Drugs acting on Autonomic Nervous System - ADAMAS University PDF

Syllabus Drugs acting on Autonomic Nervous System – Adrenergic Neurotransmitters: – Biosynthesis and catabolism of catecholamine. – Adrenergic receptors (Alpha & Beta) and their distribution. – Sympathomimetic agents: SAR of Sympathomimetic agents – Direct acting agents: Nor-epinephrine,...

Syllabus Drugs acting on Autonomic Nervous System – Adrenergic Neurotransmitters: – Biosynthesis and catabolism of catecholamine. – Adrenergic receptors (Alpha & Beta) and their distribution. – Sympathomimetic agents: SAR of Sympathomimetic agents – Direct acting agents: Nor-epinephrine, Epinephrine, Phenylephrine*, Dopamine, Methyldopa, Clonidine, Dobutamine, Isoproterenol, Terbutaline, Salbutamol*, Bitolterol, Naphazoline, Oxymetazoline and Xylometazoline. – Indirect acting agents: Hydroxyamphetamine, Pseudoephedrine, Propylhexedrine. – Agents with mixed mechanism: Ephedrine, Metaraminol. – Adrenergic Antagonists: – Alpha adrenergic blockers: Tolazoline*, Phentolamine, Phenoxybenzamine, Prazosin, Dihydroergotamine, Methysergide. – Beta adrenergic blockers: SAR of beta blockers, Propranolol*, Metibranolol, Atenolol, Betazolol, Bisoprolol, Esmolol, Metoprolol, Labetolol, Carvedilol.  Syllabus Study of the development of the following classes of drugs, Classification, mechanism of action, uses of drugs mentioned in the course, Structure activity relationship of selective class of drugs as specified in the course and synthesis of drugs superscripted (*)  Nervous system determines that it is a highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. Neurotransmitter  Autonomic Nervous System (ANS) formerly called the vegetative nervous system. Also known as visceral nervous system. - is a division of the peripheral nervous system that supplies smooth muscle and glands, and thus influences the function of internal organs. - ANS is a control system that acts largely unconsciously and regulates bodily functions, such as the heart rate, digestion, respiratory rate, pupillary response, urination, and sexual arousal. - This system is the primary mechanism in control of the fight-or- flight response. 3  Autonomic Nervous System (ANS) - ANS is regulated by integrated reflexes through the brainstem to the spinal cord and organs. - Most autonomous functions are involuntary but they can often work in conjunction with the somatic nervous system which provides voluntary control. - Autonomic functions include control of respiration, cardiac regulation (the cardiac control center), vasomotor activity (the vasomotor center), and certain reflex actions such as coughing, sneezing, swallowing and vomiting. 4  Autonomic Nervous System (ANS) Three branches of ANS: sympathetic nervous system (often considered the "fight or flight" system) parasympathetic nervous system (often considered the "rest and digest" or "feed and breed" system) enteric nervous system (or intrinsic nervous system) - In many cases, both sympathetic and parasympathetic systems have "opposite" actions where one system activates a physiological response and the other inhibits it. - Sympathetic nervous system is a "quick response mobilizing system" and the parasympathetic is a "more slowly activated dampening system", but with some exceptions, such as in sexual arousal and orgasm, wherein both play a role. - Enteric system of neurons govern the function of the gastrointestinal tract 5 Adrenergic Neurotransmitters Catecholamine ❖ A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine. ❑ Catecholamines are derived from the amino acid tyrosine, which is derived from dietary sources as well as synthesis from phenylalanine catechol  Adrenergic Neurotransmitters - Adrenaline (epinephrine), Noradrenaline and Dopamine are the catecholamine neurotransmitters released from the adrenergic nerve fiber or neuron. - The neurotransmitters are first released from the axon and then bind to the receptor site on the dendrite. - Adrenergic nerve terminals are found in the secondary neurons of the sympathetic nervous system, one of two divisions of the autonomic nervous system which is responsible for the fight-or- flight response. Dopamine noradrenaline adrenaline (epinephrine) (norepinephrine) 6  Biosynthesis of norepinephrine - Biosynthesis of norepinephrine takes place within adrenergic neurons near the terminus of the axon and junction with the effector cell. - The biosynthetic pathway begins with the active transport of the amino acid L- tyrosine into the adrenergic neuron cell. - In the first step within the cytoplasm, the enzyme tyrosine hydroxylase (tyrosine-3-monooxygenase) oxidizes the 3′ position of tyrosine to form the catechol amino acid L- dihydroxyphenylalanine (L-DOPA). This is the rate-limiting step in norepinephrine biosynthesis. - In the second step, L-DOPA is decarboxylated to dopamine by aromatic L-amino acid decarboxylase. 