Pharmacology of Autonomic Nervous System

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Yerevan State Medical University after Mkhitar Heratsi

M.G. Balasanyan, L.G. Dheryan, A.V. Baykov, A.G. Tananyan, N.A. Voskanyan

Pharmacology Guideline For the third year students Pharmacology of autonomic nervous system

Yerevan-2017-2018 Pharmacology of autonomic nervous system Nervous system is divided into 2 parts: Central nervous system (CNS) and peripheral nervous system (PNS). CNS in its` term consists of brain and spinal cord. PNS consists of all afferent (sensory) neurons, which provide impulse conduction from peripheral organs and all efferent (motor) neurons, which provide impulse conduction from center to periphery. Efferent part of nervous system includes 2 main parts: autonomic nervous system and somatic nervous system. Vegetative or autonomic nervous system acts out of human’s will and isn`t directly regulated by the human`s conscious. VNS maintains body homeostasis and regulates function of inner organs (digestion, blood supply of organs, regulation of blood pressure etc.). Synapses of SNS are localized in CNS, but peripheral synapses of VNS are localized out of CNS in ganglions. Preganglionic nerves of VNS are myelinated, postganglionic nerves are not myelinated. VNS innervates smooth muscles, myocardium and exocrine glands. Besides VNS is included also peripheral ganglions. The mediators of VNS are NA and ACH. Somatic nervous system (SNS) is regulated by conscious and regulates motor activity, breathing, position. SNS innervates skeletal muscles, synapses are located in CNS, nerve fibers are myelinated. SNS doesn`t have ganglions, the mediator of efferent ways is ACH (picture and table 1).

Picture 1. General description of somatic and autonomic nervous system

Table 1: comparative properties of SNS and VNS

Somatic Vegetative 1 Innervated organs Skeletal muscles All other organs 2 Localization of peripheral Mainly inside of Out of CNS /in synapses CNS ganglions/ 3 Neurons Myelinated Preganglionic are mielinated, postganglionic are non- mielinated 4 Existance of peripheral absent Exists ganglions 5 Efferent neurotransmitter acetylcholine Acetylcholine Noradrenaline

According to neurotransmitter which is released from synapses VNS is divided into sympathetic /mediator is noradrenaline/ and parasympathetic nervous systems /mediator is acetylcholine/: These 2 systems have afferent, central and efferent parts. Afferent way of VNS. The majority of nerves are mixed and include nonmyelinated afferent nerve fibers. Their neurons are located in

4 ganglions of dorsal roots of spinal nerves and in sensory ganglions of cerebral nerves. These ways are conducting pain, cardio-vascular, respiratory and other inner reflexes. VNS Central centers. Are located in hypothalamus. Their dorsal and lateral nuclei are symphatic, anterior and intermediate are parasymphatic. Parasymphatic central neurons have cranio-sacral location. Picture 2. The general description of location of sympathetic and parasympathetic nervous systems:

Efferent way of VNS Majority of organs receive both sympathetic and parasympathetic innervations, which are functionally controversial. Some inner organs receive only sympathetic or parasympathetic innervations. For example, majority of blood vessels, spleen, sweat glands and piloerectile muscles receive mainly sympathetic innervations, but cilliary muscle, glands system of stomach and pancreas receive mainly parasympathetic innervations.

Efferent way of VNS consists of two neurons: preganglionic and postganglionic. Bodies of preganglionic neurons of parasympathetic nervous system have craniosacral localization. Craniosacral nuclei are localized in midbrain and medulla. In this case cholinergic neuronal endings are going through the following craniocerebral neurons: lll /n.oculomotorius/, Vll /n.facialis/, lX /n. glossopharyngeus/, X /n.vagus/. Bodies of preganglionic neurons in sacral part of spinal cord are localized in lateral horns of grey substance (picture 2). Bodies of preganglionic nerves of sympathetic nervous system are localized mainly in thoracolumbal part of spinal cord in lateral horns: C8,

Th1–L3. Preganglionic axons of both sympathetic and parasympathetic neurons are interrupted in vegetative ganglia, where with ganglionar neurons they form synaptic contact. Postganglionic neurons are started from these ganglions, which innervate the organ. Sympathetic preganglionic nerves are short and their ganglions are localized far from organ in paravertebral column. Postganglionic nerves are longer (Picture 2). Parasympathetic preganglionic nerves are longer and most of them are interrupted in ganglions which are localized near organs or inside of organs. Parasympathetic postganglionar nerves are short. Mediator in all vegetative ganglions is acetylcholine, so both sympathetic and parasympathetic preganglionic nerves are cholinergic, but sympathetic postganglionic nerves are adrenergic, parasympathetic postganglionic nerves are cholinergic.

As it was mentioned above, efferent way of VNS consists of 2 neurons. There are some exceptions, for instance, efferent neurons which innervate adrenal medulla. The chromaphinic cells of adrenal medulla are close to neurons of sympathetic ganglions, so only preganglionic /cholinergic/ neurons are involved in innervation of adrenal medulla, where mediator is acetylcholine. So, here we have only one way, which consists of one neuron only and stimulation of this neurons causes release of adrenaline (Table 2). Thus, motor, vegetative preganglionar and parasympathetic postganglionar nerves are cholinergic, but sympathetic postganglionar nerves are adrenergic. Table 2. Comparative properties of Parasympathetic /PNS/ and Sympathetic /SNS/ nervous systems

SNS PNS 1 Central part thoracolumbal craniosacral /Th1-L2 or L3/ part /involved in III, of spinal cord VII, IX, X, S2-S4 neurons/ 2 Localization of ganglions Out of organs Near organs or inside of organs 3 Length of postganglionar long Short neurons 4 Neurotransmitter Noradrenaline Acetylcholine /mediator/ acetylcholine 5 Main function Mobilization of Accumulation of strength and energy, digestion defense of organism in stress and emergency situation

Intestinal neuronal system /INS/ complex of different neurons, which is localized in walls of GIT. Some authors consider INS as the third part of VNS. It consists of muscular plexus /Auerbach plexus/, submucous plexus /Plexus of Mejsnier/ and sensitive – endings of afferent neurons. This system receives preganglionic neurons from PNS and postganglionic axons of SNS. Neurons which begin from this plexus reach the mucous membrane of intestines and regulate motor activity of intestines and secretor activity of cells. INS of VNS has only modulating activity, because here there are a lot of neuromediators and neuroregulating substances: NO, neuropeptides, substance P, serotonine etc.)

Structure of synapse of autonomic nervous system Synapse consists of 1. Presynaptic membrane, from where, in response to impulse /action potential/, is taking place release of mediator, which is synthesized in axonal endings and is accumulated in vesicles. 2. Postsynaptic membrane, where mediator is recognized and the appropriate response is formed. 3. Synaptic cleft, which is the space of 20-40nm between presynaptic and postsynaptic membranes. It is polysaccharidal jelly with many tubules where mediator is diffused. 4. Connetive tissue filaments, which limits synapses and prevent diffusion of mediator to systemic blood flow (picture 3).

Picture 3. Structure of synapse

Main stages of neurotransmission 1. Synthesis and accumulation of mediator 2. Impulse transmission and release of mediator 3. Interaction of mediator with pre- and postsynaptic membrane receptors 4. Formation of postsynaptic activity 5. Mediator effect elimination 1. Synthesis and accumulation of mediator Synthesis of non-peptide mediators takes place in axonal endings and synthetized mediator is accumulated in special synaptic vesicles. Mediators with peptide properties are synthesized in neuronal bodies then go to the axonal endings are accumulated in vesicles, where they are

9 transformed into main mediators. Transport of mediators or premediators into vesicles are perfomed by means of proton pump. At rest only small quantity of mediator is released into synaptic cleft and they form tiny postsynaptic potential /0,1-3mV/. This process provides physiological reactivity of effector organ. Synaptic vesicles are localized and accumulated near presynaptic membrane in special part which is called «active zone» (picture 4). 2. Impulse transmission and release of mediator. Permeability of axonal membrane for K+ and H+ ions at rest is very high, and the quantity of K+ and H+ ions inside of cell is very high, but in outside of cell Na+ and Cl- are in large quantity. As a result the inner surface of cell membrane has negative charge compare to upper surface of membrane. Depolarization of axonal ending brings to opening of potential dependent Na+–channels and influx of Na+-ions which cause change of charge. This is the first stage of depolarization. On the second stage of depolarization inactivation of potential dependent Na+–channels and opening of K+-channels takes place which brings to limitation of depolarization and repolarization of presynaptic membrane. Ionic ratio comes back to initial level in refractory period due to activity of Na+ / K+ – ATPase. Increase of level of Na+ and mainly Ca2+-ions in presynaptic part result in interaction between proteins of synaptic vesicles /synaptotagmine, synaptobrevin /VAMP-vesicle-associated membrane protein // and proteins of presynaptic membrane /neurexin /SNAP-synaptosomal- associated protein/, syntaxin/. Because of interaction of synaptic vesicles with presynaptic membrane synaptopores are formed, which releases mediator into synaptic cleft /picture 4 /. 10

3. interaction of mediator with pre- and postsynaptic membrane receptors Released mediator can interact with both pre- and postsynaptic receptors. Interaction of mediator with receptors of postsynaptic membrane result in changing of permeability of membrane toward different ions. There are three main types of changing of permeability which are: 1. Increase of permeability of postsynaptic membrane toward Na+, sometime toward Ca2+ions, which results in depolarization of postsynaptic membrane and formation of excitation postsynaptic potentials /EPSP/. 2. Selective increase of permeability of postsynaptic membrane toward Cl--ions, which results in hyperpolarization and formation of inhibitory postsynaptic potential /IPSP/. 3. Increase of permeability of postsynaptic membrane toward K+-ions, which result in outflow of K+-ions, stabilization of postsynaptic membrane and formation of hyperpolarization. By interaction with presynaptic receptors release of mediator is regulated. Thus mediator can regulate own release (picture 4). 4. Formation of postsynaptic activity: because of EPSP channels are activated which result in formation of action potential which can be formed in postsynaptic membrane of neurons, smooth muscles, skeletal muscles, etc. EPSP is more typical for neurons and smooth muscles rather then skeletal muscles. It stabilizes postsynpatic membrane and resists to depolarizing impulses (picture 4).

5. Limitation of mediator effect . Free mediator can be removed from synaptic cleft by the following ways: 1. Reuptake of mediator by presynaptic membrane`s transporter. In the nerve ending mediator is partially degraded and partially is accumulated in the vesicles. 2. Extraneuronal reuptake of mediator, and mediator is accumulated in effector organ and after is degraded by COMT. 3. Destroy of mediator by enzymes /destroy of acetylcholine by acetylcholine esterase/ (Picture 4).

MCMP 407 + Na PrecursorÝ³Ë³Ý ÛáõÃ choline/thyrosineËáÉÇÝ/ÃÇñá½ÇÝ nonPds êÇSynapticÝ³åïÇÏ cleft ×»Õù Ý³precursorË³ÝÛá õÃ Pds Ù»mediator¹Ç³ïáñ H/P

ÜPresynaptic³Ë³ëÇÝ³å nerveë³ÛÇ Ý Ïaccumulationáõï³ÏáõÙ ÝcellÛ³ñ ¹³ÛÇÝ µçÇç Órelease»ñµ³½³ ïáõÙ Ca2+ ÀReceptorsÝÏ³ÉÇãÝ»ñ

PostsynapticÐ»ïëÇÝ³åë ³ÛÇÝ nerveÝÛ³ñ¹³ cellÛÇ Ý µçÇç

Comediators. <> model in vegetative nervous system is very seldom. In stimulation the majority of central and peripheral neurons release more then one active mediators. So, in VNS besides of direct mediators /noradrenaline, acetylcholine/ as comediators can be released purines, peptides and prostaglandines. In many vegetative

12 cholinergic synapses VIP (vasoactive intestinal peptide, neuropeptide Y or NPY, substance P, encephalins, somatostatine etc. and prostaglandins) In many autonomic cholinergic neurons VIP is combinated with acetylcholine, and ATP is combinated with acetylcholine and noradrenaline. Comediators usually are accumulated in the same neurons, but in different vesicles, but there are some exceptions, i.e. ATP is accumulated with noradrenaline in the same vesicle. The adrenergic vascular neurons consisting of NPY leading to more long-lasting vasoconstriction. Comediators are accumulated in the same neurons, but in the different synaptic vesicles. The exception is ATP, which is accumulated with NA in the same vesicles. Comediators which are released into the synaptic cleft with direct mediator can control and regulate release of direct mediator from presynpatic membrane and/or sensitivity of the postsynaptic membrane toward this mediator.

