Chapter 9 adrenoceptor blocking drugs (Adrenoceptor antagonists) α-R antagonists β-R antagonists α 、 β-R antagonists

Section 1 α-R antagonists α 1, α 2 -R antagonists α 1 -R antagonists α 2 -R antagonists

Basic actions of α-R antagonists 1.CVS effects (1)α 1 -R antagonistic effects: Endogenous CA blockage: BP↓ (Postural hypotension) Exogenous CA blockage: “adrenaline reversal” (2) α 2 -R antagonistic effects: presynaptic  2 antagonism –NE release ↑ CNS  2 antagonism - sympathetic activity ↑

Basic actions of α-R antagonists 2.other effects (1) Prostate and bladder sphincter α 1 -R antagonism: dilation (2) insular α 2 -R antagonism: insulin ↑

Classification Ⅰ. α 1, α 2 -R antagonists  1.short-term acting: phentolamine ( 酚妥拉明 ), tolazoline ( 妥拉唑啉 )  2. long-term acting: phenoxybenzamine( 酚苄明 ) Ⅱ. α 1 -R antagonists: prazosin ( 哌唑嗪 ) Ⅲ. α 2 -R antagonists: yohimbine( 育亨宾 )

α 1, α 2 -R antagonists phentolamine ( 酚妥拉明, regitine, 立其丁 ) competitive α-R antagonists pharmacological actions 1.vessels : dilation; BP ↓  Mechanism: (1) direct action (2)  1 -R blockade: “adrenaline reversal”

pharmacological actions 2.heart: excitation, CO ↑ HR ↑ Mechanism: (1) BP ↓  excite heart (2)  2-R blockade 3.other effects: cholinergic action histamine-like action

clinical uses 1. peripheral vasospasmatic disorders:  eg. Raynaud’s syndrome, 雷诺氏综合征 2. local vasoconstrictor excess (eg, NA) 3. shock : a. dilate vessel  peripheral resistance↓ ( 肺血管 ) b. excite heart  Co↑ c. pulse pressure↑  improve viscera hemoperfusion, relief microcirculation disturbance Phentolamine+ NE

4. CHF and AMI Pathophysiology: Cardia insufficiency  arteriovenous reflex contraction Phentolamine: dilate vessel  cardiac load↓  Co↑ 5. diagnosis and treatment of pheochromocytoma 6. others: male sexual dysfuction  甲磺酸酚妥拉明分散片（伟哥）

adverse reactions 1.cardiovascular reaction:  Postural hypotension, tachycardia, angina, arrhythmia 2.gastrointestinal reaction:  stomachache, diarrhea, vomiting, ulceration

Tolazoline( 妥拉唑啉 )  Characteristics (compared with phentolamine ) weaker in  antagonism, stronger in cholinergic and histamine-like effects.  Used to treat peripheral vasospasmatic disorders and pheochromocytoma

phenoxybenzamine( 酚苄明 )  Noncompetitive antagonism  Pharmacokinetics : Slow onset(1h), long duration(3-4d)

pharmacological actions 1.α 1 -R antagonistic effects : slow, strong and long. (Postural hypotension) 2. HA-R antagonistic effects

clinical uses 1. peripheral vasospasmatic disorders 2. pheochromocytoma 3. Shock 4. Urinary obstruction caused by benign prostatic hyperplasia

adverse reactions Postural hypotension, tachycardia (palpitation), nasal congestion CNS inhibition

α 1 -R antagonists Prazosin( 哌唑嗪 ) Terazosin （特拉唑嗪） Doxazosin （多沙唑嗪） Actions: decrease BP, but weak influence on HR Clinical uses: 1. HBP 2. CHF 3. Urinary obstruction caused by benign prostatic hyperplasia

Tamsulosin ( 坦洛新 ) Block α 1A -R ( prostate ) > α 1B -R (blood vessel) High effect on prostatic hyperplasia (compare with phenoxybenzamine and prazosin) Phenoxybenzamine: ↓BP, palpitation Prazosin: ↓BP Tamsulosin: have no effect on BP and HR