7  Biosynthesis of norepinephrine - The dopamine formed is then taken up by active transport into storage vesicles or granules located near the terminus of the adrenergic neuron. Within these vesicles, the enzyme dopamine β-hydroxylase stereo- specifically introduces a hydroxyl group in the (R) absolute configuration on the carbon atom β to the amino group to generate the neurotransmitter norepinephrine. - The norepinephrine remains in the vesicles until released into the synapse during signal transduction. 8  Biosynthesis of epinephrine - The pathway for epinephrine biosynthesis in the adrenal medulla is the same as for norepinephrine with the additional step of conversion of norepinephrine to epinephrine by the enzyme phenylethanolamine-N-methyltransferase. 9  Catabolism of norepinephrine ❑After its release, norepinephrine diffuses through the intercellular space to bind reversibly to α- or β- adrenoceptors on the effector cell. ❑Once it has been released and is stimulating its various receptors, there must be mechanisms for removing the norepinephrine from the synapse and terminating the adrenergic impulse. 10  Catabolism of norepinephrine 1. Part of the norepinephrine taken into the presynaptic neuron by uptake-1 is metabolized to 3,4-dihydroxyphenylglycolaldehyde (DOPGAL) by mitochondrial monoamine oxidase (MAO). 2. and another part of norepinephrine is sequestered in the storage vesicles to be used again as a neurotransmitter. A less efficient uptake process, called uptake-2, operates in a variety of other cell types but only in the presence of high concentrations of norepinephrine. The part of norepinephrine that escapes uptake-1 diffuses out of the synapse and is metabolized in extraneuronal sites by catechol-O-methyltransferase (COMT), which methylates the meta hydroxyl group of norepinephrine to give normetanephrine. 10  Catabolism of norepinephrine AD: aldehyde dehydrogenase; AR, aldehyde reductase; COMT, catechol-O-methyltransferase; MAO, monoamine oxidase. 11  Adrenergic receptors ❑ A class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body. ❑ Specific molecular structures in or on effector cells with which catecholamines or sympathomimetic drugs react in order to elicit the characteristic response(s) of the cells. ❑ Adrenergic drugs are a broad class of medications that bind to adrenergic receptors throughout the body. ❑ These receptors include: alpha-1, alpha-2, beta-1, beta-2, beta-3. ❑ Adrenergic drugs will bind directly to one or more of these receptors to induce various physiologic effects.  Adrenergic receptors (α and β) and their distribution Adrenergic receptors were subclassified by Ahlquist in 1948 into α- and β- adrenoreceptor classes according to their responses to different adrenergic receptor agonists, principally norepinephrine, epinephrine, and isoproterenol. 12 Adrenergic receptors (α and β) and their distribution 13  Sympathomimetic agents Sympathomimetic agents or drugs are stimulants or stimulating compounds which mimic the effect of endogenous agonist (adrenaline or nor-adrenaline) of the sympathetic nervous system. Agents or drugs can make the stimulating action partially or completely. 3  Classification of sympathomimetic agents Classification based on the mechanism of action: 1. Direct-acting agonists e.g. epinephrine, nor-epinephrine, phenylephrine, Salbutamol Dopamine, Methyldopa, etc 2. Indirect-acting agonists e.g. amphetamine, cocaine, Propylhexedrine 3. Mixed-action agonists e.g. Ephedrine, pseudo-ephedrine, meta-araminol 4  Classification of sympathomimetic agents Classification based on the chemical structure i.e. catechol ring (presence/absence): 1. Catecholamines Presence of catechol ring in the structure Non-effective orally Quickly metabolized by MAO enzymes Quick action compared to non-catecholamines Do not readily cross BBB No significant CNS side effects Act directly on the adrenergic receptors e.g. epinephrine, nor-epinephrine, salbutamol, dopamine, methyldopa, etc 5  Classification of sympathomimetic agents Classification based on the chemical structure i.e. catechol ring (presence/absence): -- continued 2. Non-catecholamines Absence of catechol ring in the structure Effective orally Relatively resistant to metabolism by MAO enzymes Prolonged action compared to catecholamines Readily cross BBB Have significant CNS side effects Act directly on the adrenergic receptors as well as indirectly e.g. amphetamine, cocaine, ephedrine, pseudo- ephedrine 