Structure of cholinergic nervous system`s synapse Acetylcholine (Ach), which provides neurotransmission in cholinergic synapses is synthesized within the axoplasm of presynaptic nerve terminal from acetyl coenzyme A (AcCoA) and choline by the presence of a cytosolic enzyme choline acetyltransferase (CAT). Acetyl CoA is synthesized in mitochondrions, choline is taken up from the extracellular spaces into the axoplasm of nerve terminal by a specific sodium-dependent carriers /proteins/. Most of the ACh synthesized is accumulated into presynaptic vesicles along with ATP and neuropeptides (Y, VIP). During depolarization triggered by the calcium ions Ach releases from presynaptic vesicles into synaptic cleft and acts on cholinoreceptors (picture 5). Picture 5. Structure of cholinergic synapse

Most of released Ach which has no any action on receptors hydrolized by acetylcholinesterase /AchE/. Small part is diffused or is reuptaked. AchE is present in axons, dendrits, pre- and postsynaptic membranes. During hydrolysis two compounds are formed - choline and acetic acid. 50% of this choline is normally recaptured by the nerve terminals /neuronal reuptake/ and could be used again in the process of Ach synthesis. Acetic acid is oxidized in the Krebs cycle. There is also false cholinesterase enzyme /pseudocholinesterase or butyrilcholinesterase/, which is located mainly in blood, liver, neuroglia and is participating in hydrolysis of choline.

Cholinoreceptors Cholinergic receptors are glycopeptides and contain several subunits. By the affinity to their ligands cholinergic receptors divided into the following types: 1. M–muscarinic receptors which are selectively activated by muscarine, the active principle of the poisonous mushroom Amanita muscaria and can be blocked by atropine. 2. N–nicotinic receptors which are selectively activated by small doses of nicotine and blocked by high doses of nicotine. All types of receptors are discussed in detail below.

M–cholinoreceptors M–cholinoreceptors are metabotropic receptors which are coupled with G-proteins. There are 5 types of M–cholinoreceptors, distinguishing by their transduction mechanism, location and evoked actions.

M1-cholinoreceptors (neuronal) Transduction mechanism:

They couple with Gq-proteins, activate phospholipase-C (DAG + ITP3 - Ca2+ ) Location and effects: 1. CNS : limbic system, reticular formation, basal ganglias -activation, regulation of psychomotor activity, activation of wakening reactions and learning process. 2. Autonimic ganglia- Depolarization and development of slow excitatory postsynaptic potential. 3. Enterochromaphine cells –stimulation of secretory function through histamine (picture 6).

Postsynaptic M2-cholinoreceptors (cardiac) Transduction mechanism:

They are coupled with inhibitory GI-protein. Activation of these cholinoreceptors leads to inactivation of adenylatecyclase ( cAMP): As a result inhibitory action is developed. Location and effects: Heart 1. Sinoatrial node - decrease in frequency of spontaneous diastolic depolarization - bradycardia 2. Atriums - shortening of potential action duration in atrial muscle, decrease in contractility of atrial muscle 3. Atrioventricular node - decrease in atrio-ventricular conduction 4. Ventricular muscle (small quantity) – insignificant decrease in ventricular contraction (Picture 6). 16

Presynaptic M2-receptors These receptors regulate Ach release. Stimulation of such receptors inhibits Ach release from presynaptic membrane.

Postsynaptic M3-receptors (glandular) Transduction mechanism:

Similar to M1-receptors. They are coupled with Gq-protein. Location and effects: 1. Smooth muscles  Contraction of the pupillary constrictor muscle /m. sphincter pupillae/, causing a reduction in pupil size called miosis, and contraction of ciliary muscle /m. ciliaris/ relaxing ligament of Zinn and increasing in lens curvature to cause cyclospasm or spasm of accomodation - a loss of ability to accommodate to far vision. This evokes the eye to accommodate for near vision. Besides that miosis and ciliary muscle contraction reduce intraocular pressure due to tension on the trabecular meshwork, opening its pores and facilitating outflow of the aqueous humor into the canal of Schlemm.  Bronchospasm  Increase in peristalsis of the gastrointestinal tract, relaxation of sphincters  Increase in tone of biliary tracts  Increase in tone of urinary tract, constriction of bladder, relaxation of sphincters  Contraction of uterus

2. Exocrine glands  Lacrimation  Copius sweating  Copious, watery, with a lack of proteins) salivary secretion  Increased bronchial secretion  Increased stomach juice secretion (Picture 6)

Extrasynaptic M3-receptors

Like postsynaptic receptors are coupled with Gq- proteins. These receptors located mainly on the endothelial cells of the vasculature. Activation of these receptors leads to production of NO (endothelium- derived relaxing factor) relaxing smooth muscles and dilating vessels.

M4-, M5-receptors: These types of receptors are not investigated enough yet. Transduction mechanism of M4-receptors is similar to that of

M2-receptors. M5-receptors are similar to M1-,M3-receptors. Picture 6. The general description of M-cholinoreceptors

M -cholinoreceptors

M1 neuronal M2 cardiac M3 glandular M4 M5 Gq Gq Gi Gq Gi

CNS and Heart Smooth muscles autonomic and exocrine ganglias glands

N-cholinoreceptors

There are two types of nicotinic receptors Nm-muscular and Nn– neuronal receptors. Transduction mechanism These receptors are coupled with ion channels f.e. Na+-, Ca2+-, K+- channels. To open ion channels Ach`s two molecules must bind to each receptor.

Nn–cholinoreceptors Location and effects of stimulation 1. CNS: cerebral cortex, medulla oblongata, neurohypophysis, Renshaw cells of spinal cord. Stimulation of these receprtors provides control of psychical and motor functions, wakefulness and learning as well as increased release of vasopressin (ADH) from the neurohypophysis. 2. Autonomic ganglia: Stimulation increases frequency of impulse conduction. 3. Adrenal medulla: Stimulation enhances secretion of epinephrine and norepinephrine.

4. Carotid sinus: Activation of Nn–cholinoreceptors causes reflex stimulation of respiratory center. 5. Presynaptic membranes: Stimulation augments release of Ach.

Nm-cholinoreceptors Location and effects of stimulation These receptors located mainly in neuromuscular synapses. Stimulation of such receptors causes depolarization of the endplate and contraction of skeletal muscles.

The pharmacological correction of cholinergic neurotransmission is realized by the action on the following stages of cholinergic neurotransmission. 1. Inhibition of acetylcholine synthesis. Hemicholinum inhibits the action of sodium-dependent membrane transporter, which is participating in the transport of choline. In the experimental conditions it can be used for the inhibition of ACH synthesis. 2. Action on the vesicular transport and storage. Vesamicol inhibits the transporter, which is transporting ACH from axoplasm into the vesicles. As a consequence vesicular transport and storage of ACH is disturbed. It`s also used in experimental conditions. 3. Action on the ACH release. Botulinum toxin (Botox), by interaction with synaptic vesicles` membrane protein – synaptobrevine, disturbs the release of ACH into the synaptic cleft. The paralytic activity of Botulinum toxin is used in the treatment of some diseases, which are describing by the high muscle tone: spasm of esophagus, achalazia, blepharospasm. it`s used in cosmetology to prevent wrinkles` formation. Release of ACH from presynaptic membrane can be regulated by the changes in activity of M2 and Nn receptors. By blocking presynaptic M2 receptors or by activating presynaptic Nn receptors we can increase release of ACH. Decrease in ACH release can be noticed in the case of activation of presynaptic M2 receptors and inhibition of presynaptic Nn receptors.

4. Stimulation or inhibition of cholinoreceptors. Drugs, which are interacting with cholinoreceptors are devided into 2 groups: cholinomimetics and cholinolytics. 5. Changes in the activity of enzymes participating in the neutralization of ACH. There are reversible (Edrophonium, Neostygmine) and irreversible inhibitors of Acetylcholinesterase (Dyphlos). Drugs acting on the cholinergic system Classification of drugs acting on the cholinergic system

Agonists of Antagonists of

cholinoreceptors cholinoreceptors

Cholinolytics Cholinomimetics

Direct Indirect M-Cholinolytics N-Cholinolytics (inhibitors of (Agonists of acetylcholinestera receptors) se)

Ganglioblockers Myorelaxants

Cholinomimetic drugs These are drugs directly or indirectly stimulating cholinoreceptors. Classification I. M, N or universal cholinomimetics 1.direct, when drug directly stimulates cholinoreceptor (Acetylcholine, Carbachol) 2.indirect (anticholinesterases), they don`t directly stimulate cholinoreceptors, are inhibiting cholinesterase enzyme, increase amount of ACH, which stimulates cholinoreceptors. II. M-cholinomimetics (Pilocarpine, Betanechol) III N-cholinomimetics (Nicotine, Lobeline) M, N – cholinomimetics Acetylcholine chloridum Pharmacodynamics. Acetylcholine chloridum exerts strong but very short pharmacological action, because of its fast in vivo metabolism by acetylcholinesterase enzyme. All effects of Acetylcholine chloridum effects are dose- dependent. 1. In low doses it mainly exerts M-cholinomimetic action 2. In high doses it stimulates both M-and N-cholinoreceptros Selective N-cholinomimetic action is notable only in case of block of M-cholinoreceptors. Pharmacological actions Clinically important pharmacological actions of Acetylcholine chloridum are mentioned below:

1. Generalized vasodilatation contributing to fall in blood pressure

/stimulation of extrasynaptic M3-cholinoreceptors activates release of NO – endothelium-derived relaxing factor/. 2. Sinoatrial node: Decrease in frequency of spontaneous diastolic depolarization contributing to slowing the pacemaker rate and

development of bradycardia /stimulation of M2–cholinoreceptors/ 3. Decrease in force of contractility of atria, decrease in AV-

conductivity /stimulation of M2–cholinoreceptors/ 4. Decrease in AV conductivity (M2 receptor stimulation) 5. Insignificant decrease in force of contractility of ventricles

/stimulation of M2–cholinoreceptors/

6. Increase of peristalsis of intestines /stimulation of M3- cholinoreceptros/

7. Increase in tone of urinary bladder /stimulation of M3- cholinoreceptros/

Clinical use Prevention of increase in intraocular pressure and for miosis during surgical interventions in the anterior chamber of the eye (cataract, keratoplasty, etc.). Miosis is developed immediately within 20 minutes. Carbachol In contrast to Acetylcholine chloridum Carbachol is stable towards acetylcholinesterase enzyme, thus could exert longer but at the same time more poor action. Pharmacological effects are similar to those of Acetylcholine chloridum. Has experimental significance.

M–cholinomimetics Pilocarpine Pilocarpine is natural phytogenic alkaloid. Pharmacological actions Has both local and resorptive action. Local effects of Pilocarpine: eye effects 1. miosis 2. Reduction of intraocular pressure. Because of miosis ciliary muscle becomes thinner. It leads to opening of eye anterior chamber and facilitation of outflow of the aqueous humor into the lymphatic spaces of iridocorneal angle called Fontana spaces and then into the canal of Schlemm flowed in viens of eyebulb. 3. Spasm of accommodation 4. Macropsia – all subjects in the range of vision seem bigger. This effect is also temporal (picture 7 ).

Relaxed ciliary muscle

Tensed ligaments

Far vision Smooth lens

Constricted ciliary muscle

Relaxed ligaments

Short vision

Extrarounded lens

Resorptive or systemic effects of Pilocarpine 1. Bradycardia, slowing of atrioventricular conduction velocity, decrease in force of contractility of atria and insignificant of ventricles.

2. Stimulation of M3-cholinoreceptors of smooth muscles end exocrine glands causes excessive sweating and salivation. Clinical use 1. Complex treatment of the open angle glaucoma in eye drops. 2. Treatment of Sjogren syndrome (dry mouth - xerostomia or dry eyes-xerophtalmia). Side effects of selective M–cholinomimetics They are dose-dependent. Marked bradycardia, atrioventricular block at different degrees, excessive sweating, salivation, diarrhea, optical disturbances, headache, singultus and other effects subject to activation of cholinergic system.

Selective Nn-cholinomimetics

Nn-cholinomimetics are drugs which bind to Nn-cholinoreceptors and activate them. It is was mentioned above that Nn-cholinoreceptors are 25 ionotropic receptors. Activation of Nn receptors causes depolarization of neuronal cells, but their prolonged activation may reduce effector response and then prevent further depolarization and contribute to so-called “depolarization block” (picture 8). Picture 8. structure of N-cholinoreceptors

Nn-cholinomimetics are Nicotinum, Lobelinum which action has 2 stages- first excitation then inhibition. Nicotin – alkaloid of tobacco leaves.

Nicotin acts on both central and peripheral Nn-cholinoreceptors.

