Direct Acting Antagonists PDF

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic Noradrenergic transmission Direct acting noradrenergic drugs YFRM202 2  Lecture Overview In this lecture you can expect to learn abou...

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic Noradrenergic transmission Direct acting noradrenergic drugs YFRM202 2  Lecture Overview In this lecture you can expect to learn about adrenergic antagonists that oppose the effects of the sympathetic nervous system. You have previously learned about adrenergic agonists that mimic the effects of the sympathetic nervous system. In this lecture you will build upon that knowledge and further explore the indications and adverse effects of the alpha and beta- blockers. Throughout this lecture it will become clear that the selectivity of a drug is for a particular kind of receptor mirrors the expected adverse effects. 3  Learning Outcomes At the end of this lecture, you should be able to:  Differentiate between the direct-acting alpha antagonists in terms of their selectivity for the various alpha receptors  Describe the pharmacological effects, clinical uses and adverse effects of the alpha antagonists  Differentiate between the direct-acting beta antagonists in terms of their selectivity for the various beta receptors  Describe the pharmacological effects, clinical uses and adverse effects of the beta antagonists  Describe the pharmacological effects, clinical uses and adverse effects of the mixed alpha and beta receptor antagonists 4  Sympatholytic drugs Sympatholytic drugs block the effects of adrenergic receptor activation Alpha receptors: α1, α2 Beta receptors: β1, β2, β3 Results in the opposite effect to that of NA or an adrenergic agonist binding to the receptors. Effects mimic activation of the parasympathetic system Since the sympatholytics depress the sympathetic division, they result in parasympathetic effects. Rang and Dale’s pharmacology. 2024. Chapter 15. Page 205. 5 α-Antagonists (α blockers) Selective and non-selective YFRM202 6  α-Antagonists α-Antagonists Non- α1-selective α2-selective selective Rang & Dale’s Pharmacology. 2024. Chapter 15. Page 217. 7  Alpha receptor antagonists will have the opposite effect Table 15.1 Distribution and actions of adrenoceptors Rang and Dale’s pharmacology. 2024. Chapter 15. Page 207. 8  Non-selective α-Antagonists Bind to and block both α1 and α2 receptors: Phenoxybenzamine Non-competitive irreversible antagonist Forms very stable, long-lasting covalent bonds to the receptor Long duration of action is ~3-4 days Phentolamine Competitive reversible antagonist Can be displaced by NA or agonists as bond formed is not as strong Duration of action is ~3-4 hours Rang & Dale’s Pharmacology. 2024. Chapter 15. Page 217. 9  Effect of non-selective α-antagonists Cause a fall in arterial pressure: Block of α1-receptor-mediated vasoconstriction Postural hypotension Reflex response to the fall in arterial pressure cause and increase in cardiac output and heart rate Inhibit presynaptic α2 receptors. This prevents the inhibitory effect of the α2 receptors, so more NA is released which is capable of binding to postsynaptic adrenergic receptors - enhancing the reflex tachycardia Rang & Dale’s Pharmacology. 2024. Chapter 15. Page 217. Phentolamine blocks α2-adrenoceptor–mediated inhibition of NE release. This increases the stimulation of cardiac β1-adrenoceptors (β1) and results in tachycardia. 10  Effect of non-selective α-antagonists PHARMACOLOGIC ADVERSE DRUG CLINICAL USE EFFECTS EFFECTS Postural Preparing hypotension patients with Vasodilation Tachycardia Phenoxybenazamine pheochromoc ↓BP Nasal ytoma for congestion surgery Impotence Postural hypotension Vasodilation Tachycardia Phentolamine ↓BP Rarely used Nasal congestion Impotence Rang & Dale’s Pharmacology. 2024. Chapter 15 Table 15.5 Adrenoceptor antagonists. Page 212, 217 Brenner and Steven’s pharmacology. 2023. Chapter 9. Table 9.1 Mechanism, effects and clinical use of adrenoceptor antagosists. Page 96-97. Pheochromocytoma is a tumor of the adrenal medulla that secretes huge amounts of catecholamines, causing extremely high blood pressure. In this setting, phenoxybenzamine is used to control hypertension until surgery can be performed to remove the tumor 11  α1-selective Antagonists PHARMACOLOGIC DRUG ADVERSE EFFECTS CLINICAL USE EFFECTS Vasodilation Urinary symptoms Postural hypotension caused by benign Prazosin ↓BP Nasal congestion (α1) Relax bladder, urethral and prostatic hyperplasia Impotence prostate smooth muscle Hypertension Vasodilation Urinary symptoms Doxazosin Postural hypotension caused by benign ↓BP (α1) Nasal congestion Relax bladder, urethral and prostatic hyperplasia Impotence prostate smooth muscle Hypertension Tamsulosin Relax bladder, urethral and Urinary symptoms (α1A) prostate smooth muscle Failure of ejaculation caused by benign (uroselective) prostatic hyperplasia Rang & Dale’s Pharmacology. 