6  SAR sympathomimetic agents The parent structure for many of sympathomimetic drug is B-phenylethylamine. I. Phenyl ring substitution II. Substitution at nitrogen III. Substitution on the carbon side Chain 7  SAR sympathomimetic agents I. Phenyl ring substitution 1. Substitution on the meta and para positions of the aromatic ring and on the amino, α, and β positions of the ethylamine side chain influences the mechanism of sympathomimetic action and receptor selectivity of the drug. 2. Maximal activity is seen in β-phenyl ethylamine derivatives, containing hydroxyl groups in the meta and para positions of the aromatic ring (catechol) and a β- hydroxyl group of the correct stereochemical configuration on the ethylamine portion of the molecule. 3. Although the catechol moiety is an important structural feature to obtain maximal agonistic activity at adrenergic receptors, it can be replaced with other substituted phenyl moieties to provide selective adrenergic agonism. For example, replacement of the catechol function of isoproterenol with the resorcinol structure gives the drug metaproterenol, which is a selective β2- receptor 7 agonist.  SAR sympathomimetic agents I. Phenyl ring substitution 4. In another approach, replacement of the meta hydroxyl of the catechol structure with a hydroxymethyl group afforded Salbutamol, which shows selectivity to the β2 receptor. 5. The naturally occurring noradrenaline has 3, 4-dihydroxy benzene ring (catechol) active at both α and β receptors. However, it has poor oral activity because it is rapidly metabolized by COMT, the change in substitution pattern 3, 5-dihydroxy as in metaproterenol gives good oral activity. This is due to its resistance to metabolism by COMT. It also provides selectivity for β2 receptors. 7  SAR sympathomimetic agents II. Substitution at nitrogen 1. Amino group in phenylethylamines is important for direct agonistic activity. 2. The amino group should be separated from the aromatic ring by two carbon atoms found among the potent direct- acting agonists. 3. As the bulk of the nitrogen substituent increases, α-receptor agonistic activity decreases and β-receptor activity increases. 4. Thus, NE that is an effective β1- receptor agonist is also a potent α-agonist, while epinephrine is a potent agonist at α, β1, and β2 receptors. 5. N-tertiary butyl group enhances β2 selectivity. 6. As the size increases from hydrogen in Noradrenaline to methyl in adrenaline, isopropyl in isoproterenol, the activity of α receptor decreases and Beta receptor increases. 7. Primary and secondary amines are more potent direct acting agonists than 3° or 4° amines.  SAR sympathomimetic agents III. Substitution on the carbon side Chain 1. Methyl or ethyl substitution on the α-carbon of the ethylamine side chain reduces direct receptor agonist activity at both α and β receptors. 2. Importantly, an α-alkyl group increases the duration of action of phenylethylamine agonist by making the compound resistant to metabolic deamination by MAO. 3. α-substitution also significantly affects receptor selectivity. 4. Another effect of α-substitution is the introduction of a chiral centre which has pronounced effects on the stereo-chemical requirements for activity. 7  Direct-acting sympathomimetic agents Nor-epinephrine Mechanism of action & Uses: - Similar to epinephrine Works by constricting/narrowing the blood vessels and increasing blood pressure and blood glucose levels. 8  Direct-acting sympathomimetic agents They act through binding with specific adrenergic receptors. Epinephrine Mechanism of action & Uses: Used in emergencies to treat serious allergic reactions to insect stings/bites, drugs or other substances. It acts quickly to improve breathing, stimulate the heart, raise a dropping blood pressure, reduce swelling of the face, lips and throats. 7  Direct-acting sympathomimetic agents Salbutamol IUPAC Name: (RS)-4-[2-(tert-Butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol Mechanism of action & Uses: This drug is a short-acting β2adrenergic receptor agonist, relaxes the smooth muscle in the lungs and opens airways to improve breathing. It is used to treat asthma, chronic bronchitis, emphysema and to prevent exercise-related asthma. The most common side effects are fine tremor, anxiety, headache, muscle cramps, dry mouth, and palpitation Rare side effects: myocardial ischemia, angioedema, urticaria, hypotension 9  Direct-acting sympathomimetic agents Phenylephrine IUPAC Name: (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol Mechanism of action & Uses: - a selective α1-adrenergic receptor activator which results in the constriction of both