α 2 -R antagonists Yohimbine ( 育亨宾 ) uses 1. tool agent for research 2. impotence ( 阳痿 ) ：痿必治

Section 2 β-R antagonists β 1,β 2 -R antagonist β 1 -R antagonist α 、 β -R antagonist

classification  1.β 1,β 2 -R antagonist 1A ： Propranolol( 普萘洛尔 ), Timolol （噻吗 ~ ） 1B ： pindolol （吲哚 ~ ）  2.β 1 -R antagonist 2A ： atenolol （阿替 ~ ）, metoprolol （美托 ~ ） 2B ： Acebutolol( 醋丁 ~)  3. α,, β -R antagonist Labetalol （拉贝 ~ ）, carvedilol( 卡维地洛 )

Intrisic sympathomimetic activity (ISA) partial agonistic activity (PAA)

Characteristics of Pharmacokinetics: affected by liposolubility 1.absorption: first pass elimination (propranolol is obvious, atenolol is not ) 2.distribution:BBB (propranolol, atenolol) 3.elimination: hepatic metabolism and Kidney excretion (propranolol, atenolol) 4. individual variation

basic actions of β-R antagonist 1. β-R blocking action: 1) cardiovascular effects:  heart : depression ( β1 )  vessels: contraction a. blockβ 2 -R b. Co ↓  vasoconstriction  BP↓

basic actions of β-R antagonist 2) bronchial smooth muscle : β2 3) metabolism: β2 a. Delay recovery of blood glucose after insuline (insuline  hypoglycemia  increase CA release  activate α, β  glycogenolysis  blood glucose↑) b. Inhibit lipoclasis

4) Renin release: β 1 (propranolol) 5) ↓intraocular pressure (timolol)

basic actions of β-R antagonist  2.intrinsic sympathominetic activity(ISA) partial agonistic activity (PAA) Characteristic of drugs with ISA

basic actions of β-R antagonist 3.membrane stabilizing action: in large dose (local anesthetic action )

clinical uses  1.arrhythmias ( tachyarrhythmia)  2. hypertension  3. angina pectoris, myocardial infarction  4.CHF  5.others: hyperthyroidism, glaucoma

adverse actions  1. bronchial asthma  2. cardiovascular reaction  3. induce Raynaud’s syndrome  4. rebound phenomenon:  5. others: hypoglycemia, depression

Some β-R antagonists 1A Propranolol( 普萘洛尔 ), Timolol （噻吗洛尔） 1B Pindolol （吲哚洛尔） 2A Atenolol （阿替洛尔） Metoprolol （美托洛尔） 2B Acebutolol( 醋丁洛尔 ) 3 Labetalol （拉贝洛尔）

1A ： nonselective, no ISA Propranolol( 普萘洛尔 ), 1.pharmacokinetics: high liposolubility 2.uses: HBP, arrhythmia, CHF, myocardial ischemia, hyperthyroidism Timolol （噻吗洛尔） 1.actions: strongest 2.uses: glaucoma (block β-R of ciliary body  aqueous humor ↓)

1B:nonselective, ISA Pindolol （吲哚洛尔） Actions: stronger than propranolol Uses: HBP

2A: selective, no ISA Atenolol （阿替洛尔, 氨酰心安 ） : long t1/2 Metoprolol （美托洛尔, 美多心安 ）

3: α 、 β-R antagonists Labetalol （拉贝洛尔, 柳胺苄心定 ） 1.β-R blockage>α-R blockage 2. β-R blockage<propranlol 3.α-R blockage<phentolamine 4. ISA (β2-R) 5. used in HBP, angina pectoris

3: α 、 β-R antagonists carvedilol ( 卡维地洛 ) 1.β-R blockage>α-R blockage 2. used in HBP, CHF