Pharmacology LE 2 - Sympathetic Depressants_Alpha Adrenoceptor Blockers PDF

PHARMACOLOGY | TRANS 2 LE Sympathetic Depressants / Alpha Adrenoceptor Blockers...

PHARMACOLOGY | TRANS 2 LE Sympathetic Depressants / Alpha Adrenoceptor Blockers 02 DR. ALFARETTA LUISA T. REYES, M.D., FPSECP | September 17, 2024 | Version 1 OUTLINE I. GENERAL CLASSIFICATION OF SYMPATHETIC I. General classification of IV. Peripherally-acting alpha DEPRESSANTS sympathetic depressants adrenergic receptor antagonist Table 1. Centrally acting sympathetic depressants. II. Common side effects that A. Classification Clonidine interfere with sympathetic B. General considerations Methyldopa neuron function C. Mechanism of Action A. Alpha adrenoceptor D. Conventional α-receptor Centrally acting Guanfacine blockers antagonists Lofexidine B. Beta adrenoceptor E. Selective α1 Guanabenz blockers adrenoceptor blockers III. Centrally acting α2 receptor F. α2 receptor antagonists Table 2. Peripherally acting α and β adrenoceptor blockers agonists V. References Peripherally acting α adrenoceptor blockers A. Location and action of α2 VI. Formative Quiz receptors VII. Appendix Phentolamine Conventional B. Clonidine Phenoxybenzamine C. Methyldopa Prazosin D. Guanfacine Selective α1 receptor Terazosin E. Guanabenz blockers F. Apraclonidine Doxazosin G. Brimonidine Tamsulosin Selective α1A receptor H. Rilmenidine & Alfuzosin blockers Moxonidine Silodosin I. Tizanidine Peripherally acting β adrenoceptor blockers Propranolol Must Lecturer Book Previous Youtube Nadolol ❗️ Know 💬 📖 📋 Trans 🔺 Video Nonselective β receptor blockers Timolol Pindolol SUMMARY OF ABBREVIATIONS Carteolol NT Neurotransmitter Penbutolol PVR Peripheral vascular resistance Metoprolol BP Blood pressure Esmolol HR Heart rate Nebivolol CO Cardiac output Cardioselective β1 Atenolol NE Norepinephrine receptor blockers Betaxolol Acebutolol EPS Extrapyramidal symptoms Alprenolol LEARNING OBJECTIVES Celiprolol ✔ Classify the various sympathetic depressants affecting Labetalol Mixed α and β sympathetic neuron function according to site and Carvedilol receptor blockers mechanism of action, receptors blocked. Bucindolol ✔ Explain the mechanism of occurrence of the common Reserpine side effects that interfere with sympathetic neuron Adrenergic neuron Methyldopa function. blocker Guanethidine ✔ Discuss the pharmacokinetics and pharmacodynamics, Bethanidine including the MOA of: Trimethaphan o Centrally-acting α2 receptor agonists Ganglionic blockers Mecamylamine o Alpha receptor antagonists ▪ Non-selective receptor blockers II. COMMON SIDE EFFECTS THAT INTERFERE WITH ▪ Selective α1 and α1A blockers SYMPATHETIC NEURON FUNCTION ✔ Apply process of rational drug use in choosing and Postural Hypotension - Guanethidine; ganglionic prescribing drugs for given conditions like hypertension, blockers. (loss of vasoconstrictive reflex mechanism → benign prostatic hyperplasia. peripheral pooling of blood) ✔ As future primary care physician, identify conditions Sedation or CNS depression - Centrally acting α2 when to refer your patient to proper healthcare receptor agonists; reserpine; phenoxybenzamine professionals/ facilities. INC GI motility and diarrhea - Parasympathetic predominance Sexual dysfunction (inhibition of ejaculation) - α1 receptor blockade; caused by ganglionic blockers, guanethidine, non-selective α blockers LE 2 TG 7 | C. Reyes, I. Reyes, K. Reyes, L. Reyes, TE | C. Sanchez, R. Ramos AVPAA | P. Pinlac PAGE 1 of 11 TRANS 2 P. Reyes VPAA | M. Pelayo PHARMACOLOGY | LE 2 Sympathetic Depressants/ Alpha Adrenoceptor Blockers | Dr. Alpharetta Luisa T. Reyes, M.D., FPSECP INC blood volume and sodium retention - DEC BP → α2 RECEPTOR AGONIST DRUGS activates renin-aldosterone-angiotensin II system Table 3. α2 receptor agonist drugs. (non-selective α blockers, guanethidine, ganglionic DRUG FEATURES blockers) Clonidine Nasal stuffiness – Reserpine, guanethidine, centrally Methyldopa acting α2 agonists (clonidine, methyldopa, guanfacine) Centrally acting Guanfacine Extrapyramidal symptoms (EPS) – DEC dopamine levels → catecholamine depletion (methyldopa, reserpine) Guanabenz Tizanidine Centrally-acting muscle relaxant A. SIDE EFFECTS LIMITED TO ALPHA Brimonidine For treatment of glaucoma to DEC ADRENOCEPTOR BLOCKERS Apraclonidine intraocular pressure Postural hypotension Sedation or CNS depression B. CLONIDINE INC GI motility and diarrhea CHEMISTRY AND PK Sexual dysfunction (inhibition of ejaculation) An imidazoline derivative INC blood volume and sodium retention Lipid soluble; bioavailability of 95% Nasal stuffiness Rapidly enters the CNS Reflex tachycardia Peak concentration in 1-3 hours after an oral dose; elimination t½ ranges from 8-12 hours B. SIDE EFFECTS LIMITED TO BETA ADRENOCEPTOR BLOCKERS MECHANISM OF ACTION OF CLONIDINE CVS: bradycardia, DEC Fc, DEC CO (β1 receptor Inhibits adenylyl cyclase activity → DEC cAMP blockade) Activation of central presynaptic α2A receptors → Respiratory: bronchoconstriction (β2 receptor blockade) suppression of central sympathetic outflow Metabolic: hypoglycemia (β2 receptor blockade), DEC → Modulation of NE release from the synapses → lipolysis (β1 and β3 receptor blockade) suppression of sympathetic outflow and DEC BP Activation of peripheral presynaptic α2 receptors in the III. CENTRALLY ACTING α2 RECEPTOR AGONISTS adrenergic nerve terminals → suppression of release of A. LOCATION OF α2 RECEPTORS AND THEIR NE, ATP, NPY from postganglionic sympathetic nerves ACTIONS May activate imidazoline (I1) receptors Adrenergic nerve ending → Being an imidazoline derivative → Presynaptically ▪ Regulate/modulate NT release from post ganglionic Regulation of Blood Pressure: Autonomic and sympathetic nerves Hormonal Control of CVS Function → Postsynaptically ▪ α2B on vascular smooth muscle → vasoconstriction CNS → Presynaptic ɑ2A receptors ▪ At brainstem, medulla → DEC sympathetic outflow from VMC → DEC BP ▪ At medullary centers involved in the control of salivation → dry mouth → Centrally-acting α2 agonists bind more tightly to α2 than to α1 adrenoreceptors COMMON ADVERSE EFFECTS PHARMACOLOGICAL ACTIONS AND EFFECTS OF Drowsiness or sedation CLONIDINE Dry mouth (xerostomia) Initially tested as a topical nasal decongestant, but was Decreased blood pressure found to cause: Bradycardia → Hypotension Withdrawal syndrome (rebound phenomenon) with abrupt → Sedation cessation of chronically administered drug → Bradycardia COMMON THERAPEUTIC USES Currently, indicated for patients with hypertension Administration: Treatment of hypertension → Oral (tablets) → Clonidine → Transdermal patch: produce less sedation than tablets → Methyldopa ▪ If administered as a single application, the BP is → Guanfacine reduced for 7 days. The drug plasma application → Guanabenz remains stable for approximately 8 hours. Ocular hypertension and open-angle glaucoma → Apraclonidine CARDIOVASCULAR SYSTEM → Brimonidine DEC HR, DEC SV, relaxation of the smooth muscles of capacitance vessels → DEC CO, DEC PVR → DEC arterial BP Space intentionally left blank → DEC HR, DEC SV leads → DEC CO → Smooth muscles of capacitance vessels are relaxed → DEC PVR PHARMACOLOGY Sympathetic Depressants/ Alpha Adrenoceptor Blocker PAGE 2 of 11 PHARMACOLOGY | LE 2 Sympathetic Depressants/ Alpha Adrenoceptor Blockers | Dr. Alpharetta Luisa T. Reyes, M.D., FPSECP → Clonidine lowers the HR and CO more than MAJOR ADVERSE EFFECTS methyldopa Dry mouth (xerostomia) and sedation (lethargy) DEC renal vascular resistance → Centrally mediated and dose-dependent → Like methyldopa, DEC BP in supine position → Occurs in 50% of patients taking clonidine → RARELY causes postural hypotension → Lesser incidents of adverse effects if given Given as I.V. Infusion transdermally → Activation of postsynaptic ɑ2B receptors in vascular Sexual dysfunction: Delayed or retrograde ejaculation smooth muscle → transient vasoconstriction → acute → Caused by the activation of peripheral presynaptic ɑ2 INC BP receptors → modulation of release of NE from ▪ Due to the direct stimulation of the alpha sympathetic nerve terminals adrenoceptors in the arterioles Marked bradycardia observed in some patients → Followed by more prolonged hypotensive response → Due to INC parasympathetic tone → DEC HR, DEC due to DEC central sympathetic outflow, partly from BP activation of presynaptic ɑ2A receptors in brainstem. → Activation of imidazoline receptors may contribute to LESS COMMON SIDE EFFECTS this effect CNS → Transient hypertensive response generally NOT SEEN → Sleep disturbance with vivid dreams or nightmares with ORAL drug administration → Restlessness RENAL SYSTEM May DEC renin release 💬 → Mental depression Should not be given in patients with suicidal tendencies or those with depression → Resulting from DEC adenylyl cyclase activity → DEC Contact dermatitis may occur with transdermal cAMP → DEC JG cells stimulation to release renin administration EYES THERAPEUTIC USES OF CLONIDINE 💬 Clonidine and its congeners Treatment of central hypertension (major indication) → DEC intraocular pressure by DEC aqueous humor Not a First-line drug production Off-label indications (not approved by respective FDAs) Brimonidine and apraclonidine (congeners) → Diabetes-associated diarrhea with diabetic autonomic → Used in the treatment of glaucoma neuropathy ▪ INC NaCl and fluid absorption ADVERSE EFFECTS AND TOXICITY OF CLONIDINE ▪ Inhibit secretion of bicarbonates Avoid giving drugs to those who are: → Prepare and treat addicted subjects for withdrawal from → At risk for mental depression since clonidine will (reduces symptoms): modulate NE release ▪ Narcotics, opioid 📋 → Concomitantly taking tricyclic antidepressants (TCAs) Acts like cocaine ▪ Blocks the anti-hypertensive effect of clonidine ▪ Alcohol ▪ Tobacco (smoking cessation) → Reduce incidence of menopausal hot flashes ▪ BlockS the neuronal uptake of NE at sympathetic ▪ Given as transdermal patch ❗ nerve terminals (α blocking action) Avoid abrupt discontinuation after protracted use especially with high dosage of >1 mg/day → Restless leg syndrome → Tourette’s syndrome and tics → Treatment of ADHD in children (clonidine and → Will result to withdrawal syndrome (rebound guanfacine) phenomenon) ▪ Headache, nervousness, apprehension, tremors, C. METHYLDOPA abdominal pain, sweating, tachycardia, hypertensive CHEMISTRY AND PK crisis (rebound hypertension) Analog of L-dopa TREATMENT FOR HYPERTENSIVE CRISIS Centrally-acting α2 agonist like clonidine Converted to α-methyldopamine and Reinstitute oral clonidine therapy α-methylnorepinephrine 📋 → At a slow or minimal effective dose Start with low-dose I.V. clonidine infusion Combination of ɑ and β adrenoceptor blockers → Active metabolites that act as false NT in peripheral neurons (peripheral action) → Stored in adrenergic nerve vesicles and replaces NE → Administration of adrenoceptor blocker with ɑ blocking → Released by nerve stimulation ❗ properties (labetalol, carvedilol) ❗ Administer ɑ receptor blocker initially Avoid administering β blockers first, nor giving it alone → Enters the brain via the aromatic amino acid transporter Bioavailability: 25%; T½: 2 hours Maximal effect ▪ May also cause rebound