycardia).
2) PVD (peripheral vascualr disease) (Raynaud’s phenomenon) : da y3ny blood vessels fl
periphery (hand and legs) 7asal feha vasospasm (which is an alpha1 effect…y3ny blocking it ,
ylghy this vasospasm) (da l byegy l b3d l nas in winter w leads to cold blue hand and toes )
3) Pheochromocytoma. (tumor fl adrenal medualla l btl3 l noreadrenaline w l adrenaline)
moshklto: en l release of noreadrenaline mn l tumor msh constant, momkn yzeed msln b
pressure (y3ny doctor yegy ykshf 3ala batn l patient, yro7 dayes 3l tumor, yro7
noreadrenaline tale3), noreadrenaline ytl3 and can lead to hypertension, bs using alpha1
blocker: leads to unopposed beta2 effetc: vasodilation…decrease in blood pressure.
N3mll a?
1) try to remove the tumor bs before operation b afew weeks edy alpha blockers 3shan w l
doctor by7awel yshelo momkn 7aga tetl3 t3ml mashakel fl patient lw alpha msh blocked)
2) mnf3sh edy alpha blockers w 5alas.
• Side effect:
1) Postural hypotension (=orthostatic hypotension): One of the most common side effects….l
wa7ed lama yegy y2om mara wa7ed, blood ydl2 l mfrood f by7sl reflex vasoconstriction
3shan mydl2sh ….this reflex vasoconstriction needs alpha1 3shan tshtghl 3leih…fa blocking
them will lead to orthostatic hypotension.
2) Tachycardia . (as explained above, one reason mn l selective and two from the non
selective).
• Eye:
alpha1 kanet mwgooda 3l radial muscle, upon sympathetic activation contraction of this
muscle Mydriasis…..yb2a blocking it y3ml miosis.
• Nasal congestion:
side effect lel alpha blockers (ela ganed the orthostatic hypotension and tacycardia).
Alpha1 by3ml VC fa y2lely the mucus secretions fl nasal cavity.
Blocking the alpha1….no VC….blood vessels by7sl feha unopposed beta2 effect…
vasodialtion….>increase in secretions and nasal congestion
• Urinary tract:
Another use lel alpha blockers: Decrease urinary retention due to benign prostatic
hypertrophy (BPH)(Note: BPH leads to urinary retention and pain during urination)…why?
Sympatheric kan by3ml contraction of bladder sphincter and contraction of smooth muscles
of the prostate (alpha1 effect) ….therefore blocking alpha1 leads to relaxation of the bladder
sphincter and prostate (unopposed beta2 effect) causing a decrease in urinary retention and
decrease in pain associated with urination in BPH.
• Tamsulosin.
Is an alpha1A blocker….da subtype mn l alpha receptors la2o predominant fl prostate.
Fa they used tamsulosin for BPH.
• Side effet kaman : Retrograde ejaculation.
In the picture: semen lama ytl3 mn the seminal
vesicles, sphincter bta3tl urinary bladder bt2fl
3shan semen mykonsh odamo gheir going
through the urethra to outside.
Lw wa7ed 3ndo BPH w edeito alpha1 blocker, w 7asal
relaxation of the sphincter, semen momkn yrg3 in the
other direction upward.
W y3ml: Retrograde ejaculation.
 Beta blockers
• 1) Heart
howa beta1….blocking it, ylghy kol 7aga…
decrease in the heart rate (negative chronotropic)
decrease in the force of contraction (negative inotropic)
decrease in the AV conduction (negative dromotropic)
y3ny decrease in cardiac output, heart hedy 5ales w its work 2al w b2a msh m7tag oxygen
kteer.
Note : effects of beta blockers on the heart tban only during exercise. Y3ny when the
sympathetic system is activated, bs lw wa7ed relaxed w para howa l activated w
predominant , effects do not appear.
• 2) Blood vessels….2olna fehom alpha1 w beta2, l marady 2flna l beta2….fa l mafrood
unopposed alpha1 effet, y3ny VC and increase in peripheral resistance.
--Bs la2o en l kalam da by7sl initially only (initial increase in peripheral resistance)
Chronic use leads to decreasing the peripheral resistance! W 7ato kam hypothesis trying to
explain this:
• 1) Presynaptic beta2 …(beta2 is Gs ya3ny activating), when activated, btzwd l release of
NA….when blocked, t2lel l release of NA…vasodilation …decrease in PR.
2) Renin release.
Kidney feha Beta1 l ms2ol 3n release of renin which leads to VC….blocking beta1…mfeesh
renin….VD instead and decrease in PR.
• 3) Blood pressure.
Decreases madam chronic use by2lel PR .
 Uses and side effects of beta blockers
• Uses:
1) Hypertension.
2) Angina …imbalance bein oxygen demand of the heart and blood supply.
Beta blockers bt2lel kol 7aga fl heart, fa bt2lel l cardiac demand…therefore used in angina.
3) Pheochromocytoma.
M3 l alpha blocker…bs important note: we give beta blocker after the alpha blocker and not
vice versa?
-alpha blocker: unopposed beta2 effect VD decrease BP.
After that y7sl refex tachycardia,,,lw edeit beta blocker mt7slsh .
Why not beta before alpha?
Lw beta l awl…unopposed alpha1 effect….increase gamed fl blood pressure wana asln ba7awl
a3alg a hypertensive patient!
4) Arrrhythmias
5) After miocardial infarction.
6) Chronic heart failure (not acute)?
• Heart failure= heart fails to pump blood lel oragans kwys w msh 3aref ycontract.
