Adrenergic System - Part 2 PDF

## Adrenergic Antagonists According to the mechanism of action, adrenergic antagonists are divided into: * **Adrenergic Neuron Blockers:** * They interfere with the synthesis, storage, and/or release of the adrenergic neurotransmitter. * **Receptor Antagonists:** * They compete with NE for...

## Adrenergic Antagonists According to the mechanism of action, adrenergic antagonists are divided into: * **Adrenergic Neuron Blockers:** * They interfere with the synthesis, storage, and/or release of the adrenergic neurotransmitter. * **Receptor Antagonists:** * They compete with NE for α or β-receptors. * They have higher affinity for the receptor than agonists but lack intrinsic activity. * The effect is reversible (Competitive antagonists). * Some receptor blockers are irreversible and form stable complexes with the receptor. ### 1. Receptor Antagonists Receptor antagonists are drugs that bind to the receptors but do not trigger the usual receptor-mediated intracellular effects. * They have affinity but no efficacy. #### 1.A) α-Blockers ##### α-Adrenergic Blocking Agents * They comprise a mixture of chemical classes and bear little resemblance to agonists. * They block α₁-adrenergic receptors in arteries and smooth muscles. * Cause vasodilatation and decrease blood pressure, so are therapeutically used as antihypertensive agents. **Compare: Norepinephrine and these compounds:** Structure 1: * HO- * NH2 * R * HO Structure 2: * CH3 * HC * CI * H3CO * HO * NH2 * N Structure 3: * H3CO * H3CO * HO * NH2 * N ##### α-Adrenergic Blocking Agents * α-Adrenergic antagonists are classified into: * **Non-selective irreversible (non-competitive) blockers.** * B-Haloalkylamines: e.g. Phenoxybenzamine. * **Non-selective reversible (competitive) blockers.** * Imidazolines: e.g. Phentolamine. * Their clinical applications are limited to treating the symptoms of pheochromocytoma (tumor of the adrenal medulla composed of chromaffin cells). * **Selective α₁-adrenergic, reversible (competitive) blockers.** Azosins (Quinazolines): e.g. Prazosin. Structure 4: * CH3 * H3C * CI * HO * H3CO * N * NH2 Structure 5: * H3CO * α * N * N #### 1. Nonselective α-Antagonists ##### Non-selective irreversible blockers (β-Haloalkylamines): * **Phenoxybenzamine (dibenzyline):** * It is the only irreversibly acting adrenergic antagonist. * It spontaneously generates an electrophilic aziridinium cation that is readily attacked by α-receptor nucleophiles. * It alkylates α-receptors (forming strong covalent bonds), making the α-blockade irreversible and long-lasting. * Because of its receptor non-selectivity and toxicity, its use is limited to treating the symptoms of pheochromocytoma (patients with a benign NE/Epi-secreting tumor of the adrenal glands causing hypertension and generalized sympathetic stimulation). Structure 6: * CH3 * α-receptor * CH3 * CH3 * Phenoxybenzamine * aziridinium ion * Allkylated recptor ##### Non-selective reversible blockers (Imidazolines ): * They structurally similar to the imidazoline α-agonists (such as naphazoline and xylometazoline). * Examples include: Tolazoline and phentolamine. * They have antihypertensive activity. * Tolazoline has clear structural similarities to the imidazoline α1-agonists, such as naphazoline, but does not have the lipophilic substituents required for agonist activity. * Their clinical applications are limited to treating the symptoms of pheochromocytoma. * Both drugs stimulate Gl-smooth muscle and stimulate gastric secretion, possibly through release of histamine. Structure 7: * .HCI * Xylometazoline HCI * (Otrivin) Structure 8: * N * Tolazoline * H3C * N * IN Structure 9: * HO * Phentolamine #### 2. Selective α₁-Antagonists ##### Azosins (quinazoline-containing compounds): * They are 4-amino-6,7-dimethoxyquinazolines with related C2 side chains. * Side chain chemistry impacts physicochemical properties. * Terazosin structure differs from that of prazosin only in having tetrahydrofuran instead of furan ring. Structure 10: * H3CO * N * H3CO * H3CO * N * Tetrazosin * H3CO * NH2 * NH2 * N * CH3 Structure 11: * H3CO * N * H3CO * Prazosin * H3CO * NH2 Structure 12: * H3CO * N * H3CO * Doxazosin * NH2 Structure 13: * H3CO * Ο * H3CO * Alfuzosin * NH2 ##### Azosins (quinazoline-containing compounds): * Reduction of the furan into THF affected the pharmacokinetic properties: * Increased hydrophilicity, and hence Better bioavailability. * Altered