Adrenergic Agonist PPT PDF

Adrenergic agents SSMU Pharmacology department Associate professor Klimkina E.I. 2024 1 2  Adrenergic Synapses the main mediator of sympathetic nervous system is Nоradrenaline (Norepinephrine), so sympathetic innervatio...

Adrenergic agents SSMU Pharmacology department Associate professor Klimkina E.I. 2024 1 2  Adrenergic Synapses the main mediator of sympathetic nervous system is Nоradrenaline (Norepinephrine), so sympathetic innervation is called as noradrenergic one. Adrenergic agents act on adrenergic synapses Perypheral adrenergic synapses located where postganglionic Where are part of adrenergic they nerve fiber meets located? effector cell 3  Adrenergic synapses can be also central Adrenergic neurones are located in the CNS (locus coeruleus of midbrain, pons Varolii, medulla and central sympathetic ganglia). 4  Adrenergic synapses can be peripheral Cente rs N-ChR АR of pre- gangli - onic fibers 5  Adrenergic mediators Noradrenaline is the main mediator at postganglionic sympathetic terminals (except sweat glands, hair follicles and some vasodiating fibers) and in certain areas of brain. Adrenaline has a transmitter role in brain. Dopamine is a major transmitter in basal ganglions, limbic system, CTZ, anterior pituitary, etc. and in limited manner in the periphery. SYNTHESIS OF CAs Tyrosine Dopamine- TYROSINE DОPА Dоpаmine hydroxylase hydroxylase Noradrenaline ofin adrenals medulla Adrenaline is secreted to the blood interacts with adreno-R catecholamines produced from tyrosine 6 7  Uptake of CAs After dissociation of complex “noradrenalin-adrenoceptor”, the mediator is inactivated by a few mechanisms. Neuronal uptake which occurs in two steps Axonal uptake (uptake-1) – active Na+ coupled transport by amine pump across presynaptic membrane Vesicular uptake with another amine pump by exchanging with H+ ions. 8 NET – norepinephrine transporter 9  Uptake of CAs Extraneuronal uptake (uptake-2) with neuroglia, fibroblasts, cardiomyocytes, endothelial cells and myocytes of blood vessel wall About 80% noradrenaline undergoes neuronal reuptake 10% undergoes extraneuronal reuptake 10% undergoes enzymatic desintegration 10  Metabolism of CAs 1. МАО (monoamine oxydase) inactivates CAs in synapse. Part of NA leaking out from vesicle to cytoplasm as well that taken up by axonal transport is attacked by MAO. There are two types MAO: МАО-А (deaminates NA and Adr) and МАО-В (provides DA catabolism) 2. CОМТ (catechol-о-methyl-transferase) attacks CAs in the liver and other tissues 11 NA recycling 12 Adrenergic synapse as object of pharmacological intervention 13  Adrenergic agents change activity of sympathetic nervous system There are 2 big How? groups: adrenergic agonists (sympathomimetics) adrenergic antagonists (sympatholytics) 14  Adrenergic receptors ❑ R. Ahlquist (1948) classified them into two types α- and β. ❑ Molecular clonning in the mid 1970s has further identified 3 subtypes of α1 (α1A- α1B- α1D) and 3 subtypes of α2 (α2A- α2B- α2C) α1- adrenoceptors are located on postsynaptic membrane (postjunctional): α1A receptors in Vas deference, seminal vesicle, prostate, prostatic urethra are responsible for ejaculation) radial muscle of iris (dilatator pupillae) are responsible for midriasis α in 1B/1D peripheral blood vessels (arterioles) of skin, mucosa and internal organs are responsible for vasoconstriction, increase in t.p.r., increase in BP!!!15 16  Adrenergic receptors α1 - receptors are located also in smooth muscles and sphincters of GIT and spleen capsule are responsible for decrease in tone of smooth muscles of GIT and increase in tone of sphincters 17  α – adrenoceptors: α2-adrenoreceptors can be located both on postsynaptic and on presynaptic