Autonomic Drugs - Adrenergic Antagonists - Ch 7 .docx

Autonomic Drugs -- Adrenergic Antagonists (Ch 7) Overview: - Adrenergic antagonists (also called adrenergic blockers or sympatholytics) bind to adrenoceptors but do not activate the receptors. - These drugs attach to the adrenoceptors, thus preventing activation by endogenous or e...

Autonomic Drugs -- Adrenergic Antagonists (Ch 7) Overview: - Adrenergic antagonists (also called adrenergic blockers or sympatholytics) bind to adrenoceptors but do not activate the receptors. - These drugs attach to the adrenoceptors, thus preventing activation by endogenous or exogenous agonists. α-Adrenergic Blocking Agents - α~1~ blockers - Drugs that block α~1~ -adrenoceptors profoundly affect blood pressure - Blockade of these receptors reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance and a reduction in blood pressure. - α~2~ blockers - These agents have limited clinical utility +-------------+-------------+-------------+-------------+-------------+ | **Drug** | **Mechanism | **Actions** | **Therapeut | **Adverse | | | of Action / | | ic | Effects** | | | Pharmacokin | | Uses** | | | | etics** | | | | +=============+=============+=============+=============+=============+ | Phenoxybenz | Nonselectiv | Prevents | Used in the | Postural | | amine | e, | α~1~ | treatment | hypotension | | | noncompetit | receptor | of sweating | , | | | ive | vasoconstri | and | nasal | | | (irreversib | ction | hypertensio | stuffiness, | | | le) | of | n | GI | | | blocker of | peripheral | associated | irritation, | | | α~1~ and | blood | with | and | | | α~2~ | vessels | pheochromoc | inhibition | | | adrenergic | caused by | ytoma | of | | | receptors | endogenous | | ejaculation | | | | catecholami | (Pheochromo | | | | | nes, | cytoma- | | | | | which leads | a | | | | | to | catecholami | | | | | decreased | ne | | | | | peripheral | secreting | | | | | resistance | tumor of | | | | | and | cells | | | | | resultant | derived | | | | | reflex | from the | | | | | tachycardia | adrenal | | | | | | medulla\_ | | | | | Blocking | | | | | | presynaptic | Used | | | | | α~2~ | off-label | | | | | receptors | for | | | | | leads to | hypertensiv | | | | | increased | e | | | | | release of | crisis | | | | | norepinephr | caused by | | | | | ine, | sympathomim | | | | | which | etic | | | | | increases | amines and | | | | | the heart | some | | | | | rate and | urinary | | | | | cardiac | issues | | | | | output | | | | | | mediated by | | | | | | β~1~ | | | | | | receptors. | | | | | | | | | | | | Reverses | | | | | | the α | | | | | | agonist | | | | | | actions of | | | | | | epinephrine | | | +-------------+-------------+-------------+-------------+-------------+ | Phentolamin | Nonselectiv | | Used for | | | e | e, | | the | | | | competitive | | diagnosis | | | | (reversible | | and | | | | ) | | short-term | | | | blocker of | | management | | | | α~1~ and | | of | | | | α~2~ | | pheochromoc | | | | adrenergic | | ytoma | | | | receptors | | | | | | | | Used | | | | Effects | | locally to | | | | last 4 | | prevent | | | | hours | | dermal | | | | | | necrosis | | | | | | following | | | | | | extravasati | | | | | | on | | | | | | or | | | | | | norepinephr | | | | | | ine | | | | | | and other | | | | | | vesicants | | | | | | | | | | | | Useful to | | | | | | treat | | | | | | hypertensiv | | | | | | e | | | | | | crisis due | | | | | | to abrupt | | | | | | withdrawal | | | | | | of | | | | | | clonidine | | | | | | or | | | | | | ingestion | | | | | | of | | | | | | tyramine-co | | | | | | ntaining | | | | | | foods in | | | | | | patients | | | | | | taking | | | | | | MAOIs | | +-------------+-------------+-------------+-------------+-------------+ | Prazosin | Selective, | Decrease | Used for | "First-dose | | | competitive | peripheral | hypertensio | " | | | blocker of | vascular | n, | effect- | | | α~1~ | resistance | but not as | exaggerated | | | adrenergic | and lower | monotherapy | orthostatic | | | receptors | blood | | hypotensive | | | | pressure by | *Other | response | | | | causing | agents are | | | | | relaxation | used for | Dizziness, | | | | of both | BPH and are | lack of | | | | arterial | discussed | energy, | | | | and venous | in later | nasal | | | | smooth | chapters* | congestion, | | | | muscle | | headache, | | | | | | drowsiness, | | | | Cause | | and | | | | minimal | | orthostatic | | | | changes in | | hypotension | | | | cardiac | | | | | | output, | | | | | | renal blood | | | | | | flow, and | | | | | | glomerular | | | | | | filtration | | | | | | rate | | | +-------------+-------------+-------------+-------------+-------------+ | Terazosin | | | | | +-------------+-------------+-------------+-------------+-------------+ | Doxazosin | | | | | +-------------+-------------+-------------+-------------+-------------+ | Yohimbine | Selective, | Works in | | | | | competitive | the CNS to | | | | | blocker of | increase | | | | | α~2~ | sympathetic | | | | | adrenergic | outflow to | | | | | receptors | the | | | | | | periphery | | | | | See | | | | | | attachment | | | | | | for full | | | | | | discussion | | | | | | of | | | | | | NO-himbine | | | | +-------------+-------------+-------------+-------------+-------------+ β-Adrenergic Blocking Agents (-olol) - All clinically available β-blockers are competitive antagonists - Nonselective β-blockers act at both β~1~ and β~2~ receptors - Drugs differ in intrinsic sympathomimetic activity (ISA), CNS effects, blockade of sympathetic receptors, vasodilation, and pharmacokinetics - They do not induce postural hypotension because the α-adrenoceptors remain functional - Effective for treating systemic as well as portal hypertension, angina, cardiac arrythmias, myocardial infarction, heart failure hyperthyroidism, and glaucoma. They are also used for the prophylaxis of migraine +-------------+-------------+-------------+-------------+-------------+ | **Drug** | **Pharmacok | **Actions** | **Therapeut | **Adverse | | | inetics** | | ic | Effects** | | | | | Uses** | | +=============+=============+=============+=============+=============+ | Propranolol | Nonselectiv | Cardiovascu | Hypertensio | Bronchocons | | | e | lar | n | triction | | | β-blocker | | | | | | (antagonist | -Negative | does not | Arrhythmias | | | ) | inotropic | reduce | | | | | and | blood | -Treatment | | | Good oral | chronotropi | pressure in | with | | | absorption | c | people with | β-blockers | | | | effects | normal BP\* | must never | | | Subject to | (decreases | | be stopped | | | first-pass; | force and | Angina | abruptly | | | only \~25% | rate) | pectoris | because of | | | reaches | decrease | | the risk of | | | systemic | cardiac | Decreases | precipitati | | | circulation | output | oxygen | ng | | | | | requirement | cardiac | | | Readily | -Directly ↓ | of heart | arrhythmias | | | crosses the | sinoatrial | muscle, | , | | | blood-brain | (SA) and | effective | which may | | | barrier | atrioventri | in reducing | be severe. | | | | cular | chest pain | The | | | | (AV) nodal | on exertion | β-blockers | | | | activity | that is | must be | | | | resulting | common in | tapered off | | | | in | angina | gradually | | | | bradycardia | | over a | | | | that limits | Useful for | period of | | | | the dose | the | at least a | | | | | management | few weeks. | | | | -Reduces | of chronic | Long-term | | | | expected | stable | treatment | | | | sympathetic | angina | with a β | | | | activity | | antagonist | | | | during | Myocardial | leads to | | | | exercise or | infarction | up-regulati | | | | stress | | on | | | | | Protective | of the β | | | | -Decreases | effect on | receptor. | | | | cardiac | the | On | | | | output, | myocardium | suspension | | | | workload, | | of therapy, | | | | and oxygen | Protects | the | | | | consumption | against | increased | | | | to make | 2^nd^ MI | receptors | | | | this drug | | can | | | | useful for | Administrat | precipitate | | | | angina | ion | worsened | | | | | immediately | angina or | | | | -Useful for | following | hypertensio | | | | some | MI reduces | n | | | | arrythmias | infarct | through | | | | | size and | action of | | | | Peripheral | early | endogenous | | | | vasoconstri | mortality | catecholami | | | | ction | | nes | | | | | Reduces | on the | | | | -Nonselecti | incidence | up-regulate | | | | ve | of sudden | d | | | | blockade | arrhythmic | β | | | | prevents | death after | receptors. | | | | β~2~-mediat | MI | | | | | ed | | Metabolic | | | | vasodilatio | Migraine | disturbance | | | | n | | s | | | | in skeletal | Effective | | | | | muscles, ↑ | in reducing | -Fasting | | | | peripheral | migraine | hypoglycemi | | | | vascular | episodes | a | | | | resistance | when used | may occur | | | | | prophylacti | | | | | -Reduction | cally | -Can | | | | in cardiac | | prevent the | | | | output | Lipophilic | counterregu | | | | leads to ↓ | nature | latory | | | | BP, which | allows it | effects of | | | | triggers a | to | catecholami | | | | reflex | penetrate | nes | | | | peripheral | the CNS | during | | | | vasoconstri | | hypoglycemi | | | | ction | Hyperthyroi | a. | | | | | dism | Thus, the | | | | -In pts w/ | | perception | | | | HTN, total | Effective | of symptoms | | | | peripheral | in blunting | of | | | | resistance | the | hypoglycemi | | | | returns to | widespread | a | | | | normal or ↓ | sympathetic | such as | | | | w/ | stimulation | tremor, | | | | long-term | that occurs | tachycardia | | | | use of | in | , | | | | propranolol | hyperthyroi | and | | | | as a result | dism | nervousness | | | | of down | | are blunted | | | | regulation | In acute | by | | | | of the β | hyperthyroi | β-blockers | | | | receptor | dism, | | | | | | β-blockers | -may have | | | | -Gradual ↓ | may be | increased | | | | of both | lifesaving | triglycerid | | | | systolic | in | es | | | | and | protecting | and reduced | | | | diastolic | against | high-densit | | | | BPs occurs | serious | y | | | | in HTN | cardiac | lipoprotein | | | | patients | arrhythmias | ("good" | | | | | | cholesterol | | | | Bronchocons | | ) | | | | triction | | through | | | | | | β-blockade | | | | -Blocking | | | | | | β~2~ | | CNS effects | | | | receptors | | | | | | in the | | -Propranolo | | | | lungs of | | l | | | | susceptible | | has | | | | patients | | numerous | | | | causes | | CNS-mediate | | | | contraction | | d | | | | of the | | effects, | | | | bronchiolar | | including | | | | smooth | | depression, | | | | muscle | | dizziness, | | | | | | lethargy, | | | | -Can | | fatigue, | | | | precipitate | | weakness, | | | | an | | visual | | | | exacerbatio | | disturbance | | | | n | | s, | | | | in patients | | hallucinati | | | | with | | ons, | | | | chronic | | short-term | | | | obstructive | | memory | | | | pulmonary | | loss, | | | | disease | | emotional | | | | (COPD) or | | lability, | | | | asthma- | | vivid | | | | contraindic | | dreams | | | | ated | | (including | | | | with | | nightmares) | | | | asthma, | | , | | | | avoid use | | and | | | | with COPD | | depression | | | | | | | | | | Disturbance | | Drug | | | | s | | interaction | | | | in glucose | | s | | | | metabolism | | | | | | | | -Drugs that | | | | -Decreased | | inhibit the | | | | glycogenoly | | metabolism | | | | sis | | of | | | | and | | propranolol | | | | decreased | | - | | | | glucagon | | such as | | | | secretion | | cimetidine, | | | | | | fluoxetine, | | | | -Pronounced | | paroxetine, | | | | hypoglycemi | | and | | | | a | | ritonavir, | | | | may occur | | may | | | | after | | potentiate | | | | insulin | | its | | | | injection | | antihyperte | | | | | | nsive | | | | -Attenuate | | effects | | | | the normal | | | | | | physiologic | | -Those that | | | | response to | | induce its | | | | hypoglycemi | | metabolism- | | | | a | | such as | | | | | | barbiturate | | | | | | s, | | | | | | phenytoin, | | | | | | and | | | | | | rifampin, | | | | | | can | | | | | | decrease | | | | | | its effects | | | | | | | | | | | | -Nonselecti | | | | | | ve | | | | | | β-blockers | | | | | | such as | | | | | | propranolol | | | | | | may prevent | | | | | | the rescue | | | | | | effects of | | | | | | epinephrine | | | | | | in | | | | | | anaphylaxis | | | | | |. | +-------------+-------------+-------------+-------------+-------------+ | Nadolol | Nonselectiv | | | | | | e | | | | | | β-blocker | | | | | | (antagonist | | | | | | ) | | | | | | | | | | | | More potent | | | | | | than | | | | | | propranolol | | | | | | | | | | | | Long | | | | | | duration of | | | | | | action | | | | +-------------+-------------+-------------+-------------+-------------+ | Timolol | Nonselectiv | Decrease | Topical | *Pilocarpin | | | e | the | products | e | | Cartelol | β-blocker | secretion | used to | is still | | | (antagonist | of aqueous | reduce | the drug of | | | ) | humor by | intraocular | choice for | | | | the ciliary | pressure in | emergency | | | | body | glaucoma | lowering of | | | | | | intraocular | | | | Do not | Used only | pressure | | | | affect | for chronic | (anticholin | | | | pupil size | management | ergic- | | | | or ability | of glaucoma | muscarinic) | | | | of the eye | | * | | | | to focus | | | +-------------+-------------+-------------+-------------+-------------+ | **Drug** | **Pharmacok | **Actions** | **Therapeut | **Adverse | | | inetics** | | ic | Effects** | | | | | Uses** | | +-------------+-------------+-------------+-------------+-------------+ | Acebutolol, | Selective | Lower blood | Useful in | | | atenolol, | β~1~ | pressure in | hypertensiv | | | betaxolol, | antagonists | hypertensio | e | | | bisoprolol, | | n | patients | | | esmolol, | Minimize | and | with | | | metoprolol, | unwanted | increase | impaired | | | & nebivolol | bronchocons | exercise | pulmonary | | | | triction | tolerance | function | | | | (β~2~ | in angina | | | | | effect) | | First-line | | | | | Fewer | therapy for | | | | Cardioselec | effects on | chronic | | | | tivity | pulmonary | stable | | | | is most | function, | angina | | | | pronounced | peripheral | | | | | at low | resistance, | Bisoprolol | | | | doses and | and | and the | | | | is lost at | carbohydrat | extended-re | | | | high doses | e | lease | | | | Cardioselec | metabolism- | formulation | | | | tivity- | use with | of | | | | antagonize | caution in | metoprolol | | | | β1 | patients | are | | | | receptors | with asthma | indicated | | | | at doses | | for the | | | | 50- to | Since these | management | | | | 100-fold | drugs have | of chronic | | | | less than | less effect | heart | | | | those | on | failure | | | | required to | peripheral | | | | | block β2 | vascular β2 | Esmolol is | | | | receptors | receptors, | only | | | | | coldness of | available | | | | | extremities | intravenous | | | | | (Raynaud | ly | | | | | phenomenon) | (very short | | | | | , | half life) | | | | | a common | and is used | | | | | side effect | to control | | | | | of | blood | | | | | β-blockers, | pressure or | | | | | is less | heart | | | | | frequent. | rhythm in | | | | | | critically | | | | | | ill | | | | | | patients | | | | | | and those | | | | | | undergoing | | | | | | surgery or | | | | | | diagnostic | | | | | | procedures | | +-------------+-------------+-------------+-------------+-------------+ | Acebutolol | Antagonists | These | β-Blockers | | | (selective | with | partial | with ISA | | | β~1~ | partial | agonists | are | | | antagonists | agonist | stimulate | effective | | | ) | activity- | the β | in | | | | ISA- | receptor to | hypertensiv | | | & pindolol | intrinsic | which they | e | | | (nonselecti | sympathomim | are bound, | patients | | | ve | etic | yet they | with | | | β-blocker) | activity | inhibit | moderate | | | | | stimulation | bradycardia | | | | Minimize | by the more | , | | | | the | potent | because a | | | | disturbance | endogenous | further | | | | s | catecholami | decrease in | | | | of lipid | nes, | heart rate | | | | and | epinephrine | is less | | | | carbohydrat | and | pronounced | | | | e | norepinephr | with these | | | | metabolism | ine. | drugs | | | | | The