rate of metabolism →→ Longer duration of action → once-a-day dosing. (As Doxazocin) Structure 14: * H3CO * H3CO * NH2 * H3CO * N * H3CO * N * N * N * Prazosin * Tetrazosin * H3CO * H3CO * Doxazosin * H3CO * Alfuzocin * NH2 * NH2 * NH ##### Azosins (quinazoline-containing compounds): * Selective competitive α₁-antagonists. Block the α₁-receptors in: * Bladder neck, prostate, ureter, and urethra. Relaxation of smooth muscle in these tissue → decreases resistance to urinary flow, reduces discomfort associated with Benign prostatic hyperplasia (BPH), and facilitates passage of kidney stones. * Vasculature. Without an increase from β2-blockers. * Tissues over the gland, over the urine bladder. * **Prazosin** is used for the prostate and the urethra. * **Alfuzosin** is used in the four tissues listed above. * It is clinically recommended for the prevention of symptoms. * **Terazosin** is used in the urethra. #### 2. Selective α₁-Antagonists ##### Tamsulosin and silodosin * Tamsulosin and silodosin (and alfuzosin) are selective α₁ receptor antagonists that have preferential selectivity for the α1A-receptor in the prostate versus the α₁B-receptor in the blood vessels (high uro-selectivity). * Thus, they are first-line drugs for the treatment of signs and symptoms of BPH. * They have no utility in treating hypertension. * Tamsulosin is an aryl sulfonamide analogue. * They don't decrease the overall size of the prostate in men with BPH, and is not recommended for prevention of prostate cancer. Structure 15: * F3C * CH3 * CH3 * OCH2CH3 * H3CO * HO * Tamsulosin * NH2 * Silodosin #### 3. Selective α₂-Antagonists ##### Yohimbine * Yohimbine, an indole alkaloid. * It is an α-antagonist with greater selectivity for α₂- than for α₁- adrenoceptors, but it also is a serotonin antagonist. * It has actions both in the CNS and in the periphery, inducing hypertension and increases in heart rate. * It has been used to treat erectile dysfunction in male (not as aphrodisiac). * Its reported clinical benefits were modest and it has largely been superseded by the PDE5-inhibitors e.g., sildenafil. * Also used in postural hypotension. Structure 16: * H * Yohimbine * H3C-O * OH * Remember; the antidote of tramadol overdose? ### B) β-Adrenergic Antagonists #### β-Adrenoceptors * There are three types of β-Adrenoceptor * **B₁-Adrenoceptor** * Predominant receptor in heart muscle * Activation results in cardiac muscle contraction * Antagonists of this receptor are potential cardiovascular drugs * **B2-Adrenoceptor** * Predominant receptor in bronchial smooth muscle * Activation results in smooth muscle relaxation * **B3-Adrenoceptor** * Predominant receptor in fat cells * Activation results in fat metabolism ### SAR of β-blockers * Before we start, a word about adrenergic agonists. * **Noradrenaline** is a neurotransmitter. * Structure 17: * HO * NH2 * R * HO * **Adrenaline** is a hormone. * Structure 18: * OH * HO * NHMe * R * HO * Adrenaline activates all adrenergic receptors. No selectivity. * **Isoprenaline** * Structure 19: * HO * H * OH * HO * Is a synthetic compound * Is a β-agonist (not antagonist). * Shows selectivity for β-adrenoceptors, over α receptors. * The N-Isopropyl group is responsible for β-selectivity. * Is there structural similarity of antagonist with agonists? * β-blockers bear structural similarity to the prototype agonist isoprenaline. #### SAR of β-blockers: Structural Features * **Aromatic ring (lipophilic):** * **Spacer:** * In the spacer is either: * X =no thing → 2 carbons spacer; ethanol→ arylethanolamines * All compounds in this class are non-selective * Or X = OCH₂ → oxypropanol spacer → aryloxypropanolamines. * Carbinol carbon is asymmetric, in case of: * Arylethanolamines: R is most active. * Aryloxypropanolamines: S is most active. * Alcohol is essential as a H-bonding group. * **Amine:** * Amine is ionized and forms an ionic bond with the binding site. * Amine must be secondary. * The substituent (R) is a β-directing group: Isopropyl, t-butyl, aralkyl. * Branched N-alkyl group fits a hydrophobic pocket. * Extension of N-alkyl group with N-arylethyl group is beneficial. #### SAR of β-blockers: Structural Features * **Aryl nucleus (Ar):** * In aryloxypropanolamines * If Naphthyl gr (as in propranolol): Non-selective. * Substituted naphthyl: also Non-selective * Naphthalene of propranolol is replaceable with heteroaromatic rings. * Heteroaromatic rings: non-selective; e.g. Pindolol