Especially Nn-cholinoreceptors of vegetative ganglia are more sensitive to Nicotin which exerts two phases action. The first phase is the excitation which can result in depolarization of membranes of gangliar neurons. The second phase is depression which is result of inhibition of repolarization. CNS: There are also two phases of the action. At small doses excitation is prevalented. Nicotine at high doses leads to depression. Because of the action on brain cortex Nicotine alters subjective condition. Nicotin can directly activate respiratory center, but at high doses it exerts inhibitory action. At these doses Nicotin can also cause centrally generalized vomiting and seizures.

Nicotin stimulates release of vasopressine /ADH/ from neurohypophysis and thus reduce urine production. Chemoreceptors: Because of stimulation of chemoreceptors of carotid sinus Nicotine reflexly activates both respiratory and vasomotor centers. At the high doses it could mediate inverse reaction. Cardiovascular system: At the beginning of action Nicotine causes bradycardia /because of stimulation of both vagal center and intramural parasympathetic ganglia/, which is followed by tachycardia /because of activation of sympathetic ganglia and increase of epinephrine release from adrenal medulla/. At small doses Nicotine increases blood pressure. It is explained by stimulation of vasomotor center and sympathetic ganglia, increased release of epinephrine and direct vasomotor activity. Gastro-intestinal tract: Nicotine increases peristalsis of intestines, at high doses it leads to inverse reaction.

Adrenal medulla: At small doses Nicotine stimulates Nn- cholinoreceptors of medullary chromaphine cells and thus increases release of epinephrine. At high doses it inhibits release of epinephrine. Exocrine glands: Nicotine at the beginning of the action stimulates secretion of salivary and bronchial glands and then inhibits. In case of nicotine chronic poisoning /smoking/ tolerance is gradually developed towards mentioned above effects. Nicotine in the different drug forms (chewing gum, aerosole, tablets) is used as a nicotine substitutive therapy in smokers to prevent nicotine dependence.

Anticholinesterase drugs Anticholinesterase drugs /AchE/ are the drugs which inhibit acetylcholinesterase enzyme and prevent break of Ach, so they manifest the indirect cholinomimetic activity in vivo. Some of AChE drugs have additional direct action on cholinoreceptors.

Table 3: Differences between real and pseudocholinesterases

Acetylcholinesterase Butyrylcholinesterase (true ChE ) (pseudo ChE )

1 Location Cholinergic synapses, CNS Blood plasma, liver, . grey substance, intestines, CNS white Erythrocytes substance

2 Hydrolysis of ACH Very quick Slow . 3 Is inhibited Is more sensitive toward Is more sensitive toward . Physostigmine Phosphororganic substances 4 Significance elimination of ACH action Hydrolysis of ethers . Classification of AchE drugs According to the reversibility 1. AChE drugs with reversible action Simple alcohols Edrophonium Carbamates Physostigmine /Ezerine/ Rivastigmine Neostigmine /Proserine/ Pyridostigmine 28

2. AChE drugs with irreversible action Phosphororganic substances (POS) Dyflos

Pharmacodynamics Mechanism of action AChE drugs as well as Ach interact with acetylcholinesterase enzyme. Ach binds to the two centers of AchE: anionic and esterasic. Binding to the anionic center is performed by means of ionic bond due to positively charged nitrogen of Ach, with esterase center - by means of carbon of carbonyl group. Ach after binding to the active centers of AchE enzyme undergoes hydrolyses and form free choline and acetylated enzyme. During the second phase due to hydrolyses covalent bond between acetyl and enzyme is broken. This whole process takes only 150 mili second (picture 9). Edrophonium reversibly are bond to the anionic center of enzyme and prevent binding of Ach to the enzyme. AchE drug-enzyme complex doesn’t have covalent bond so they have only short action /desinhibition is developed not due to hydrolyses of this complex but due to diffusion of AchE drug from this complex and that's why the period of action is 2-10 min / picture 9/. Carbamates in the same time are bound to the both anionic and esterase centers of the enzyme and as in case of Ach are undergone to hydrolyses in two stages /I stage – acetylation of serine of AchE enzyme and remove of choline, II stage – remove of acetic acid from the serine- residue under the action of water/. During the second stage carbamates

29 form carbamylation of serine residue of enzyme which is more stable than acetylated serine-residue in case of Ach (30 min-6 hours)/ picture 9/.. Phosphoorganic substances are bound to the esterase centre of the enzyme and phosphorilated enzyme doesn’t interact with water or interact very slow /100 and more hours – irreversible inhibitors/. Phosphorylated enzyme can become “aged” due to removal of alkyl group and it becomes more stable toward hydrolyse /picture 9/.

Picture 9. Action mechanism of AchE

Effects on organ-systems Effects of AchE drugs are similar to the effects of direct ChM. But there are some peculiar properties.

Lipophilic AchE drugs /Physostigmine, PhOS/ have more muscarinic and central effects /stimulate vegetative ganglions/, effects on skeletal muscle aren’t obvious.

Lipid insoluble AchE drugs /neostigmine and other substances which contain quaternary ammonium/ have more effect on skeletal muscles /in muscle they have some direct cholinomimetic activity/, stimulate vegetative ganglions, but muscarinic effects are less. These drugs can’t penetrate blood-brain barrier and they don’t have central effect. Eye. The effects are the following.  Narrowing of pupil /miosis/  Spasm of accommodation.  Decrease of intraocular pressure,  Lacrimation

CNS. In small doses lipid-soluble AchE drugs activate CNS /desynchronization of EEG/. In high doses AchE drugs causes inhibition of CNS. In toxic doses they can cause seizures, which can be ended by coma and respiratory paralyses. Autonomic ganglia. In ganglions local hydrolyses of small quantity of Ach take places its neutralization mainly performed after diffusion to the blood, where it’s undergone to hydrolyses. Stimulation of ganglions by AchE drugs has performed due to direct action on receptors. High doses of AchE drugs cause stable depolarization of nicotinic receptors and inhibition of neurotransmission. Neuromuscular synapses. In neuromuscular synapses Ach doesn’t undergo hydrolyses immediately. It binds to the appropriate receptors, and

32 increase the tonus of skeletal muscles. In high doses they causes stable depolarization of postsynaptic membrane, due to which inhibition of neuromuscular neurotransmission is developed which result in weakness and paralyses. Some carbamate AchE drugs which has quaternary ammonium, like neostygmine, can have direct agonistic activity toward nicotinic receptors, which will increase their value as a drug for the treatment of myasthenia gravis. Cardiovascular system. The effects are complicated. The action on heart muscle is dominate and similar to the action of vagus nerve. The decrease of blood pressure is insignificant. In high doses only expressed bradycardia and falls of BP is developed. Respiratory system and respiratory center. They can cause bronchospasm, stimulate secretor function of bronchial glands. Gastrointestinal tract. AchE drugs stimulates peristalsis of GIT and secretion,which is developed due to the stimulation of M-receptors and intramuscular /auerbach/ plexus of intestines. Exocrine glands: Secretion from exocrine glands /bronchial, gastric, sweat, lacrimary glands etc/is stimulated. Urinary system: Increase of tonus of bladder and urethra, increase of urination Pharmacokinetics. Carbamates, which contain quaternary ammonium absorbed from the different surfaces very hardly and aren’t solved in lipids. They don’t penetrate BBB. Compounds, which contain tertiary ammonium, like physostigmine are very well absorbed from the skin and mucous membrane. They

33 penetrate BBB, so compare to polar carbamates they are more toxic. Are metabolized by cholinesterase. Phosphororganic AchE drugs absorbed from the skin and mucous membranes very easily that’s why they are very dangerous, as they are used in agriculture as insecticides. Indications. Edrophonium Rapid and short action of edrophonium allows to take it for diagnosing the myasthenia gravis. Neostigmine /Prozerine/ and Piridostigmine 1. The treatment of myasthenia gravis. 2. The treatment of atony of intestines and urinary bladder. 3. Prevention of neuromuscular blockade induced by competitive myorelaxants Physostigmine 1. Glaucoma treatment 2. Due to ability to penetrate though blood-brain barrier, physostigmine is used systematically for prevention of the central and peripheral effects caused by overdose of antimuscarinic agents in surgery. Dyflos It is a phosphororganic compound, an insecticide, and a substrate for chemical weapons as well (neuroparalytic gases). Previously has been used topically in ophthalmology as miosis causing substance. Intoxications caused by AchE drugs. AchE drugs are used in agriculture as insecticides. So they can cause intoxication very often, because they are very lipophilic and penetrate skin and mucous membrane and irreversibly block AChE enzyme. 34

The clinical symptoms of intoxication are the following  lacrimation, salivation, sweatness, miosis, breathlessness, colics, involuntary urination and defecation  Decrease of BP, reflex tachycardia  Inhibition of respiratory, respiratory insufficiency  Irritation, ataxia, convulsion, death

Treatment 1. First of all fresh air, washening of skin and mucose membranes with 3-5% solution of sodium hydrocarbonate, in a case of emergency-stomach leavage, forced diuresis, hemosorbtion, hemodialyses and peritoneal dialyses. 2. Artificial respiration 3. Maintaining of BP, prevention of convulsions 4. Specific treatment which includes,  Atropine, is very useful in intoxication caused by AchE drugs. It doesn’t prevents paralyses of muscles, which is stipulated by overactivation of nicotinic receptors.  Reactivators of cholinesterases (Pralidoxim). These drugs are used in PhOS intoxication to recover the neuromuscular neurotransmission. As it was mentioned, phosphorilated AchE is very slow interacts with water. However, when the number of reactive OH groups is high, enzyme is recovered vey quicker.  Pralidoxim contains quaternary nitrogen, bind to the anionic part of enzyme, which is not occupied by PhOS. Its oxim ending interacts with the atom of phosphor which is bond to

esterase part and causes oximphosphonate which is removed from the enzyme and recover the enzyme. It’s not effective when intoxication was caused by carbamates AchE drugs, because anionic part is occupied in this case and pralidoxim can’t bind to the enzyme. Pralidoxim should be used before “aging” of enzyme, as it’s very stable toward hydrolyses (picture 10). The action mechanism of Pralidoxime

List of main drugs Neostigmine (generic, Prostigmin): 15mg tablets, 0,05%-1 ml ampoules Physostigmine (generic Eserin): 0.25% eye ointment, 0.25%, 0.5% eye drops, 0,1%-1mlampoules Pyridostigmine (Mestinon, Regonol): 30, 60, 180(SR)mg tablets, 60mg dragees, 0,5%-1ml ampoules

Tests All mentioned statements are true, except a) edrophonium reversibly binds to active center of acetylcholinesterase enzyme and have short action b) carbamates cause carbamylation of serine residue of acetylcholinesterase enzyme c) phosphororganic substances bind to anionic center of acetylcholinesterase enzyme d) phosphororganic substances irreversibly block acetylcholinesterase enzyme Answer` d

Anticholinesterase drugs 1. in small doses activates CNS 2. in high doses causes stable depolarization of nicotinic receptors of vegetative ganglions 3. can directly stimulate muscarinic receptors of vegetative ganglions 4. leads to bronchodilatation a)all are correct b) 3, 4, c) 1, 2, 3 d) 1,2 Answer c The effects of anticholinesterases on neuro-muscular synapses are: 1. increase in skeletal muscle tone 2. inhibition of neuro-muscular transmission in high doses 3. neostigmine can have direct agonistic activity on nicotinic receptors 4. high doses can lead to muscle weakness and paralysis a) 1.3.4 b) 2.4 c) 1.3 d) the all Answer d Choose the correct answer a) edrophonium has long action b) physostigmine doesn’t penetrate blood-brain barrier c) lipophilic anticholinesterase drugs possess more muscarinic and central effects d) PhOS are very poor absorbed through skin and mucous membrane Answer c

Cholinolytics

Cholinolytics (ChL) are drugs blocking cholinoreceptors and preventing a development of acetylcholine actions. As it is known there are two types of ChR: M and N, so according to the type of cholinoreceptor blockage, ChL are classified into: 1. M-ChL 2. N-ChL which are divided into two groups;  Ganglion blocking agents (Nn-blockers)  Myorelexants (Nm-relaxants)

M-Cholinolytics M-ChL are competitive antagonists of M-cholinomimetics and ACh. Since ChL’s affinity for M-cholinoreceptors is higher than cholinomimetics` affinity, that`s why antagonism has only one direction. M-ChL prevent the action of parasympathetic nervous system, cause domination of sympathetic effects on organs. Classification According to the origin M-ChL are classified into 1. natural alkaloids  Atropine sulfate  Hyoscine (Scopolamine) hydrochloride 2. Semisynthetic cholinoblockers  Ipratropium bromide 3. Synthetic cholinolytics  Pirenzepine  Tropicamide 39