phenomenon and produce → 4 to 6 hours after an oral dose rebound hypertension → May be delayed for 6 to 8 hours after an oral or IV ▪ Activity of the ɑ receptors in the vascular smooth dose muscle will be left unopposed and up-regulation of → Effects may persist up to 24 hours even if parent drug the receptors which makes them more sensitive → has disappeared from the circulation vasoconstriction, INC PVR, INC BP ▪ Effect depends on the amount of stored metabolite in Administer Sodium Nitroprusside the adrenergic vesicles of nerve endings → For a more rapid response → Dose is readily titrated PHARMACOLOGY Sympathetic Depressants/ Alpha Adrenoceptor Blocker PAGE 3 of 11 PHARMACOLOGY | LE 2 Sympathetic Depressants/ Alpha Adrenoceptor Blockers | Dr. Alpharetta Luisa T. Reyes, M.D., FPSECP MECHANISM OF ACTION OF METHYLDOPA D. GUANFACINE Activates presynaptic α2 receptors in the brainstem → PHARMACOKINETICS DEC adenylyl cyclase → DEC cAMP Well-absorbed after an oral administration α-methylnorepinephrine (active metabolite) stimulates Large volume of distribution (Vd) presynaptic α2 adrenoceptors in the brainstem → Implication: has extensive tissue uptake → Modulates release of NE → DEC central sympathetic 50% of the drug excreted as urine in unchanged form outflow → DEC BP through the kidneys An autoreceptor, exerts a negative feedback PHARMACOLOGICAL ACTIONS AND EFFECTS OF 💬 T½: 12 to 24 hours Longer than clonidine METHYLDOPA MECHANISM OF ACTION CARDIOVASCULAR SYSTEM Like clonidine, it stimulates α2A receptors in the brainstem DEC PVR without much change in CO and HR →DEC central sympathetic outflow → DEC BP In patients with sinoatrial (SA) node dysfunction, severe DEC adenylyl cyclase activity → DEC cAMP production bradycardia may occur DEC CO in elderly patients PHARMACOLOGICAL ACTIONS AND EFFECTS → Due to DEC HR and DEC SV More selective in activating α2 receptors than clonidine → Secondary to relaxation of vascular smooth muscles of Efficacy for the treatment of hypertension is similar as veins and ↓ preload clonidine DEC Renal vascular resistance → Not used as a first-line drug Pattern of adverse effects is similar as clonidine, but with RENAL SYSTEM DEC secretion of renin from JG cells Salt and water retention with prolonged use 📖 milder and less frequently Withdrawal Syndrome (rebound phenomenon) [Brunton, 13th ed. C.2017] (pseudotolerance) → May result after abrupt cessation → DEC BP → activation of RAAS → NaCl + H2O retention → Milder and less frequent than clonidine withdrawal → edema → Reflective of its longer T½ → Resolved with concurrent use of diuretics THERAPEUTIC USE ADVERSE EFFECTS AND PRECAUTIONS OF Hypertension METHYLDOPA MAJOR ADVERSE EFFECTS Most common undesirable effect is sedation at onset of 📖 → Seldom used clinically nowadays Second-line drug for ADHD and as short-term treatment in children 6-17 Years old [Brunton, 2017] treatment → Most effective in children ≤ 12 y/o Dry Mouth → MOA: unknown → Involves the medullary center that controls salivation → Used in combination with other medications for ADHD Long term treatment: Persistent mental lassitude and E. GUANABENZ 💬 impaired mental concentration Like clonidine, it can cause mental depression and nightmares. Be very careful in giving this to patients CHEMISTRY AND PHARMACOKINETICS Closely related chemically and pharmacologically with with a history of depression. Guanfacine Decreases BP by a mechanism similar to those of clonidine OCCASIONAL ADVERSE EFFECTS and guanfacine Mental depression, nightmares, vertigo, EPS Extensively metabolized by the liver → EPS due to depleted dopamine and catecholamine → T½: 4-6 hrs levels Decreased libido MECHANISM OF ACTION Lactation in both men and women Stimulates α2A receptors in the brainstem → DEC central → Associated with increase in prolactin secretion which sympathetic flow → DEC BP is mediated by inhibition of dopaminergic mechanism in ADVERSE EFFECTS AND PRECAUTIONS the hypothalamus Dry mouth (xerostomia), sedation, drowsiness Positive Coombs test in 10-20% of patients due to → Discontinued due to causing lethargy autoantibodies against Rh antigen on erythrocytes (for Dose adjustment needed in patients with hepatic cirrhosis longer than 12 months use) → Rarely associated with hemolytic anemia Hepatotoxicity associated with drug fever Discontinuation of the drug leads to prompt reversal of these abnormalities THERAPEUTIC USE OF METHYLDOPA Preferred drug for treatment of hypertension during Space intentionally left blank pregnancy → Based on good efficacy and safety both in the mother 💬 and fetus In general, not a first-line drug in treatment of hypertension PHARMACOLOGY Sympathetic Depressants/ Alpha Adrenoceptor Blocker PAGE 4 of 11 PHARMACOLOGY | LE 2 Sympathetic Depressants/ Alpha Adrenoceptor Blockers | Dr. Alpharetta Luisa T. Reyes, M.D., FPSECP F. APRACLONIDINE IV. PERIPHERALLY-ACTING ALPHA ADRENERGIC CHEMISTRY AND PHARMACOKINETICS RECEPTOR ANTAGONISTS Also called Iopidine, a clonidine derivative A. CLASSIFICATION Relatively selective α2 receptor agonist that may activate Conventional α-receptor antagonists α1 to a lesser extent → Competitive/Equilibrium blockers Does not cross the BBB ▪ Phentolamine Peak effect: ~2hrs (ocular hypotensive effect) → Non-equilibrium blockers T½:~8hrs ▪ Phenoxybenzamine α1 receptor blockers MECHANISM OF ACTION → Non-selective (blocks all receptor subtypes α1A/B/D) Exact mechanism is unknown ▪ Prazosin, Terazosin, Doxazosin Related to α2 receptor-mediated action → Selective α1A receptor blockers → DEC aqueous humor secretion from the ciliary body ▪ Tamsolusin, Alfuzosin, Silodosin