and Timolol * If phenyl: * Non-substituted phenyl: non-selective β-antagonism. * Substituted phenyl: * P-substitution with H-bonding forming gr→B₁ selectivity: Chemical nature affects potency but not selectivity. * Small O-substituents retain ẞ₁ selectivity. * Other substituents (i.e. m-): non-selective β-antagonism #### SAR of β-blockers: Structural Features * Why Para-substitution is required for ẞ₁ selectivity? * Must be para - substituted for ẞ₁-selectivity * Extra H-bonding interaction takes place * Not possible with B₂-adrenoceptor #### SAR of β-blockers: Structural Features * Involved in H-bonding- to receptor. * Substitution lowers activity. * Branching and extension are beneficial. * Fits hydrophobic pocket. * Essential ionic bonding interaction. * Essential H-bonding interaction. * Must be secondary ### Members of β-adrenergic blockers #### A. 1st generation (Non-selective) β-adrenergic blockers * They block both ẞ₁ and B₂-receptors * Used for treatment hypertension, angina, arrhythmia and glaucoma * Caution should be considered when administered to patients with asthma or other pulmonary diseases (since they block B₂ receptors) #### B. 2nd generation (Selective) β₁-adrenergic blockers * They block only ẞ₁-receptor * Used for treatment of hypertension, angina and arrhythmia * Safe when administered to patients with asthma or other pulmonary diseases ### 1st generation: non-selective β-blockers #### Propranolol HCl * It is the prototype of aryloxypropanolamine nonselective ẞ-blockers. * S(+) is 100X more active than R(-), (Marketed as racemic mixture). * Aromatic ring: naphthalene (non-selective), and lipophilicity. * Relatively lipophilic → significant first pass metabolism → expect a decrease in duration of action (DOA) (but it is not true, why?) * One active metabolite (p-OH); the glucuronic acid conjugate is stored in tissue (expect it to be excreted) but is cleaved to release the active metabolite, increasing DOA. * Highly protein bound ----> Increases DOA * Lipophilicity increases CNS side effects (avoided in patients with depression and mental confusion). #### Propranolol HCl * It is indicated in hypertension, angina pectoris, cardiac arrhythmias; Myocardial Infarction; Control of tachycardia/tremor associated with anxiety & hyperthyroidism. * It is also used in migraine prophylaxis. * It is contraindicated in asthmatic patients or in bronchitis due to blockade of B₂-receptors. #### Propranolol HCl * **Structural Features in Propranolol** * Naphthalene is replaceable with heteroaromatic rings. * Ether acts as a hydrogen bond acceptor (HBA). * Ether can be replaced with an alternative HBA (O or NH). * Alcohol is essential as a hydrogen bonding group. * Amine is ionized and forms an ionic bond with the binding site. * Amine must be secondary:- * N-ispopropyl is a β-directing gr. * Branched N-alkyl group fits a hydrophobic pocket * Extension of N-alkyl group with N-arylethyl group is beneficial #### Propranolol HCl * All are Non selective aryl(heteroaryl)oxypropanolamines #### Nadolol (Corgard®) * It is indicated in angina pectoris and hypertension. * Available as tablets. * **SAR Notes:** * Oxypropanolamine structure. * Substituted naphthyl ring: non selective β-antagonist * It has a greater water solubility than propranolol with intermediate Log P. * It escapes extensive first pass effect → long duration of action. * Primarily excreted unchanged. * May accumulate in kidney disease. #### Timolol (Timoptic®) * Available as maleate salt. * Used as ophthalmic solution in management of chronic open glaucoma and ocular hypertension (reduces intraocular pressure). * Also used in tablet form as antihypertensive and antianginal agent. * **SAR notes:-** * DOA similar to propranolol. * If given topically, avoid 1st pass metabolism, thus DOA = 24 hr, slow to penetrate the eye. * Some CNS effects reported due to systemic absorption. * Use with caution in patients with pre-existing CHF or pulmonary disease. #### Pindolol (Visken) * **SAR Notes:** * Indole ring: non selective β-blocker. * Intrinsic sympathomimetic activity (ISA) (also Acebutolol) makes it safer to use in patients with respiratory disease (side effect from ẞ2 antagonism in lungs) and bradycardia. * Less effect on lipid profile, Less effect on carbohydrate metabolism: so suitable for diabetic patients. * Lipophilic: readily metabolized*. #### 2nd generation: selective β₁-blockers * Propranolol acts against both ẞ₁ and B₂-adrenoceptors. * Propranolol cannot be used with asthmatic patients. * Antagonism of B₂-adrenoceptors constricts airways. * Second generation B-blockers are designed to be B₁-selective. * Must be _para_-substituted aryoxypropanolamine. * Extra H-bonding interaction takes place, that not possible with B₂-adrenoceptors * They are designed to avoid ẞ₂-antagonism (bronchospasm). #### 2nd generation: selective β₁-blockers * **Acebutolol (has ISA?)