Principles of Drugs Autonomic Pharmacology PDF

Principles of Drugs Autonomic Pharmacology Ass.Pro De Labech H.Al ahadeen Introduction to Autonomic Pharmacology The nervous system is divided into central nervous system ( CNS ; the brain and spinal cord ) and the peripheral nervous system ( nervous tissues out side the CNS ). The motor n...

Principles of Drugs Autonomic Pharmacology Ass.Pro De Labech H.Al ahadeen Introduction to Autonomic Pharmacology The nervous system is divided into central nervous system ( CNS ; the brain and spinal cord ) and the peripheral nervous system ( nervous tissues out side the CNS ). The motor nervous system can be divided into. The somatic division is largely concerned with consciously controlled functions such as movement , posture. ) , The autonomic nervous system ( ANS largely autonomous ( independent ) in that its activities are not under direct conscious control.It is concemed primarily with visceral functions - cardiac output , blood flow to various organs , digestion , etc - that are necessary for life. In the nervous system , chemical transmission occurs between nerve cells and between nerve cells and their effectors cells. Chemical transmission takes place through the release of small amounts of transmitter substances from the nerve terminals into the synaptic cleft. By using drugs that mimic or block the actions of chemical transmitters , we can selectively modify many autonomic functions. These functions involve a variety of effectors tissues , including cardiac muscle , smooth muscle , vascular endothelium , exocrine glands , and pre synaptic nerve terminals. Autonomic drugs are useful in many clinical conditions. Conversely , a very large number of drugs used for other purposes have unwanted effects on autonomic function Principles of Drugs Autonomic Pharmacology Ass.Pro Dr Labeeb H.Al ahadon Anatomy of the Autonomic Nervous System The autonomic nervous system division into two major portions : the Sympathetic ( Thoraco - lumbar ) division and the Parasympathetic ( cranial - sacral ) originate. Sympathetic preganglionic fibers leave the CNS through the thoracicand lumbar spinal nerves. Theparasympathetic pre ganglion fibers leave the central nervous system through thecranial nerves ( third , seventh , ninth , and tenth ) and third and fourth sacral spinal Neurotransmitter Chemistry of the Autonomic Nervous System An important classification of autonomic nerves is based on the primary transmitter molecules - acetylcholine or norepinephrine - released from terminal fibers.A large number of peripheral autonomic nervous system fibers synthesize and release acetylcholine ; they are cholinergic fibers , these include all preganglionic efferent autonomic fibers and the somatic ( non autonomic ) motor fibers to skeletal muscle as well. Thus , almost all efferent fibers leaving the central nervous system are cholinergic. In addition , most parasympathetic postganglionic and a few sympathetic postganglionic fibers are cholinergic.. Most postganglionic sympathetic fibers release norepinephrine ( noradrenalin ) ; they are noradrenergie ( often called simply " adrenergie " ) fibers - i.e. , they act by releasing norepinephrine. , a few sympathetic fibers release acetylcholine.. Adrenal modularly cells , which are embryologically analogous to postganglionic sympathetic neurons , release a mixture of epinephrine and norepinephrine. Five key features of neurotransmitter function represent potential targets of pharmacologic therapy : 1 - Synthesis of neurotransmitter 2- Storage neurotransmitter 3 - Release of neurotransmitter 4 - Activation of receptors by neurotransmitter 5- Termination of action of neurotransmitter Principles of Drugs Autonomic Pharmacology An. Pre.Dr Labeeb H.Al abaden Cholinergic and Anticholinergic Drugs Acetylcholine is a widespread chemotransmitter in the body , mediating a broad range of physiological effects. There are two distinct classes of receptor for acetylcholine defined on the basis of their activation by the alkaloids , nicotine ( from tobacco ) and muscarine ( from a fungus , Amanita muscaria ). At cholinergic