through constriction of afferent ciliary blood vessels α2 receptor antagonists → INC uveoscleral outflow → Yohimbine Topically used to DEC IOP Minimal effects on cardiovascular and pulmonary B. GENERAL CONSIDERATIONS parameters Blockade of α1 adrenergic receptors → Inhibits vasoconstriction of the blood vessels induced by THERAPEUTIC USE endogenous catecholamines Short-term adjunctive therapy in patients with open-angle → Leads to vasodilation of arteriolar resistance vessels glaucoma whose IOP are not controlled by other and veins pharmacologic agents ▪ Arteriolar and venous tone are determined to a large Prevention or DEC of intraoperative and post-operative extent by the α receptors on the vascular smooth INC in IOP before or after ocular laser trabeculoplasty or muscles iridotomy when used prophylactically → Recall: BP = CO x PVR G. BRIMONIDINE ▪ Some vessels are dually innervated by SNS (may CHEMISTRY AND PHARMACOKINETICS have α1 or both α1 and β2 receptors) ▪ Activation of α1 = vasoconstriction = INC PVR Clonidine-derivative ▪ Activation of β2 = vasodilation = DEC PVR → Unlike apraclonidine, it can traverse the BBB ▪ If dually innervated: if you block α1 receptors, β2 → Causes hypotension and sedation but milder compared receptors are left unopposed to clonidine → DEC PVR → DEC BP (postural/orthostatic Relatively selective α2 receptor agonist hypotension) MECHANISM OF ACTION ▪ DEC in PVR and BP → activate the baroreceptor DEC aqueous humor production reflex mechanism → activate RAAS → INC Na+ INC uveoscleral outflow through the uveoscleral pathway and water reabsorption → fluid retention and Neuroprotective in retinal ganglion cells and their peripheral edema. projections from damage independent of its effects on IOP ▪ Produce compensatory reflex INC in HR and CO also known as reflex tachycardia. ADVERSE EFFECTS AND PRECAUTIONS Blockade of presynaptic α2 adrenergic receptors Administered topically → Removes negative feedback or autoinhibition DEC IOP in patients with ocular hypertension and produced by activation of presynaptic α2 adrenergic open-angle glaucoma receptors May be combined with other topically administered drugs: → Results to enhanced released of NE from sympathetic → β receptor blockers (e.g. Betaxolol) nerve terminals → stimulation of postsynaptic β1 → Carbonic anhydrase inhibitors (e.g. Dorzolamide) receptors in the heart and JG cells → INC HR and renin For short-term treatment only secretion Not used as an anti-hypertensive agent Pressor responses to α blockers following administration of sympathomimetics: H. RILMENIDINE & MOXONIDINE → Phenylephrine: CHEMISTRY AND PHARMACOKINETICS ▪ No pressor response Imidazolines used as anti-hypertensive drugs ▪ α1 receptors are completely blocked Pharmacological profiles same as clonidine (activate I1 → Norepinephrine: receptors) ▪ Reduced pressor response I. TIZANIDINE ▪ Incompletely blocked; diminished pressor effect of α1 THERAPEUTIC USE agonists; cardiac β1 receptor stimulation is Ocular hypertension unopposed Acute/chronic open and closed-angle glaucoma ー NE directly stimulates cardiac β1 receptors Centrally-acting muscle relaxant → Epinephrine: Treatment for muscle spasticity ▪ Vasodepressor effect ▪ Unopposed β2 receptor activity → vasodilation of blood vessels (epinephrine reversal) Space intentionally left blank PHARMACOLOGY Sympathetic Depressants/ Alpha Adrenoceptor Blocker PAGE 5 of 11 PHARMACOLOGY | LE 2 Sympathetic Depressants/ Alpha Adrenoceptor Blockers | Dr. Alpharetta Luisa T. Reyes, M.D., FPSECP Blockade of α1 adrenoceptors to alleviate symptoms of → Presynaptic α2 receptor blockade → INC NE release benign prostatic hypertrophy (BPH) from sympathetic nerves → cardiac β1 stimulation → → The prostate and lower urinary tract tissue contain a plus sympathetic activation of baroreceptor reflex high proportion of α1A receptors mechanisms → INC HR → Administration of α1 receptor blockers → DEC smooth ▪ Blockade of presynaptic α2 receptor = removal of muscle tone and relaxation of smooth muscles in the auto-inhibition prostate and bladder neck → DEC resistance to urine ▪ Results in an enhanced/augmented release of outflow → INC urine flow norepinephrine from the nerve endings. Other important effects of α receptor blockade Other effects → α2 receptor blockade → facilitate insulin release by β → Inhibits responses to 5-HT or serotonin islet cells of pancreas so that the β2 receptor response → Stimulates muscarinic, as well as H1 and H2 receptors will be unopposed → Facilitates insulin release (α2 blockade) → Reduce glucose release from liver ▪ By the β2 receptors which are located in the β islet ▪ Catecholamines increase output of glucose from the cells of the pancreas liver mediated by β receptors and some α receptors ▪ Attributed to the blockade of α2 receptors in the β islet → α1 receptor blockade cells of the pancreas which act by decreasing insulin ▪ Radial smooth muscles → miosis release ▪ Mucous membranes → nasal stuffiness → Stimulates GI smooth muscle contraction and gastric acid secretion C. MECHANISM OF ACTION REVERSIBLE BLOCKADE PHARMACOKINETICS OF PHENTOLAMINE Competitive, equilibrium, or surmountable blockade of α Poor oral absorption, extensively metabolized in the liver receptors → Administered intravenously (IV) or intramuscularly (IM) → No intrinsic activity with α receptors → Undergoes extensive metabolism → May be surmounted with sufficient high concentration of Rapid onset, short duration of action α receptor agonists → T½: about 19 minutes after IV administration Graded dose-response curve: ADVERSE EFFECTS & TOXICITY OF PHENTOLAMINE → Shifts to the right → Maximal response not decreased Hypotension is the major adverse effect Duration of action is dependent on T½ and rate of → May be acute and prolonged dissociation Reflex cardiac stimulation → tachycardia, cardiac Examples: arrhythmias, ischemic cardiac events → Selective α1 receptor blocker - Prazosin*, Terazosin, → Tachycardia is baroreceptor reflex-mediated Doxazosin ▪ Resulting from: → Selective α1A receptor blocker - Tamsulosin*, ▪ DEC in BP Alfuzosin, Silodosin ▪ Blockade of the presynaptic α2 receptors → removal → Conventional α receptor blockers - Phentolamine* of the auto-inhibition of the negative feedback *NOTE: Drug prototypes mechanism → enhanced NE release → stimulation of the cardiac β1 receptors. IRREVERSIBLE BLOCKADE GI stimulation: Nausea, abdominal pain, exacerbation of α adrenoceptor blocker covalently binds to α receptors → peptic ulcer (due to histamine and muscarinic receptor irreversible non-equilibrium blockade → persists long stimulation) after the drug has been cleared from the plasma → → Caution: In patients with coronary artery disease & formation of a reactive intermediate, Ethyleneimonium myocardial infarction, and history of peptic ulcer & acid α blocker does not dissociate from the α receptor and peptic diseases can not be surmounted Inhibition of ejaculation (retrograde) Graded dose-response curve: Nasal congestion → Maximal response reduced → Stuffy nose may also occur Restoration of the tissue responsiveness is dependent on the synthesis of new receptors (takes several days) PHENOXYBENZAMINE (PBZ) Drug prototype: Phenoxybenzamine (non-selective) A halo alkylamine, alkylating agent → Related to nitrogen mustard D. CONVENTIONAL α-RECEPTOR ANTAGONISTS MOA: PHENTOLAMINE → Irreversible receptor blockade; covalently conjugates Synthetic imidazoline with α receptors with α1 and α2 affinities in a ratio of Reversible non-selective α-receptor blocker 100:1 (α1 > α2) Competitive antagonist at both α1 and α2 receptors, of → Inhibition of NE neuronal and extraneuronal tissue similar affinities at a ratio of 1:1 (α1 = α2) uptake → Binding affinity is equal to both receptors ▪ Results in the decrease of norepinephrine clearance PHARMACOLOGIC ACTION & EFFECTS from the sympathetic nerves CVS → α1 receptor blockade and possibly α2 blockade on vascular smooth muscles → DEC PVR → DEC BP ▪ Results to unopposed β receptor activity, causing Space intentionally left blank vasodilation of blood vessels and the corresponding DEC in PVR and markedly DEC BP PHARMACOLOGY Sympathetic Depressants/ Alpha Adrenoceptor Blocker PAGE 6 of 11 PHARMACOLOGY | LE 2 Sympathetic Depressants/ Alpha Adrenoceptor Blockers | Dr. Alpharetta Luisa T. Reyes, M.D., FPSECP PHARMACOKINETICS OF PHENOXYBENZAMINE ▪ During surgery, there are rises in BP due to NE Absorbed after oral administration, low bioavailability release (20-30%) ▪ Phentolamine for the short term control since it is → Lipid-soluble more readily titrated with a short duration of action. Extensively metabolized in the liver ▪ Nowadays, nitroprusside is more preferred, Onset of action: 1 hour compared to phentolamine Duration of action: 14-48 hours → Chronic treatment of inoperable or metastatic cases of → T½: approximately 24 hours pheochromocytoma (rare occurrence) - Phenoxybenzamine or reversible α1 selective PHARMACOLOGIC ACTION & EFFECTS OF antagonists or Ca2+ channel blockers PHENOXYBENZAMINE → β receptor blockers may be used after adequate α CVS receptor blockade to prevent rebound phenomenon → DEC PVR → DEC BP → Metyrosine is a competitive inhibitor of tyrosine ▪ Blockade of the α1 receptors in the blood vessels hydroxylase, which is the rate-limiting step in the causes vasodilation due to unopposed β2 receptor synthesis of catecholamines activity, leading to a progressive DEC in PVR, ▪ Can traverse the CNS and may DEC dopamine followed by marked DEC in BP levels → development of extrapyramidal symptoms → Reflex INC HR accentuated by enhanced NE release → Pseudo-obstruction of the bowel of patients due to α2 blockade → INC CO ▪ Result of inhibitory effects of the catecholamines in ▪ Decreased BP is followed by reflex sympathetic the intestinal smooth muscles (although there are nerve stimulation, manifested as reflex tachycardia better drugs nowadays) → Causes “epinephrine reversal” Reversal of local anesthesia with vasoconstrictor in soft ▪ A result of the administration of phenoxybenzamine tissue sites - local phentolamine has been approved in after an α-adrenoceptor agonist 2008 by the US FDA for this indication → Compensatory INC blood volume with long term use Prevention of dermal necrosis - Phentolamine ▪ The vasodilating effect of β2 receptors in the blood → Caused by the inadvertent extravasation of an α vessels is more pronounced as a result of α1 receptor agonist blockade → Phentolamine can be given to block α1 receptors, ▪ With long term use of phenoxybenzamine, as a result leaving β2 receptors effects unopposed of the marked increase in BP, RAAS is activated, HPN crisis following clonidine withdrawal or ingestion of resulting in compensatory INC in blood volume large amount of tyramine-containing food - Phentolamine and edema formation → Newer drugs that result in less adverse effects are CNS preferred over conventional α receptor blockers → Slow IV → sedation, fatigue, nausea Male erectile dysfunction - intracavernous injection of → Rapid IV → CNS excitation, INC motor activity phentolamine (causes fibrotic reaction with long term use) Other effects → The use of this drug has been superceded by