arteries and veins. - primarily used as a decongestant, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids - Common side effects include nausea, headache, and anxiety 10  Direct-acting sympathomimetic agents Salbutamol also known as Albuterol IUPAC Name: (RS)-4-[2-(tert-Butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol Mechanism of action & Uses: This drug is a short-acting β2adrenergic receptor agonist, relaxes the smooth muscle in the lungs and opens airways to improve breathing. It is used to treat asthma, chronic bronchitis, emphysema and to prevent exercise-related asthma. The most common side effects are fine tremor, anxiety, headache, muscle cramps, dry mouth, and palpitation Rare side effects: myocardial ischemia, angioedema, urticaria, hypotension 2  Synthesis of Salbutamol (Albuterol) Route 1:  Synthesis of Salbutamol (Albuterol) Route 2: 1-(4-hydroxyphenyl)ethan-1-one  Direct-acting sympathomimetic agents Phenylephrine IUPAC Name: (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol Mechanism of action & Uses: - a selective α1-adrenergic receptor activator which results in the constriction of both arteries and veins. - primarily used as a decongestant, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids - Common side effects include nausea, headache, and anxiety 5 Synthesis of Phenylephrine 6  Direct-acting sympathomimetic agents Clonidine Clonidine is used to treat high blood pressure, ADHD, drug withdrawal (alcohol, opioids, or smoking), menopausal flushing, diarrhea, spasticity and certain pain conditions. IUPAC Name: N-(2,6-Dichlorophenyl)-4,5--1H-imidazol-2-amine Common side effects include dry mouth, dizziness, headaches, and sleepiness.. Severe side effects include hallucinations, heart arrhythmias, and confusion. Mechanism of Action: Clonidine treats high blood pressure by stimulating α2 adrenergic receptors in the brain stem, which decreases peripheral vascular resistance, lowering blood pressure. 7  Direct-acting sympathomimetic agents Dopamine IUPAC Name: 4-(2-Aminoethyl)benzene-1,2-diol 3,4-dihydroxyphenethylamine Mechanism of action & Uses: It works by improving the pumping strength of the heart and improves blood flow to the kidneys. It is used to treat certain conditions that occur when you are in shock caused by heart attack, trauma, surgery, heart failure, kidney failure and other serious medical conditions. 8  Direct-acting sympathomimetic agents Methyldopa IUPAC Name: (S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propanoic acid Mechanism of action & Uses: It is used alone or with other medications to treat high blood pressure (hypertension). Lowering high blood pressure helps to prevent strokes, heart attacks and kidney problems. It works by relaxing blood vessels and improve blood flow. 9  Direct-acting sympathomimetic agents Dobutamine IUPAC Name: (RS)-4-(2-{[4-(4-hydroxyphenyl)butan-2-yl]amino}ethyl)benzene-1,2-diol Mechanism of action & Uses: It is used in the treatment of cardiogenic shock and severe heart failure. It may also be used in certain types of cardiac stress tests. It primarily works by direct stimulation of β1receptors, which increases the strength of the heart's contractions. Common side effects include a fast heart rate, an irregular heart beat, and inflammation at the site of injection. 10  Direct-acting sympathomimetic agents Isoproterenol also known as Isoprenaline IUPAC Name: (RS)-4-[1-hydroxy-2-(isopropylamino)ethyl]benzene-1,2-diol Mechanism of action & Uses: It is used for the treatment of bradycardia (slow heart rate), heart block, and sometime for asthma. It is used to treat episodes of Adams-Stokes syndrome that are not caused by ventricular tachycardia or fibrillation, in emergencies for cardiac arrest until electric shock can be administered, for bronchospasm occurring during anesthesia. It is a non-selective βadrenoceptor agonist that is the isopropylamine analog of epinephrine (adrenaline). 11  Direct-acting sympathomimetic agents Isoproterenol (contd.) Adverse effects of isoprenaline include nervousness, headache, dizziness, nausea, visual blurring, tachycardia, palpitations, angina, Adams-Stokes attacks, pulmonary edema, hypertension, hypotension, ventricular arrhythmias, tachyarrhythmias, difficulty breathing, sweating, mild tremors, weakness, flushing, and pallor. Isoproterenol has been reported to cause insulin resistance leading to diabetic ketoacidosis. 