CHOLINOMIMETIC DRUGS RHS - 366

Cholinomimetic Drugs (Parasympathomimetic Drug

Parasympathetic nerves use ACh as a neurotransmitter. Cholinomimetic drugs mimic the action of ACh at its

receptors.

Knowledge of distribution of receptor subtypes (muscarinic or nicotinic)

helps in predicting drug response.

Cholinergic site Neuroeffector junctions Ganglionic synapses

Receptor subtype Muscarinic Nicotinic

Classification of Cholinomimetics: 1. Direct-acting (receptor agonists) Muscarinic receptors Nicotinic receptors 2. Indirect-acting (cholinesterase inhibitors) Reversible Irreversible

Direct-acting Cholinergic Receptor Agonists: A) Muscarinic receptor agonists: Drugs that mimic ACh at neuroeffector junctions of PNS Mechanisms: Cholinergic receptors are coupled to G proteins (in tramembrane transducers that regulate second messengers):

Agonist ----> increase in cGMP ----> activation of IP3, DAG cascade DAG opens smooth muscle Ca2+ channels IP3 ----> release of Ca2+ from sarcoplasmic reticulum Agonist selectivity is determined by muscarinic receptor subtype and G protein in cell.

Types of direct acting muscarinic receptor agonists: A) Esters of choline (eg. acetylcholine, pilocarpine, carbachol, bethanechol chloride) Poorly absorbed Susceptibility to hydrolysis by cholinesterase affects duration of action b) Alkaloids (eg. muscarine) Well absorbed, not used clinically Mushroom poisoning (Amanita muscaria) 1. Acetylcholine Highly susceptible to hydrolysis IV bolus lasts 5-20 seconds Limited use in topical application in ophthalmology 2. Pilocarpine Acts on smooth muscles of eye to constrict the pupil

(miosis). Used to treat glaucoma. Contracts ciliary muscles by stimulating muscarinic Receptors. Penetration (15-30 min) and long duration (8 hrs). Increased aqueous outflow.

3. Carbachol Carbamyl ester of choline. Used mainly in ophthalmology for cataract surgery (causes rapid miosis). Decreases intraocular pressure by opening drainage angle of anterior chamber of eye. Used in glaucoma (when resistant to pilocarpine or physostigmine). 4. Bethanechol Chloride Choline ester Persistent effects because it is resistant to cholinesterases Selectively stimulates urinary and gastrointestinal tracts Facilitates emptying of neurogenic bladder in patients after surgery or parturition or with spinal cord injury.

B) Nicotinic receptor agonist Natural alkaloid found in tobacco which mimics the effects of ACh at nicotinic receptors at Autonomic ganglionic synapses (both SNS & PNS) Skeletal neuromuscular junctions Nicotine still used in some insecticides Mechanism:

 Activates nicotinic receptor (transmembrane polypeptide comprised of

cation-selective ion channel subunits Nicotinic agonists Conformational change in receptor Opens cation channels Na+/K+ diffusion into cell Depolarization of nerve cell or neuromuscular endplate Clinical use: No therapeutic action but important for its toxicity Available as a transdermal patch or as chewing gum Used as an aid in cessation of smoking Toxicity: Both stimulant and depressant (affects both SNS & PNS ganglia). Stimulates nicotinic receptors in CNS ----> mild alerting action. Also acts centrally ----> tremor & convulsions. Can increase or decrease HR. Increased respiratory rate. Vomiting due to activation of chemoreceptor trigger zone. Larger doses ----> CNS and respiratory depression by muscle endplate depolarization blockade 2. Indirect-acting Cholinomimetic Drugs Characteristics: Anticholinesterase drugs ie. inhibitors of ACh metabolism. Similar effects to direct-acting cholinomimetics. Mechanism:

 Normally ACh is rapidly degraded in cholinergic synapse. (T1/2=40ms)

Acting cholinomimetics block the enzymatic hydrolysis of acetylcholine ---->

increases local concentrations of Ach consequently effect of ACh is amplified, leading to muscarinic or nicotinic effects, depending on the organ. Effect can be therapeutic or life threatening Classification

A)

Reversible Inhibitors All are poorly absorbed from conjunctiva, skin & lungs except physostigmine which is well absorbed from all sites. Used topically in eye. More commonly used clinically than organophosphates. Quaternary alcohols Bind reversibly to active site of ACh esterase and prevents access by Ach.

 No covalent bond between enzyme inhibitor complex , so short T1/2 (2-10

min), eg. Edrophonium.

