Adrenergic antagonists I (alpha blockers) Dr. Asmaa Fady PhD., MSC., M.B, B.Ch اسم ورقم المقرر – Course Name and No. 8/20/2019

Learning objectives: At the end of this lecture the student should: Identify the location & action of adrenergic receptors Classify the adrenergic antagonists based on the mechanism of action Describe the mechanism of action of each class List the therapeutic uses of each class Identify & explain the adverse effects of each class اسم ورقم المقرر – Course Name and No. 8/20/2019

اسم ورقم المقرر – Course Name and No. 8/20/2019

Sympathetic versus parasympathetic nervous system اسم ورقم المقرر – Course Name and No. 8/20/2019

اسم ورقم المقرر – Course Name and No. 8/20/2019

Location & action of adrenergic receptors Presynaptic Alpha (α 2 mainly, α 1) & Beta (β) receptors The pre-synaptic receptors are found in CNS and on the surface of adrenergic nerves & mediate the negative feed back which control release of NA (auto-receptors) Stimulation of presynaptic α2 : Decreased release of NA Stimulation of presynaptic β: Increased release of NA اسم ورقم المقرر – Course Name and No. 8/20/2019

Location & action of adrenergic receptors Postsynaptic alpha (α 1, α 2) – Beta (β 1, β 2, β 3). α1 (Gq) α2 (Gi) Β (Gs) CVS: (Heart) Increased all cardiac properties β1 *Increased Contractility (Positive inotropic) *Increased rate (Positive chronotropic) *Increased conductivity (Positive dromotropic) *Increased excitability CVS (blood vessels) Vasoconstriction “VC” skin & mucus membranes blood vessels α1 VasodilatationVD of coronary & Skeletal BV β2 Smooth muscle fibers 1- Relaxation of wall of GIT α1 2- Contraction of All sphincter (GIT, urinary). α1 3- Male sex organs: contraction of corporal muscles (ejaculation) α1 Relaxation of ▪ Bronchi β2 ▪ Wall of GIT β2 ▪ Wall of urinary bladder β2 ▪ Wall of uterus β2 اسم ورقم المقرر – Course Name and No. 8/20/2019

Location & action of adrenergic receptors Postsynaptic alpha (α 1, α 2) – Beta (β 1, β 2, β 3). Liver, pancreas , kidneys & adipose tissues - Decreased Insulin secretion α 2 - Decreased Lipolysis α2 -Decreased Renin α2 ▪ Increased glycogenolysis β2 ▪ Increased insulin secretion β2 ▪ Increased lipolysis in fat cells β1* -β3 ▪ Increased renin production β1 Eye: Dilator pupillae active mydriasis α1 decreased aqueous humor formation α2 Increased aqueous humor formation β1* -β2 اسم ورقم المقرر – Course Name and No. 8/20/2019

SYMPATHETIC DEPRESSANTS [Sympatholytics] 1- Adrenergic receptor blockers A- Alpha adrenergic blockers e.g. Phentolamine. B- Beta adrenergic blockers (BB) e.g. propranolol. C- Combined Alpha & Beta adrenergic blockers e.g. labetalol. 2- Adrenergic neuron blockers or Antiadrenergic drugs A- Drugs inhibiting release of noradrenaline from sympathetic nerve endings e.g. Guanethidine. B- Drugs depleting noradrenalin from sympathetic nerve endings e e.g. Reserpine. 3- Centrally acting symp.depressant drugs (--VMC in brain stem -- sympathetic outflow NA release • Alpha 2 agonists: e.g. alpha-methyldopa, clonidine, guanfacine and guanabenz. • Imidazoline Receptor agonists (I1): – Rilmenidine – Moxonidine. 4- Ganglion blockers: Blocking transmission in sympathetic ganglia. SYMPATHETIC DEPRESSANTS [Sympatholytics] اسم ورقم المقرر – Course Name and No. 8/20/2019

Non selective α blocker (α1 & α2) Alpha blockers α blockers: block α receptors mostly in blood vessels so produce VD (except ergot). Alpha blockers Non selective α blocker (α1 & α2) A- Ergot alkaloids Ergotamine: Partial agonist on α-1 & 5-HT receptors B- Phentolamine. C-Phenoxybenzamine Selective α1 blocker Prazosin, Trimazosin Tamsulosin terazosin, doxazosin. Selective α2 blocker Yohimbine. MAP= COP * SVR اسم ورقم المقرر – Course Name and No. 8/20/2019

Pharmacological action of alpha blockers α1 site agonist Blocker Side effect BV VC *Veins: VR (Preload). *Arteries: TPR systolic & diastolic BP * reflex bradycardia VD * veins: VR (preload). * Arteries (congestion)& BP. *Reflex tachycardia *postural hypotension * nasal stuffiness Eye (dilator puipllae ms) Active mydriasis miosis Sphincters (UB, GIT) Contract sphincters Relax sphincter Male sex organ ejaculation Delayed or failed ejaculation α2 presynaptic Noradrenaline release tachycardia 8/20/2019 اسم ورقم المقرر – Course Name and No.