12  Direct-acting sympathomimetic agents Terbutaline IUPAC Name: (RS)-5-[2-(tert-Butylamino)-1-hydroxyethyl]benzene-1,3-diol Mechanism of action & Uses: It is used as a fast-acting bronchodilator (often used as a short-term asthma treatment) and as a tocolytic to delay premature labor. The inhaled form of terbutaline starts working within 15 minutes and can last up to 6 hours. It is a β2 adrenergic receptor agonist 13  Direct-acting sympathomimetic agents Terbutaline The tertiary butyl group in terbutaline makes it more selective for β2 receptors. Since there is no hydroxy group on position 4 of the benzene ring, the molecule is less susceptible to metabolism by the enzyme catechol- O-methyl transferase (COMT). Side effects: Adult — tachycardia, anxiety, nervousness, tremors, headache, hyperglycemia, hypokalemia, hypotension, pulmonary edema. Fetal — tachycardia and hypoglycemia 14  Drugs acting on Autonomic Nervous System – Adrenergic Neurotransmitters: – Biosynthesis and catabolism of catecholamine. – Adrenergic receptors (Alpha & Beta) and their distribution. – Sympathomimetic agents: – Direct acting agents: Nor-epinephrine, Epinephrine, Phenylephrine*, Dopamine, Methyldopa, Clonidine, Dobutamine, Isoproterenol, Terbutaline, Salbutamol*, Bitolterol, Naphazoline, Oxymetazoline and Xylometazoline. – Indirect acting agents: Hydroxyamphetamine, Pseudoephedrine, Propylhexedrine. – Agents with mixed mechanism: Ephedrine, Metaraminol. – Adrenergic Antagonists: – Alpha adrenergic blockers: Tolazoline*, Phentolamine, Phenoxybenzamine, Prazosin, Dihydroergotamine, Methysergide. – Beta adrenergic blockers: SAR of beta blockers, Propranolol*, Metibranolol, Atenolol, Betazolol, Bisoprolol, Esmolol, Metoprolol, Labetolol, Carvedilol. 2  Direct-acting sympathomimetic agents Bitolterol Bitolterol is a prodrug of colterol. IUPAC Name: (RS)-[4-(1-Hydroxy-2-tert-butylamino- ethyl)-2-(4-methylbenzoyl)oxy-phenyl] 4- Colterol methylbenzoate Mechanism of action & Uses: It is a short-acting β2adrenergic receptor agonist. It relaxes the smooth muscles present continuously around the bronchi and bronchioles facilitating the flow of air through them. It is used for the relief of bronchospasm in conditions such as asthma and COPD (Chronic obstructive pulmonary disease). 3  Direct-acting sympathomimetic agents Naphazoline IUPAC name: 2-(naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole Mechanism of action & Uses: It is a sympathomimetic agent with marked alpha-adrenergic stimulating activity. It is used as a decongestant. It is a vasoconstrictor with a rapid action in reducing swelling when applied to mucous membrane. It acts on alpha-receptors in the arterioles of the conjunctiva to produce constriction, resulting in decreased congestion. Adverse effect: Extended use may cause rhinitis medicamentosa, a condition of rebound nasal congestion. 4  Direct-acting sympathomimetic agents Oxymetazoline IUPAC name: 3-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol Mechanism of action & Uses: It activates to α1 adrenergic receptors and α2 adrenergic receptors It is a over-the-counter medicine used as a topical decongestant. Due to its vasoconstricting properties, oxymetazoline is also used to treat nose bleeds and eye redness due to minor irritation. In July 2020, oxymetazoline received approval by the FDA for the treatment of acquired drooping eyelid. Adverse effect: Rebound congestion, rhinitis medicamentosa. 5  Direct-acting sympathomimetic agents Xylometazoline also spelled xylomethazoline IUPAC name: 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]- 4,5-dihydro-1H-imidazole Mechanism of action & Uses: It works by stimulating α1 and α2 adrenergic receptors on the lamina propria of blood vessels in the nose. It is used to reduce symptoms of nasal congestion, allergic rhinitis, and sinusitis The decongestant effect is due to constriction of large veins in the nose which swell up during the inflammation of any infection or allergy of the nose. Adverse effect: rhinitis medicamentosa. 6  Indirect-acting sympathomimetic agents Hydroxyamphetamine Other names: 4-Hydroxyamphetamine para-Hydroxyamphetamine Oxamphetamine Norpholedrine α-methyltyramine IUPAC name: 4-(2-aminopropyl)phenol It is a major metabolite of amphetamine Mechanism of action & Uses: It acts as an indirect sympathomimetic and causes the release of norepinephrine from nerve synapses which leads to mydriasis (pupil dilation). It is used in eye drops to dilate the pupil (a process called mydriasis) so that the back of the eye can be examined. This is used in the diagnostic test for Horner's syndrome. 7  Indirect-acting sympathomimetic agents Pseudoephedrine (PSE) IUPAC name: (S,S)-2-methylamino-1-phenylpropan-1-ol Mechanism of action & Uses: It acts as an indirect sympathomimetic and causes the release of norepinephrine from nerve synapses. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses. It reduces tissue hyperemia, edema, and nasal congestion commonly associated with colds or allergies. It can be used either as oral or topical decongestant. However, due to its stimulating qualities, the oral preparation is more likely to cause adverse effects, including urinary retention 8  Indirect-acting sympathomimetic agents Propylhexedrine IUPAC name: (±)-1-cyclohexyl-N-methylpropan-2-amine Mechanism of action & Uses: It acts as an indirect sympathomimetic and causes the release of norepinephrine from nerve synapses. It is a nasal decongestant, appetite suppressant, and psychostimulant medication. It is used to treat acute nasal congestion related to common cold, allergies and hay fever. Propylhexedrine should not be used if a MAO inhibitor has been used in the past 14 days, or is being currently used, as this can lead to a hypertensive crisis. People with cardiovascular disease should not use propylhexedrine. 9  Mixed-action sympathomimetic agents Ephedrine 2 enantiomers of ephedrine: (1R,2S)-(−)-ephedrine, or (−)-erythro-ephedrine, or L-ephedrine, and (1S,2R)-(+)-ephedrine, or (+)-erythro-ephedrine. IUPAC name: (R,S)-2-(methylamino)-1-phenylpropan-1-ol 10  Mixed-action sympathomimetic agents Ephedrine Mechanism of action & Uses: Ephedrine works by increasing the activity of the αand βadrenergic receptors. It increases blood pressure and act as bronchodilators. It may decrease motion sickness, but it has mainly been used to decrease the sedating effects of other medications used for motion sickness. It promotes modest short-term weight loss, specifically fat loss. Adverse effects: Cardiovascular: tachycardia, cardiac arrhythmias, angina pectoris, vasoconstriction with hypertension Dermatological: flushing, sweating, acne vulgaris Decreased urination due to vasoconstriction of renal arteries Restlessness, confusion, insomnia, mild euphoria, mania/hallucinations Dyspnea, pulmonary edema 11  Mixed-action sympathomimetic agents Metaraminol also known as metaradrine IUPAC name: (1R,2S)-3-[-2-amino-1-hydroxy-propyl]phenol Mechanism of action & Uses: It is an α1-adrenergic receptor agonist with some βeffect. It is used in the prevention and treatment of hypotension, particularly as a complication of anesthesia. 12  Drugs acting on Autonomic Nervous System – Adrenergic Neurotransmitters: – Biosynthesis and catabolism of catecholamine. – Adrenergic receptors (Alpha & Beta) and their distribution. – Sympathomimetic agents: – Direct acting agents: Nor-epinephrine, Epinephrine, Phenylephrine*, Dopamine, Methyldopa, Clonidine, Dobutamine, Isoproterenol, Terbutaline, Salbutamol*, Bitolterol, Naphazoline, Oxymetazoline and Xylometazoline. – Indirect acting agents: Hydroxyamphetamine, Pseudoephedrine, Propylhexedrine. – Agents with mixed mechanism: Ephedrine, Metaraminol. – Adrenergic Antagonists: – Alpha adrenergic blockers: Tolazoline*, Phentolamine, Phenoxybenzamine, Prazosin, Dihydroergotamine, Methysergide. – Beta adrenergic blockers: SAR of beta blockers, Propranolol*, Metibranolol, Atenolol, Betazolol, Bisoprolol, Esmolol, Metoprolol, Labetolol, Carvedilol. 2  Adrenergic Antagonists or Blockers An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors by either reducing or blocking the signals of adrenergic agonists or sympathomimetic agents. Adrenergic antagonists are also known as sympatholytic agents because such agents inhibit the function of sympathetic nervous system. Broadly, there are two categories of adrenergic antagonists: α-adrenergic antagonists or blockers β-adrenergic antagonists or blockers 3  Mechanisms of Action of Adrenergic Antagonists Three different types of Mechanisms of Action: Competitive Non-competitive Uncompetitive 4  Mechanism of Action of Competitive Adrenergic Antagonists Competitive antagonists are a type of reversible antagonists. A competitive antagonist binds to the same binding site of the receptor that the agonist binds to. Even though it is in activator region/binding-site, the antagonist does not activate the receptor. This type of binding is reversible as increasing the concentration of agonist will outcompete the concentration of antagonist, resulting in receptor activation. While only a few α-adrenergic antagonists are competitive, all β- adrenergic antagonists are competitive antagonists. Adrenergic competitive antagonists are shorter lasting than the other two types of antagonists. e.g. Propanolol, Phentolamine 5  Mechanism of Action of Non-competitive Adrenergic Antagonists Non-competitive antagonists are a type of irreversible antagonists. A non-competitive antagonist can either bind to the agonist binding site of the receptor or other site called the allosteric site. Such