2024. Chapter 15 Table 15.5 Adrenoceptor antagonists. Page 212, 217 Brenner and Steven’s pharmacology. 2023. Chapter 9. Table 9.1 Mechanism, effects and clinical use of adrenoceptor antagosists. Page 96-97. The bladder sphincters are caused to constrict under the influence of the catecholamines NA and Adrenline.. They also cause the bladder itself to relax. The α1-receptor antagonists cause relaxation of the smooth muscle of the bladder neck and prostate capsule, and inhibit hypertrophy of these tissues, and are therefore useful in treating urinary retention associated with benign prostatic hypertrophy. Tamsulosin, an α1A-receptor antagonist, shows some selectivity for the bladder, and causes less hypotension than the less selective α1-receptor antagonists. The main uses of α-adrenoceptor antagonists are related to their cardiovascular actions, and are summarised in the clinical box (below) These drugs have only limited therapeutic applications. Non-selective α-blocking drugs are unsatisfactory in treating hypertension, because of their tendency to produce tachycardia, postural hypotension and gastrointestinal symptoms. Selective α1-receptor antagonists (especially the longer- acting compounds doxazosin and terazosin) are, however, useful. They do not directly affect cardiac function appreciably, and postural hypotension is less troublesome than with prazosin or non-selective α-receptor antagonists. They have a place in treating 12 severe hypertension, where they are added to treatment with first- and second-line drugs, but are not used as first-line agents 12  Benign prostatic hypertrophy (BPH) Anatomic enlargement of the prostate gland, which produces a physical block at the bladder neck and thereby obstructs urinary outflow Excessive α adrenergic tone of the stromal component of the prostate gland, bladder neck, and posterior urethra, which results in contraction of the prostate gland around the urethra and narrowing of the urethral lumen Lee M, & Sharifi R (2023). Benign prostatic hyperplasia. DiPiro J.T., & Yee G.C., & Haines S.T., & Nolin T.D., & Ellingrod V.L., & Posey L(Eds.), DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill. 13  Autonomic drugs acting on the bladder Autonomic drugs acting on the bladder Obstructive symptoms Overactive bladder associated with BPH syndrome Problem is narrowing and Problem is contraction of contraction of the sphincter the detrusor muscle: muscle: M3 antagonists: α1 antagonist: oxybutynin, darifenacin doxazosin β3 agonists: α1A selective: mirabegron tamsulosin Where would drugs with anticholinergic adverse effects feature here? Hyoscine butylbromide (Buscopan®) Anti-histamines: chlropheniramine (Allergex®) Image Source: Çakıcı, Ö.U., Dinçer, S. The effect of amino acids on the bladder cycle: a concise review. Amino Acids 54, 13–31 (2022). https://doi.org/10.1007/s00726-021- 03113-5 Image address: https://www.researchgate.net/publication/356708887/figure/fig4/AS:11192263749468 17@1643855770135/The-figure-demonstrates-the-main-receptors-and-relevant- neurotransmitters-in-control-of.png Date accessed: 13 May 2023. 14  α2-selective Antagonists Not used clinically as they cause hypertension and don’t have any desirable pharmacological effect Yohimbine is a naturally occurring alkaloid A selective α2 antagonist Claimed to be an aphrodisiac Rang & Dale’s Pharmacology. 2024. Chapter 15 Table 15.5 Adrenoceptor antagonists. Page 212 15  β-Antagonists (The Beta Blockers) Selective and non-selective YFRM202 16  Beta-receptor antagonists β-Antagonists Non- β1-selective β2-selective selective None available – no clinical reasoning for such selectivity Brenner and Steven’s pharmacology. 