nerve endings and in erythrocytes there is an enzyme that destroys acetylcholine , true cholinesterase or acetylcholinesterase. In various tissues , especially plasma , there are other esterase which are not specific for acetylcholine but which also destroy other esters These are called nonspecific or pseudo cholinesterase Stimulation of cholinoceptors in autonomic ganglia and at the postganglionic endings affects chiefly the following organs : Eye : meiosis and spasm of the ciliary muscle occur so that the eye is accommodated for near v 1. Intraocular pressure falls. Exocrine glands : increase secretion of the salivary , lachrymal , bronchial and sweat glands. The sweat glands are cholinergic , although anatomically part of the sympathetic system ; some  sweat glands , e.g. auxiliary , may be adrenergic. Heart : bradycardia with atrioventricular block and eventually cardiac arrest. Principles of Drugs Autonomic Pharmacology Ass.Pre.Dr Labeeb Al ahadon Bronchi : bronchoconstriction and mucosal hyper- secretion that may be clinically serious in asthmatic subjects , in whom cholinergic drugs should be avoided , as far as possible. Gut : motor activity is increased and may cause colicky pain. Y / secretion is increased. Tone in anal sphincters falls which may cause defecation Bladder and ureters contract and the drugs promote micturiti ition. Neuromuscular ( voluntary ) junction : neuromuscular junction a cholinergic nerve ending and so is activated causing muscle fasciculation. Choline ester : A cholinomimetic drug consisting of choline ( an alcohol ) or a choline derivative , esterified with an acidic substance ( eg , acetic or carbamic acid ) ; usually poorly lipid - soluble Cholinergic crisis : The clinical condition of excessive cholinoceptors activation it may include skeletal muscle weakness and parasympathetic effects. Cholinomimetic alkaloid : A drug with weakly alkaline properties ( usually an amine of plant origin ) whose effects resemble those of ACH usually lipid - soluble Direct acting cholinomimetics : A drug that binds and activates cholinoceptors ; the effects mimic those of acetylcholine Indirect - acting cholinomimetic A drug that amplifies the effects of endogenous acetylcholine by inhibiting acetylcholinesterase. Muscarinic agonist : A cholinomimetic drug that binds muscarinic receptors and has primarily muscarine - like actions Neonicotinoids : Class of insecticides with nicotine - like effects on neurons ; much more potent in insects than in vertebrates V Principles of Drugs Autonomic Pharmacology Ass.Pro Dr Labech H.Al alsadoon Nicotinic agonist : A cholinomimetic drug that binds nicotinic receptors and has primarily nicotine - like actions Organophosphate : An ester of phosphoric acid and that inhibits cholinesterase Organophosphate aging : A process whereby the organophosphate , after binding to cholinesterase , is chemically modified and becomes more firmly bound to the enzyme Parasympathomimetic : A drug whose effects resemble those of stimulating the parasympathetic nerves Cholinergic drugs ( cholinomimetics ) Direct acting ( receptor agonists ) Choline esters Alkaloids which act selectively on end - organs of postganglionic , cholinergic neurons. Indirect - acting Cholinesterase inhibitors , or anticholinesterases ( physostigmine , neostigmine , pyridostigmine , donepezil ) , which inhibit the enzyme that destroys acetylcholine , allowing the endogenous transmitter ( acetylcholine ) to persist and produce intensified effects. Principles of Drug Autonomic Pharmacology Ass.Pre.Dr Labeeb H.Al aladon CHOLINE ESTERS Acetylcholine Y / A Since acetylcholine has such great importance in the body it is notuse it in therapeutics by due to rapid distraction by cholinesterase Carb is not destroyed by cholinesterase actions most pronounced on theb... and gastrointestinal tract , used now much diminished. , Bethanechol resembles carbachol in its actions but is some 10 - fold less potent andhas no significant nicotinic effects at clinical doses Alkaloids Nicotine is a social drug use as an adjunct to stopping its own abuse as tobacco. It is available as gum to