Tb beta blockers decrease force of contraction of the heart, y3ny by logic , it would worsen
the case
bs la2o homa by trials en chronic use of beta blockers + using small doses w gradually
increasing the dose can decrease mortality rates fl 3ndohom heart problems. ( lw la2et tafser
akn3 shwya I’ll mention fl thread isA or lw 7d knows sth plz mention it :) )
l mohem; Chronic use + small doses, w zawdeha gradually.
• 7) Thyrotoxicosis (hyperthyrodism)
leads to increase fl tissue senstivity to sympathetic tone….beta blockers would block this
increased senstivity.
Side effects:
1) Bradycardia.
2) Hypotension.
3) Increase in heart block due to decrease in the AV conduction.
4) Cold hands and feet in winter (Raynaud’s phenomenon) due to unopposed alpha1 effect.
Special beta blockers:
1) Carvediol and labetalol:
beta blocker + some alpha1 blocking effect …blocking l alpha y3mly unopposed beta 2
effect….VD….reflex tachycardia, bs beta blocker ymn3 this refle TC
2) Nebivolol: beta blocker + it increases NO production in endothelium…VD
• Respiratory system.
Beta2…bt3ml bronhodilation…
blocking it Bronchoconstriction (contraindicated in asthma and COPD)
Tb lw 3ayez ady an asthmatic patient a beta blocker 3shan howa 3ndo hypertension ?
Give him a beta blocker with intrinsic symphatomimetic activity (see later)
tb can I use selective beta 1 blocker?
- la2 3shan seelctivty msh btb2a gamda awi keda w b act brod 3l beta 2 !
• Eye:
beta receptors are involved in aqueous humor formation (which involves cAMP, beta
receptors are Gs , y3ny byzwdo cAMP l m7tago 3shan a3ml aqueous humor..blocking them,
blocks formation of aqueous humor , decreasing intraocular pressure, use in treatment of
glaucoma.
Note: No effect 3l pupil size (mafesh miosis wala mydriasis) wala effect 3l accomodation.
Unlike Parasympathomimetics which were also used in glaucoma bs they lead to loss of
accomodation and miosis
y3ny beta blockers a7la (no effect 3l pupil size wla accomodation)
• Metabolic effects:
Sympathetic kan byzwd blood glucose level (BGL) 3n tari2 beta2 fl liver by glyocgenolysis and
glucose release from liver.
Blocking beta…blocks these effects fl liver + it decreases release of glucagon from pancreas
net effect: decrease in BGL (3ks l effect of sympathetic)
Note: Diabetics should take care if they are taking beta blockers, why?
1) Diabetics suffer from hypoglycemia if insulin is not well controlled which can lead to a
hypoglycemic shock….the body tries first to respond to this hypogylcemia by activating the
sympatheic system w release of catcholamines (CA) 3shan t3ml glyocgenolysis and increase
BGL…blocking beta, blocks these effects!
2) l bygelo hypoglycemia, byysuffer from some signs y3rf mn 5lalha eno 3ndo hypoglycemia
fa yro7 yshrb 7aga sugary 3shan yl72 nafso…..these signs zy sweating, tremors, increase in
heart rate (kolha 7aga sympathetic), lw beta receptors are blocked, l ragel msh 7yshof l signs
di! W yo2a3 mara wa7da.

W chronic use of beta blockers leads do increase in VLDL (bad cholesterol) and decrease in
HDL (good cholesterol),3shan keda , l bya5od beta blocker y3mly lipid profile monitoring
e7tyaty.
• CNS effects.

Some beta blockers are able to pass BBB and cause CNS effects (mainly sedative effects).
They are used as anxiolytics ( stage fright for example), how??
1) cental effect
2)7ata lw l drug can’t pass BBB. lw bygelo stage fright brdo bsweat, w his heart rate by3la, w
gesmo ytr3sh…lw edeit beta blocker , 7lghy all these sympathetic effects fa l ragel my7sh eno
5ayef. (SYMPTOMATIC RELIEF, relieved the symptoms of anxiety)
• Side effects: Fatigue and sleep disturbance.
• Intrinsis sympathomimetic activity (partial agonists)
Pindolol
Acebutolol
Carteolol
Penbutolol.
Homa beta blockers ah bs msh 100%, ya3ny 80% blocked w 20% la2
Effects are less than beta blockers, less effect on heart rate for patients with excessive bradycardia,
and asthmatic patients ( 3shan my7slsh bronchorconstriction gamed awi, yfdl fe shwyt beta2
activity tl72 l ragel,)
• Local anesthetic (LA) activity.
Pindolo
Acebutalol
Metoprolol.
LA: they block Na channels to act…l beta blockers dol block Na channels brdo so they are useful lw
patient also suffers from arrhythmia ( antiarrhythmic drugs act on Na channels)
If theses drugs are taken systemically: msh 73mlo major effect mn l blocking of Na channels.
Bs if taken topically (zy eye drops msln for treatment of glaucoma…y3mlo LA effect 3l cornea which
is not a nice effect.
Bottomline: those drugs are best used lw l ragel 3ndo arrhythmia as well
• Beta blockers should not be stopped suddenly?
- blocking beta receptors for a long time, y5ly l
body y3ml upregulation of receptors 3shan y3wd
l na2s..fa lw ana batlat beta blockers fg2a…wana
3ndy overexpression of receptors…rebound
tachycardia and increase gamed fl blood
pressure. (Exaggerated response)
• Di a5er lecture fl autonomic nervous system.