membrane of adrenergic synapses or can be extrasynaptic These can be inhibitory or stimulatory. Stimulation of presynaptic (prejunctional) α -receptors 2 inhibits release of noradrenaline from vesicles to synaptic cleft according to negative feed back mechanism. Stimulation of postsynaptic (postjunctional) central α2-receptors located in the brainstem inhibits activity of vasomotor center and decreases sympathetic outflow that leads to fall in BP and bradycardia. Postsynaptic (postjunctional) α2-receptors ✔ located in peripheral blood vessels, they have stimulant character the same like alpha1B/D and ✔ in ciliary body they reduce aqueous humor secretion, means have inhibitory character. 18  α – adrenoceptors: out-synaptic (non-innervated, extrajunctional) α2-receptors (R of Adr) they are located in peripheral blood vessels, on platelets, in GIT, pancreas. They are stimulated by adrenaline circulating in the blood their activation causes vasoconstriction in skin and mucosa, platelet aggregation, inhibition of GIT motility and inhibit insulin secretion. 19  β-adrenoceptors: β1-adrenoreceptors are located on postsynaptic membrane of myocardium cells stimulation of β1-receptors increases all cardiac functions: ✔ automatism ✔ A-V conduction ✔ excitability, ✔ heart rate ✔ Contractility ✔ Myocardium oxygen demand is increased ✔ Tachycardia occurs at excess amount of CAs in the blood β1-adrenoreceptors are located in juxtaglomerular apparatus - they increase renin secretion in kidney 20  β-adrenoreceptors: β2-adrenoceptors can be located presynaptically, postsynaptically and extrasynaptically: Extrasynaptic β2-adrenoceptors are located in Smooth muscles & glands of bronchi (smaller bronchioli) & trachea. They provide bronchodilation and decrease bronchial secretion. Platelets - inhibition of platelet aggregation. Pancreas – stimulation of glucagon secretion. Liver - glycogenolysis and gluconeogenesis that increase in glucose level in blood. 21  β-adrenoceptors: Postsynaptic β2-adrenoceptors are located in uterus, urinary bladder, gall bladder, GIT – they provide decrease in tone of myometrium, urinary bladder detrusor, GIT & biliary tract. blood vessels of skeletal muscle also, coronary, pulmonary, cerebral & hepatic blood vessels. They are responsivle for dilation of vessels in skeletal muscles, dilation of coronaries, pulmonary, hepatic and cerebral vessels. Presynaptic β2-adrenoceptors function according to positive feed back and stimulate NA release at insufficient activation of adrenoceptors 22  β-adrenoceptors: β3-adrenoreceptors have been found on membranes of adipocytes ✔ high concentration of catecholamines excite them what stimulates lipolysis in adipose tissue and thermogenesis in skeletal muscles. ◆ Adrenoceptors participate in regulation of carbohydrate, lipid and energy metabolism. ◆ Their excitation by catecholamines stimulate metabolism and increase oxygen demand. ◆ In the urinary bladder it is thought to cause relaxation of the bladder and prevention of urination. 23 TRANSDUCER MECHANISMS OF ADRENOCEPTORS Adrenergic receptors are membrane bound G-protein coupled receptors which function primarily by increasing or decreasing the intracellular production of second messengers cAMP or IP3/DAG. In some cases the activated G-protein itself operates K+ or Ca2+ channels or increases prostaglandin production 24  TRANSDUCER MECHANISMS OF ADRENOCEPTORS α1-receptors via Gq-protein are coupled to phospholipase C. Activation of membrane phospholipases leads to increase in Ca2+ influx cross membrane and liberation of deposited Ca2+ from intracellular stores. α2-receptors (presynaptic and central postsynaptic) via Gi-protein inhibit adenylyl cyclase and decreases cAMP formation. They increase permeability of membranes for K+. That leads to hyperpolarization and block of Ca2+ channels. 