2023. Chapter 9. Table 9.2 Pharmacologic properts of B-adrenoceptor antagonists. Page 100. No clinical reason to want to cause bronchoconstriction or vasoconstriction in skeletal muscle 17  Tissues and effects β1 β2 β3 Smooth muscle Blood vessels — Dilate — Bronchi — Dilate — Gastrointestinal tract — Relax — Uterus — Relax — Bladder detrusor — Relax Relax Seminal tract — Relax — Iris (radial muscle) — — — Beta receptor Ciliary muscle — Relax — antagonists will have Heart the opposite effect a Rate Increase Increase — a Force of contraction Increase Increase — Other tissues/cells Skeletal muscle — Tremor Thermogenesis Increased muscle mass and speed of contraction Glycogenolysis Liver (hepatocytes) — Glycogenolysis — Fat (adipocytes) — — Lipolysis Thermogenesis Kidney (juxtaglomerular cells) Activation of renin-angiotensin- - — aldosterone system Table 15.1 Distribution and actions of adrenoceptors Rang and Dale’s pharmacology. 2024. Chapter 15. Page 207. 18  Examples of beta-receptor antagonists Non-selective β1-selective Propranolol Atenolol Timolol Bisoprolol Brenner and Steven’s pharmacology. 2023. Chapter 9. Table 9.2 Pharmacologic properts of B-adrenoceptor antagonists. Page 100. 19  Propranolol Specific pharmacological properties affecting its clinical uses and adverse effect profile: It is highly lipophilic Able to cross the BBB Can be used for migraine prophylaxis Can cause depression and bad dreams as a side effect Can be used for familial tremor and definitely for tremor and anxiety of thyrotoxicosis Has a membrane-stabilising effect Almost like a local anaesthetic effect , thus propranolol is not used topically in the treatment of glaucoma Brenner & Stevens’ Pharmacology. 2023. Chapter 9. Page 101 Rang & Dale’s Pharmacology. 2024. Table 15.5. Page 212, 218 In addition to producing β-receptor blockade, some drugs exhibit membrane-stabilizing (local anesthetic) activity, the therapeutic relevance of these properties has never been clearly established. Propranolol, acebutolol, and pindolol exhibit varying degrees of membrane-stabilizing activity. Hence, these agents are not employed as eye drops in the treatment of glaucoma. 20  Indications of beta-blockers Non-selective Selective for B1 Thyrotoxicosis (propranolol) Ischaemic heart disease: angina, Anxiety (to control somatic myocardial infarction symptoms, tachycardia, tremor) Arrhythmias (associated with Migraine prophylaxis tachycardia) Benign essential tremor Hypertension (last line, unless compelling reason for use) Glaucoma (timolol eye drops) Heart failure (carvedilol) Rang & Dale’s Pharmacology. 2024. Page 220 Not every beta blocker is used for all of these clinical uses. They each differ with regards to their pharmacological properties (e.g. lipophilicity, membrane-stabilising effect, selectivity, etc.) which affects their clinical actions. Refer to Brenner & Stevens’ Pharmacology’s Table 9.1 for the clinical uses for each individual drug. 21  Beta-blockers decrease blood pressure Their antihypertensive effect develops over a few days They ↓ BP through various complex mechanisms: ↓ Cardiac output ↓ Renin release from the juxtaglomerular cells of the kidney Inhibits activation of the renin-angiotensin-aldosterone (RAA) system A central action, reducing sympathetic activity Inhibition of presynaptic β2 receptors prevents further NA release Rang & Dale’s Pharmacology. 2024. Page 219. Blockade of cardiac β1-adrenoceptors reduces heart rate, cardiac contractility, and atrioventricular conduction velocity. Beta-blockers reduce cardiac output and blood pressure, and all of the orally administered β-blockers are used to treat arterial hypertension. In the kidneys, β1-receptor blockade reduces renin secretion from the juxtaglomerular cells, leading to reduced synthesis of angiotensin, and thereby contributing to a reduction in blood pressure. Beta-blockers reduce cardiac oxygen demand and many of the drugs are used to treat angina pectoris. A few, including acebutolol, are used to treat cardiac dysrhythmias 22  Adverse effects of beta-blockers Non-selective Selective for B1 Adverse effects are mostly ascribed Adverse effects are mostly because to β2 antagonist effects in the lungs, of these drugs’ action on the liver, and vascular smooth muscle: cardiovascular system: Bronchoconstriction Cardiac depression Hypoglycaemia – see notes – very Fatigue important Bradycardia Decreased peripheral blood flow Need to consider these effects during exercise especially in active individuals who Cold extremities are playing sport, exercising etc. Fatigue Rang & Dale’s Pharmacology. 