Carbamate esters Two step hydrolysis like Ach. But the covalent bond of carbamylated enzyme is more resistant to hydration

(T1/2=30-60 min) eg. neostigmine, physostigmine Clinical use: Primary target organs of anticholinesterase drugs: eye Skeletal muscle Neuromuscular junctions Gastrointestinal tract Urinary tract Respiratory tract Heart Effects are similar to direct acting cholinergic agonists Major uses in treatment of: Glaucoma Myasthenia gravis Stimulation of gastrointestinal and urinary tract motility (eg. neostigmine) -same effects as with agonists. Reversal of neuromuscular blockade. Atropine poisoning A) Glaucoma: An ocular disease caused by increased intraocular pressure due to inadequate drainage of aqueous humour at filtration angle ----> damage to the retina & optic nerve. Intraocular pressure is determined by the balance between fluid input & drainage out of the globe.

 Aqueous humour produced by ciliary epithelium and drained at the filtration

angle of the anterior chamber.

Therapy: Objective: increase outflow & decrease production of aqueous humour by local treatment with: 1. Muscarinic cholinomimetics Direct-acting: pilocarpine, carbachol Indirect-acting: physostigmine ----> contracting the smooth muscle of iris sphincter (contraction of pupil) ----> contraction of ciliary muscle ----> iris pulled from angle of anterior chamber ----> widening the filtration angle and opening the trabecular network ----> increased outflow of aqueous humour ----> decreased intraocular pressure. 2. Adrenoceptor agonists: eg. Epinephrine ----> contraction of dilator muscle of iris ----> increased aqueous outflow. Used mainly for treatment of closed angle glaucoma along with surgery. 3. B- adrenoceptor blockers: eg. Timolol ----> decreased production of aqueous humour by ciliary epithelium B) Myasthenia gravis

 Autoimmune disease resulting in destruction of nicotinic receptors ---->

progressive weakness, fatigue, difficulty speaking & swallowing Resembles neuromuscular block by curare. Treated with indirect acting cholinesterase inhibitors (eg neostigmine) ----> increased strength of contraction of muscles c) Reversal of neuromuscular blockade Short-acting cholinesterase inhibitors (eg. neostigmine, edrophonium Cl) ----> increased ACh concentration which then competes with neuromuscular blocker for nicotinic receptors. B) Irreversible Inhibitors
Organophosphates (Parathion, malathion).

Mechanism: Act by covalently phosphorylating the hydroxyl group of serine on cholinesterase. A few organophosphate pesticides are selective in toxicity to insects e.g. malathion is rapidly metabolized by plasma esterases .: safer

Aging occurs when an alkyl or alkoxy group is lost

----> increased strength of phosphorus-enzyme bond ----> stable enzyme-inhibitor complex which is difficult to split Before aging occurs patients can be treated with strong nucleophiles eg. pralidoxime which breaks the phosphorus-enzyme complex and regenerates the enzyme. Signs of Toxicity: A) Mild exposure: Pupillary constriction. Tightness of the chest. Watery discharge from the nose. Wheezing

B) Severe exposure (see DUMBELS): More intensified symptoms Visual disturbances Muscle fasciculation Bronchoconstriction & pulmonary edema Pronounced muscle weakness Shallow respiration Vomiting and diarrhea CNS effects, anxiety, headache, tremor, seizures, depression. Death

DUMBELS: D U M B E L S DIARRHEA URINATION MIOSIS BRONCHOCONSTRICTIO N EXCITATION (skel. musc. & CNS) LACRIMATION SALIVATION, SWEATING

Treatment: Muscarinic blocking drugs, e.g. atropine

Overview of Therapeutic Applications of Cholinomimetic Drugs Tissue Effect Use/drug Muscarinic agonists Eye contraction of ciliary GI tract m./sphincter m. of iris increased peristalsis, Urinary sphincter relaxation bladder increased contraction of detrusor m./sphincter relaxation ACh esterase inhibitors Skeletal increased muscle activity m. similar to agonists Eye

Glaucoma (pilocarpine) Paralytic ileus (bethanechol Cl) Urinary retention (bethanechol Cl)

Myasthenia gravis (neostigmine) Glaucoma (physostigmine)

ADRENERGIC RECEPTORS

RHS-366
:Alpha adrenoceptors .1 .Alpha1: postsynaptic, mediate mainly vasoconstriction .Alpha2: presynaptic or postsynaptic .Presynaptic: mediate negative feedback on NE release Postsynaptic: central or peripheral Central tractus solitarius : stimulation causes reduction in central sympathetic .discharge and fall of blood pressure Peripheral postsynaptic receptors mediate inhibition of adenyl cyclase in platelets .and lipocytes :Beta adrenoceptors: postsynaptic .2 .B1: present mainly in the heart causing its stimulation B2: causes bronchodilatation, uterine relaxation, skeletal and coronary .vasodilatation Presynaptic B1: facilitate NE release :Alpha adrenoceptor agonists Alpha1 + Alpha2: epinephrine, norepinephrine Alpha1: phenylephrine, methoxamine .Alpha2: clonidine, alpha-methyl NE