chew , as dermal patches , inhalation. Pilocarpine acts directly on end - organs innervated by postganglionic nerves ( parasympathetic system plus sweat glands ). The chief clinical use of pilocarpine is to lower intraocular pressure in chronic simple glaucoma ,; it produces miosis , opens drainage channels improves theoutflow of aqueous humour. Oral pilocarpine is available for the treatment of xerostomia ( dry mouth ) in Sjogren's syndrome , or following irradiation of head and neck tumours. The commonest adverse effect is sweating  Principles of Drugs Autonomic Pharmacology Au Pre.Dr Labeeb H.Al ahedoon ANTICHOLINESTERASES Chemicals which inactivate esterases ( anticholinesterases ) are used in medicine and in agriculture as pesticides. They act by allowingnaturally synthesized acetylcholine to accumulate instead of being destroyed. Physostigmine is an alkaloid , acts for a few hours. Physostigmine is used synergistically with pilocarpine to reduce intraocular pressure. It has been shown to have some efficacy in improving cognitive function in Alzheimer - type dementia Neostigmine AL - A ( tl / 22 h ) is a synthetic reversible anticholinesterase. principally used in myasthenia gravis , to stimulate the bowels and bladder after surgery , and as an antidote to competitive neuromuscular blocking agents. Neostigmine is effective orally , and by injection ( usually s.c. ). Pyridostigmine ( mestinone ) is similar to neostigmine but has a less powerful action that is slower in onset and slightly longer in duration , It is used in myasthenia gravis.Donepezil and rivastigmine A more recent anticholinesterase drugs has been to improve cognitive function in patients with Alzheimer's disease Anticholinesterase poisoning The anticholinesterases used in therapeutics are Reversibly inactivate cholinesterase only for a few hours. Poisoning with reversible anticholinesterases is appropriately treated by atropine andthe necessary general support ; it lasts only hours. In poisoning with irreversible agents the organophosphate insecticide irreversibly inactivate cholinesterase which used in agricultural , industrial , used in war called nerve ' gas ' Features of acute poisoning AL Sade also involve the gastrointestinal tract ( salivation , vomiting , abdominal cramps , diarrhea , involuntary defecation ) , the respiratory system ( bronchorrhoea , bronchoconstriction , cough , wheezing , dyspnoea ) , thecardiovascular system ( bradycardia ) , the genitourinary system ( involuntary micturition ). Death is due to a respiratory failure ( SLUDAGE MM ) Treatment. Contaminated clothing should be removed and the skin washed. Gastric lavage is needed if any of the substance has been ingested. 2 Atropine ; 2 mg is given i.m. or i.v. as soon as possible and repeatedevery 15-60 min. Enzyme reactivation pralidoxime , I g of which should be given 4 - hourly i.m. or ( diluted ) by slow i.v. infusion. Anticholinergic Drugs Acetylcholine antagonists ( blockers ) that block the nicotine - like effects ( neuromuscular blockers and autonomic ganglion blockers ). Acetylcholine antagonists that block the muscarine - like effects , e.g.atropine , are called anticholinergics. The more precise term antimuscarinic is preferred here Anticholinergic : A drug that blocks muscarinic or nicotinic receptors , Antimuscarinic : at blocks muscarinic but not nicotinic receptors Atropine fever : AL Sagoo Hyperthermia induced by antimuscarinic drugs ; caused mainly by inhibition of sweating Atropine flush : Marked cutaneous vasodilation by toxic doses of antimuscarinic drugs , especially atropine ; mechanism unknown Cholinesterase regenerator : A chemical antagonist that binds the phosphorus of organophosphates and displaces AChE Cycloplegie : A drug that Paralyzed accommodation ; inabilitng focus on close objects Miotic : A drug that constricts the pupil Mydriatic : A drug that dilates the pupil Parasympatholytic , parasympathoplegic : A drug that reduces the effects of parasympathetic nerve stimulation , usually by blockade of the muscarinic receptors of autonomic effector tissues Principles of Drugs Principles of Dru Antinicotinic