Atropine Pharmacodynamics

Atropine reversibly blocks all M1, M2 and M3 receptors. But different receptors manifest different sensitivity toward atropine. Mainly are inhibited that functions, which are under the strong influence of parasympathetic system. Atropine in low dosages inhibits salivary, sweat and bronchial gland secretion /M3/. Intermediate dosages lead to ocular effects /M3/ and tachycardia /M2/. Higher dosages lead to relaxation of smooth muscles /M3/. The highest dosages lead to inhibition of parietal cell secretion. Pharmacological effects Systemic effects CNS Atropine in therapeutic dosage has slight effect on CNS and leads to slight stimulation of respiratory and vagal centers. In toxic doses stimulation of brain becomes more prominent and hyperactivation, irritation, hallucination, delliriums are developed. In higher doses inhibition follows stimulation leading to lethal outcome. Atropine has antitremor activity and decreases motor disturbances in Parkinsonyan disease (when in striatum under the inhibited phone of dofaminergic system cholinergic system activation is observed). Atropine, as exctraction of Beladdonna plant was the first drug for the treatment of Parkinsonyan disease. Cardio-vascular system In the middle therapeutic doses atropine by blocking M2 receptors of sinus node, prevents inhibitory action of vagus nerve on the heart and causes nit significant tachycardia. The higher is the initial tone of 40 parasympathetic system, the more is cardiac effects of atropine. To this effects belongs increase in AV conductivity and increase in heart oxygen demand. In toxic doses atropine causes block of ventricular conductivity (the mechanism isn`t clear), so atrial and ventricular trembling is developed. In general atropine has no significant effects on hemodynamics. It’s stipulated by the absence of majority of vessels having no parasympathetic innervations. In normal and toxic doses M-ChL causes dilation of skin vessels mainly of upper part of body (the mechanism is unknown). It’s assumed that the reason of vasodilatation is compensatory activation of body heat irradiation through convection. Respiratory system Atropine causes relaxation of upper respiratory tract muscles (M3) and inhibition of secretory function of bronchi (M3). Atropine prevents reflector bonchospasm /in general anaesthesia). Gastrointestinal tract Atropine after binding to muscarinic receptors inhibits motor activity of GIT and secretory function. However, even in total blocking of M-ChR, activity of these organs is not completely abolished, as they are regulated by local hormones and non-cholinergic intramural neurons of INS. Atropine significantly decreases salivation (M3), which results in dryness of mouth, difficulties in swallowing and speaking. Insignificantly secretor activity of pancreas and intestine glands is decreased. Secretion of bile isn`t changed, because it is not under the influence of cholinergic system.

Atropine decreases tonus of intestine, gall bladder, biliary ducts, stomach and inhibits perystalsis, so the period of emptying of stomach is increased, constipation is developed. Atropine eliminates diarrhea caused by M-Cholinomimetics and anticholinesterase drugs. Urogenital tract Atropine relaxes smooth muscles of urine bladder and prolongs the period of urination and can provoke development of urine retention. Atropine has no significant effect on uterus. Sweat glands Sympathic cholinergic neurons are innervating sweat glands and their muscarinic receptors are blocked by Atropine. As a result sweating is decreased, skin becomes dry and hot, which can increase body temperature. Local effects Eye: Atropine by blocking the circular muscle of pupile (M3 receptors), causes mydriasis (dilation of pupile). The normal reflector constriction of pupile toward light is absent and photophobia is developed. The main eye effect of atropine is also ability of atropine to relax ciliar muscle (M3), which regulates lens curvature. As a result Cinnyan ligaments are strengthened and lens become more thin, far vision is developed. Atropinized eye can't see object of near localization. This state is called cycloplegia. Due to mydriasis and cycloplegia outflow of intraocular liquid is difficult, which results in intraocular pressure enhancement. Midriasis lasts 7-10 days, cycloplegia- 8-12 days. 42

The next eye effect is inhibition of lacrimary glands` secretion. Patients very often complain of eye dryness or «presence of sand in eye» symptom.

Pharmacokinetics Atropine easily absorbs from GIT and other biological membranes, has big volume of distribution, crosses BBB. The elimination half-life is 2 hours. Approximately 60% is excreted in unchanged form, the rest part is exposed to hydrolysis and conjugation.

Indications 1. as spasmolytic in GIT problems 2. premedication in general anaesthesia (during surgical procedures prevention of muscarinic effects - laryngospasm, hypersalivation, bronchospasm and heart arrest). 3. acute symptomatic bradycardia 4. intoxications by anticholinesterases 5. as antitoxin in fungal intoxications Intoxication by Atropine In high doses atropine causes intoxication, which can happened after eating the fruits of belladonna. During intoxication 2 stages can be developed. Stimulation  Hallucination, disorientation, delirium, muscle cramps, breathlessness

 Inhibition of secretion – dryness of mouth, skin, aphonia, difficulties in swallowing and chewing, increase of body temperature

 Relaxation of smooth muscles – mydriasis, paralyses of accommodation, diplopia, photofobia, retention of urination, constipation

Inhibition  Collapse  Paralysis of respiratory center  Amnesia, coma, absence of reflexes

Treatment of intoxication 1. washing the stomach, administration of activated carbon, forced diuresis, Decrease of temperature of patient is possible by cooling /wet covering/. In order to decrease photophobia it’s recommended to put patient in dark room. 2. As specific treatment acetylcholinesterase reversible inhibitors are used, which can penetrate through BBB. 3. Anxiolytics are used to remove excitation 4. β-adrenoblockers are used to remove expressed tachycardia 5. Artificial respiration in a case of necessity

Hyoscine (Scopolamine) Pharmacological effects of scopolamine are similar to atorpine, but in contrast to atropine in inhibits CNS. Antivomiting activity of scopolamine is more prominent /it inhibits trigger zone/ and so it is useful in sea diseases and during vestibular disturbances. It has also amnestic and sedative-hypnotic effect. It has also antiseizure activity and decreases motor impairments during Parkinsonyan disease or drug Parkinsonism. The effects of scopolamine on eye, exocrine glands comparing to atropine is more prominent. Indications 1. Prevention of air and seasickness 2. Premedication 3. Spasm of smooth muscles of inner organs

Ipratropium Ipratropium bromide (Atrovent) blocks all types of M-receptors and so it inhibits M-receptors which decrease release of Ach. It has no effect on CNS. Parenteral administration of Ipratropium leads to bronchodilation, tachycardia, inhibition of glandular secretion. When Ipratropium is used by inhalation way its effects are limited only by action on upper respiratory ways. Dryness of mouth is the most often developed side effect in this case. Ipratropium is used as aerosol or solution for the treatment of bronchial asthma and pulmonary obstructive disease. Effect lasts 4-6 hours.

Pirenzepine Affinity of Pirenzepine to M1 /as well as M4/ receptors is very high, compare to M2 and M3 receptors. It has selective antimuscarinic effect and pirenzepine inhibits secretion of HCl and pepsinogen even in small doses. Besides it improves stomach blood supply and regeneration of stomach and manifest gastroprotective effect. Uses Complex treatment of peptic ulcer

Tropicamide Is used as eye drops for midriasis and cycloplegia. M-cholinolytics side effects are: 1. dryness of mouth 2. transient cycloplegia 3. tachycardia 4. constipation 5. urine retention 6. allergic reactions (dermatitis, conjunctivitis, edema of eyelids)

Main list of drugs Atropini sylfas: 0.4, 0.6 mg tablets; 1ml - 0.1% solution of injections; 0.5, 1, 2% eye drops; 0.5, 1% ointments Hyoscine 0.25 mg tablets, 1ml - 0.05% solutions for injections, 0.25% eye drops Tropicamide 0.5, 1% eye drops

Examples of tests All drugs causes paralyses of accommodation, except a) atropine b) tropicamide c) hyoscine d) prozerine Answer` d Atropine inhibits a) synthesis of acetylcholine b) release of acetylcholine c) destroy of acetylcholine d) effects of acetylcholine on M-receptors Answer: d

M-Cholinolytics decrease tonus of 1. radial muscle of iris 2. sphincter muscle of iris 3. skeletal muscle 4. bladder muscle a) 1,2 b) 3,4 c) 2,3 d) 2,4 Answer: d

M-cholinolytics 1. causes midriasis 2. decrease intraocular pressure 3. causes bradycardia 4. inhibits secretion of bronchial glands a) 1,2 b) 1,4 c) 2,3 d) 2,4 Answer b 47

Ganglioblockers Ganglioblockers (GB) inhibit effects of Ach on Nn cholinoreceptors, which are localized in vegetative ganglions /sympathetic and parasympathetic/, in adrenal medulla, and sinus caroticus. 1. Trimetaphan (Arfonad)- Quaternary amine Pharmacodynamics: Mechanism of action. Blocks Nn-receptors. Effects of blocking of vegetative ganglions. GB cause pharmacological denervation, since they block both sympathetic and parasympathetic nervous systems. First of all the dominated vegetative effects of organs are removed /table 4/ Table.1 Blocking effects of vegetative ganglions

Localization Dominated innervation Effects after blocking of ganglions

Arteries sympathetic (adrenergic) Vasodilatation, improvement of peripheral circulation, decrease of BP

Veins Sympathetic (adrenergic) Vasodilatation, decrease of vein return, decrease of stroke volume

heart Parasympathetic Tachycardia conductivity (cholinergic) negative inotropic effect contractility sympathic (adrenergic)

Iris Parasympathetic Mydriasis (cholinergic)

m. ciliaris of eye Parasympathetic Cycloplegia (far view (cholinergic) vision)

GIT Parasympathetic Decrease of tonus and (cholinergic) peristalsis, constipation, decrease of secretion

urinary bladder Parasympathetic Urine retention (cholinergic)

Salivary glands Parasympathetic xerostomia (dryness of (cholinergic) mouth)

Sweat glands Sympathetic Anhydroses (absence of (cholinergic) sweating)

Effects of blocking of sympathetic ganglions. 1. Decrease of BP. GB decrease the BP due to inhibition of nicotinic receptors in sympathetic ganglia and adrenal medulla. Tertiary and secondary amines penetrate BBB and inhibit secretion of vasopressin (antidiuretic hormone). GB dilate arteries and veins and can cause orthostatic collapse. GB relax precapillary sphincters and improve tissues blood supply and microcirculation. 2.Decrease of preload /due to dilation of veins/ and postload /due to dilations of arteries/ of heart. They improve the contractile function of left ventricle of heart. Effects of blockade of parasympathetic ganglia 1. Tachycardia  due to decrease of effects of vagus nerve

 reflector response because of fall in BP and vein return decrease 2. Relaxation of smooth muscles /bronchi, intestines, bile ducts, urinary tract, etc/ 3. Decrease of secretor function of salivary, sweat, lacrimary, stomach glands 4. Dilation of pupil and paralyses of accommodation

Pharmacokinetics Quaternary amines` absorbtion from GIT isn`t full and is unpredictable. After absorption they are usually distributed in extracellular spaces and eliminated through kidneys usually unchanged.

Uses. Trimetaphan can lead to orthostatic hypotension and loss of vasoconstrictive reflex, that`s why only is used in clinical practice for these cases. 1. during surgical interventions to obtain controllable hypotension for prevention of bleeding 2. Hypertensive crisis and aorta aneurism to inhibit sympathetic reflexes Side effects.  Orthostatic collapse  stimulation of angina pectoris  inhibition of exocrine gland, gastric juice secretion  atonic constipation, development of “paralytic illeus”  retention of urine 50

 mydriasis, increase of intraocular pressure, paralyses of accommodation  dryness of skin, mouth, disarthria, disphagia

Drugs blocking neuromuscular neurotransmission These drugs are also called curare-like drugs or muscle relaxants. There are central and peripheral myorelaxants. Effects of central MR are stipulated by the action of these drugs on appropriate centers of spinal cord Tizanidine (Sirdalud). Peripheral MR, bind to the Nm receptors of neuromuscular synapses, block neuromuscular neurotransmission on the postsynaptic level and bring to reduction of skeletal muscle tone and bring to the paralyses development.

