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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5265_Библиотеки_им_академика_М_И_Перельмана.pdf
Drugs Acting on Autonomic Nervous System 187
Chemical Name: 2-benzyl-4,5-dihydro-1H-imidazole
Properties: It occurs as a white to almost white, hygroscopic, crystalline solid, odorless. It is
freely water soluble, and slightly soluble in ethanol and DMSO.
Uses: Tolazoline is used to treat a number of conditions including:
➢ Scleroderma (disease that affects the skin, connective tissue and internal organs)
➢ Thromboangiitis obliterans (Buerger disease) caused by small blood vessels that become
inflamed and swollen
➢ Peripheral vascular diseases.
➢ Persistent foetal circulation syndrome.
➢ Arteriosclerosis abliterans (arterial disease most prominently affecting the abdominal
aorta, as well as the small and medium-sized arteries).
➢ Causalgia (burning pain that results from injury to a peripheral nerve).
Dosage Forms: Tolazoline is available in the following forms:
➢ Injectable solution
➢ Oral tablet
➢ Tolazoline 25 mg/mL intravenous solution
Storage and Stability: Store the medicine in a closed container at room temperature, away from
heat, moisture and direct light. Keep from freezing.
6.2.2 Phentolamine
Brand Name: Regitine, OraVerse
Phentolamine is a synthetic imidazoline derivative that is a reversible non-selective
α-adrenergic antagonist used for the control of hypertensive emergencies. The chemical
structure of Phentolamine is:
Chemical Name: 3-[4,5-dihydro-1H-imidazol-2-ylmethyl-(4-methylphenyl)amino]phenol
188 Text Book of Pharmaceutical Chemistry
Properties: Phentolamine occurs as a white to off-white, odorless crystalline powder. It is freely
soluble in water and in alcohol, and slightly soluble in chloroform, practically insoluble
in acetone, ethyl acetate. Melting point is 174.5°C.
Uses: Phentolamine is used to treat a number of conditions including:
➢ Hypertensive emergencies, most notably due to pheochromocytoma
➢ Cocaine-induced cardiovascular complications
➢ Vasospasm of raynaud disease and frostbite
➢ Clonidine withdrawal syndrome
➢ Impotence
➢ Peripheral vascular disease
Dosage Forms: Powder for injection (5 mg) and injectable solution (0.4 mg/1.7 ml)
Storage and Stability: Phentolamine mesylate injection is stable for 48 hours at room
temperature or 1 week at 2°C to 8°C. However, the manufacturer recommends that the
reconstituted injection be used immediately and not stored.
Marketed Preparations:
➢ Regitin 10 mg/mL (Phentolamine) – Novartis
➢ Fentanor Inj 10 mg/mL (Phentolamine Injection BP) – Shraddhha Pharma and Surgicals
➢ Actiza Liquid Phentolamine Injection 5 mg – Casid Pharmaceuticals Pvt. Ltd.
Officials:
➢ Phentolamine Mesylate, I.P.
➢ Phentolamine Mesylate Injection, I.P.
6.2.3 Phenoxybenzamine
Brand Name: Dibenzyline
Phenoxybenzamine is a non-selective, irreversible alpha blocker. It is an aromatic amine. It
contains a stereocenter. So, there are two enantiomers, the (R)-forms and the (S)-forms. The
chemical structure of Phenoxybenzamine is:
Chemical Name: N-benzyl-N-(2-chloroethyl)-1-phenoxypropan-2-amine
Drugs Acting on Autonomic Nervous System 189
Properties: Phenoxybenzamine hydrochloride is a colorless, white crystalline powder, odorless
with a molecular weight of 340.3, which melts between 136 and 141°C. It is soluble in water,
alcohol and chloroform; and insoluble in diethyl ether.
Uses: Phenoxybenzamine is used to treat a number of conditions including:
➢ High blood pressure
➢ Heavy sweating due to a certain tumor of the adrenal glands (pheochromocytoma)
➢ Bladder problems such as urgency, frequency, and inability to control urination in
patients with neurogenic bladder, functional outlet obstruction, and partial prostatic
obstruction
➢ Paroxysmal hypertension
Dosage Forms: Phenoxybenzamine comes as a capsule to take by mouth; oral capsule (10 mg).
Storage and Stability: Store the medicine in a closed container at room temperature, away from
heat, moisture and direct light. Keep from freezing. Store at 25°C (77°F); excursions permitted to
15°C to 30°C (59°F to 86°F).
