Sympathomimetic Drugs PDF

1 Deepali M. Nahar Assistant Professor Pharmaceutical Chemistry Department St. John Institute of Pharmacy and Research, Palghar 2 Adrenergic Drugs  The sympathetic system activates and prepares the body for vigorous muscular activity, stress, and emergencies.  Adr...

1 Deepali M. Nahar Assistant Professor Pharmaceutical Chemistry Department St. John Institute of Pharmacy and Research, Palghar 2 Adrenergic Drugs  The sympathetic system activates and prepares the body for vigorous muscular activity, stress, and emergencies.  Adrenergic drugs stimulate the adrenergic nerves directly by mimicking the action of norepinephrine or indirectly by stimulating the release of norepinephrine.  Therapeutically, these drugs are used to combat life-threatening disorders, which include acute attacks of bronchial asthma, shock, cardiac arrest, and allergic reactions.  In addition these drugs are used as nasal decongestants and appetite suppressants. 3 Adrenergic Nerve Transmission  Norepinephrine is released from the nerve ending in response to a nerve impulse or drug.  NE interacts with alpha and beta-receptor sites.  Its receptor action is terminated by recapture and storage in the original nerve ending or inactivated by an enzyme. 4 Adrenergic Neurotransmitters Adrenergic nerves release the neurotransmitters; Norepinephrine (noradrenaline, (NE)) Epinephrine (E) Dopamine (DA) 5 6  Life cycle of NE 7  Life cycle of NE 8 Biosynthesis of catecholamine 9 Biosynthesis of Catecholamine 10 11 Biosynthesis of Catecholamine 12 Biosynthesis of Catecholamine 13 Summary of biosynthesis  Five enzymes are involved in the pathway of the biosynthesis of adrenaline.  The first enzyme is the iron containing phenylalanine-hydroxylase (also called phenylalanine-4- monooxygenase).  The second enzyme, tyrosine-hydroxylase, contains iron, too, and catalyses the conversion of tyrosine to L-β-(3,4-dihydroxyphenyl)-α-alanine (DOPA).  After decarboxylation of DOPA to dopamine (aromatic amino-acid decarboxylase AAAD), the copper-containing enzyme dopamine-β-hydroxylase converts dopamine to noradrenaline.  The final enzyme noradrenaline N-methyltransferase then methylates noradrenaline to adrenaline.  The noradrenaline formed in the adrenergic nerve endings remain stored in vesicles as its adenosine triphosphate complex.  The adrenal medulla also synthesizes and stores noradrenaline and adrenaline. 14 Storage & Release  A 15 Metabolism and distribution of catecholamine  The actions of adrenaline and noradrenaline are terminated by three processes ;  1. Re-uptake into the nerve terminal  2. Dilution by diffusion from the junctional cleft and uptake at non-neuronal sites, and  3. Metabolic transformation 16 Catabolism of Catecholamine 17 Catabolism: MAO PATHWAY 18 Catabolism: COMT PATHWAY  Summary Metabolism of NE and E 21 Adrenergic receptors (Alpha & Beta) and their distribution  Adrenergic drugs exert their effects by direct action on adrenergic receptors.  There are at least two adrenergic receptor sites (alpha (α) and beta (β)).  Norepinephrine activates primarily alpha-receptors and epinephrine activates primarily beta receptors, although it may also activate alpha receptors.  Stimulation of alpha receptors is associated with constriction of small blood vessels in the bronchial mucosa and relaxation of smooth muscles of the intestinal tract.  Beta receptor activation relaxes bronchial smooth muscles which cause the bronchi of the lungs to dilate.  In addition beta receptor stimulatory effects cause an increase in the rate and force of heart contractions.  As a result increased amounts of blood leave the heart and is diverted from nonactive organs to areas that actively participate in the body’s reaction to stress such as skeletal muscles, brain, and liver. 