Peripheral MR. Classification: 1. Antidepolarizing MR Competitively acting MR, which are classified according to the duration of action:  MR with long duration of action /80-180 min/ - d – Tubocurarine, Pancuronium  MR with intermediate duration of action /30-40 min/ - Vecuronium, Atracurium  MR with short duration of action /10-20 min/ - Mivacurium Non-competitively acting MR – Prestonalum 2. Depolarizing MR - Succinylcholine( Dithylin, Suxamethonium)

Pharmacodynamics 1. Antidepolarizing MR Mechanism of action. These block Nm receptors and by this way prevent depolirazing action of acetylcholine on postsynaptic membranes. Blockade of Nm cholinoreceptors can be competitive and non-competitive.  In case of competitive mechanism MR competes with Ach for the same receptors. These drugs usually have more affinity to the Nm receptors, but they don’t have mimetic activity. In vitro the effects of these drugs can be removed by high doses of acetylcholine, but in vivo – with anticholinesterase drugs.  Non competitive MR, in contrast to Ach, bind to the other subunits of receptors preventing the binding of Ach with Nm receptors . 2. Depolarizing MR have affinity toward Nm receptors and intrinsic mimetic activity. These drugs open sodium channels of Nm receptors, cause depolarization of skeletal muscles, and at the beginning they can cause convulsions and tremor. These drugs after binding to the receptors are not dissociated very quickly, and they cause long depolarization of muscle cell which results in sodium channel deactivation due to which effects of acetylcholine is inhibited. Effect of Ach is inhibited and the activation of muscle fiber is prevented. Effects on organ-systems Relaxation of skeletal muscles. Antidepolirizing MR (i/v administration) cause relaxation of skeletal muscle in the following order: at first mimic muscles of face are relaxed, then finger muscles, after that paralyses is extended to the hands, legs, and intercostals muscles and at the 52 end diaphragm is relaxed which brings to stoppage of respiration. Recovering of skeletal muscles starts in the opposite order and is started from the diaphragm. Depolarizing MR before paralyses cause constriction of muscles which lasts short, only seconds. CNS: All MR have quaternary ammonium and they can’t penetrate BBB. So intravenous injection of these drugs doesn’t cause any central effect. Vegetative ganglia. As in vegetative ganglia nicotinic receptors mainly exist, competitive MR less cause ganglion blockage. This effect is more prominent for Tubocurarine but new drugs don’t have the mentioned property. Succynilcholine can even activate ganglia, because it has an agonistic activity on receptors. Cardio-vascular system. Tubocurarine decreases BP. Mechanisms of BP decrease are: blockage of vegetative ganglia, histamine release, reduced vein reflow, stipulated by paralyses of legs and respiratory muscles. Due to inhibition of n. vagus tachycardia can develop. GIT. Competitive MR can worsen the postoperative atonia of intestines.

Pharmocokinetics All Muscle relaxants are quaternary substances, aren`t used by enteral way, primary are used by i/v way.

Uses 1. Surgical interventions for making myorelaxation 2. Intratracheal intubation for making myorelaxation

3. Inhibition of spontaneous respiration and making artificial respiration 4. Prevention of convulsions when efficiency of antiepileptic drugs is absent 5. Myorelaxation in a case of bone fracture Side effects: 1. Long paralyses of respiratory muscles and apnoe 2. Hypotension /mainly Tubocurarine/ 3. Release of histamine /mainly Tubocurarine, Atracurium/ which causes bronchospasm, increased activity of excretory glands of upper airways, hypersalivation and fall of BP. 4. In some patients succinylcholine can cause severe complications stipulated by hereditary absence of pseudocholinesterase enzyme, which hydrolyzes succinylcholine. In these cases effects of Ditiline can be removed by injection of fresh blood plasma. 5. Depolarizing MR can causes minor traumas, and muscle pain. 6. Arrhythmias, even heart arrest /depolarizing MR/ 7. Malignant hyperthermia –is a result of mutations of Ca2+ ion channels . It leads to release of Ca ions from sarcoplasmic reticulum and activation of catabolism. In this case Dantrolene is used as antidote, because it blocks ryanodine receptors and prevents release of Ca2+ ions from sarcoplasmic reticulum. Advantages of new MR 1. Less ganglion blocking activity, less cardiovascular effects 2. Less or absence of histamine release 3. Mostly short duration of action and easy are recovery of their effects.

Main list of drugs Trimethaphan (Arfonad): 250mg ampules Tests Which drugs are ganglioblockers? a) atropine b) thyramine c) edrophonium d) trimethafan answer: d All mentioned are pharmacodynamic properties of ganglioblockers, except: a) blocking of Nn - receptors b) blocking of sympathetic ganglions c) blocking of parasympathetic ganglions

d) stimulation of α1 - adrenoreceptors answer: d There are the following groups of myorelaxants: 1. MR with competitive mechanism of action 2. repolarizing MR 3. MR with additional inner sympathomimetic 4. depolarizing MR activity a) all b) 2,3 c) 1, 4 d) 1,2,4 answer: c Mechanism of action of MR is a) blocking of Nn - receptors

b) stimulation of α1 - adrenoreceptors c) stimulation of dopamine receptors d) 55

d) blocking of Nm - receptors answer: d Effects of MR on organ-systems include: 1. stimulation of CNS 2. relaxation and paralyses of skeletal muscles 3. release of histamine 4. increase of peristalses and tonus of bowels a)1,3,4 b)2,3 c)1,3,5 d)all answer: b

Drugs acting on adrenergic /sympathetic/ nervous system Neurotransmission stages of adrenergic nervous system as drug targets 1. Synthesis. Catecholamines are synthesized from phenylalanine amino acid. In the liver phenylalanine converts to tyrosine by the presence of hydroxylase enzyme. Tyrosine is captured by neuronal terminals by special aromatic aminoacid carriers. The first stage of norepinephrine (NE) synthesis is the oxydation of tyrosine by tyrosine hydroxylase enzyme with formation of dihydroxyphenylalanine (DOPA). By the presence of decarboxylase enzyme DOPA is converted to dopamine, which is transported into the vesicle by the (VMAT-vesicular monoamine transporter). Inside of vesicles dopamine is converted into norepinephrine by dopamine-β-hydroxylase enzyme (picture 11). In the adrenal medulla and other cells norepinephrine is further converted to epinephrine due to methylation by phenylethanolamine-N- methyltransferase enzyme (picture 11). 2. Storage: After being synthesized norepinephrine is stored in presynaptic vesicles, where its concentration can rich level of 100mmol. To stabilize osmotic pressure stipulated by high concentration gradient of NE, norepinephrine is stored along with ATP and chromogranin protein. Also different enzymes and regulatory neuropeptides like encephalines and neuropeptide Y were discovered in the content of vesicles (picture 12).

Picture 11. The main stages of Noradrenaline and Adrenaline synthesis

Cathecolamine sythesis Thyrosinee

Thyrosine hydroxylase Thy DOPA

Aromatic L-aminoacid decarboxylase

Dopamine

Dopamine β-hydroxylase

Noradrenaline

Phenylethanolamine N- methyltransferase

Adrenaline

3. Release: As it was mentioned depolarization of presynaptic membrane mediates opening of Ca2+ channels and Ca2+ ions inflow in direction to axoplasm leading to increase of Ca2+ ions level which trigger norepinephrine release from presynaptic vesicles. After its release into synaptic cleft NE acts on corresponding adrenoreceptors, which are located in both presynaptic and postsynaptic membranes (picture 12). 4. Inactivation of released NE: After dissociation of NE-receptor complex norepinephrine is inactivated by one of the following mechanisms: Neuronal reuptake or reuptake-1: In this case at first NE is actively transported from synaptic cleft back to the axoplasm of the neuronal terminal by the special transporter called NET /norepinephrine transporter/ which transports NE using difference of concentration

58 gradient of Na+ ions. Further from axoplasm NE is transported to the synaptic vesicles via ATP-dependent proton translocase. This translocase in order to carry one molecule of NE into the vesicle eliminates two protons. Approximately 80% -of NE is exposed to neuronal reuptake, thus released NE springs up from two sources – de novo synthesized molecules and molecules which are reuptaked from the synaptic cleft. Extraneuronal reuptake or reuptake-2: In this case NE is captured by the surrounding tissues f.e. neuroglia, fibroblasts, myocard, endothelium of vessels, smooth muscles. Approximately 10% of NE is undergone extraneuronal reuptake, meanwhile this mechanism has predominant significance for the inactivation of cathecholamines circulating in blood (picture 12). Inactivation by enzymes: Two enzymes are responsible for inactivation of catecholamines: MAO /monoamine oxydase/ and COMT /catechol-0- methyltransferase/ enzymes. MAO is a mitochondrial enzyme existed in two isoforms MAO-A and MAO-B. Both enzymes have specificity towards ligands. MAO-A inactivates mainly serotonine, norepinephrine and dopamine. MAO-B inactivates dopamine more rapidly than serotonine and norepinephrine. MAO enzyme provides deaminization of catecholamines with formation of biogenic aldehydes. COMT is a cytosolic enzyme found in the liver. COMT causes methylation of catecholamines (picture 12).

Picture 12. The main stages of adrenergic neurotransmission

Adrenoreceptors

Adrenoreceptors are located in presynaptic, postsynaptic membranes as well as in those organs which doesn`t receive adrenergic innervation (extrasynaptic). Extrasynaptic adrenoreceptors are activated by norepinephrine and epinephrine circulated in the blood. All adrenoreceptors are coupled with G proteins. There are α and β adrenoreceptors. α receptors are divided into α 1, α2adrenoreceptors and β

–adrenoreceptors are divided into β 1, β 2, β 3 types.

α1-adrenoreceptors

Transduction mechanism: These receptors couple mainly with Gq protein. They are responsible for regulation of membrane phospholipids activity as well as for permeability of L-type Ca2+ channels. Activation of such receptors located in smooth muscles of the most organ systems increases level of Ca2+ ions leading to activation of calmodulin-dependent kiynase of light chains of myosin which is necessary to stimulate interaction of actomyosin and contraction of smooth muscles. Only in stomach and intestine activation of α1 –adrenoreceptors opens Ca2+-dependent potassium channels and thus cause hyperpolarization of sarcolemma and relaxation of smooth muscles. Activation effects: 1. Contraction of the radial pupillary dilator muscle of the iris causing midriasis 2. Vasoconstriction of skin, renal, cerebral, GIT vessels. 3. Rise in blood pressure 4. Constriction of spleen capsule leading to outflow of deposited blood into the bloodstream

5. Contraction of sphincters of GIT and urine bladder 6. Decrease in both tone and motility of stomach and intestine 7. Contraction of pilomotor muscles of skin causing movement of hairs and gooseflesh (table 5).

α2-adrenoreceptors by the location can be post- and pre- and extrasynaptic.

Transduction mechanism: These receptors are coupled mainly with Gi – proteins. Thus activation of such receptors causes inhibition of adenylatecyclase, decrease in level of intracellular cAMP, increase in permeability of potassium ions and inhibition of Ca2+ channels of L-, N- types. Location and activation effects:

Postsynaptic α2–adrenoreceptors:  constriction of vessels of eye cilliary body, decrease in intraocular fluid formation, decrease in intraocular pressure  Vasoconstriction of the skin and mucous vessels.  Decrease in motility of GIT  Inhibition of secretory function of intestines (picture 5)

Presynaptic α2–adrenoreceptors Activation of such receptors causes inhibition of norepinephrine release from presynaptic membrane. This mechanism operates in case of high concentration of released norepinephrine in synaptic cleft (negative inhibitory feedback mechanism).

Extrasynaptic α2–adrenoreceptors:  Vasoconstriction  Decrease in secretion of insulin  Stimulation of platelet aggregation 62

β-adrenoreceptors: Transduction mechanism: All of three types of β-adrenoreceptors are coupled with Gs protein. Activation of β-adrenoreceptors leads to activation of adenylatecyclase and increase in cAMP, activation of different protein kinases. In smooth muscles increase in cAMP, stipulated by activation of β- adrenoreceptors, leads to activation of proteinkinase A, which in its` turn inhibits calmodulin-dependent kinase of light chains of myosine, which is necessary for actomyosin interaction. Thus we have inhibition of actomyosine complex formation and relaxation of smooth muscles.

β1-adrenoreceptors Location and activation effects  heart: tachycardia, increase of velocity conduction through the conducting system of heart, increase in contractility force and oxygen consumption.  Stimulation of renin secretion in juxtaglomerular cells in kidneys  Decrease in motility of intestine  Activation of cAMP dependent lipolysis in fatty tissues (table 5)

Postsynaptic, extrasynaptic β 2 –adrenoreceptors Location and activation effects  Stimulation of intraocular fluid secretion  Dilation of coronary, pulmonary vessels as well as vessels of skeletal muscles  Bronchodilation  Inhibition of motor function of GIT  Relaxation of gallbladder, urinary bladder, uterus

 Stimulation of cAMP-dependent glycogenolysis and glyconeogenesis in the liver and stimulation of glycogenolysis in skeletal muscles.  Stimulation of insulin secretion  Inhibition of degranulation of mast cells, basophils

Presynaptic β 2 -adrenoreceptors Activation effects. According to the positive feedback mechanism activation of such receptors causes stimulation of norepinephrine release.