drug Autonomic Pharmacology Ass.Pre.Dr Labeeb H.Al alsad Ganglion - blocking drugs These agents competitively block the action of acetylcholine and similar agonists at nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia.. The ganglion - blocking drugs are important and used in  pharmacologic and physiologic research because they can block all autonomic outflow. However , lack of selectivityconfers such a broad range of undesirable effects that they have limited clinical use. Hexamethonium was developed and was introduced clinically as the first drug effectivefor management of hypertension ,. Trimethaphan , a short - acting ganglion blocker , is inactive orally andis given by intravenous infusion. Neuromuscular blocking. Drugs There are two principal mechanisms by which drugs used clinically interfere with neuromuscular transmission : By competition with acetylcholine ( atracurium , pancuronium , rocuronium , vecuronium ). These drugs are competitive antagonists of acetylcholine By depolarization of the motor endplateSuch agonist drugs activate the acetylcholine receptor on the motorendplate ( suxamethonium ). USES OF NEUROMUSCULAR BLOCKING DRUGS 1- They are used to provide muscular relaxation during surgery and occasionally to assist mechanical ventilation in intensive therapy units. 2- They are used during electroconvulsive therapy to prevent injuryto the patient due to excessive muscular contraction. abec Autonomic Pharmacology AnPro.Dr Labeeb H.Al alsadoon Principles of Drugs Antimuscarinic drugs which act principally at postganglionic cholinergic ( parasympathetic ) nerve endings.Muscarinic receptors can be subdivided according to their principalsites , namely in the brain and gastric parietal cells ( MI ) , heart ( M2 ) and glandular and smooth muscle cells ( M3 ). Atropine Atropine is an alkaloid from the plant ( Atropa belladonna ). Atropine is the prototype drug of this group In general , the effects of atropine are inhibitory but in large doses it stimulates the CNS Atropine also blocks the muscarinic effects of cholinergic drugs bothperipherally and on the central nervous system. The clinically important actions of atropine at parasympathetic postganglionic nerve endings are mostly the opposite of the activatingeffects on the parasympathetic system produced by acetylcholine and cholinergic drug It does not oppose cholinergic effects at the neuromuscular junction orsignificantly at the autonomic ganglia ,.. Exocrine glands. All secretions except milk are diminished. Dry mouth , dry eye. Gastric acid secretion is reduced , Bronchial secretions are reduced Smooth muscle is relaxed. the gastrointestinal tract there is reduction of tone and peristalsis. Atropine relaxes bronchial muscle , that is useful in some asthmatics. Micturition is slowed and urinary retention may I induced Ocular effects. Mydriasis occurs with a rise in intraocular pressure in eyes. An attackof glaucoma may be induced. The ciliary muscle is paralysed and so the eye is accommodated for distant vision. Cardiovascular system. Atropine reduces vagal tone thus increasing the heart rate , and enhancing conduction in the bundle of His Atropine has no significanteffect on Principles of Drugs Autonomic Pharmacology Ass.Pro.Dr Labeeb H.Al alsadoon peripheral blood vessels in therapeutic doses Principles of Drugs Autonomic Pharmacology AnPro.Dr Labeeb Alabad Other antimuscarinic drugs Hyoscine ( scopolamine ) is structurally related to atropine. Elderly patients are often confused by hyoscine and so it is avoided in their anesthetic premedication. Mydriasis is also briefer than with atropine. Hyoscine butylbromide ( Buscopan ) an effective relaxant of smooth muscle ,, the pyloric antral region and the colon , which properties are utilized by radiologists and endoscopic. It useful for colic Homatropine is used for its ocular effects ( 1 % and 2 % solutions as eye drops ). Its action is shorter than atropine Ipratropium ( Atrovent ) used by inhalation as a bronchodilator , can be useful when cough is a pronounced symptom in asthmatic patient. PT / Flavoxate is used for urinary frequency , because it increasesbladder capacity and reduces unstable detrusor contractions Oxybutynin is also used for detrusor instability , butantimuscarinic adverse effects may limit its value.  