PDE-5 → At higher doses, PBZ irreversibly inhibits responses to reductase inhibitors that are administered orally (e.g., 5-HT, Ach, and histamine sildenafil & tadalafil) for the management of ED ADVERSE EFFECTS & TOXICITY OF PBZ Peripheral vascular diseases such as Raynaud’s Major adverse effect is postural hypotension often phenomenon & Berger’s disease - Phenoxybenzamine or accompanied by reflex INC HR and other forms of prazosin; Ca2+ channel blocker (CCB) is preferred arrhythmias Table 4. Summary of Therapeutic uses of alpha receptor Nasal stuffiness Given for 1-3 weeks prior to surgical → Results from parasympathetic predominance removal of pheos Ejaculatory dysfunction (retrograde ejaculation) Chronic treatment of inoperable or Mutagenic in Ames test (experimental animal studies) metastatic cases of pheos (alternatives: THERAPEUTIC USES OF CLASSICAL α RECEPTOR Phenoxybenzamine reversible α1 selective antagonists or BLOCKERS CCB) Pheochromocytoma (pheos): Tumor of the adrenal Treatment of Raynaud’s phenomenon & glands Berger’s disease (Prazosin, or CCBs is → Major use of classical α receptor blockers preferred) → Prior to surgical removal of the tumor (administered for 1-3 wks) - Phenoxybenzamine Used in the operative manipulation of ▪ α1 receptor blockers (e.g., prazosin & doxazosin) pheos for the short term control of BP and β receptor blockers (e.g., propranolol, nadolol, (preferred: nitroprusside) atenolol, & metoprolol) are also given several days Reversal of local anesthesia with ❗ after starting the administration of the α blockers Do NOT give the β blockers initially or alone ー α blockers are given first and after several days, β Phentolamine vasoconstrictor in soft tissue sites Prevention of dermal necrosis Treatment of male erectile dysfunction blockers can then be administered (PDE-5 reductase inhibitors are ー β blockers that have been administered first will prescribed more) cause “rebound phenomenon” HPN crisis following clonidine → Operative manipulation - phentolamine but withdrawal or ingestion of large amount nitroprusside is preferred of tyramine-containing food PHARMACOLOGY Sympathetic Depressants/ Alpha Adrenoceptor Blocker PAGE 7 of 11 PHARMACOLOGY | LE 2 Sympathetic Depressants/ Alpha Adrenoceptor Blockers | Dr. Alpharetta Luisa T. Reyes, M.D., FPSECP Competitive tyrosine hydroxylase DECREASE IN BLOOD PRESSURE Metyrosine inhibitor, for the treatment of excessive Prazosin relaxes both arteriolar and venous vascular sympathetic stimulation in pheos. smooth muscles and produces vasodilation. DEC CNS sympathetic outflow E. SELECTIVE α1 ADRENORECEPTOR BLOCKERS BP = CO x PVR Non-selective: α1ABD >>> α2 This is a result of α1 receptor blockade in vascular smooth → α1:α2 selectivity 1000:1 muscles leading to vasodilation due to unopposed β2 ▪ Prazosin receptor effect ▪ Doxazosin DEC BP due to DEC PVR and DEC venous return ▪ Terazosin → Partially explain the relative/insignificant absence of ❗ FIRST DOSE EFFECT Marked postural hypotension and syncope seen 30-90 tachycardia from these drugs Selective α1A receptor blockers minutes after initial dose of prazosin and 2-6 hours after → Tamsulosin initial dose of doxazosin → Silodosin Syncopal episodes may occur with rapid increase in → Alfuzosin dosage or with addition of a second antihypertensive drug if patient is concomitantly taking a large dose of THERAPEUTIC INDICATIONS prazosin Hypertension (mild to moderate) Reduction in central sympathetic outflow may contribute to → Non-selective α1ABD receptor blockers may be used this effect Lower urinary tract symptoms (LUTS) associated with The risk can be minimized by the following: BPH → Limiting the initial minimum effective dose to be → Selective α1A receptor blockers are primarily used if still administered (e.g. 1 mg) amenable to pharmacologic treatment → It should be given at bedtime → Nonselective α1ABD blockers are used if the patient has → Dosage should be increased slowly concomitant mild hypertension → Be cautious in introducing additional antihypertensive Congestive heart failure drug → Prazosin may be indicated for short term use METABOLIC EFFECTS ADVERSE EFFECTS Produce no change or they may improve plasma lipid FIRST DOSE EFFECT profiles and glucose-insulin metabolism in patients with Development of postural hypotension with syncopal hypertension who are at risk for atherosclerotic disease episodes seen after intake of initial dose of α1 receptor INC HDL, DEC LDL, and DEC triglycerides blocker → MOA is unknown More common with quinazolines derivatives CARDIAC OUTPUT Less likely to occur with tamsulosin and silodosin INC CO and DEC pulmonary congestion in patients with LIPID PROFILE CHANGES pulmonary edema Quinazolines either produce improvement or no change on Dilates both arteries and veins → DEC preload and the plasma lipid profile afterload Used for short term effects in the treatment of patients ALFUZOSIN with congestive heart failure Causes increased risk of prolongation of QT interval in LIMITED APPLICATION susceptible individuals Should not be used with CYP3A4 inhibitors (E.g. Management of hypertensive emergencies Cimetidine, Ketoconazole) → Other drugs such as Labetalol, a mixed α1 and β → Can increase plasma drug level of alfuzosin receptor blocker, have been used for this condition. TERAZOSIN AND DOXAZOSIN TAMSULOSIN AND SILODOSIN For mild to moderate hypertension Greater incidence to cause abnormal ejaculation In men with concurrent mild hypertension and lower (retrograde ejaculation) urinary tract symptoms (LUTS) associated with BPH Cause intraoperative floppy iris syndrome (IFIS) First dose effect in Doxazosin → characterized by bellowing of the flaccid iris with → Marked postural hypotension and syncope seen 2-6 propensity for iris prolapse and progressive hours after initial dose intraoperative pupillary constriction Hypertension associated with pheochromocytoma PRAZOSIN AND ITS CONGENERS Off-label medical expulsion therapy (MET) for distal IMPORTANT ACTIONS AND EFFECTS ureteral calculi MINIMAL OR ABSENCE OF REFLEX TACHYCARDIA Alleviation of nightmares associated with post traumatic stress disorder (PTSD) Selective α1 receptor blockade in arterioles and venules → Antihydrotic in relation to SSRI use chronic prostatitis producing vasodilation and DEC PVR Voiding dysfunction in men and women (primary bladder Do not block presynaptic α2 receptors neck obstruction) → Do not promote NE release from sympathetic nerve endings → Do not remove the negative feedback or autoinhibition DEC cardiac preload → little tendency to INC CO and HR Space intentionally left blank PHARMACOLOGY Sympathetic Depressants/ Alpha Adrenoceptor Blocker PAGE 8 of 11 PHARMACOLOGY | LE 2 Sympathetic Depressants/ Alpha Adrenoceptor Blockers | Dr. Alpharetta Luisa T. Reyes, M.D., FPSECP F. ALPHA 2 RECEPTOR ANTAGONISTS They produce specific mechanism of action, YOHIMBINE pharmacological actions and effects in the CVS, urinary A carboline alkaloid derived from yohimbe, an evergreen tract, prostate gland, adrenal gland, and in lipid tree native to western and central Africa metabolism α1 receptor blockers are clinically used in the MECHANISM OF ACTION management of patients with hypertension, BPH, Selective competitive α2 receptor blocker peripheral vascular diseases, and pheochromocytoma Presynaptic α2 receptor blockade in sympathetic nerve endings → INC NE levels in the body III. REVIEW QUESTIONS → Remove autoinhibition or negative feedback 1. Which of the following drugs selectively blocks Blocks α2 receptors in the CNS →INC central sympathetic alpha-2 receptors? activation and in periphery → INC NE release from a. Methyldopa noradrenergic fibers → INC BP and HR b. Phentolamine c. Prazosin PHARMACOLOGIC PROPERTIES d. Yohimbine Half life: 0.25 to 2.5 hours Readily enters the CNS 2. Which among the following drugs is used for BPH, → High doses: INC central sympathetic outflow → INC BP but not for HPN? and HR a. Terazosin INC motor activity → produces tremors b. Prazosin Compounds found in the bark used for: c. Doxazosin → Erectile dysfunction d. Tamsulosin → Improved athletic performance 3. The following sympathetic blockers are correctly → Weight loss matched with the adverse effect usually associated → Aphrodisiac with their use EXCEPT: No inclusive evidence that it is effective in the treatment of a. Clonidine - extrapyramidal symptoms male sexual dysfunction b. Tamsulosin - intraoperative floppy iris syndrome (IFIS) Legally sold as dietary/herbal supplement in the US c. Methyldopa - sedation Renewed interest that it may benefit those with d. Phenoxybenzamine - postural hypotension psychogenic causes 4. Used as hypertension treatment for pregnant patients CONTRAINDICATIONS a. Tramadol Hypertension b. Clonidine Angina c. Methyldopa Renal impairment 5. Guanfacine’s half-life IV. SUMMARY a. 12 to 24 hours Sympathetic depressants are classified according to: b. 6 to 12 hours → Site of action c. 3 to 6 hours ▪ Centrally acting: Guanfacine, Methyldopa, Clonidine 6. The mechanism(s) of action of prazosin include(s) ▪ Peripherally acting: conventional drugs a-blockers, a. Relaxation of vascular smooth muscles in selective α1-blockers, and α1A receptor blockers hypertension → Type of receptor subtypes blocked b. Reflex cardiac stimulation for management of heart → Adrenergic structures blocked at nerve endings: failure receptor subtypes, adrenergic neuron, or ganglion c. Relaxation of smooth muscles in the prostate in benign They produce common side effects that interfere with prostatic hypertrophy sympathetic neuron function according to type of receptors d. A and C blocked → Postural orthostatic hypotension, conventional 7. Also used to treat ADHD α-blockers have the worst among these groups: a. Guanfacine Phentolamine, Phenoxybenzamine b. Guanabenz The more profound the orthostatic hypotension → the c. Clonidine more intense the reflex tachycardia that it will produce Other side effects ANS: 1. D. Yohimbine is a selective alpha-2 blocker with Tamsulosin & → Sedation, increase in GI motility, nasal stuffiness & Alfuzosin. diarrhea 2. D. Terazosin, Prazosin, and Doxazosin are used to treat BPH AND ▪ Usually arise from lipid-soluble drugs that traverse HPN. the CNS (clonidine, reserpine, phenoxybenzamine) 3. A. Clonidine is an alpha-2 agonist with the following adverse → Sexual dysfunction, intense reflex tachycardia due to effects α-receptor blockade 4. C. Tramadol - weak opioid. Clonidine is not recommended during → INC BV & sodium retention as a result of decreased pregnancy. 