β3-adrenoreceptors activation of such receptors leads to stimulation of lipolysis in fatty tissue.

Table 1.Adrenoreceptors, their transduction mechanism, location, activation effects

Adrenoreceptor Transduction Location Action mechanism α 1 Gq/activation of Smooth muscles of Contraction protein kinase vessels ↑ Sphincters of urinary Contraction inositoltriphosphate bladder ↑ diacylglycerol Smooth muscles of Relaxation 2+ ↑Ca GIT Gi/Go Sphincters of GIT Contraction Spleen capsule Contraction Radial pupillary Contraction / enhancement dilator muscle of the in pupil size - mydriasis / iris Pilomotor muscles of Contraction skin α 2 Gi/ ↓cAMP β cells of pancreas Inhibitionofinsulinsecretion ↓ Ca2+ channels /extrasynaptic/ ↑K+ channels Platelets Aggregation Go /extrasynaptic/ Neuronalterminals Decrease in norepinephrine /presynaptic/ release Smooth muscles of Relaxation GIT /postsynaptic/ Secretor function of Inhibition 64

intestine /postsynaptic/ Smooth muscles of Contraction vessels /extrasynaptic/ β1 Gs / ↑cAMP Heart /sinoatrial Positive inotropic, node, atria, chronotropic and atrioventricular dromotropic effects node, His-Purkinje conducting system, ventricles/ juxtaglomerular cells Stimulation of rennin ofkidney secretion β2 Gs/ ↑cAMP Neuronal terminals Stimulationof NA release /presynaptic/ Smooth muscles / Relaxation upper airways, GIT, genitourinary tract, uterus, vessels//postsynaptic/ Ciliar muscle of iris Relaxation /postsynaptic/ Vessels Dilation /postsynaptic/ Liver Stimulation of /extrasynaptic/ glycogenolysis and glyconeogenesis β cells of pancreas Stimulation of insulin /extrasynaptic/ secretion Bronchial glands Inhibition of secretor /postsynaptic/ function Skeletal muscles glycogenolysis /postsynaapticն/ Mast cells, inhibition of degranulation basophils β 3 Gs / ↑cAMP Fatty tissue Lipolysis

Quantitative ratio of α and β adrenoreceptors is differ in different tissues. Thus, α1adrenoreceptors prevalent in intestine, skin, renal vessels,

65 sphincters of GIT, spleen capsule. β1 –adrenoreceptors prevalent in myocardium and β2 adrenoreceptors located mainly in bronchial, skeletal muscles, pulmonary and coronary vessels. So, pharmacological intervention in adrenergic neurotransmission is possible in the following stages: 1. Inhibition of NA synthesis, f.e. α – methylthyrosine inhibits thyrosine hydroxylase enzyme and could be used in experemental pharmacology to inhibit NA synthesis. 2. Influence on vesicular transport: Vesicular monoamine transporter is a non specific transporter and carries all chemical compounds which are structurally similar to norepinephrine. This property is very important from pharmacological point of view, for example usage of sympatholytics (reserpine) 3. Influence on storage of norepinephrine in vesicles Indirect sympathomimetics /thyramine/, simpathomimetics of mixed action /amphetamine/ evoke release of norepinephrine from its` storage.

4. Change of activity of regulatory α2 and β2 receptors to manage release of norepinephrine from presynaptic membrane. Phentolamine

by inhibiting presynaptic α2–receptors causes increase in NA release into synaptic cleft due to suppression of negative feedback mechanism. The same action is noticed in case of activation of

presynaptic β2-receptors /f.e. Isoprenaline/ leading to enhancement of positive feedback mechanism. Thus, decrease in neurotransmitter

release is observed in case of stimulation of presynaptic α2 –receptors

/clonidine/ or inhibition of presynaptic β2 –receptors /propranolol/. 5. Inhibition of norepinephrine reuptake. Thus reuptake-1 could be inhibited by tricyclic antidepressants or cocaine.

6. Influence on those enzymes activity which inactivate norepinephrine. There are MAO inhibitors (Clorgilin, Selegilin) and COMT inhibitors /tolcapon, entocapon/. 7. Activation or inhibition of adrenoreceptors: adrenomimetics and adrenoblockers.

Sympathomimetics

Sympathomimetics Indirect Sympathomimetics Tyramine

α, β- α – β- Mixed adrenomimetics adrenomimetics ardenomimetics Sympathomimetics Amphetamine

Ephedrine

Adrenaline

(β1, β2, α1, α2)

Noradrenaline (β1, β1, β2- β2, α2) adrenomime β1- tics β2- Dopamine adrenomime- adrenomi- (D1>D2) Isoprenaline metics tics

Salbutamol Dobutamine

α1- α2- adrenomimetics adrenomimetics Phenylephrine Clonidine

There are direct sympathomimetics /adrenomimetics/, indirect sympathomimetics and mixed sympathomimetics. Indirect 67 sympathomimetics increase noradrenaline release from presynaptic membrane. Direct sympathomimetics activate directly adrenoreceptors /AR/.

Due to affinity toward receptors there are: 1. α and β-agonists (Adrenaline, Noradrenaline) 2. selective α1 adrenomimetics (Phenylephrine) 3. primary α2 adrenomimetics (Clonidine, Halazoline) 4. selective β1 adrenomimetics (Dobutamine) 5. selective β2 adrenomimetics (Salbutamol, Terbutaline) 6. β1, β2, β3- adrenomimetics (Isoprenaline or Isadrine) Indirect sympathomimetics are those drugs, which sympathomimetic activity is determined by stimulation of NA release from presynaptic membrane. Mixed acting sympathomimetics not only increase release of NA, but also directly stimulating adrenoreceptors.

α and β-agonists Adrenaline /Epinephrine/: Adrenaline (A) is endogenous catecholamine, it is synthesized in the adrenal medulla and it’s considered as hormone of fear and anxiety, as in emergency situation it mobilizes the most important vegetative function of organism /rescue, escape/. It’s derivative of phenylalkylamine. Pharmacodynamics: A. directly activates both α - and β – AR. In small doses it activates mainly β1, β2 – AR, but in high doses the effects of α1 – AR are dominated. Effects on organ-systems. CNS. As a polar substance it doesn’t penetrate BBB

Cardio-vascular system

Heart. In heart β1 – AR dominate and their stimulation causes positive inotropic /increase of heart force/, chronotropic effect /increase of heart rate because of increase of diastolic depolarization rate of pacemаker cells of sinoatrial node, positive dromotropic /increase of conduction through atrio-ventricular node, His' bundle/ and bathmotropic effects /shortenage of refractor period, and increase of automatism/. Stroke volume is increased, systole is decreased, oxygen demand is increased.

Blood Pressure A. after s/c or slow i/v injection increase systolic BP and decrease diastolic

BP. Peripheral resistance is decreased, as β2 AR of vessels are very sensitive to small doses of A than α1 – AR. Average BP is also increased. Quick i/v injection of A. increases BP by three phases. 1. Rapid increase of both systolic and diastolic pressure which is

stipulated due to stimulation of α1- AR of vessels 2. After several seconds BP is returned to the initial level 3. Average BP is reduced due to decrease of A quantity /enzyme destroy, extraneuronal reuptake/, as it’s known that small doses of A.

activates β2 AR. Effects on the other vessels. Arterioles and precapillary sphincters are very sensitive to A., whereas large veins and arteries are affected in high doses. Vasoconstrictive effects of A. dominate on skin, mucous membrane and renal vessels by means of α1- AR, and extrasynapticα2 AR, last one is stimulated by circulating catecholamine. Vasodilating effects dominate in skeletal muscle, liver and coronary vessels /by means of β2 AR/: A. has no

69 direct effects on cerebral vessels and cerebral blood flow is changed with changes in BP. Respiratory system: A. dilates bronchi. This effect is more obvious in the case of bronchospasm. A. prevents release of c-AMP-dependent histamine, serotonin and leucotriens from mast cells, alveolar macrophages, basophiles. /β2 AR/: GIT: decrease of stomach tonus, constriction of pyloric and ileocecal sphincters and reduce of tonus of intestine and peristalsis. These effects are very short and they don’t have clinical meaning. Urogenital system. A. Relaxes detrusor muscle of bladder and constricts sphincter. This effect can cause urine retention, mainly in adenoma of prostate. Effects of A. on uterus depends on hormonal status of body and stage of pregnancy. A. constricts spleen capsule, too. Spleen. A. contracts spleen capsule Eye. Constriction of radial muscle of iris and dilation of pupil is developed. This effect is less obvious in case of local usage of A, as it penetrates through the eye membrane with difficulties. Decrease of intraocular pressure is obvious in the case of open angular glaucoma. Mechanisms of decreasing in intraocular pressure are the followings. Constriction of ciliar body vessels, decrease in intraocular liquid production / α1- AR/. Metabolic effects of A. A. stimulates glycogenolysis and gluconeogenesis, and causes hyperglycemia /β2 AR/. Secretion of insulin is also reduced /α2

AR/. Lipolysis is activated /β1β3 - AR/, which brings to the increase of level of free fatty acids in the blood. Release of potassium ions from liver is activated and hyperkaliemia can be developed than long hypokaliemia can be developed, as potassium ions are uptaken by the skeletal muscles. 70

Pharmacokinetics. A. is not used per os as in GIT and liver it’s conjugated very easily and oxidized. In case of subcutaneous injection A. is absorbed very slowly which is explained by vasoconstrictor activity of A. In the body A. is destroyed by COMT and MAO. A. also can be used by inhalation way. Side effects: 1. Transitional anxiety, heartbeat, tremble 2. Increase of BP which can be accompanied with cerebral hemorrhage, arrhythmias 3. Increase of ventricles automatism, formation of ectopic and heterotopic foci which can be reason of development of extrasystoles and fibrillation of ventricles. Such type of arrhythmias can be in ischemic disease of heart, arterial hypertension, thyreotoxicoses, intoxication by cardiac glycosides, general anesthesia. 4. Exhaustion of metabolic and functional reserves of heart, which can be developed in acute onset of angina pectoris or cardiac infarction. Indications: 1. A is used with local anesthetics which prolong the period of action of local anesthetics and also prevent the resorbtive actions on organism 2. Solutions with A. solution are used to stop bleedings 3. Cardiac arrest. In this case A. with 10ml physiological solution is administered intracardial directly into the left ventricle cavity.

4. Bronchial asthma and anaphylactic shock. In this case A. improves heart work, increases BP, dilates bronchi, stabilizes mast cells. Noradrenaline /norepinephrine/: In CNS and peripheral synapses NA is neurotransmitter in adrenergic synapses, it’s 10-20% of catecholamine’s in adrenal medulla.

Pharmacodynamics. NA stimulates α1 - ¨ β1 - AR, has insignificant action on β2 – AR. Cardio-vascular system. NA increases stroke volume of heart and has positive chronotropic effect which is overcomed by the effect of vagus nerve (due to reflector activation of center of vagus nerve in response to increase of BP), stroke volume of heart stays unchanged, as heart rate is decreased and we have bradycardia. Both systolic and diastolic pressures and peripheral resistance of vessels are increased. Compare to A, NA 5-10 times stronger increases BP, as NA has no effect on β2 - AR. Other effects. NA constricts mesenteric vessels and limits blood flow in spleen and liver. It decreases blood flow in kidneys, skeletal muscles as well. In high doses NA can cause hyperglycemia. Pharmacokinetics. Like A., NA is also can not be used per os. So, it’s not used subcutaneously, because it causes severe spasm of vessels, ischemia and necroses. NA is injected i/v droply, with glucose. Side effects Are the similar with NA, but increase in BP can be more significant. In i/v injection if drug enters to tissues leads to tissue necrosis. Indications. NA has very limited usage in medicine. It’s mainly used in shock to increase BP.

Selective α -adrenomimetics (AM)

α1 -AM Phenylephrine (mesatone)

Pharmacodynamics. Mesatone stimulates directly α1– AR. It increases both systolic and diastolic BP and peripheral vascular resistance. Effects of mesatone on BP is less than affects of A, but it acts longer (20 min in i/v and 50 min in i/m injection). It’s stipulated by the its stability toward COMT. Phenylephrine has no direct action on heart. But increase of BP activates center of vagus nerve and causes bradycardia. It constricts also vessels of kidney, skin and spleen. Phenylephrine dilates pupil without cycloplegia. Due to vasoconstriction it can decrease the intraocular pressure in open angle glaucoma. Side effects. Increase of BP, headache, bradycardia, retention of urine. Indications. Mesatone is used as decongensant in rhinitis, antritis. In ophthalmology it’s used to exam eye bottom, to treat conjunctivitis. It’s used also in hypotension (orthostatic collapse, shock).