22 Adrenergic receptors Alpha Beta (α) (β) receptor receptor Adrenergic Receptors 23 Subtypes of receptors 24 Subtypes of receptors 25 Alpha receptor site  Important features of alpha adrenergic receptor sites in order of preference are ; ✓1. An anionic site. The alpha-adrenergic receptor carries a negatively charged group (phosphate). The anionic site binds with the positive ammonium group. ✓2. One hydrogen bonding area ✓3. A flat area. A non-polar area for the aromatic ring binding.  The alpha receptors fall into two groups;  (i) α1-Adrenergic receptor: They are found in the smooth muscles of iris, arteries, arterioles and veins.  (ii) α2-Adrenergic receptors: They mediate the inhibition of adrenergic neurotransmitter release. 26 Beta receptor site  Important features of this receptor site are:  1. An anionic site. It is shown that an anionic negative acid group which binds with the positive ammonium group.  2. Two hydrogen bonding areas. It is shown as two serine with alcohol (-OH) groups form hydrogen bonding with the phenolic -OH groups of the NE.  3. A flat area. A non-polar area for the aromatic ring. 27 Beta receptor site  β-Adrenergic receptors are of three types.  (i) β1-Adrenergic receptors. They are found in the myocardium where their stimulation increases the force and rate of myocardial contraction.  (ii) β2-Adrenergic receptors. These are found in bronchial and vascular smooth muscles where their stimulation causes smooth muscle dilation or relaxation.  (iii) β3-Adrenergic receptors. These receptors are expressed on fat cells and their stimulation causes lipolysis. 28 29 30 Functions of Receptor 31 32 Mechanism of action MOA of α1-Agonist MOA of α2-Agonist MOA of β-Agonist MOA of β1-Agonist 37 SAR Ref: Wilson & Griswold 38 SAR 39 40 41 42 43 44 45 46 47 48 49 Classification of Adrenergic agonists 50  Alpha-Agonist Beta-Agonist Direct acting agonist  Direct acting α- Agonist Non- Selective selective Norepinephrine α1-Selective α2- selective Epinephrine Phenylephrine Clonidine naphazoline Methyldopa Oxymetazoline Guanabenz Xylometazoline Guanafacine ɑ-Adrenergic agonist Chemical Classification A. Catecholamines: e.g. Epinephrine, Norepinephrine, Isoprenaline B. Non-catecholamines I. Phenylethanolamine: e.g. Phenylephrine, methyldopa II. 2-arylimidazolidines: e.g. Naphazoline, oxymetazoline, xylometazoline III. 2-aminoimidazolidines: e.g. Clonidine A. Ring opened analog of Clonidine Guanabenz, Guanafacine Epinephrine  Chemically it is 1-(3,4-dihydroxyphenyl)-2- methylaminoethanol.  Non-selective agonist  Adrenaline is available as adrenaline acid tartarate.  Adrenaline is a potent stimulator of both α and β receptors  Shows prominent actions on the heart and vascular smooth muscle  The oral intake of adrenaline has no effect. Therefore it has to be administered parenterally. 56  Adrenaline is one of the most potent vasopressors, given by IV route, it evokes a characteristic rise in blood pressure.  The mechanism of the rise in blood pressure with adrenaline is; 1. Direct myocardial stimulation (positive inotropic effect) 2. An increased heart rate (positive chronotropic effect) 3. Peripheral vasoconstriction 57 Uses:  It is used as sympathomimetic (drugs which support the beating of the heart),  Broncholytic (drugs which relax the bronchial muscles) and  Antiasthmatic (drugs against asthma).  It is also used to prevent bleedings during surgery or in the case of inner organ bleeding.  Because adrenaline leads to constriction of blood vessels, it is administered in combination with local anesthetics. In this combination, anesthetics have a longer lasting effect and can be administered in smaller doses.  Phenylephrine* Chemical name: (R)-3-[-1-hydroxy- 2-(methylamino)ethyl]phenol Phenylephrine differs from adrenaline only by lacking the 4-OH group on the benzene ring subsequently is resistant to COMT has predominantly α-agonist effects. Metabolism: Intestinal 3’-O-glucuronidation (ACTIVE) and sulphation  Methyldopa Chemical name: (S)-2-amino- 3-(3,4-dihydroxyphenyl)-2- methyl-propanoic acid Chemically it is phenyl ethanolamine and differs from L-DOPA in only additional α-methyl group which imparts α2-Selectivity It is a prodrug acts via its active metabolite α-methyl NE Methyldopa  Dopamine DA is rapidly metabolized by COMT and MAO has a short DOA with no oral activity. It is used intravenously in treatment of shock. 