:Alpha adrenoceptor antagonists .Alpha1 + Alpha2: phentolamine .Alpha1: prazosin .Alpha2: yohimbine :B- adrenoceptor agonists .B1 + B2: isoproterenol, epinephrine .B1: NE, dobutamine, pronalterol .B2: salbutamol, terbutaline, albuterol :Beta adrenoceptor antagonists .B1 + B2: propranolol, timolol, nadolol .B1: atenolol, metoprolol, acebutolol .B2: butoxamine .N.B. labetalol blocks both alpha and beta-adrenoceptors :Steps of synthesis of catecholamines and drugs affecting them Phenylalanine by phenylalanine hydroxylase to tyrosine -1 Tyrosine by tyrosine hydroxylase to Dopa. This step is inhibited by alpha-methyl -2 .tyrosine and 3-iodotyrosine Dopa by aromatic L-amino acid decarboxylase to dopamine. This step is inhibited by -3 .alpha-methyldopa, carbidopa and benserazide Dopamine by dopamine B-hydroxylase to norepinephrine. This step is inhibited by -4 .disulfiram Norepinephrine by N-methyl transferase to epinephrine. This step is inhibited by -5 .glucocorticoids :Fate of catecholamines :Enzymatic catabolism of circulating CAs

Norepinephrine by COMT to normetanephrine-1 .Epinephrine by COMT to metanephrine-2 Both normetanephrine and metanephrine by MAO to 3-methoxy 4-hydroxy mandelic -3 .aldehyde methoxy 4-hydroxy mandelic aldehyde to vanillyl mandelic acid (VMA) and 3- -3 -4 (methoxy, 4-hydroxy phenylglycol (MOPEG :Enzymatic catabolism of neuronal CAs .Both norepinephrine and epinephrine by MAO to 3,4-dihydroxy mandelc aldehyde-1 dihydroxy mandelc aldehyde is converted to 3,4-dihydroxy mandelic acid (DOMA) -3,4 -2 .(and then by COMT to vanillyl mandelic acid (VMA dihydroxy mandelc aldehyde is converted to 3,4-dihydroxy phenylglycol (DOPEG) -3,4 -3 .(and then by COMT to 3-methoxy, 4-hydroxy phenylglycol (MOPEG :Uptake of catecholamines .Neuronal uptake (uptake I): prevented by cocaine -1 .Granular uptake: prevented by reserpine -2 Non-neuronal uptake (uptake II) prevented by glucocorticoids anf phenoxybenzamine -3 :Types of MAO isoenzymes .MAO-A: in peripheral tissues, inhibited selectively by clorgyline -1 .MAO-B: in brain, inhibited selectively by deprenyl -2 Non-selective MAOIs include hydrazines (e.g. iproniazid) and non-hydrazines -3 ((tranylcypromine :Molecular mechanism of action of CAs

B-receptor stimulation results in activation of adenyl cyclase with increased -1 .intracellular c-AMP Alpha1-receptor activation increases intracellular calcium through activation of -2 phospholipase-C Alpha2-receptor activation inhibits adenylate cyclase and decreases intracellular c-AMP -3 :Functions of alpha1-adrenoceptors .Vasoconstriction -1 .Mydriasis -2 .Decrease gut motility -3 .Contraction of pregnant uterus -4 .Ejaculation -5 :Functions of B-adrenoceptors .B1: stimulation of all properties of the heart, increase lipolysis and rennin release B2: Coronary and skeletal vasodilatation, bronchodilatation, relaxation of pregnant uterus, .decrease gut motility, inhibition of of mast cell degranulation

Metabolic actions of CAs Alpha1: increase hepatic glycogenolysis, hyperkalemia -1 .Alpha2: decrease lipolysis, rennin secretion, insulin release -2 .B1: increase lipolysis and rennin secretion -3 B2: increase hepatic glycogenolysis and insulin release, hypokalemia -4 :Reversal effect of epinephrine on blood pressure IVI of epinephrine leads to rapid rise of blood pressure (alpha1-action). When an alpha adrenoceptor blocker is given the vasodilator effect (B2-action) of epinephrine is unmasked resulting in a drop of blood pressure. This reversal effect does not occur with .pure alpha-agonists :Epinephrine, norepinephrine and isoproterenol on HR