25  TRANSDUCER MECHANISMS OF ADRENOCEPTORS β1 receptors via Gs-proteins stimulate adenylyl cyclase and phosphorilation of calcium channels that leads to their opening. Ca2+ inflows to sarcoplasm and is mobilized from sarcoplasmic reticulum of myocardium. β2 receptors activate adenylyl cyclase and increase cyclic AMP content in smooth muscles. Cyclic AMP binds free Ca2+ that leads to hyperpolarization of membrane. β3 receptors increase cAMP dependent lipolysis. 26  CLASSIFICATION OF ADRENERGIC AGONISTS increase transmission of nerve impulse in adrenergic synapses Adrenergic agonists of direct action: 1) α-,β- adrenergic agonists (non-selective) – stimulate all types of adrenoceptors: Noradrenaline hydrotartrate Adrenaline hydrochloride (Norepinephrine) (Epinephrine) Dopamine 27  2) α-adrenergic agonists: 1. α1, α1 - agonists: Naphazoline, Xylometazoline, Oxymethazoline, Tetrizoline 2. α1 – agonists: Phenylephrine, Etilefrine, Midodrine, Methoxamine 3. α2- agonists: Clonidine,α-Methyldopa, Apraclonidine,Brimonidine 28  CLASSIFICATION OF ADRENERGIC AGONISTS 3) β-adrenergic agonists: 1.β1 -β2 –adrenergic agonists: 2. β1-adrenergic agonists Isoprenaline (cardioselective): Orciprenaline ✔Dobutamine 3. β2-adrenergic agonists: 4. β3-adrenergic agonists: Salbutamol , Salmeterol Mirabegron Fenoterol,Terbutaline, Clenbuterol Hexoprenaline, Formoterol, Bambuterol 29  CLASSIFICATION OF ADRENERGIC AGONISTS Adrenergic agonists of indirect action (indirect sympathomimetics): ✔ Ephedrine hydrochloride ✔ Phenylpropanolamine Combined preparations: ✔ Aerosol «Berodual» (fenoterol + ipratropium bromide) ✔ Aerosol «Ditec» (fenoterol + cromolyn sodium) ✔ Intal plus (salbutamol + cromolyn sodium) ✔ Coldrex (paracetamol, phenylephrine, ascorbic acid) 30 Classification of direct adrenergic agonists according to origin Cathecholamines Endogenous Dopamine Adrenaline Noradrenaline Exogenous Dobutamine Isoprenaline ❑ Non-cathecholamines 31 Classification of adrenergic agonists according to uses (clinical classification) 32  α-,β-adrenergic agonists The main representatives: Adrenaline (more beta agonist) & Noradrenaline (more alfa agonist) PHARMACOLOGICAL EFFECTS: Action on vascular tone Noradrenaline mostly activates α1-receptors of peripheral vessels (pressor action).That leads to ✔ Vasoconstriction, increase in t.p.r., ABP, increase in afterload on the heart and increase in myocardium oxygen demand ✔ Vasoconstrictant effect of Noradrenaline is powerful, but short-term: increase in ABP with redistribution of the blood to vitally important organs (vessels of the brain, the heart, the lungs dilate as they have beta2 receptors of inhibitory type. 33  PHARMACOLOGICAL EFFECTS OF α-,β-ADRENERGIC AGONISTS Action on vascular tone ✔ Adrenaline takes more marked stimulant action on β2-receptors of vessels than on alpha. ✔ That leads to constriction of skin vessels and vessels of internal organs (via α1-receptors) and dilation of cerebral, coronary vessels & vessels of skeletal muscles (via β2-receptors) ✔ ABP is increased ✔ but pressor action of adrenaline is usually followed by moderate hypotension (due to stimulation of β2-receptors of blood vessels of skeletal muscles and their dilation) 34 Action of Adr on ABP in single i.v. introduction 35  PHARMACOLOGICAL EFFECTS OF α-,β-ADRENERGIC AGONISTS Action on the heart Due to Noradrenaline action, ABP is increased (via alpha1) Noradrenaline stimulates β -receptors and increases 1 myocardium contractility and stroke volume That causes reflex stimulation of baroreceptors in aorta and large vessels, reflex is closed in Vagus center. Vagus sends inhibitory comands towards the heart via M2 receptors. Heart rate is decreased by reflex mechanism. Reflex vagus bradycardia negates stimulant influence of Noradrenaline on β1-receptors of the heart Finally cardiac output is not significantly changed. 