Pharmacokinetics. Atropine is readily absorbed from the gastrointestinal tract and may also be injected by the usual routes.. Atropine is in part destroyed in theliver and in part excreted unchanged by the kidney. for chronic use it has largely been replaced by other antimuscarinic drugs..Poisoning with atropine ( and other antimuscarinic drugs ) presents with obvious dry mouth ( with dysphagia ) , mydriasis , blurred vision , hot , flushed , dryskin , and ,, hyperthermia , restlessness , anxiety , excitement , hallucinations , delirium , mania , and coma Therapeutic Applications AL Sa 1 - CENTRAL NERVOUS SYSTEM DISORDERS a - Parkinson's disease : useful as adjunctive therapy in some patients. b- Motion sickness : Certain vestibular disorders respond to antimuscarinic drugs ( Scopolamine is effective and more recently introduced agent , given byinjection , by mouth , or as a TDS 2- OPHTHALMOLOGIC DISORDERS. antimuscarinic agents , administered topically , are very helpful in doing a complete examination Antimuscarinic drugs should never be used for mydriasis unless cycloplegia or prolonged action is required 1. RESPIRATORY DISORDERS The use of atropine became part of routine preoperative medication because these irritant anesthetics markedly increased airway secretions. ( Ipratropium ) , a synthetic analog of atropine , is used as an inhalational drug in asthma. 4 - CARDIOVASCULAR DISORDERS Marked reflex vagal stimulation may depress sinoatrial or atrioventricular node function sufficiently to impair cardiac output. Parenteral atropine or a similar antimuscarinic drug is appropriate therapy in this situation 5 - GASTROINTESTINAL DISORDERS : Antimuscarinic agents can provide relief in abdominal colic , a traveler's diarrhea and other mild or self - limited conditions of hypermotility. They are often combined with an opioid antidiarrhealdrug. Antimuscarinic agents are now rarely used for peptic ulcer disease 6- URINARY DISORDERS Atropine and other antimuscarinic drugs have been used to provide symptomatic relief in the treatment of urinary urgency caused by minor inflammatory bladder disorders Oxybutynin , selective for M3 receptors , is used to relieve bladder spasm after urologic surgery , improve bladder capacity and continence 7-. OTHER APPLICATIONS Hyperhidrosis ( excessive sweating ) reduced by antimuscarinic agents. SIDE EFFECT At higher concentrations , atropine causes block of all parasympathetic functions. However , atropine is a remarkably safedrug in adults produce dry mouth , mydriasis , tachycardia , hot and flushed skin , agitation , and delirium for as long as a week. Body temperature is frequently elevated Contraindications. 000 Antimuscarinic drugs are contraindicated in patients with glaucoma..In elderly men , antimuscarinic drugs should always beused with caution and should be avoided in those with a history of prostatic hyperplasia , BPH Pyloric stinosis , Bladder neck obstraction H. A Principles of Drugs Autonomic Pharmacology Au Pro.Dr Labeeb H.Al alsadoon Adrenergic mechanisms The sympathetic nervous system is an important regulator of the activities of organs.The effects of sympathetic stimulation are mediatedby release of catecholamine ( Adrenaline , noradrenalin and dopamine ) from nerve terminals that to activate the adrenoceptors on postsynaptic sites. Also in response to a variety of stimuli such as stress , the adrenal medulla releases Adrenaline , noradrenalin transported in the blood to target tissues. Catecholamine are formed in the body. The natural synthetic path is : Tyrosine - Dopa- > Dopamine- > Noradrenalin- > Adrenaline Tyrosine Rate - limiting step Tyrosine hydroxylase HO HO HO DOPA DOPA decarboxylase Dopamine Dopamine hydroxylase CHCHINH Noradrenaline Phenylethanolamine N - methyltransferase QH HO HO -CH - CH - NH - CH , Adrenaline © Elsevier Ltd. Rang et al : Pharmacology SE  Principles of Drugs Autonomic Pharmacology Ass.Pro.Dr Labeeb H.Al abadon The