** * **Atenolol** * **Betaxolol** * **Bisoprolol** * **Esmolol** * **Metoprolol** #### Metoprolol (Lopressor) * Its bitartrate salt is indicated in hypertension; angina pectoris; MI. * It is available in the form of tablets and solution for injection. * **Structural Features** * _p_-substituted phenyl: β₁ selective at therapeutic doses. * Relatively lipophilic. * Changes in the _p_-substituent (e.g. Bisoprolol (Concor®), Betaxolol, Esmolol, ) retain ẞ₁ selectivity. #### Esmolol (Brevibloc®) * Selective β₁-adrenergic receptor antagonists. * It has a rapid onset of action and short duration, 8 min., Why???? * Designed specifically to possess a very short action. * The short duration is the result of: * Rapid hydrolysis of ester functionality by esterases found in RBCs. * The resultant carboxylic acid is an extremely weak β₁-antagonist. * For this reason, its t1/2 = 8 min. and is used to control supraventricular tachycardia during surgery. * Administered: Parenteral by continuous I.V. infusion. * Note: incompatible with sodium bicarbonate. ### Mixed α₁, β-adrenergic blockers #### Labetalol * Labetalol is a unique arylethanolamine with a₁ and ẞ-blocker blocking activity → decreased peripheral vascular resistance without significant alteration of heart rate or cardiac output. * Labetalol has two chiral centers so exists as 4 stereoisomers: * (S,S)- and (R,S)- forms are inactive. * * (S,R)-isomer:-a powerful a₁-blocker. * * (R,R)-isomer (known as Dilevalol): a mixed nonselective β-blocker and selective a₁-blocker- The β:α antagonism is 3:1. * It is useful in the treatment of pregnancy-induced hypertension and in hypertensive emergencies. #### Carvedilol * It is an aryloxypropanolamine (structural motif of β-antagonists). * It is marketed as a racemic mixture of two stereoisomers. * The R isomer is a selective a₁-antagonist. * The S enantiomer is nonselective β-blocker. * It is indicated in the treatment of mild to severe congestive heart failure (CHF) and hypertension. * Carvedilol also possesses antioxidant activity. * It thus has a neuroprotective effect and has the ability to provide major cardiovascular organ protection. ### 2. Adrenergic Neuron Blocking Agents * Drugs interfere with the synthesis, storage and/or release of the adrenergic neurotransmitter. * Decreased sympathetic tone → inhibition of adrenergic transmission → vasodilation & reduced blood pressure. * They are transported to adrenergic neuron by uptake-1 and bind to the storage vesicles and prevent release of NE from sympathetic nerve terminals in response to a neuronal impulse. * They cause stabilization of the neuronal membrane or the membrane of the storage vesicle. * Thus, membranes become less responsive to nerve stimulation, thereby, inhibiting the release of NE into the synaptic cleft. * RBG-G: Reserpine, **Bretylium** , **Guanethidine** , and Guanadrel. #### Adrenergic Neuron Blocking Agents * **Guanethidine, and Guanadrel:** * They selectively block the peripheral sympathetic pathways (but not from the adrenal medulla). * They are orally active hypertensive agents. * They have largely been replaced by more effective agents but are noteworthy because of their oral administration and the mechanism by which they block the release of neurotransmitters from sympathetic nerve endings. * **Remember: a2-agonist** #### Adrenergic Neuron Blocking Agents * **Bretylium Tosylate** * It is an class III antiarrhythmic agent (Potassium channel blocker). * It blocks the release of NE from nerve terminals. * In effect, it decreases output from the peripheral sympathetic nervous system (quaternary ammonium salt: so given by injection). * Its clinical utility is limited to cardiac arrhythmias: ventricular arrhythmias that are resistant to other therapy. * **SAR:** * A quaternary ammonium compound; thus it is poorly absorbed from the GIT, erratic oral absorption of the quaternary ammonium compound and is so administered parenterally. * Excreted unchanged in the urine.