36  PHARMACOLOGICAL EFFECTS OF α-,β-ADRENERGIC AGONISTS Action on the heart Adrenaline takes more marked action on the heart (mostly stimulates β1-receptors) It increases heart rate and strength of heart beats Increases activity of sinoatrial node and rate of impulse conduction along A-V node. Refractory period ↓, cardiac output ↑ Increase in ABP and heart rate stimulate Vagus center by reflex reflex bradycardia can occur 37  PHARMACOLOGICAL EFFECTS OF α-,β-ADRENERGIC AGONISTS Action on eye dilate pupil due to contraction of radial muscle (dilatator pupillae) of iris decrease in intraocular tension (due to stimulation of α1A-receptors and constriction of ciliary vessels, they reduce aqueous humor production; stimulation of α2-receptors located on ciliary epithelium leads to reduction of aqueous humor secretion also, but stimulating β2-receptors, they increase production of aqueous humor 38 Regulation of aqueous humor secretion in ciliary epithelium 39  PHARMACOLOGICAL EFFECTS OF α-,β-ADRENERGIC AGONISTS Action on bronchial muscles Adrenaline stimulates β2-receptors, dilates bronchi, relieves bronchospasm The action of Noradrenaline on bronchi is very weak and has no practical value 40  PHARMACOLOGICAL EFFECTS OF α-,β-ADRENERGIC AGONISTS Action on GIT ✔ a tone and motility of g.i.t. are decreased because of stimulation of all adrenergic receptors ✔ sphincters of g.i.t., are constricted due to stimulation of α1-receptors. ✔ These effects are brief and of no clinical value 41  PHARMACOLOGICAL EFFECTS OF α-,β-ADRENERGIC AGONISTS Bladder, prostate, vas deferens detrusor is relaxed (via β2 and β3)and trigone is constricted(α1): both actions tend to oppose bladder voiding. The tone of prostatic muscle is increased by activation of α1receptors. Rhythmic contractions of vas deferens and seminal vesicles which participate in ejaculation are also mediated through α1 receptors. 42 Urinary bladder control 43  PHARMACOLOGICAL EFFECTS OF α-,β-ADRENERGIC AGONISTS Uterus. Adr can both contract and relax uterine muscle, respectively through and receptors. The overall effect varies with species, hormonal and gestational status. Human uterus is relaxed by Adr at term of pregnancy, but at other times, its concentrations are enhanced. 44  PHARMACOLOGICAL EFFECTS OF α-,β-ADRENERGIC AGONISTS Skeletal muscle neuromuscular transmission is facilitated. In contrast to action on autonomic nerve endings, α receptor activation on motor nerve endings augments ACh release, probably because it is of the α1 subtype. The direct effect on muscle fibres is exerted through β2 receptors and differs according to the type of fibre. The active state is abbreviated and less tension is developed in the slow contracting red fibres. There is incomplete fusion of individual responses. This along with enhanced firing of muscle spindles is responsible for the tremors produced by β2 agonists. The action on rapidly contracting white fibres is to prolong the active state and increase the tension developed. 45  PHARMACOLOGICAL EFFECTS OF α-,β-ADRENERGIC AGONISTS CNS Adr, in clinically used doses, does not produce any marked CNS effects because of poor penetration in brain, but restlessness, apprehension and tremor may occur. Activation of α2 receptors in the brainstem (by selective α2 agonists like clonidine) results in decreased sympathetic outflow, fall in BP and bradycardia. 