63  2-ARYLIMIDAZOLINE Examples: 1. Naphazoline 2. Xylometazoline 3. Oxymetazoline These are ɑ1-selective agonist all contain one carbon bridge between C-2 of imidazoline ring and a phenyl substituent. Therefore it mimics the general structure of phenylethylamine.  Naphazoline, Oxymetazoline and Xylometazoline Naphazoline Chemical name: 2-(Naphthalen-1- yl)methyl-4,5-dihydro-1H-imidazole  Xylometazoline and Oxymetazoline Uses: They have potent vasoconstriction effect. Therefore they are used as nasal decongestant, mydriatic, Treatment of Rhinitis medicamentosa (condition of rebound nasal congestionbrought on by extended use of topical decongestant) Epistaxis (Nose bleeding)  2-AMINOIMIDAZOLINES: Clonidine Differs from 2-arylimidazoline ɑ1-agonists mainly by the presence of o-chlorine groups and a NH bridge. The o-chlorine groups afford better activity than o-methyl groups at ɑ2 sites. Clonidine 70 Ring opened analog of clonidine  Both are α-2 agonist and MOA is same as clonidine.  Used as antihypertensive agent  Beta- Agonist Non- Selective selective Beta1- Beta2- Isoproterenol Selective selective Terbutaline Salbutamol Colterol Dobutamine Metaproterenol Ritodrine Isoxuprine Isoproterenol  Nonselective beta-agonist Dobutamine Terbutaline  Terbutaline is a non- catecholamine, therefore is resistant to COMT  Use: Short term asthma and used as Tocolytic (agents used to suppress premature labor) Salbutamol (Albuterol)*  It has strong β2 adrenergic activity.  It is useful in the treatment of acute myocardial infarction, severe left ventricular failure.  It has been used to arrest premature labor and is effective in ocular hypotension by topical application.  It is used only as a bronchodilator and is the drug of choice in the treatment of bronchial asthma.  Long duration of action 76  Bitolterol  It is a prodrug of Colterol (a 2-selective agonist) in which the catechol OH groups have been converted to di-p-toluate esters, providing increased lipid solubility caused by the presence of the two lipophilic di-p-toluate esters  Shows rapid onset of action within 2-5 min and lasts up to 4-6 hrs.  The presence of the bulky di-ester and bulky N- tert-butyl groups also prolong the DOA (8 hours) because it is resistant to COMT and MAO metabolism  Propylhexedrine Phenyl Amphetamine isopropylamine Methamphetamine Hydroxyamphetamine Phenyl Pseudoephedrine propanolamine  Propylhexedrine  Uses. Propylhexedrine is used as  1) Nasal decongestant  2) adrenergic agent (vasoconstrictor) Propylhexedrine is 1-cyclohexyl-2-methylaminopropane, which occurs as racemic mixture.  Hydroxyamphetamine  Hydroxyamphetamine occurs as hydrobromide salt.  Uses. Hydroxyamphetamine is used in the following conditions ; ❑ (a) Narcolepsy (sudden attack of sleep in completely inappropriate situations) ❑ (b) Hyperkinetic syndrome in children ❑ (c) As an anorexiant in the treatment of obesity Pseudoephedrine ❖ These drugs act both directly with the receptor sites and partly by the release of endogenous norepinephrine.  Ephedrine  Occurs naturally in many plants, being the principal alkaloid of Ma Huang which has been used in China for over 2000 years.  It has agonist activity at both α and β-receptors.  It contain two asymmetric carbon atoms, four compounds are available only racemic and L-ephedrine are clinically in use.  Ephedrine differs from adrenaline mainly by its,  1. effectiveness after oral administration  2. longer duration of action  3. more pronounced central actions  4. much lower potency  It produces a sharp rise in systolic, diastolic and pulse pressures, with a reflex bradycardia, similar to adrenaline but lasting for 10 times as long. Metaraminol  Chemically metaraminol is (1R,2S) 3- hydroxyphenyl isopropanolamine.  Metaraminol is an isomer of phenylephrine.  Uses. Metaraminol is used for its pressor action for maintaining blood pressure during anesthesia, haemorrhage and other hypotensive states. 85 86