α2 -Adrenomimetics /AM/

α2 - selective agonists can activate both presynpatic and postsynaptic α2-

AR. Clonidine stimulates α2-AR of vasomotor center, inhibits activity of sympathetic nervous system on cardiovascular system. Also in vessels it activates α2 - AR and decreases NA release from presynaptic membrane into the synaptic cleft.

Mainly on α2 - AR acts xylometasoline /galazoline/. Xylometazoline is derivative of imidazole and has local vasoconstrictor effect. Long duration of usage of this drug /more than 5 days/ causes development of quick tolerance /tachyphylaxis/. Mainly they are used as 73 nose drops in rhinitis, antritis, otitis. They are contraindicated in high BP, arrhythmias, atherosclerosis as this drugs can be absorbed from mucous membrane and have resorbtive effect. β- AM Isoprenaline /Isadrine/ is non-selective agonist of β – AR and it’s derivative of NA. Pharmacodynamics. Isadrine decreases peripheral resistance, in i/v injection, as it dilates skeletal muscle, mesenterial and renal vessels. Diastolic pressure is decreased, but systolic pressure is unchanged or it’s increased due to β1- effects. As it has positive ino- and chronotropic effects, stroke volume is increased. Isoprenaline relaxes tonus of smooth muscles. This effect is more obvious on bronchi and GIT muscles. It dilates bronchi muscle of the patients with bronchial asthma and also it prevents release of histamine and other products of inflammation from basophils, limphocytes and alveolar macrophages.

Isoprenaline activates glycogenolysis, gluconeogenesis / β2-AR/, lypolysis

/β1-, β3-AR/. Compare to adrenaline, isadrine has less activity to cause hyperglycemia, as it activates β-receptors of Lanherhance islets of pancreas and stimulate insulin secretion. Pharmacokinetics. Isoprenaline is used by parenteral way and as aerozoles. Metabolism is in liver and it’s metabolized by COMT. Compare to A. and NA. It’s metabolized by MAO very slowly and it’s not undergone to extraneuronal reuptake. Side effects. Palpitation, arrhythmia, ischemic disease of hear. In spite of it penetrates BBB very poorly, it can cause vomiting, headache, insomnia,

74 tremor of hands. Isadrine can cause tolerance, which decreases quantity of β-AR (down-regulation). Indications. It is rarely used in bradycardia which is not sensitive toward atropine and different types of cardiac AV – blockades to stimulate heart function.This drug is not used in bronchial asthma very often, as it is not selective and has side effects on heart.

Selective β1-AM Dobutamine/dobutrex/ is structural derivative of dopamine. Pharmacodynamics: I/v droply injection of dobutamine increases cardiac output . Also peripheral resistance and resistance of vessels of small blood circulation is decreased, renal and coronary blood flow is improved, excretion of potassium and sodium is stimulated. Side effects.Tachycardia, arrhythmias, hypertension, retrosternal pains, vomiting, nausea, phlebitis in the place of injection. During 2-3 days tolerance is developed. Indications: 1. It is used in cardiogen shock leading to acute cardiac insufficiency

Selective β2-AM

β2-AM are divided into the following groups: 1. Short acting drugs /period of action is about 4 hours/ - salbutamol, terbutaline 2. Long acting drugs /period of action is more than 6 hours/ - salmeterol

Pharmacodynamics: These drugs dilated bronchial muscles and decrease airway resistance. Also decrease tone of uterus and increase potassium ion uptake by skeletal muscles. Salmeterol is more selective drug from this group

Side effects. As selective β2 –agonists are not completely selective agonists of β2-AR, they can have side effects, like tachycardia and arrhythmias

/stimulation of β1-AR/. The most common side effect is skeletal muscle tremor (β2 -AR). Specific way of usage of these drugs can increase selectivity of drugs toward β2 –AR of target organs and prevent the systemic action. Indications. 1. Bronchial asthma and obstructive diseases of respiratory system. In this case selective AM are used both per os /syrup, tablets/ and aerosols. Short acting drugs are effective in onsets of bronchial asthma; long acting drugs are active for prevention of onsets of bronchial asthma. 2. Prevention of abortion and early delivering, as they decrease tonus of uterus.

List of main drugs Dobutamine 12.5 mg/ml in flacons with 20 ml volume Epinephrine (Adrenalin) 0,1%-10 ml flacons for external usage, 0,1%-1ml ampoules for injections, 0,1, 0,5, 1, 2% eye drops, 0.1% nasal drops Xylometazoline 0.05, 0.1% nasal drops

Some examples of tests 1.All mentioned drugs are direct adrenomimetics, except: a/ adrenaline b/ ephedrine c/ noradrenalin d/ dobutamine 2. Phenylephrine 1. constricts the vessels 2. is injected only I/V 3. causes reflex bradycardia 4. is used in hypotension and collapses a/ 1,3,4 b) 2,4 c) 1,3 d) 2,3,4 3. Indications of adrenaline are the followings: 1. prolongation of local anaesthetic’s effect 2. arterial hypertension 3. anaphylactic shock 4. onsets of bronchial asthma a/ the all b) 1,3,4 c) 1,4 d)2,3 4. Noradrenaline

1. stimulates α1-AR 2. increases BP 3. causes reflex bradycardia 4. injected only intravenously a/ all b) 2,4 c) 1,3 d)1, 2,3

5.β1-adrenomimetics a/dilate pupils b/ increase secretion of insuline 77 c/ increase the rate and force of cardiac construction d/ dilate skeletal muscle vessels

Indirect and mix sympathomimetics

Indirect sympathomimetics (SM) are the drugs which increase amount of NA in synaptic cleft and enhance its interaction with adrenoreceptors, so the effects of sympathetic nervous system are developed. Indirect SM is thyramine, mixed are ephedrine, amphetamine. The possible action mechanisms of sympathomimetics. 1. They have similar to NA structure and they are reuptaken from presynaptic membrane and by this way they limit reuptake of NA (reuptake-1). 2. These drugs after reuptake enter into the vesicles instead of NA by vesicular monoamine transporter (VMAT) and as a result NA is accumulated in cytoplasm. Some part of NA is destroyed by MAO, another part is released into the synaptic cleft. 3. Destroy of NA reuptake and also increase of NA release into the synaptic cleft increase level of NA, which provokes long interaction between neurotransmitter and adrenoreceptors. 4. They can increase amount of NA by inhibition of MAO enzyme. Ephedrine: Is a natural alkaloid Pharmacodynamics: It’s mixed SM. Mechanisms of action are:  Inhibition of NA neuronal reuptake  Release of NA from vesicles into the synaptic cleft  Inhibition of MAO  Direct and indirect stimulation of adrenoreceptors 78

Ephedrin is in the list of drugs under surveillance. Local effects: Eye:  Midriasis  Insignificant decrease in intraocular pressure Resorbtive effects: CNS: psychomotor activation, which can be expressed by  Increase of mental and physical activity, euphoria, awareness, decrease of sleep demand  Activation of respiratory and vasomotor centers Ephedrine can cause psychological dependence during long duration treatment. Cardiovascular system: Compare to A. it has weak effect, but about 7-10 time longer effects than A.  Positive chrono-, ino- and dromotropic effects  Vasoconstriction and increase of peripheral resistance because

of activation of a1 and α2-AR and stimulation of vasomotor center. As a result heart contraction volume and blood pressure is increased. Respiratory system  Bronchodilation  Decrease of edema of airways mucous membrane GIT:  Decrease of intestine and stomach tonus and peristalsis  Constriction of sphincters

Urogenital tract:  Decrease of bladder tonus 79

 Constriction of sphincters Ephedrine decreases the tonus of uterus, causes hyperglycemia

Repeated usage of ephedrine causes development of tachyphylaxis. This phenomenon is stipulated by exhaustion of NA in vesicles, and for restoration of NA time is needed. Amphetamine: Pharmaodynamics: Mix sympathomimetic mechanisms of amphetamine are the following. 1. Inhibition of biogenic amines’ neuronal reuptake 2. Inhibition of MAO 3. Increase of amines’ release from vesicles and their transport into the synaptic cleft 4. Direct activation of receptors 5. Increase of adrenaline secretion from adrenal medullary gland

Amphetamine has the following effects:  CNS stimulation, euphoria  Slightly analgesic effect, is potentiating narcotic analgesics` action  Stimulation of respiratory center /it’s more evident when the center is inhibited/ increase of respiratory motor activity and depth  Anorexia – inhibition of appetite, because of inhibition of hunger center and stimulation of center of saturation. Peripheral effects of amphetamine are similar to peripheral effects of other sympathomimetics.

Side effects: Now amphetamine is not used for clinical purposes because psychic and physical dependence development and it is under the supervision. Thyramine: it’s intermediate product of metabolism of tyrosine. It also in high concentration can be found in some foods /cheese, liver of chicken, marinated fish, wine, beer/. It’s metabolized very quickly in GIT by MAO and completely neutralized in liver. The patients who receive inhibitors of MAO, thyramine in food is not neutralized, so it goes into the systemic blood, reuptaked by neurons and increases blood pressure very expressively. Indications of indirect adrenomimetics: 1. Narcolepsy /pathological sleep/ – amphetamine 2. Rhinitis – ephedrine decreases edema of mucous membrane, has decongestant effect 3. Hyperactive syndrome and lack of attention in children /amphetamine/

The main drug list Ephedrine 25, 50 mg, syrup 20mg/5ml, 5%-1ml ampules Tests 1. Indirect sympathomimetics are drugs a) directly stimulating adrenoreceptors b) increasing level of NA in synaptic cleft c) decreasing level of NA in synaptic cleft d) acting on the synthesis of neuromediators

2. Incorrect: Ephedrine has the following effects a) leads to tachyphylaxis b) leads to physical and psychological dependence c) decreases intraocular pressure and leads to midriasis d) decreasis cardiac output and blood pressure e) decreases tone and motility of GIT and increases tone of sphincters

3. Amphetamine 1. inhibits NA, DA, 5-HT neuronal reuptake 2. inhibits MAO 3. directly stimulates adrenoreceptors and serotonine receptors 4. increases secretion of adrenaline from adrenal medullary cleft a) 1.4.5 b) the all c) 1.2.3 d) 3.4

Drugs inhibiting adrenergic neurotransmission

Sympatholytics Reserpine adrenoblockers

α, β- -adrenoblockers Labetalol β- β1,2-

-adrenoblockers -adrenoblockers Propranolol

α-

adrenoblockers β1-

-adrenoblockers Atenolol

α1,2-adrenoblockers

α2-adrenoblockers Phenoxybenzamine Yohimbine

α1-adrenoblockers

Prazosine

α – Adrenoblockers

α – adrenoblockers (AB) inhibit α – ARs and prevent interaction of NA with ARs. According to interaction with α – ARs, AB are divided into the following groups: 1. Non selective α - AB– Phentolamine, Phenoxybenzamine

2. Selective α1 - AB - Prazosine, Doxazosin, Terazosin, Tamsulosin

3. Selective α2 – AB - Yohimbine

Non selective α - AB

Non selective α-AB inhibits presynaptic, postsynaptic α1α2-AR and extrasynaptic α2- AR. Inhibition of presynaptic α2 – AR increases NA release. Pharmacodynamics: Cardio-vascular system. 1. General peripheral resistance and arterial pressure are decreased because of relaxation of smooth muscles of vessels /arteries, arteriols, precapillary sphincters/. The mechanisms of these effects are  Inhibition of α – ARs of vessels

 Activation of postsynaptic β2 -AR of vessels by catecholamines Relaxation of peripheral vessels improves intraorgan blood supply, prevent ischemia in tissues, promote synthesis of ATP and aerobic processes of bioenergetic. 2. Reflex tachycardia (due to decrease in BP). Non selective blockers block presynpatic α2-ARs and increase release of NA leading to stimulation

84 of heart β1 receptors leading to tachycardia, increase in heart contraction force, increase in heart oxygen demand. 3. High doses of α-adrenoblockers dilate veins leading to development of orthostatic collapse. Other effects: treatment with α-AB causes dominant effects of parasympathetic nervous system and myosis /usually accommodation is not changed/, stimulation of peristalsis and secretory function of GIT are developed, edema of nasal cavity. Phentolamine:

It’s derivative of imidazole, competitively and reversibly block α1 - and α2 – AR. It’s antagonist of serotonin receptors, agonist of M and histamine H1 and H2 receptors. Mainly it’s administered i/v.