اسم ورقم المقرر – Course Name and No. 8/20/2019

A) Non-selective α blockers: 1- phentolamine & Phenoxybenzamine: Mechanism: Phentolamine: competitive antagonist of α1&2 receptors (its action last only for 4 hours ) Phenoxybenzamine: prodrug: the most potent alpha blocker irreversible non competitive antagonists of α1&2 receptors (delayed onset & its action lasts for 2-3 days) Actions: α1 blockade vasodilation ↓ peripheral resistance (may ↓ BP, BUT cause PROFOUND reflex tachycardia) Block presynaptic α2 in heart more NE release & bind to β1 ↑ C.O & tachycardia . 8/20/2019 اسم ورقم المقرر – Course Name and No.

A) Non-selective α blockers: 1- phentolamine & Phenoxybenzamine Additional actions: Phentolamine: additional histamine like action (vasodilation, bronchospasm & increased HCL secretion & motility) Phenoxybenzamine: Anti histaminic. Anti Ach (anti muscarinic (atropine like). Anti-shock effect: prevent irreversible stage of shock a- α blocking action VD (improve tissue perfusion). b- excess release of ADH (vasopressin) by hypothalamus VD [ADH causes VC of coronary, mesenteric, renal Bl.V. irreversible shock]. 8/20/2019 اسم ورقم المقرر – Course Name and No.

A) Non-selective α blockers: 1- phentolamine & Phenoxybenzamine Therapeutic uses: Phentolamine Diagnosis of pheochromocytoma Peripheral Vascular diseases. Phenoxybezamine Treatment of pheochromocytoma (It may be used prior to surgical removal of the tumor to prevent a hypertensive crisis) + Beta blocker Shock (hemorrhagic): pretreatment with plasma & blood first, then give phenoxybenzamine [fill up, then, open up]. Remember: Non-selective α blockers are NOT USED for routine management of primary hypertension اسم ورقم المقرر – Course Name and No. 8/20/2019

Adverse effects of Phenoxybenzamine & Phentolamine: α blocking ( VD produces nasal stuffiness, dizziness and postural hypotension). Reflex tachycardia Failure of ejaculation sedation & fatigue with Phenoxybenzamine اسم ورقم المقرر – Course Name and No. 8/20/2019

B) Selective α1 blockers: Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin Mechanism of action: Prazosin, Terazosin, Doxazosin, Alfuzosin Competitive selective antagonists of α1 vasodilation ↓ peripheral resistance ↓ BP. + Direct smooth muscles relaxation (phosphodiesters enzymes inhibitors cAMP free Ca++ VD) This VD action is less accompanied by reflex tachycardia Tachycardia Brady cardia اسم ورقم المقرر – Course Name and No. 8/20/2019

B) Selective α1 blockers: Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin less selective for α1B receptors found in the blood vessels and more selective for α1A receptors in the prostate and bladder Blockade of the α1A receptors ↓ tone in the smooth muscle of the bladder neck and prostate and improves urine flow with less pronounced hypotension اسم ورقم المقرر – Course Name and No. 8/20/2019

B) Selective α1 blockers: Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin Therapeutic uses: Hypertension (essential & secondary hypertension) (Prazosin, Terazosin, Doxazosin, Alfuzosin) The 1stdose may produce an exaggerated orthostatic hypotensive response that can result in syncope (fainting). This action called “first-dose” effect. may minimized by starting with small dose & taking drug at bedtime. Peripheral vascular disease Benign Prostatic hyperplasia (BPH): (All α1-selective blockers): Tamsulosin (preferred) due to its selectivity. Heart failure: VD on both arteries & veins, decreased both Peripheral Resistance & Venous return so decreasing both preload and after load اسم ورقم المقرر – Course Name and No. 8/20/2019

adverse effects of selective α1 blockers: This VD action is less accompanied by reflex tachycardia since: a- It is selective alpha 1-blocker (non selective blockers block alpha 2-receptors with 2ry increase in NA). b- balance between cAMP & cGMP productions. VD of cerebral BVs اسم ورقم المقرر – Course Name and No. 8/20/2019

اسم ورقم المقرر – Course Name and No. 8/20/2019

C) Selective competitive α2-blocker: Yohimbine NO CLINICAL USES Dilates skin and m.m. blood vessels more in sex organs by unexplained mechanism: used as sexual stimulant & for erectile dysfunction (aphrodisiac). Adverse effects: cardiovascular disease, psychiatric conditions, and renal dysfunction اسم ورقم المقرر – Course Name and No. 8/20/2019

Therapeutic uses of alpha-blockers 1- Essential hypertension (Selective α1 blockers). 2- Secondary Hypertension (non selective α blockers): due to pheochromocytoma. should be combined with BB. 3- Peripheral vascular diseases. 4- Benign prostatic hyperplasia (BPH): antagonize smooth muscle contraction in enlarged prostate. 5- Heart failure: prazosin.(decreases both pre & afterload) اسم ورقم المقرر – Course Name and No. 8/20/2019

اسم ورقم المقرر – Course Name and No. 8/20/2019