antagonist also does not activate the receptor. This type of binding is irreversible. If the non-competitive antagonist binds to the allosteric site and an agonist binds to the ligand site, the receptor will remain inactivated. e.g. Phenoxybenzamine (a non-selective α-adrenergic antagonist) 6  Mechanism of Action of Uncompetitive Adrenergic Antagonists Uncompetitive antagonists differ from non-competitive antagonists in that they require receptor activation by an agonist before they can bind to a separate allosteric binding site. It means that the action of an uncompetitive antagonist is dependent on the receptor's prior activation. This type of antagonism produces a kinetic profile in which "the same amount of antagonist blocks higher concentrations of agonist better than lower concentrations of agonist". No adrenergic antagonists are reported as uncompetitive antagonist. Memantine, used in the treatment of Alzheimer's disease, is an uncompetitive antagonist of the NMDA receptor. 7  Classification of Adrenergic Antagonists/Blockers α-adrenergic antagonists / blockers e.g. Tolazoline, Phentolamine, Phenoxybenzamine, Prazosin, Dihydroergotamine, Methysergide, etc β-adrenergic antagonists / blockers e.g. Propranolol, Metipranolol, Bisoprolol, Atenolol, Metoprolol, Esmolol, Nebivilol, Oxprenolol, Timolol, Pindolol, Nadolol, Pindolol, Acebutolol, Sotalol, Betaxolol, etc Mixed-action or both α and β, or Non-selective adrenergic antagonists / blockers e.g. Labetalol, Carvedilol 8  α-Adrenergic Antagonists or Blockers Tolazoline IUPAC Name: 2-Benzyl-4,5-dihydro-1H-imidazole It is a non-selective competitive α-adrenergic receptor antagonist. It is a vasodilator that is used to treat spasms of peripheral blood vessels (as in acrocyanosis). It has also been used (in conjunction with sodium nitroprusside) successfully as an antidote to reverse the severe peripheral vasoconstriction which can occur as a result of overdose with certain 5-HT2A agonist drugs. It is however most commonly used in veterinary medicine, to reverse xylazine-induced sedation. 9  α-Adrenergic Antagonists or Blockers Tolazoline Synthesis 10  α-Adrenergic Antagonists or Blockers Phentolamine IUPAC Name: 3-[(4,5-Dihydro-1H-imidazol-2-yl- methyl)(4-methylphenyl)amino]phenol It is a reversible nonselective α-adrenergic antagonist. Its primary action is vasodilation due to α1 blockade. It is used for the control of hypertensive emergencies, most notably due to pheochromocytoma. It is also used in the treatment of cocaine-induced cardiovascular complications. Adverse effects: Orthostatic hypotension 11  α-Adrenergic Antagonists or Blockers Phenoxybenzamine IUPAC Name: (RS)-N-Benzyl-N-(2-chloroethyl)-1-phenoxypropan-2-amine It is a reversible nonselective α-adrenergic antagonist. It is used for the control of hypertensive emergencies, most notably due to pheochromocytoma. It has a slower onset and a longer-lasting effect (bind covalently with α-adrenergic receptors) compared with other α-adrenergic blockers. It is also used in the treatment of hypoplastic left heart syndrome and complex regional pain syndrome (CRPS) type 1. Adverse effects: reflex tachycardia 12  Drugs acting on Autonomic Nervous System – Adrenergic Neurotransmitters: – Biosynthesis and catabolism of catecholamine. – Adrenergic receptors (Alpha & Beta) and their distribution. – Sympathomimetic agents: – Direct acting agents: Nor-epinephrine, Epinephrine, Phenylephrine*, Dopamine, Methyldopa, Clonidine, Dobutamine, Isoproterenol, Terbutaline, Salbutamol*, Bitolterol, Naphazoline, Oxymetazoline and Xylometazoline. – Indirect acting agents: Hydroxyamphetamine, Pseudoephedrine, Propylhexedrine. – Agents with mixed mechanism: Ephedrine, Metaraminol. – Adrenergic Antagonists: – Alpha adrenergic blockers: Tolazoline*, Phentolamine, Phenoxybenzamine, Prazosin, Dihydroergotamine, Methysergide. – Beta adrenergic blockers: SAR of beta blockers, Propranolol*, Metibranolol, Atenolol, Betazolol, Bisoprolol, Esmolol, Metoprolol, Labetolol, Carvedilol. 2  α-Adrenergic Antagonists or Blockers Prazosin IUPAC Name: [4-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-1-piperazinyl](2-furyl)methanone It is a selective α1-adrenergic antagonist. It is primarily used to treat high blood pressure, symptoms of an enlarged prostate, and posttraumatic stress disorder (PTSD). Side effects: dizziness, sleepiness, nausea, heart palpitations, orthostatic hypotension, and depression 3  α-Adrenergic Antagonists or Blockers Dihydroergotamine IUPAC Name: (2R,4R,7R)-N-[(1S,2S,4R,7S)-7-benzyl-2-hydroxy-4-methyl-5,8-dioxo-3-oxa-6,9- diazatricyclo[7.3.0.02,6]dodecan-4-yl]-6-methyl-6,11- diazatetracyclo[7.6.1.02,7.012,16]hexadeca-1(16),9,12,14-tetraene-4-carboxamide 4  α-Adrenergic Antagonists or Blockers Dihydroergotamine It is an ergot alkaloid used to treat migraines. It is a derivative of ergotamine. It acts as an agonist to the serotonin receptors and antagonist for adrenergic receptors. It is administered as a nasal spray or injection for the treatment of migraines. Nausea is a common side effect. 