2024. Page 220. Bronchoconstriction: - This is of little importance in the absence of airways disease, but in asthmatic patients the effect can be life-threatening. It is also of clinical importance in patients with other forms of obstructive lung disease (e.g. chronic bronchitis, emphysema), although the risk–benefit balance may favour cautious treatment in individual patients and, as mentioned previously, it has been hypothesised that β- receptor antagonists might actually be of value in treating stable asthmatic patients. Hypoglycaemia - The mechanism responsible for β-blocker–induced hypoglycaemia involves inhibition of hepatic glucose production, which is promoted by sympathetic nervous stimulation. In addition, adrenergic counter regulation is diminished, resulting in a reduction in glycogenolysis. Non-cardioselective β-blockers such as propranolol are more likely to cause hypoglycaemia than cardioselective ones such as atenolol and metoprolol. Nevertheless, patients on the latter should still be cautioned about the potential for drug-induced hypoglycaemia. Furthermore, β-blockers have the potential for masking symptoms of hypoglycaemia. The catecholamine-mediated neurogenic hypoglycaemic symptoms masked by this class of medications include tremor and palpitations. Hunger, tremor, irritability, and confusion may be concealed as well. Sweating, however, remains unmasked and may be the only recognizable sign of hypoglycaemia in individuals treated with β-blockers. Ref :- 23 https://diabetesjournals.org/spectrum/article/24/3/171/32354/Drug-Induced-Glucose- Alterations-Part-1-Drug Hypoglycaemia: Glucose release in response to adrenaline is a safety device that may be important to diabetic patients and to other individuals prone to hypoglycaemic attacks. The sympathetic response to hypoglycaemia produces symptoms (especially tachycardia) that warn patients of the urgent need for carbohydrate (usually in the form of a sugary drink). β-Receptor antagonists reduce these symptoms, so incipient hypoglycaemia is more likely to go unnoticed by the patient. There is a theoretical advantage in using β1-selective agents, because glucose release from the liver is controlled by β2 receptors. In diabetic patients, the use of β-receptor antagonists increases the likelihood of exercise-induced hypoglycaemia, because the normal adrenaline-induced release of glucose from the liver is diminished. Furthermore, β-receptor antagonists may alter the awareness of hypoglycaemia by blunting its symptom Fatigue: This is probably due to reduced cardiac output and reduced muscle perfusion in exercise. It is a frequent complaint of patients taking β-receptor-blocking drugs. Cold extremities: This is common, due to a loss of β-receptor-mediated vasodilatation in cutaneous vessels. Theoretically, β1-selective drugs are less likely to produce this effect, which may also be less marked in patients treated with β-adrenoceptor antagonists with additional vasodilating properties, but it is not clear that this is so in practice. Cardiac depression: - Cardiac depression can occur, leading to signs of heart failure, particularly in elderly people. Patients suffering from heart failure who are treated with β- receptor antagonists often deteriorate symptomatically in the first few weeks before the beneficial effect develops. Bradycardia: - Sinus bradycardia can progress to life-threatening heart block, particularly if β-adrenoceptor antagonists are co-administered with other antidysrhythmic drugs that impair cardiac conduction 23  Treatment of glaucoma Intraocular pressure Ocular angle https://classconnection.s3.amazonaws.com/360/flashcards/855360/png/untitled1327354918608.png (Date accessed: 31 Mar 17) M3 receptors Alpha 1 receptors Beta 2 receptors Fig. 14.5 The anterior chamber of the eye, showing the pathway for secretion and drainage of the aqueous humour Rang and Dale’s pharmacology. 2024. Chapter 27. The eye. Figure 27.2 The anterior chamber of the eye, showing the pathway for secretion and drainage of the aqueous humour. Page 385. The βblocking agents produce ocular hypotensive effects by decreasing the production of aqueous humor by the ciliary body without producing substantial effects on aqueous humor outflow facility. The mechanism by which βblockers decrease aqueous humor inflow remains controversial, but it is most frequently attributed to β2adrenergic receptor blockade in the ciliary body. Alpha2 agonists reduce IOP by decreasing the rate of aqueous humor production (some increase in uveoscleral outflow also occurs with brimonidine). Reference: Fiscella