termination of action of catecholamine released at nerve endingsby 1- Reuptake into nerve endings where it is stored also subject to MAO mono amino oxidase degradation 2- Diffusion away from the area of the nerve ending and the receptor3- Metabolism ( by extra neuronal MAO and catechol - o - methyltransfrase COMT ) Sadb ADRENOCEPTORS BETA ( B ) ADRENOCEPTORS Subtypes of ẞ receptors , designated ( B1 ). ( B2 ) and ( B ) ) receptors ALPHA ADRENOCEPTORS two major groups of a receptors a , and a₂ ( Auto receptor ) DOPAMINE RECEPTORS The dopamine receptor subtypes , termed D ,, D , D3 , D4 , and Ds SELECTIVITY FOR ADRENOCEPTORS The classification of sympathomimetics and antagonists is based on selectivity for receptors and on use. But selectivity is relative , not absolute ; some agonists act on both a- and ẞ receptors. Catecholamine : A dihydroxyphenylethylamine derivative ( eg , norepinephrine , epinephrine dopamine ) , a relatively polar molecule that is readily metabolized by catechol - O - methyltransferase Decongestant An a - agonist drug that reduces conjunctival , nasal , or oropharyngeal mucosal vasodilation by constricting blood vessels in the submucosal tissue Selective a or ẞ adrenoceptor agonist Drugs that have relatively greater effects on a or ẞ adrenoceptors ; selective or specific Sympathomimetic A drug that mimics stimulation of one or more components of the sympathetic autonomic nervous system Reuptake inhibitor An indirect - acting drug that increases the activity of transmitters in the synapse by inhibiting their reuptake into the presynaptic nerve ending. May act selectively on noradrenergic , serotonergic , or both types of nerve endings ADRENERGIC DRUGS Directly By binding on adrenoceptors : as agonists ( adrenaline ) or antagonists ( propranolol ) Indirectly Sympathomimetic drugs 1 - Discharging noradrenalin stored in nerve endings ( amphetamine ) 2. By preventing reuptake into the adrenergic nerve ending of released noradrenaline and dopamine ( cocaine , tricyclic antidepressants and noradrenaline - selective reuptake inhibitors AL 3- By preventing the destruction of catecholamine in the nerve ending ( mono amine oxidase ) inhibitors 4 By depleting the stores of noradrenalin in nerve endings ( reserpine ) 5 By preventing the release of noradrenalin from nerve endings in response to a nerve impulse ( guanethidine ) 6- By activation of adrenoceptors on adrenergic nerve endings that inhibit release of noradrenaline ( a2 autoreceptors ) ( clonidine ) 7. By blocking sympathetic autonomic ganglia ( trimetaphan ). 8- False neurotransmeters ( Methyl dopa ) SYMPATHOMIMETIC DRUGS Drugs that mimic the actions of catecholamine have a wide range of effects , can be grouped by mode of action , receptors that they activate. Cardiovascular System A. BLOOD VESSELS : Alpha receptors increase arterial resistance , whereas B₂ receptors promote smooth muscle relaxation B. HEART : Stimulation of ẞ receptors increases rate , cardiac output C. BLOOD PRESSURE : The effects on blood pressure can be explained on the basis of their effects on the heart , blood vessels Eye : The radial papillary dilator muscle of the iris contains a ẞ receptors ; activation causes mydriasis Respiratory Tract : Bronchial smooth muscle contains B₂ receptorsthat cause relaxation. Activation of these receptors results in bronchodilation Gastrointestinal Tract : Relaxation of GIT smooth muscle by aẞ stimulant agents Genitourinary Tract : uterus contains ẞ2 receptors. mediate relaxation clinically useful in pregnancy.The bladder base , urethral sphincter , and prostate contain a receptors that mediate contraction and promote urinary continence. B 2 receptors of the bladder wall mediate relaxation. Metabolic Effects : Activation of ẞ3 in fat cells increased lipolysis. Effects on Endocrine Function : insulin secretion is stimulated receptors and inhibited by a receptors. Individual sympathomimetics Catecholamine Adrenaline ( epinephrine ) ( a- and ẞ - adrenoceptor effects ) very potent vasoconstrictor and cardiac stimulants used : 1- as a vasoconstrictor i.e. with local anesthetics 2 as a topical mydriatic 3 - for severe allergic reactions i.m. , i.v. ( or s.c. ) 4 - Adrenaline is used in anaphylactic shock Noradrenaline ( norepinephrine ) AL Sadoon ( chiefly a and.