Phenoxybenzamine: It binds mainly to the α1-AR and less to α2-AR by irreversible bonds. It also inhibits reuptake of NA, blocks H1 receptors, cholinoreceptors and serotonin receptors. Side effects: 1. Dizziness, headache 2. Edema of nasal mucous membrane 3. Nausea, diarrhea, ulcer disease, gastritis 4. Tachycardia, arrhythmias, impairment of angina pectoris 5. Orthostatic collapse /high doses/. Indications. Nowadays non-selective α – ABs have limited usage, and mainly are used in hypertonic crises in pheochromocytoma and copious sweating.

Selective α1 - AB This group of drugs includes prazosine, tamsulozine.

Pharmacodynamics.There are three subtypes of α1-AR: α1A, α1B, and α1C

:α1A -AR are mainly localized in smooth muscles of urogenital tract.

Prazosine, terazosine and doxazosine inhibits three subtypes of α1-AR equally, but tamsulozine blocks mainly α1A-AR and has less effects on α1B- and α1C-AR.

The drugs from this group inhibit α1 – AR of arteriols and venuls, decrease peripheral vascular resistance, and reduce vein back flow to the heart. As

α2 presynaptic receptors are not blocked, so the probability of reflector tachycardia is decreased. Prazosine blocks phosphodiesterase enzyme, which induces increase in cAMP level in vessels smooth muscle leading to more expressive vasodilation. Besides of this quantity of threeglycerides and lipoproteins with law density is decreased, level of lipoproteins with high density is increased. These effects are less common for tamsulozin. Side effects: Side effects of prazosine and its derivatives are the first dose- dependent effect, which is manifested by orthostatic collapse. Tolerance toward prazosine is developed very quickly. Indications: 1. Arterial hypertension. 2. Benign hyperplasia of prostate (tamsulosin).

β - adrenoblockers Classification of β -adrenoblockers (AB) 1. Accordine to the selectivity

1.1. Non-selective β-AB, which block β1, β2-AR – propranolol, nadolol 86

1.2. Selective, cardioselective b1-AB, which block only

β1-AR – atenolol, metaprolol, bisoprolol 2. According to their intrinsic mimetic activity 1.1 β-AB, which possess intrinsic mimetic activity- talinolol , oxprenolol, pindolol 1.2 β -AB, which don’t possess intrinsic mimetic activity- Propranolol 3.Additional a-adrenoblocking effect β-AB, which inhibit a-AR- labetalol, carvedilol 4.According to period of action 4.1 long-acting drugs– nadolol, atenolol, bisoprolol 4.2 drugs with intermediate duration – Propranolol, Metoprolol 4.3 short-acting drugs– oxprenolol, acebutolol 4..4 ultrashort-acting drugs - esmolol Pharmacodynamics. β -AB are competitive blockers of β-AR. Some of these drugs are partial agonists. So, these drugs inhibit β-ARs in a case of catecholamines` high concentration, but during absence of cathecholamine`s moderately activate β-ARs. Effects on organ-system: CNS: Lipophillic β-AB by penetrating BBB, in short-term usage in stress conditions they can manifest anxiolytic effects. During long-term usage can cause effects like nightmares, depression, disturbances in memory.

Cardio-vascular system: They block β1-AR and cause negative inotropic, chronotropic, dromotropic and batmotropic effects. Diastole is prolonged. They reduce tachycardia after physical work. In short-term usage they decrease stroke volume. Also they decrease oxygen demand. Coronary blood flow in general is reduced /inhibition of β2-AR/, but the maximal 87 effect is mentioned in subepicardial part, but blood supply in subendocardial part is not changed. After long-term usage β-AB decrease BP gradually in patients with hypertension. During the first period of treatment by β-AB general peripheral resistance is increased /blockade of β2-AR and decrease in heart stroke volume/. In long-term treatment peripheral resistance is returned to the starting position, as resistive vessels are adapted to the decreased stroke volume. So systolic and diastolic pressure is decreased. Hypotensive mechanisms include also:

 blockade of presynaptic β2-AR and release of NA

 decrease of rennin secretion through β1-AR  decrease of central sympathic effects on heart by lipophilic β-AB β-AB possesses antiarrhythmic effect, decrease conductive properties and automatism of heart, reduce probability of heterotopic and ectopic foci formation /. Respiratory system: non-selective β-AB in patients with bronchial asthma can provoke the onset of bronchial asthma /blockade of β2-AR in bronchial smooth muscles/. Metabolic effects. Non-selective β-AB change metabolism of lipids and carbohydrates, inhibit induced by adrenergic neurotransmission lipolysis, and as a result level of law dense lipoproteins and triglycerids are increased, which have aterogenic effect. In heart, skeletal muscles and liver they inhibit glycogenolysis, so during insulinotherapy they increase the period of glucose level restoration. Besides, they can hide clinical symptoms of hypoglycemia in patients with diabetes. Skeletal muscles: β-AB decrease muscular thremble induced by adrenergic system. 88

Eye: decrease of intraocular liquid production, so they decrease intraocular pressure. Side effects: 1. Decrease in heart contraction force 2. Bradycardia, which is dangerous in sinus node weaknesses 3. Formation of blockades in different degrees in cardiac conductive system /like atrio-ventricular blockade/ 4. Aggravation of bronchial asthma

5. Non-selective β-AB inhibits β2-AR of coronary arteries and worsen the coronary microcirculation. 6. Decrease of blood supply in endings of body /more common for non-selective β-AB/ 7. Impairment of carbohydrates metabolism /more common for non selective β-AB/. They block β2-AR and inhibit glycogenolyses, decrease insulin secretion and in insulin-dependent patiets can causes hypoglycemia and hide the main symptoms of hypoglycemia – tachycardia, tremor. 8. Non-selective β-AB possesses atherogenic effects and increase level of triglycerides and law dense lipoproteins and decrease level of high dense lipoproteins during 1–st 2 months of administration. 9. Disturbance of sexual functions in men. 10. Lipophilic β-AB can have central effect and cause depressions, insomnia, nightmares. 11. Withdrawal phenomenon, which means that stopping of β-AB immediately can contribute the worsening of main diseases like ischemic disease of heart, even it can provoke cardiac infarction or sudden death. It’s stipulated by upregulation /increase of amount of β-AR/ of β-AR, 89 production of triiodtyronine from thyroxine is decreased, rennin secretion is reduced, also platelet aggregation is developed. So, acute stoppage of β- AB increase stimulant effects of NA on β-AR which are in high quantity, and rennin secretion, level of triiodthyronin and throboxane are enhanced. Phenomenon of Ricoshet is more common for non-selective β-AB and it’s less in β-AB with intrinsic mimetic activity. To prevent Ricoshet phenomenon taking of β-AB should be stopped gradually during 2 weeks. Indications: 1. Arterial hypertension 2. Ischemic disease of heart 3. Acute cardiac infarction /when it’s not accompanied by acute cardiac failure/, it’s used to prevent development of ventricle’s fibrillation and infarction 4. Arrhythmias /they are more useful in supraventricular tachycardia and for the treatment of different type of extrasystoles/ 5. Chronic cardiac failure /it’s used in the stage of compensation 6. Pheochromocytoma: they are used with α-AB, because without α-AB it can causes life-threatening increase of BP. 7. Thyreotoxicoses- “thyroid attack” The drug of choice is esmolol. 8. Migraine. Propranolol is effective drug for prevention of migraine 9. In stress situation lipophilic β-AB can manifest anxiolytic effect 10. Essential tremor 11. Glaucoma. The drug of choice is thimolol, which is used for both open -angle and close- angle glaucoma. 90

<<β -AB of third generation>> The drugs of this group possess additional vasodilatative effect, which is performed by the following mechanisms:

1. additional effect on α1-AR /labetalol, carvedilol/ 2. stimulation of NO production /nebivolol/

3. agonistic effect to β2 - AR /celiprolol, carteolol/ 4. blockade of Ca2+ - ions inflow /carvedilol, betaxolol/ 5. opening of K+ channels /tilisolol/

Sympatholytics

Sympatholytics (SL) are the drugs with presynaptic mechanism of action. They usually destroy the storage of NA in vesicles and release of NA into synaptic cleft and gradually decrease NA amount and inhibits adrenergic neurotransmission. Effects on adrenoreceptors are absent. Reserpine, Guanetidine /octadine/, Guanadrel are SL. Reserpine: it’s a natural alkaloid, which is received from the roots of plant Rauwolfia serpentine. Pharmacodynamics: Reseprine inhibits storing of neurotransmitter in vesicles /NA, dopamine, serotonin/, as it irreversible inhibits Mg2+/ATP- dependent transporter /it transfers amines from cytoplasm into vesicles/. This effect takes place in different tissues, both in central and peripheral nervous system, and as a result exhaustion of dopamine, serotonin and NA store is developed. Exhaustion of adrenalin in chromaffinic cells of adrenal medulla is also developed, but it’s less expressed compare to neurons. In small doses reserpine inhibits vesicle transporter gently, non-stored NA stays in cytoplasm and is neutralized by MAO. But in high doses sudden increase of NA level in cytoplasm is developed, and MAO is not enough to 91 metabolize all NA. Non-metabolized NA released into synaptic cleft and temporal sympathomimetic effect can be mentioned. As inhibition of vesicle transporters is irreversible (Reserpine can be connected with vesicular membranes for 2-4 weeks), effects of reserpine can last long period (several days – several weeks) Inhibition of adrenergic, dopaminergic, serotoninergic system is CNS by reserpine can be expressed by the following effects:  Antipsychotic effect /decrease of hallucination, deliriums, etc/  Sedative effect /decrease of anxiety, fear/ In peripheral nervous system inhibition of adrenergic nervous system causes effects similar to adrenolytics, like  Antihypertensive effect: gradual decrease of BP, which is stipulated by decrease of stroke volume, general peripheral resistance and inhibition of vasospastic reflexes. Reserpine decreases BP gradually. Stable hypotensive effect is developed during several days (7-10 days), when exhaustion of NA store takes place.  Cholinomimetic effects - miosis, hypersalivation, stimulition of motor and secretor activity of GIT, bronchospasm, etc. Reserpine was used to be used as antipsychotic drug, but now it’s not used as neuroleptics are widely used for psychosis. Reserpine as antihypertensive drug also has limited usage as cancerogen effect was described. Side effects: 1. Neuroleptic effect /emotional indifference, psychic depression/, which are stipulated by inhibition in different parts of CNS dopaminergic, serotoninergic and adrenergic neurotransmission.

2. Extrapyramidal effects, like syndrome of Parkinson, which are stipulated by inhibition of dopaminergic neurotransmission in basal ganglions 3. Stimulation of prolactine synthesis by hypophysis 4. Dyspeptic effects, hyperacidic gastritis, impairment of ulcer disease, which are stipulated by stimulation of HCl, pepsin production. 5. Edema Guanetidine /Octadine/: Pharmacodynamics: Guanetidine inhibits release of NA, alters neuronal reuptake of NA (reuptake-1), as it uses the same transporter for reuptake as NA. Then guanetidine by means of vesicle transporter enters the vesicles and stores there instead of NA and by this way it provokes NA flow from vesicles into cytoplasm, where it’s destroyed by MAO. Some part of NA can be released into the synaptic cleft and interact with adrenoreceptors, which can induce transient vasospasm. Accumulation of guanetidine in vesicles instead of NA causes exhaustion of NA and prolonged inhibition of adrenergic neurotransmission. Guanetidine doesn`t have an action on circulated catecholamines or effects of adrenomimetics. In absence of NA can be noticed changes in amount and sensitivity of adrenoreceptors (up regulation), which results in the potentiation of direct adrenomimetic drug effects. Effects of guanetidine can be blocked by Tricyclic antidepressants which inhibits neuronal reuptake. Effects of guanetidine on CNS are absent, as it doesn’t penetrate BBB. In intravenous injection of guanetidine the following double-staged changes in cardiovascular system can be described:

1. Short increase of BP(from 10min - several hours) due to the released into synaptic cleft NA and interaction of NA with

postsynaptic α1-adrenoreceptors. Peripheral resistance is increased. 2. Gradual decrease of BP which brings:  Decrease of minute volume /decrease of force of contraction and rate, negative chronotropic/.  Decrease of peripheral resistance When the drug is used per os, the first stage is absent and only gradual decrease of BP is mentioned. The real and significant decrease of BP is developed after 4-7 days and effects of drugs stay about 2 weeks after stopping drug administration. As a result of sympathoplegic action, domination of parasympathetic nervous system is developed and the effects of cholinergic system activation are mentioned. Indications: Essential and symptomatic hypertensions. Now it’s not used widely because of new generations of antihypertensive drugs. Side effects: 1. Orthostatic collapse 2. Headache, dizziness /because of hypotension/ 3. Dyspepsia: vomiting, nausea, diarrhea 4. Edema 5. Provoke the ulcer disease of stomach and duodenum Guanadrele has the similar action mechanism to Guanethidine.