5. A blood pressure 6. D. Prazosin is under selective alpha 1 adrenoceptor blocker. → EPS may result due to decreased dopamine levels by 7. A. Guanfacine is used to treat hypertension and ADHD. methyldopa → Effects on CVS, respiratory, and metabolism by β-blockers PHARMACOLOGY Sympathetic Depressants/ Alpha Adrenoceptor Blocker PAGE 9 of 11 PHARMACOLOGY | LE 2 Sympathetic Depressants/ Alpha Adrenoceptor Blockers | Dr. Alpharetta Luisa T. Reyes, M.D., FPSECP V. REFERENCES Reyes, L. (2024). ANS Pharmacology: Sympathetic Depressants & Alpha Adreno. [Asynch Lecture Video] Reyes, L. (2022). ANS Pharmacology: Sympathetic Depressants & Alpha Adreno. [Synch Lecture] 2026 Transcriptions 2025 Transcriptions Synchronous Lecture Recording: VI. FORMATIVE QUIZ Question & Choices Answer & Rationale 1. A 68/M has mild bothersome symptoms of benign Albuterol - selective β2 agonist used as an asthma drug prostatic hyperplasia. Which of the following drugs would be the most appropriate initial therapy? Atenolol & Metoprolol - β1 blockers indicated for treatment of Pheochromocytoma D A. Albuterol B. Atenolol Terazosin - non-selective α1 receptor blockers indicated for C. Metoprolol benign prostatic hyperplasia due to ability to induce apoptosis D. Terazosin in prostate smooth muscle 2. The receptor that prazosin works on is attached to Terazosin is an α1-adrenergic receptor antagonist. When an which of the following proteins? α1-receptor binds a catecholamine, the receptor changes its shape and allows the Gq protein to release GDP and bind GTP A. G inhibitory protein B instead, thereby activating it. This process triggers a cellular B. G proteins with q polypeptide response that leads to smooth muscle contraction. C. G stimulating protein α1-adrenergic receptor antagonists inhibit the activation of D. Protein kinase A these receptors. 3. Which of the following α1 adrenergic blockers is Tamsulosin selectively blocks α1A receptors, commonly found most likely to cause intraoperative floppy iris in the iris dilator muscle. A lack of dilator smooth-muscle tone syndrome? can cause iris bulging leading to iris prolapse. C A. Doxazosin Terazosin and doxazosin may cause postural hypotension and B. Prazosin syncope C. Tamsulosin D. Terazosin Other choices are controlled by beta receptors. 4. When given to a patient, phentolamine blocks which Phentolamine is an alpha receptor blocker. one of the following? Phenylephrine, an α agonist, increases BP and causes A. Bradycardia induced by phenylephrine A bradycardia through the baroreceptor reflex. B. Bronchodilation induced by epinephrine C. Increased cardiac contractile force induced by Phentolamine, through the blockade of the α-mediated norepinephrine vasoconstrictor effect, prevents bradycardia. D. Vasodilation induced by isoproterenol Phenoxybenzamine has a long duration of action of 14-48 5. Phenoxybenzamine differs from a phentolamine in hours and a half life of ~24 hours. Its binding affinities with that the former: α1and α2 receptors is in the ratio of 100:1. It is a non-competitive non-equilibrium type of blocker. Takes several A. Binds covalently to α receptor A days to restore tissue responsiveness because it takes time for B. Has a shorter duration of action the synthesis of new α receptors. C. Inhibits α2 receptors more than α1 D. Inhibits α1 and α2 receptors equally Phentolamine is a competitive, equilibrium, surmountable type of blocker. It has a fast onset and short duration of action. 6. A 33/F with pheochromocytoma is scheduled for During preparation for surgery Phenoxybenzamine is used to surgical resection of adrenal mass. Which of the prevent intraoperative catecholamine crisis. following drugs may be given to prevent intraoperative catecholamine crisis? B A. Clonidine B. Phenoxybenzamine C. Pseudoephedrine D. Terazosin 7. Which of the following drugs is a non-selective Methyldopa - centrally acting α2 agonist alpha-adrenoceptor blocker? Phenylephrine - selective α1 agonist Tamsulosin - selective α1A blocker A. Methyldopa B B. Phentolamine C. Phenylephrine D. Tamsulosin PHARMACOLOGY Sympathetic Depressants/ Alpha Adrenoceptor Blocker PAGE 10 of 11 PHARMACOLOGY | LE 2 Sympathetic Depressants/ Alpha Adrenoceptor Blockers | Dr. Alpharetta Luisa T. Reyes, M.D., FPSECP 8. Which of the following adrenergic receptors does Tamsulosin - selective α1A blocker tamsulosin block? A. α1A only A B. α2 only C. α1 and α2 D. α1, α2, and β1 9. Which of the following is one of the most important 2 major side effects of conventional alpha-adrenoceptor blockers: side effects of conventional alpha-adrenoceptor Orthostatic hypotension and Reflex tachycardia blockers? C A. Nasal stuffiness B. Miosis C.Reflex tachycardia D. Sedation 10. Which of the following is the major adverse effect of Development of postural hypotension with syncopal episodes selective alpha1 adrenoceptor blockers? (first dose syncope) seen after intake of initial dose of α1 receptor blocker due to a decrease in blood pressure. A. Reflex tachycardia B B. First dose C. Sedation D. Hypoglycemia VII. APPENDIX Table 5. Selective α1 Receptor Blockers PRAZOSIN TERAZOSIN DOXAZOSIN ALFUZOSIN TAMSULOSIN Pharmacologic Non-selective Non-selective Non-selective α1A and α1D (prostate) α1A and α1D Classification (prostate) Chemical Structure Quinazoline Quinazoline Quinazoline Quinazoline ~60-64% benzenesulfona Bioavailability 50-70% >90% (like prazosin) mide T½ 2-3 hours ~9-12 hours ~20-22 hours 10 hours 9-13 hours Duration of action 10 hours > 18 hours 36 hours Long-acting Long-acting Dosing 2-3x/day once a day once a day once a day once a day - Induce apoptosis in prostate Has pro-apoptotic Has apoptotic Apoptotic effect in prostate smooth muscle effects effect. *Silodosin smooth muscle gas the highest effect Common First dose effect ✔ ✔ ✔ ✔ Less likely as A/E Lipid Profile ✔ ✔ ✔ ✔ with silodosin HPN HPN HPN BPH only BPH only BPH BPH BPH Therapeutic Indication CHF for short term - INC risk of QT Abnormal prolongation ejaculation like silodosin Other Important Adverse Contraindicated with Effects/ Contraindications concomitant INC risk of administration of intraoperative CYP3A4 inhibitors floppy iris syndrome (IFIS) PHARMACOLOGY Sympathetic Depressants/ Alpha Adrenoceptor Blocker PAGE 11 of 11