Marketed Preparations:
➢ Fenoxene 10 mg (Phenoxybenzamine Capsules) – Genex Pharma
➢ Phenoxybenzamine Capsules B.P. 10 mg – SG Pharma Pvt. Ltd.
➢ Phenoxybenzamine 50 mg Injection – United Biotech
6.2.4 Prazosin
Brand Names: Minipress, Minizide
Prazosin is a piperazine derivative in which piperazine is substituted by a furan-2-ylcarbonyl
group and a 4-amino-6,7-dimethoxyquinazolin-2-yl group at positions 1 and 4 respectively. It is a
non-selective alpha-adrenergic antagonist (alpha-blocker) used in the therapy of
hypertension. The chemical structure of Prazosin is:
Chemical Name: [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(furan-2-yl) methanone
Properties: It occurs as white to tan crystalline powder. Its melting point is 278°C to 280°C.
Prazosin Hydrochloride is slightly soluble in various solvents: water, ethanol, methanol,
dimethylformamide, dimethylacetamide, chloroform and acetone.
190 Text Book of Pharmaceutical Chemistry
Uses: Prazosin is used to treat a number of conditions including:
➢ Heart failure
➢ Urinary retention
➢ Hypertension
➢ Pheochromocytoma
➢ Raynaud’s syndrome
➢ Prostatic hypertrophy
➢ Symptoms of an enlarged prostate
➢ Nightmares related to post-traumatic stress disorder (PTSD)
Storage and Stability: Prazosin hydrochloride should be stable for at least two years when stored
desiccated at room temperature and protected from the light. It should be stored in well closed,
light resistant containers at 15-30°C.
Dosage Form: Prazosin is available in capsule (1 mg, 2 mg and 5 mg).
Marketed Preparations:
➢ Prazosin (5 mg) Minipress – Pfizer Ltd.
➢ VEXZOSIN (Prazosin Tablets B.P. 1 mg) – Vexxa Lifesciences Pvt. Ltd.
➢ Gentrol 2.5 mg (Prazosin Hydrochloride Extended Release Tablets) – Medigen Inc.
Officials:
➢ Prazosin Hydrochloride, I.P.
➢ Prazosin Hydrochloride Tablet, I.P.
Beta-adrenergic Blockers
Beta-adrenergic blockers, often known as beta blockers, are a type of medication that binds to
beta-adrenoreceptors and prevents the binding of norepinephrine and epinephrine at these
receptors. It prevents sympathetic stimulation of the heart and reduces heart rate, cardiac
contractility, conduction velocity, and relaxation rate which decrease myocardial oxygen demand
and increases exercise tolerance.
Beta-adrenergic blockers are widely used to treat hypertension, angina pectoris and cardiac
arrhythmias, and also used for migraine prophylaxis to treat anxiety, to prevent essential tremor,
and to block the side-effects of hyperthyroidism.
Drugs Acting on Autonomic Nervous System 191
6.2.5 Propranolol
Brand Name: Inderal
Propranolol is a non-selective beta-adrenergic blocker. It is a propanolamine that is propan-2-
ol substituted by a propan-2-ylamino group at position 1 and a naphthalen-1-yloxy group at
position 3. It is a racemic mixture of two enantiomers where the S(-)-enantiomer has 100 times
the binding affinity for beta-adrenergic receptors. The chemical structure of Propranolol is:
Chemical Name: 1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-ol
Properties: Propranolol hydrochloride is a stable, white or almost white, odorless, bitter taste,
crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.80. Its
melting point is 164.0°C. It is practically insoluble in ether, benzene and ethyl acetate.
Uses: Propranolol is used for treating various conditions, including:
➢ High blood pressure (hypertension)
➢ A number of types of irregular heart rate, angina pectoris (with the exception of variant
angina)
➢ Hypertrophic cardiomyopathy
192 Text Book of Pharmaceutical Chemistry
➢ Myocardial infarction
➢ Tachycardia (and other sympathetic nervous system symptoms, such as muscle tremor)
➢ Portal hypertension, to lower portal vein pressure
➢ Prevention of esophageal variceal bleeding and ascites
➢ Performance anxiety
➢ Prevention of migraine headaches
➢ Hyperhidrosis (excessive sweating)
Storage and Stability: It is stable to heat, unstable to light. It should be protected from light and
stored at room temperature (approximately 25°C). Dispense in a well-closed, light-resistant
container as defined in the USP. Protect from light.
Dosage Forms: Inderal (Propranolol) is available as 10 mg, 20 mg, 40 mg, 60 mg and 80 mg
tablets for oral administration.