R.G., & Owaidhah O.A., & Edward D.P. (2023). Glaucoma. DiPiro J.T., & Yee G.C., & Haines S.T., & Nolin T.D., & Ellingrod V.L., & Posey L(Eds.), DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill. https://0- accesspharmacy.mhmedical.com.wam.seals.ac.za/content.aspx?bookid=3097&sectionid =271955754 24  Pupil dilation and constriction P/Eye_Anatomy/media/sphincter_dilator.gif (Date http://teaching.pharmacy.umn.edu/courses/eyeA https://s-media-cache-ak0.pinimg.com/originals/0b/2a/f2/0b2af20e3aa68e8afd982b005ae9f95c.jpg (Date accessed: 2 May 17) accessed: 2 May 17) M3 receptors Alpha 1 receptors 25  Variations in intraocular pressure Fig. 27.3 Variation in intraocular pressure depends on balance between production of aqueous humour and outflow Rang and Dale’s pharmacology. 2024. Chapter 27. The eye. Figure 27.2 The anterior chamber of the eye, showing the pathway for secretion and drainage of the aqueous humour. Page 387. 26  Drugs that lower intraocular pressure a Drug Drug class Mechanism of lowering IOP Timolol, β-adrenoceptor antagonist Decreasing the production of aqueous humour by the ciliary body without producing substantial effects on aqueous humor outflow facility. carteolol The mechanism by which βblockers decrease aqueous humor inflow remains controversial, but it is most frequently attributed to β2adrenergic receptor blockade in the ciliary body. Acetazolamide, Carbonic anhydrase Decreasing the production of aqueous humour by blocking active secretion of sodium and bicarbonate ions from the ciliary body to the dorzolamide inhibitor aqueous humour. Clonidine, α 2 -adrenoceptor agonist Decreasing the production of aqueous humour (may also increase outflow) apraclonidine Latanoprost Prostaglandin analogue Increasing the uveoscleral and, to a lesser extent, trabecular outflow of aqueous humour Pilocarpine Muscarinic agonist Increasing the trabecular outflow of aqueous humour, by physically pulling open the trabecular meshwork secondary to ciliary muscle contraction, and reducing resistance to outflow Ecothiophate Anticholinesterase Increasing the trabecular outflow of aqueous humour, by physically pulling open the trabecular meshwork secondary to ciliary muscle contraction, and reducing resistance to outflow Rang and Dale’s pharmacology. 2024. Chapter 27. The eye. Page 387. 27  Mixed α- and β-Antagonists Non-selective YFRM202 Drugs that result in inhibition of adrenergic receptors by acting as antagonists at one or more adrenergic receptors 28  Non-catecholamine adrenergic receptor agonists Act as antagonists at the following receptors: β1 Pharmacological effects include: Vasodilation β2 ↓ HR and BP in patients with α1 hypertension Carvedilol ↑ cardiac output in Drugs include: patients with heart failure Carvedilol Labetalol Brenner & Stevens’ Pharmacology. 2023. Page 100 & 101. Table 9.1 29  Mixed α- and β-Antagonists Carvedilol Labetalol Used in the treatment of: Used in the treatment of Hypertension hypertension Heart failure Usually hypertensive emergencies administered IV SAMF. 2022. C07 Beta-blocking agents. Page 165. 30  Checklist Can you...  Differentiate between the direct-acting alpha antagonists in terms of their selectivity for the various alpha receptors?  Describe the pharmacological effects, clinical uses and adverse effects of the alpha antagonists?  Differentiate between the direct-acting beta antagonists in terms of their selectivity for the various beta receptors?  Describe the pharmacological effects, clinical uses and adverse effects of the beta antagonists?  Describe the pharmacological effects, clinical uses and adverse effects of the mixed alpha and beta receptor antagonists? Did you...  Complete The Attendance Register? 31  Resources Osmosis videos: Adrenergic antagonists: alpha blockers Adrenergic antagonists: beta blockers 32  References Brenner & Stevens’ Pharmacology. 2023. Chapter 9 Adrenergic receptor antagonists. Page 95-102. Rang and Dale’s Pharmacology. 2024. Chapter 15 Noradrenergic transmission. Page 205-224. South African Medicines Formulary. 2022. C07 Beta-blocking agents. Page 162-166. 33  Feedback Please be kind enough to take a minute and rate this lesson and provide a little feedback to help us gain a better understanding of your learning experience. Let us know what you really enjoyed and what we can do better for you. Click on the link at the bottom of the lesson page on I-learn to provide feedback for this lesson. +- (2mins) 34 35 36