ẞ effects ).The main effect of administered noradrenaline is to raise the blood pressure by constricting thearterioles and so raising the total peripheral resistance Laeb Dopamine and Dobutamine It is useful in shock and in low outputheart failure NONCATECHOLAMINES Ephedrine Ephedrine is indirect sympathomimetic actions Ephedrine can be usedas a bronchodilator , in heart block , as a mydriatic and as a mucosal vasoconstrictor , but newer drugs , which are often better for these purposes , are displacing it Pseudoephedrine is similar to Ephedrine Phenylephrine has longer duration of action , up to an hour. It can be used as a nasal decongestant but sometimes irritates orally , 2-4 mg up to 4 times / day ; it also acts quickly by inhalation and the effect can last as long as 4h , which makes it suitablefor both prevention and treatment of asthma. premature labour. ( Salmeterol have low onset and long duration of action ) Mucosal decongestants Nasal and bronchial decongestants ( vasoconstrictors ) are used in allergic rhinitis , colds , coughs and sinusitis ,, as nasal drops sprays. All the sympathomimetic vasoconstrictors , have used for the purpose ,.Ischaemic damage to the mucosa is possible if they are used excessively ( more often than 3 - hourly ) or for prolonged periods ( > 3 weeks ) The occurrence of rebound congestion is also liable to lead to overuse ephedrine 0.5 % , phenylephrine 0.5 % , Xylometazoline 0.1 % ( Otrivine ) should be used , if at all , for only a few days since longer application reduces the ciliary activity and will lead to rebound congestion. Shock A state of inadequate capillary perfusion ( oxygen deficiency ) of vital tissues to an extent that adversely affects Vital function , heart ( pump blood ) brain ( consciousness , respiration ) , kidney ( urine formation ) : -Treatment of the cause : bleeding , infection , - Replacement of any fluid lost from the circulation - Perfusion of vital organs ( brain , heart , kidneys ) -Maintenance of the mean blood pressure and Blood flow Principles of Drugs Autonomic Pharmacology Adrenoceptor Antagonist Drugs Au. Pro.De Labeeb H.Al had Intrinsic sympathomimetic activity ( ISA ) Partial agonist action by adrenoceptor blockers ; typical of several ẞ blockers ( eg , pindolol , acebutolol ) Irreversible blocker A no surmountable inhibitor , usually because of covalent bond formation ( eg phenoxybenzamine ) Membrane - stabilizing activity ( MSA ) Local anesthetic action ; typical of several ẞ blockers ( eg , propranolol ) Orthostatic hypotension Hypotension that is most marked in the upright position ; caused by venous pooli ( typical of a blockade ) or inadequate blood volume ( caused by blood loss or excessive diuresis Partial agonist drug that produces a smaller effect than a full agonist and therefore can inhibit effect of a full agonist Pheochromocytoma A tumor consisting of cells that release varying amounts of norepinephrine and epinephrine into the circulation Alpha - receptor antagonists drugs Alpha - receptor antagonists may be reversible or irreversible in their interaction with these receptors , are examples of reversible antagonists Phentolamine prazosin Terazosin Doxazosin , Tamsulosin alfuzosin Phenoxybenzamine , an irreversible blockade Pharmacologic Effects A. CARDIOVASCULAR EFFECTS AL - Adoon a - receptor antagonist drugs cause a lowering of peripheral vascular resistance and lowering  blood pressure. B. OTHER EFFECTS Minor effects that the blockade of a receptors in other tissues include miosis and nasal stuffiness. CLINICAL USES Pheochromocytoma. Hypertensive Emergencies ' Chronic Hypertension Peripheral Vascular Disease Local Vasoconstrictor ExcessUrinary Obstruction Erectile DysfunctionBPH BETA - RECEPTOR ANTAGONIST DRUGS Beta - receptor antagonists antagonizing the effects of catecholamine's at ẞ adrenoceptors , occupy ẞ receptors and competitively reduce receptor occupancy by catecholamine's and otherß agonists. The major difference