46  PHARMACOLOGICAL EFFECTS OF α-,β-ADRENERGIC AGONISTS Action on metabolism Adrenaline stimulates glycogenolysis (due to stimulation of β2-receptors of muscle cells & the liver), α2-receptors inhibit insulin secretion, β2 stimulate glucagon release – hyperglycemia occurs. Lipolysis occurs, content of free fatty acids is increased in the blood due to stimulation of β3-receptors). 47 48  Indications for administration of α-,β-adrenomimetics They are used only parenterally as they are destroyed in the stomach Adrenaline is used as a medicine for emergency ✔ In anaphylactic shock (a drug of choice) ✔ In acute heart failure and A-V block ✔ In cardiac arrest ✔ For relief of bronchospasm in bronchial asthma attack (was used in past) ✔ In hypoglycemic shock ✔ Along with local anesthetics( 0.1% solution of Adr delays absorption of anesthetics, prolongs local anesthesia, prevents resorptive toxic action of anesthetic agents) ✔ For control of local bleeding 49 50 Adrenaline for self-emergency 51 52 Noradrenaline for i.v. infusion 53  Indications for administration of α-,β-adrenomimetics Adrenaline acts shortly: at intravenous introduction – 5 minutes, at s.c., i.m. introduction – 30 minutes to 2 hrs. tolerance (resistance) rapidly occurs at repeated introductions; effect decreases due to desensitization phenomenon (loss of receptor sensitivity – down regulation). Noradrenaline is used seldom for treatment of some shocks/acute hypotensions (traumatic, drug overdose or septic). It maintains blood supply of vital organs due to redistribution of blood from peripheral vessels with α1 R to cerebral, myocardial, pulmonary vessels with β2 R. 54 55  DOPAMINOMIMETICS Dopamine is the main neuromediator for dopamine receptors, which differ from α- and β-adrenoreceptors different subtypes of dopamine receptors are identified: D1-, D2-, D3-, D4-, D5- receptors it acts mainly on the CNS but sometimes Dopamine is used for regulation of peripheral nervous system function Due to activation of D2-receptors, Dopamine causes narrowing of arterioles of the skin, subcutaneous fat, skeletal muscles. Pressor effect occurs. 56  Pharmacological characteristics of Dopamine At dose 0.5-2.0 mcg dopamine stimulates D1-receptors in blood vessels Causes dilation of renal blood vessels, decreases total peripheral resistance of vessels as a result, diuresis, natriuresis and creatinine clearance are increased very rapidly At dose 2-3 mcg causes stimulation of β1-adrenoceptors that leads to increase in strength of heart beats, cardiac output and elimination of cardiac insufficiency More higher doses of dopamine can stimulate also α1-аdrenoreceptors of vessels, that leads to increase in vascular tone, ABP and decrease in renal blood flow. 57  Indications for administration dopaminomimetics are used in cardiogenic or septic shock to improve the heart work and to increase ABP for improvement of renal blood supply. Sodium nitroprusside is recommended simultaneously Dopamine is introduced intravenously to blood stream or drop-by-drop. duration of intravenous infusions of Dopamine must not be more than 2-3 days, as tolerance develops during the time and an effect is decreased 58  Adverse effects At administration of Noradrenaline: ✔ headache ✔ respiratory disorders ✔ cardiac arrhythmia ✔ necrosis of tissues at the site of injection (due to arteriole spasm) Adrenaline can cause: ✔ myocardium hypoxia, arrhythmia ✔ Adrenaline arrhythmogenic action is especially dangerous when it is injected at use of narcosis agent Halothane 59 Adverse effects of dopaminomimetics tachycardia, arrhythmia bronchospasm pulmonary hypertension oliguria inhibition of reflex from chemoreceptors of carotid bodies on CO2. high Dopamine doses can worsen blood supply of extremities (gangrene is possible) Necrosis of subcutaneous tissue 60  α1-adrenergic agonists α1-adrenergic agonists: Phenylephrine, Midodrine stimulate α1-adrenoreceptors of blood vessels mainly these cause longer vasoconstrictive action (up to 1 h), in comparison with adrenaline, as they are slower destroyed with enzymes these increase ABP these do not act on the heart markedly, but they can cause reflex bradycardia these partly pass across blood-brain barrier and slightly stimulate the CNS 61 Phenylephrine for inj. 62 Midodrine 63  α2-adrenergic agonists Clonidine and α-Methyldopa, Guanfacin, Guanabenz can be used for hypertension Apraclonidine and Brimonidine are used topically for glaucoma of open angle form. 64 Clonidine for systemic use 65 Apraclonidine for local use 66  α1, α2- ADRENERGIC AGONISTS α1-,α2-adrenergic agonists: Naphazoline, Xylometazoline,etc. stimulate simultaneously synaptic α1-receptors and extra- and postsynaptic α2- receptors these have powerful vasoconstrictant effect at intranasal application, cause rapid (5-10 min) and long-term (5-12 h) vasoconstriction in mucosa of nasal cavity and upper airways that decreases their swelling and secretion of mucous (decongestant action) At rhinitis, the action of the drugs is symptomatic Long-term use of these drugs results in atrophy of mucosa 67  ADMINISTRATION OF α- ADRENERGIC AGONISTS α1-adrenergic agonists are used as vasoconstrictants at hypotension Phenylephrine is also used in rhinitis, for treatment of open-angle glaucoma and for prolongation of local anesthetic action α1-,α2-adrenergic agonists are used locally in the form of nasal drops ❑ in rhinitis, sinusitis, eustachitis to decrease swelling and secretion of mucosa of nasal cavity, paranasal sinuses ❑ they facilitate nasal breathing 68 Phenylephrine for local use 69 Nasal decongestants 70  β1–, β2-adrenergic agonists Representatives: Isoprenaline (Isadrinum), Orciprenaline salfate (Alupent) have stimulant action on the heart due to stimulation of β1-receptors; increase automatism, myocardium excitability facilitate А-V conduction; increase strength and frequency of heart beats; Increase myocardium oxygen demands; stimulate β -receptors of smooth muscles of bronchi, 2 vessels and other smooth muscle organs; as a result, these dilate bronchi; decrease tone of g.i.t.; Orciprenaline acts on β -receptors of bronchi more 2 evidently, so it causes tachycardia more seldom, as compared to Isoprenaline. 71 Isoprenaline for inj. 72 Orciprenaline for inhalations and isoprenaline for oral intake 73 Orciprenaline for oral intake 74  Indications for administration of β1–, β2-adrenomimetics For prophylaxis and relief of bronchial asthma attacks Isoprenaline is sometimes used in marked bradycardia and in disorders of atrioventricular conduction 75  β1 –adrenergic agonists A representative is Dobutamine It takes vigorous inotropic action (increases contractility of myocardium due to stimulation of β1) That leads to increase in cardiac output. At that, heart rate and conduction are not practically changed. Against a background of acute hypoxemic hypoxia, Dobutamine decreases a pressure in pulmonary capillaries In such condition, Dobutamine is able to prevent development of pulmonary edema Dobutamine is rapidly inactivated with COMT, its half-life is 2-3 min. it is used as cardiotonic agent in acute cardiac insuficiency, accompanied by respiratory failure, in patients with cardiogenic or septic shock 76 Dobutamine for i.v. infusions 77  β2 –adrenergic agonists Representatives: Salbutamol, Fenoterol, Terbutaline, Salmeterol, Pirbuterol, Bambuterol they are selective stimulants of β2-adrenoreceptors ✔ take more marked action on smooth muscles of bronchi, dilate them ✔ produce less adverse effects, than non-selective adrenergic agonists ✔ stimulate also β2-adrenergic receptors of