Marketed Preparations:
➢ Psycool-F10 (Propranolol (SR) 40 mg + Flunarizine 5 mg) – Euro Biotech (A division of
Solitaire Pharmacia Pvt. Ltd.)
➢ Ciplar-LA20 (Propranolol Hydrochloride) – Cipla Limited
Officials:
➢ Propranolol Hydrochloride, I.P.
➢ Propranolol Hydrochloride Injection, I.P.
➢ Propranolol Hydrochloride Tablet, I.P.
6.2.6 Atenolol
Brand Names: Tenoretic, Tenormin
Atenolol is a second generation cardioselective beta-blocker. It is an ethanolamine compound
having a (4-carbamoylmethylphenoxy) methyl group at the position 1 and an N-isopropyl
substituent. The chemical structure of Atenolol is:
Chemical Name: 2-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]acetamide
Drugs Acting on Autonomic Nervous System 193
Properties: Atenolol occurs as white solid with melting point 158°C to 160°C. It is a relatively
polar hydrophilic compound with a water solubility of 26.5 mg/mL at 37°C and a log partition
coefficient (octanol/water) of 0.23. It is freely soluble in 1 N HCl (300 mg/mL at 25°C) and less
soluble in chloroform (3 mg/mL at 25°C).
Uses:
➢ Atenolol is used to treat high blood pressure (hypertension).
➢ It is used to treat heart-associated chest pain.
➢ It is used in prevention of migraines.
➢ It is used for the treatment of certain irregular heartbeats.
➢ It is used to treat chest pain (angina).
Dosage Forms: Atenolol (Tenormin) is available as oral tablet (25 mg, 50 mg and 100 mg).
Storage and Stability: Store this drug at room temperature between 68°F and 77°F (20°C and
25°C). Keep the medication tightly closed in a light-resistant container.
Marketed Preparations:
➢ Hipres-50 (Atenolol Tablets, I.P. 50 mg) – Cipla Limited
➢ Devolol 50 (Atenolol BP 50 mg) – Devlife Corporation Pvt. Ltd.
➢ DIPIN AT (Amlodipine and Atenolol Tablets) – Elikem Pharmaceuticals Pvt. Ltd.
Officials:
➢ Atenolol, I.P.
➢ Atenolol Tablet, I.P.
6.2.7 Carvedilol
Brand Name: Coreg
Carvedilol is a drug of class carbazoles; a non-selective beta- and alpha-1 receptor blocking
agent which helps in the management of congestive heart failure. It is a racemic mixture where
the S(–) enantiomer has beta-adrenoceptor blocking effect and the R(+) enantiomer is both a beta-
and alpha-1 adrenoceptor blocker. The chemical structure of Carvedilol is:
194 Text Book of Pharmaceutical Chemistry
Chemical Name: 1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy) ethylamino] propan-2-ol
Properties: Carvedilol occurs as white to off-white colorless, crystalline solid with melting point
114.5°C. It is freely soluble in dimethyl sulfoxide, soluble in methylene chloride and methanol,
sparingly soluble in ethanol and isopropanol, slightly soluble in ethyl ether, and practically
insoluble in water.
Uses:
➢ Carvedilol is used to treat mild to severe chronic heart failure.
➢ It is used to treat left ventricular dysfunction following myocardial infarction.
➢ It is used in the management of essential hypertension.
Dosage Forms: The white, oval, film-coated tablets are available in the following strengths:
3.125 mg, 6.25 mg, 12.5 mg, and 25 mg.
Storage and Stability: Store below 30°C (86°F). Protect from moisture. Dispense in a tight,
light-resistant container. In the alkaline solution, carvedilol is stable during 56 days at 25°C, but
only 28 days at 4°C and 40°C. In the aqueous suspension, carvedilol is stable during 56 days at
4°C and 25°C, but only 28 days at 40°C.
Marketed Preparations:
➢ Carvedrol 3.125 (Carvedilol 3.125 mg Tablet) – Biovia Life Sciences
➢ Carvedilol Sandoz 6.25 mg (Carvedilol 6.25 mg) – Sandoz Pvt. Ltd.
➢ CARNEX 3.125 (Carvedilol Tablets 3.125 mg) –Nexkem Pharmaceuticals Pvt. Ltd.
6.3 CHOLINERGIC DRUGS AND RELATED AGENTS
Cholinergic drugs are group of medicines that mimic the actions of acetylcholine.
Acetylcholine is the most common neurotransmitters in the body. It has actions in both the CNS
and PNS. There are two broad categories of cholinergic drugs: direct acting and indirect acting.