among the many ẞ - receptor - blocking drugs concerns their relative affinities for B1 and B2 receptors Some of these antagonists have a higher affinity for B , than for B2 receptors , and this selectivity may have important clinical implications. Since none of the clinically available ẞ - receptor antagonists are absolutely specific for ẞ , receptors , the selectivity is dose - related ; diminish at higher drug conc. Pharmacologic Effects A. Effects On The Cardiovascular System Beta - blocking drugs lower b pressure in patients with hypertension B. Effects On The Respiratory Tract Blockade of the B₂ receptors in bronchial smooth muscle may lead to an increase in airway resistance , particularly in patients with asthma.Beta- receptor antagonists such as metoprolol and atenolol may have some advantage over nonselective ẞ antagonists. However , no currently available ẞ - selective antagonist is sufficiently specific to completely avoid interactions with ; adrenoceptors. Principles of Des Automic Pharmacology Ass.Pro Dr Labeeb H.Al alsadoon C. Effects On The Eye Several ẞ blocking agents reduce IOP especially in glaucoma D. Metabolic And Endocrine Effects Beta - receptor antagonists such as propranolol inhibit lipolysis E. Effects Not Related To Beta - Blockade Local anesthetic action , also known as " membrane - stabilizing " action , is a prominent effect of several ẞ blockers. CLINICAL USES OF THE ẞ RECEPTOR - BLOCKING DRUGS Hypertension The Beta - adrenoceptor - blocking drugs have proved to be effectiveand well tolerated in hypertension , many patients respond t a Beta blocker used alone , the drug is often used with either a diuretic or a vasodilator Ischemic Heart Disease Beta - adrenoceptor blockers reduce the frequency of anginal episodes. Cardiac Arrhythmias Beta antagonists are often effective in the treatment of both supraventricular and ventricular arrhythmias Glaucoma Systemic administration of ẞ - blocking drugs for other indications was reduce intraocular pressure in patients with glaucoma. Hyperthyroidism Excessive catecholamine action is an important aspect of the pathophysiology of hyperthyroidism , especially in relation to the heartThe ẞ antagonists have beneficial effects relate to blockade of adrenoceptors and perhaps in part to the inhibition of peripheral conversion of thyroxin to triiodothyronine. The latter action may vary from one ẞ antagonist to another. Propranolol has been used extensively in patients with hyperthyroidism Neurologic Diseases Sadoon Several studies show a beneficial effect of propranolol in reducing the frequency and intensity of migraine headache. Propranolol may contribute to the symptomatic treatment of alcohol withdrawal in some patients. H Adverse Effects Of B RECEPTOR - BLOCKING DRUGS The major adverse effects of ẞ - receptor antagonist drugs relate to the consequences of ẞ blockade. Beta - receptor blockade associated withthe use of nonselective agents commonly causes worsening of asthmaand other forms of airway obstruction without having these consequences in normal individuals , if at all , in patients with reactive airways. Beta- selective antagonists are generally well tolerated  Propranolol is the prototype of ẞ - blocking drugs , a nonselective agent withnegligible effects at a and muscarinic receptors Metoprolol , Atenolol are ẞ - selective group. may be safer in patients who experience bronchoconstriction in response to propranolol. Since their ẞ , selectivity is rather modest , they should be used with great caution inpatients with a history of asthma. ). Timolol is a nonselective agent with excellent ocular hypotensive effects when administered topically in the eye. Betaxolol ( ẞ - selective ) topical ophthalmic application ( glaucoma ) Carvedilol : nonselective ẞ - receptor antagonists with some capacity to block a j - adrenergic receptors Esmolol is an ultra - short - acting ẞ 1 - selective adrenoceptor antagonist Butoxamine is a research drug selective for ẞ2 receptors. Selective B2- blocking drugs have not been actively used because there is no clinicalapplication for them ; none is available for clinical use.