uterus and cause relaxation of myometrium 78 Salbutamol as spray for inhalation and Salbutamol for oral use 79 Powder of Salbutamol for inhalations 80 Salbutamol for nebulizer therapy 81 Terbutaline for oral use and for inhalations 82 Uses of β2 –adrenergic agonists they are widely used as bronchodilatory agents for relief of bronchial obstruction the drugs are administered by inhalation, orally, parenterally They are used at threatenning abortion (for prevention of preterm delivery) – Fenoterol is used in the form of solution for inj. under the name «Partusisten». “Salbupart”, Ritodrine & Isoxsupride are also tocolytics (uterine relaxants) 83 Isoxuprine for oral use 84  Uses of β3 –adrenergic agonists Mirabegron is used in overactive bladder with symptoms of urinary incontinence, urinary frequency and urinary urgency. 85  Adverse effects of β-adrenomimetics anxiety palpitation tremor of fingers giddiness, headache hyperhydrosis in such cases a dose of a drug is decreased in frequent use of β -adrenergic agonists, 2 development of tolerance and weakening of the effect are possible (down regulation or decensitization)) 86  ADRENERGIC AGONISTS OF INDIRECT ACTION (INDIRECT SYMPATHOMIMETICS) Representatives: Ephedrine hydrochloride and Phenylpropanolamine (Trimex) Ephedrine is an alkaloid of plant ephedra; it replaces noradrenaline from vesicles, inhibits MAO, inhibits NA reuptake, increases NA concentration in synaptic cleft; NA takes stimulant action on α- и β-adrenoceptors thus Ephedrine indirectly, by the way of endogenous noradrenaline, takes nonselective activating action on α- и β-adrenoreceptors 87 Ephedra disthachya 88  INDIRECT SYMPATHOMIMETICS Ephedrine also has direct stimulant action on β- adrenoreceptors mainly it narrows vessels and increases ABP (due to stimulation of α1-receptors) it increases strength and frequency of heart beats (due to stimulation of β1-receptors of myocardium) the alkaloid relaxes bronchial muscles (due to stimulation of β2-receptors) but bronchodilatory action is weaker as compared to β2-adrenergic agonists 89  INDIRECT SYMPATHOMIMETICS Ephedrine dilates pupil (due to stimulation of α1-receptors of radial muscle) it does not change intraocular tension and accomodation it increases tone of skeletal muscles, glucose level in the blood it sensitizes adrenoreceptors to catecholamines Ephedrine passes across blood-brain barrier, takes stimulant action on the CNS Features of Ephedrine action in comparison with Adrenaline: gradual development of pharmacological effects less marked, but more long-term action it is partly explained by indirect action of the drug on adrenoreceptors and gradual development of sympathomimetic action 90  Administration of sympathomimetics in hypotension, collapse to increase ABP Pseudoephedrine is administered orally as decongestant in rhinitis (narrows blood vessels of nasal mucous membrane) in ophthalmological practice for dilation of pupil Ephedrine is used at the CNS inhibition (narcolepsy, overdosage of hypnotics, tranquilizers) Nocturnal enuresis (decreases depth of sleep and increases tone of urinary bladder sphincter). 91 Ephedrine for oral and local use 92 Pseudoephedrine 93  Adverse effects of sympathomimetics excitement sleeplessness tremor loss of appetite increase in ABP palpitation 94  Combined preparations: Combined preparations (they contain preparations with с synergetic action) are frequently used. BERODUAL (fenoterol + ipratropium bromide) DITEC (fenoterol + cromoglycic acid) INTAL PLUS (Salbutamol + Cromoglicic acid) are used for bronchial asthma. COLDREX (paracetamol + phenylephrine + ascorbic acid) is used for treatment of symptoms of common cold (headache, fever, sneezing). 95 Combined preparations: 96