5  α-Adrenergic Antagonists or Blockers Methysergide IUPAC Name: (6aR,9R)-N-[(2S)-1-Hydroxybutan-2-yl]-4,7-dimethyl- 6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide It is a an agonist to the serotonin receptors and antagonist for adrenergic receptors. It is used exclusively to treat episodic and chronic migraine and for episodic and chronic cluster headaches. Side effects: retroperitoneal fibrosis/retropulmonary fibrosis 6  β-Adrenergic Antagonists or Blockers β-blockers are competitive antagonists that block the β adrenergic receptors of the sympathetic nervous system. β-blockers block receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline). e.g. Propanolol, labetolol, atenolol, timolol, and various others. 7  β-adrenergic blockers (or β-blockers) All β-blockers used clinically are competitive antagonists. Year 1958 → Discovery of Dichloroisoprenaline First β-blocker Low potency and partial agonist) Non-selective for β1 and β2 Year 1963 → Discovery of Propanolol The first clinically successful beta blocker [blocks both β1 and β2 (non-selective) and a weak activity for β3] 8  Classification of β-blockers 1) Nonselective (β1 and β2) Without intrinsic sympathomimetic activity (ISA) e.g. Propanolol, Timolol, Sotalol With intrinsic sympathomimetic activity e.g. Pindolol With additional α blocking property e.g. Labetalol, Carvedilol 2) β1 selective or Cardioselective e.g. Metoprolol, Atenolol, Acebutolol, Bisoprolol, Esmolol, Betaxolol, Celiprolol, Nebivolol 9  Propanolol blocks both β1 and β2 (non-selective) and a weak activity for β3. chiral carbon (centre) It is racemic (R or S) form. Decreases heart rate, force of contraction and cardiac output Also reduces the cardiac workload by reducing the aortic pressure. 10  Synthesis of Propanolol Naphth-1-ol Epichorohydrin 11  Structure-Activity Relationship (SAR) of β-blockers (First generation; non-selective blockers) Essential for activity; shows Essential for activity; hydrogen bonding; replacement shows hydrogen bonding Essential for activity; with S, CH2, NMe groups are shows ionic bonding; detrimental for activity. must be secondary amine Branched bulky N-alkyl Substitution on the substituents are better Variation of aromatic ring is methylene group for antagonistic activity; possible and heteroatomic rings ↑ metabolic stability shows hydrophobic can be introduced. e.g. Pindolol, and ↓ activity interaction. timolol, etc. 12 Structure-Activity Relationship (SAR) of β-blockers (Second generation; β1-selective blockers) 13  Timolol non-selective β-blocker, blocks both β1 and β2 S-stereoisomer form Used as eye drops for ocular hypertension and glaucoma, Used orally for high blood pressure, angina, to prevent further complications after a heart attack, and to prevent migraines. not recommended in those with asthma, uncompensated heart failure, or COPD. 14  Pindolol non-selective β-blocker, blocks both β1 and β2 Racemic form Used for high blood pressure (worldwide) and also for angina pectoris (outside US). also an antagonist of the serotonin 5-HT1A receptor, used in combination with Selective Serotonin Reuptake Inhibitors (SSRI) for the treatment of depression. 15  Atenolol β1 selective blocker Racemic form Primarily used to treat high blood pressure and heart-associated chest pain. Other uses include the prevention of migraines and treatment of certain irregular heart beats. 16  Acebutolol β1 selective blocker Racemic form used for the treatment of hypertension and arrhythmias. 17  Other β1-selective blockers Betaxolol Bisoprolol Celiprolol Metoprolol 18  Other β1-selective blockers Esmolol Nebivolol Metipranolol 19  Mixed-action or Non-selective adrenergic blockers Labetalol non-selective β-blocker, blocks both β1 and β2 has additional α1-blocking activity the first drug created that combined both alpha- and beta- adrenergic receptor blocking properties It decreases peripheral vascular resistance without significant alteration of heart rate or cardiac output. chiral carbon (centre) 20  Mixed-action or Non-selective adrenergic blockers Carvedilol non-selective β-blocker, blocks both β1 and β2 R-stereoisomer form It is also α-adrenergic receptor blocker (α1). Used for high blood pressure, congestive heart failure (CHF), and left ventricular dysfunction. 21