result | | | | | Do not | of these | Rarely used | | | | decrease | opposing | | | | | plasma HDL | actions is | | | | | levels | a | | | | | | diminished | | | | | | effect on | | | | | | reduction | | | | | | of cardiac | | | | | | rate and | | | | | | cardiac | | | | | | output | | | | | | compared to | | | | | | that of | | | | | | β-blockers | | | | | | without | | | | | | ISA. | | | +-------------+-------------+-------------+-------------+-------------+ | Labetalol & | Antagonists | Nonselectiv | Therapeutic | Orthostatic | | Carvedilol | of both α- | e | use in | hypotension | | | and | β-blockers | hypertensio | and | | | β-adrenocep | with | n | dizziness | | | tors | concurrent | and heart | associated | | | | α1-blocking | failure | with | | | | actions - | | α~1~-blocka | | | | produce | Labetalol | de | | | | peripheral | is used as | | | | | vasodilatio | an | | | | | n, | alternative | | | | | thereby | to | | | | | reducing | methyldopa | | | | | blood | in the | | | | | pressure | treatment | | | | | | of | | | | | Useful in | pregnancy-i | | | | | treating | nduced | | | | | hypertensiv | hypertensio | | | | | e | n | | | | | patients | | | | | | for whom | IV | | | | | increased | labetalol | | | | | peripheral | is also | | | | | vascular | used to | | | | | resistance | treat | | | | | is | hypertensiv | | | | | undesirable | e | | | | | | emergencies | | | | | Carvedilol | , | | | | | also | because it | | | | | decreases | can rapidly | | | | | lipid | lower blood | | | | | peroxidatio | pressure | | | | | n | | | | | | and | Cannot be | | | | | vascular | given to | | | | | wall | patients | | | | | thickening, | with acute | | | | | effects | exacerbatio | | | | | that have | n | | | | | benefit in | of heart | | | | | heart | failure, | | | | | failure. | but are | | | | | | beneficial | | | | | | in patients | | | | | | with stable | | | | | | heart | | | | | | failure- | | | | | | work by | | | | | | blocking | | | | | | the effects | | | | | | of | | | | | | sympathetic | | | | | | stimulation | | | | | | on the | | | | | | heart, | | | | | | which | | | | | | causes | | | | | | worsening | | | | | | heart | | | | | | failure | | | | | | over time | | +-------------+-------------+-------------+-------------+-------------+ A table with text on it Description automatically generated Classes of Drugs to Treat Glaucoma:  Drugs Affecting Neurotransmitter Release or Uptake: +-------------+-------------+-------------+-------------+-------------+ | **Drug** | **Pharmacok | **Actions** | **Therapeut | **Adverse | | | inetics** | | ic | Effects** | | | | | Uses** | | +=============+=============+=============+=============+=============+ | Reserpine | Blocks the | It has been | | | | | Mg^2+^/aden | used for | | | | | osine | the | | | | | triphosphat | management | | | | | e--dependen | of | | | | | t | hypertensio | | | | | transport | n | | | | | of biogenic | but has | | | | | amines | largely | | | | | (norepineph | been | | | | | rine, | replaced | | | | | dopamine, | with newer | | | | | and | agents with | | | | | serotonin) | better side | | | | | from the | effect | | | | | cytoplasm | profiles | | | | | into | and fewer | | | | | storage | drug | | | | | vesicles in | interaction | | | | | the | s. | | | | | adrenergic | | | | | | nerve | | | | | | terminals | | | | | | in all body | | | | | | tissues. | | | | | | | | | | | | This causes | | | | | | the | | | | | | ultimate | | | | | | depletion | | | | | | of biogenic | | | | | | amines. | | | | | | | | | | | | Sympathetic | | | | | | function, | | | | | | in general, | | | | | | is impaired | | | | | | because of | | | | | | decreased | | | | | | release of | | | | | | norepinephr | | | | | | ine. | | | | | | | | | | | | Slow onset, | | | | | | long | | | | | | duration of | | | | | | action, and | | | | | | effects | | | | | | that | | | | | | persist for | | | | | | many days | | | | | | after | | | | | | discontinua | | | | | | tion | | | | +-------------+-------------+-------------+-------------+-------------+