Direct Acting Cholinergic Agents: Direct acting cholinergic agonists are the drugs that work by
directly binding to and activating the muscarinic receptors, e.g., choline esters (acetylcholine,
methacholine, carbachol and bethanechol) and alkaloids (muscarine, pilocarpine and cevimeline).
Indirect Acting Cholinergic Agents: Indirect acting cholinergic agents are the drugs that work
by increasing the availability of acetylcholine at the cholinergic receptors.
Drugs Acting on Autonomic Nervous System 195
DIRECT ACTING AGENTS
6.3.1 Acetylcholine
Brand Name: Miochol
Acetylcholine is the major transmitter at neuromuscular junctions. Its name is derived from
its chemical structure; structure is made up of acetic acid and choline. It is an important
neurotransmitter in both the CNS and PNS; are involved in a range of physiological and
pathological functions: contracts smooth muscles, dilates blood vessels, increases bodily
secretions, and slows heart rate. Acetylcholine can stimulate a response or block a response and
thus can have excitatory or inhibitory effects. The chemical structure of Acetylcholine is:
Chemical Name: 2-acetyloxyethyl (trimethyl) azanium
Dosages of Acetylcholine: Powder for injection (20 mg)
Uses: Acetylcholine functions in both the central nervous system (CNS) and the peripheral
nervous system (PNS). It plays play a role in brain and muscle function. Imbalances in
acetylcholine are linked with chronic conditions, such as Alzheimer’s disease and Parkinson’s
disease.
Storage: Acetylcholine is stored in vesicles at the ends of cholinergic (acetylcholine-producing)
neurons. In the peripheral nervous system, when a nerve impulse arrives at the terminal of a
motor neuron, acetylcholine is released into the neuromuscular junction.
Classification of Cholinergic Drugs
Cholinomimtic, Parasympathomimetic
Direct acting
Indirect acting
Reversible
‒
Acetylcholine
‒ Pilocarpine
‒ Bethanechol
‒
Methacholine
‒ Carbachol
Irreversible
Lipid soluble
‒ Physostigmine
‒ Tacrine
‒ Don
Water soluble
‒ Neostigmine
‒
Pyridostigmine
‒ Edrophonium
Organophosphates
‒ Malathion
‒ Parathion
‒ DFP
‒ Chlorpyrifos
‒
Ecothiophate
‒ Nerve gases
Carbamates
‒ Carbaryl
‒
Propoxur
‒ Aldicarb
196 Text Book of Pharmaceutical Chemistry
6.3.2 Carbachol
Brand Names: Carbastat, Miostat
Carbachol is a choline carbamate and a positively charged quaternary ammonium compound,
also known as carbamylcholine. It is a parasympathomemetic that mimics the effect of
acetylcholine on both the muscarinic and nicotinic receptors. The chemical structure of Carbachol
is:
Chemical Name: 2-carbamoyloxy ethyl (trimethyl) azanium
Properties: It occurs as white or faintly yellow hard prismatic odorless, crystalline powder, but
develops a faint odor of aliphatic amine upon standing in an open container. Melting point is 392-
401°F. It is very slightly soluble in dehydrated alcohol; more readily sol on boiling; and
practically insoluble in chloroform, ether and acetone.
Uses:
➢ Carbachol lowers pressure in the eye by increasing the amount of fluid that drains from
the eye.
➢ It is used in ophthalmic (for the eye) to treat glaucoma (open and narrow-angle),
a condition that may eventually lead to vision loss.
➢ The drug works by constricting the iris in the eye to reduce pressure in the eye.
➢ It is also available as an injection and is given into the eye during the eye procedure.
Storage and Stability: The aqueous solution is stable even when heated. When heated to
decomposition, it emits very toxic fumes of hydrogen chloride, ammonia and nitrogen oxide.
Store at room temperature (between 59°F to 86°F). Discard unused portion. Do not store for later
use.
Dosage Form: It is available for intraocular miosis induction during surgery and to reduce
increased intraocular pressure during the first 24 hours after cataract surgery. Intraocular dosage
(Miostat 0.01% intraocular injection, USP).
6.3.3 Pilocarpine
Brand Names: Betoptic Pilo, Isoptocarpine, Minims Pilocarpine Nitrate, Salagen, Vuity
Pilocarpine is an imidazole-type natural alkaloid extracted from plants of the jaborandi
(Pilocarpus pennatifolius) leaves. It is in a class of medications called cholinergic agonists.
It works by increasing the amount of saliva in the mouth. The chemical structure of Pilocarpine is.