.Epinephrine and isoproterenol increase HR (positive chronotropic) due to B1-action Norepinephrine causes reflex bradycardia secondary to increase in mean arterial BP :Main therapeutic uses of epinephrine Anaphylactic shock .1 Cardiac arrest .2 Acute bronchial asthma .3 with local anesthetics .4 Topical hemostatic .5 :Selective B2 agonists :Advantages Less toxic effects on the heart .1 Effective orally and by inhalation .2 .Longer duration of action .3 :Therapeutic uses Bronchial asthma as salbutamol and terbutaline .1 Premature labor as retodrine -2 Peripheral vascular disease as isoxsuprine .3 :Adverse reactions Skeletal muscle tremors .1 Nervousness and weakness .2 Tachyphylaxis and hypoxemia may occur with excessive use .3

Compare between Dopamine and Dobutamine DOPAMINE Agonist to dopamine receptors, B1 and alpha .1 adrenoceptors

Dobutamine .Selective B1-agonist .1

Causes release of NE .2 Chronotropic and arrhythmogenic .3 .Given by IV infusion .4 Does not release NE .2 Much less .3 Given by IV infusion .4

Adverse reactions of ephedrine and amphetamine Ephedrine CNS stimulation .1 Palpitation and tachycardia .2 Urinary retention .3 Tachyphylaxis .4

Amphetamine CNS stimulation and .1 excitement, acute psychosis Dependence, anorexia .2 Weight loss .3 Palpitation, tachycardia .4 Arrhythmias, hypertension .5 .and hyperpyrexia

Cardiovascular uses of sympathomimetics Shock states following AMI as Dopamine or dobutamine .1 Shock state following sympathectomy as alpha agonists .2 .Complete heart block and cardiac arrest as isoproterenol or epinephrine .3 Congestive heart failure as dobutamine, prenalterol .4 Nasal decongestants as naphazoline, xylometazoline .5

Local haemostatic as epinephrine .6 .Peripheral vascular disease as isoxsuprine, nylidrin .7 Classification of B-adrenoceptor blockers :Cardioselective B-blockers Atenolol, Acebutolol and Metoprolol .1 .Less liable to cause bronchospasm or Raynaud's phenomenon .2 with minimal effects upon renal plasma flow or metabolic responses to hypoglycemia .3 :B-blockers with intrinsic sympathomimetic activity Pindolol, Oxprenolol, alprenolol .1 They have limited effect on HR, A-V conduction, myocardial contractility, peripheral .2 blood flow, bronchomotor tone and plasma lipids :Lipophilic B-blockers .Propranolol, Timolol, Alprenolol .1 Well absorbed from the GIT .2 Extensive hepatic metabolism .3 (Shorter half-life (3-5 hour .4 .Cross Blood Brain Barrier .4 :Hydrophilic B-blockers Nadolol, Atenolol .1 Less well absorbed .2 Elimination primarily by the kidney .3 (Longer half life (7-14 hours .4 Do not cross BBB .5 Beta blockers as antihypertensives .Negative inotropic and chronotropic action .1 .Inhibition of rennin secretion by the kidney .2 .Reconditioning of baroreceptors .3 .Decrease central sympathetic outflow .4 .Decrease NE release .5 .Formation of vasodilator PG .6 Beneficial effects of B-blockers in angina pectoris

Reduction of myocardial oxygen demand by decrease in heart rate, systolic BP and .1 .contractility. Decrease lipolysis and free fatty acid utilization Increase of oxygen supply by prolongation of diastolic coronary perfusion time, shift of .2 .subepicardial to subendocardial coronary blood flow and inhibition of platelet aggregation :Therapeutic uses of B-adrenoceptor blockers .Hypertension .1 .(Ischemic heart disease (angina pectoris and acute phase of myocardial infarction .2 .Arrhythmias .3 Hypertrophic obstructive cardiomyopathy .4 .Migraine prophylaxis .5 .Open angle glaucoma .6 .Hyperthyroidism .7 (Pheochromocytoma (+ alpha blocker .8 .GI bleeding in hepatic cirrhosis .9 :Adverse reactions of B-adrenoceptor blockers :B1-mediated Cardiac failure .1 Bradycardia .2 A-V block .3 Hypotension .4 B2-mediated Bronchospasm .1 Prolongation of insulin hypoglycemia .2 Intermittent claudication .3 Cold extremeties .4 Fatigue .5 Reduced blood flow to liver and kidney .6 Abrupt cessation after prolonged therapy can lead to dysrhythmias, hypertension, and .worsening of angina Other side effects: night mares, mental depression, increase in plasma triglycerides and decrease HDL

Characteristic features and uses of Labetalol Selective alpha1 blocker and non-selective B-blocker .1 .Has a rapid antihypertensive effect .2 Used for emergency control of severe hypertension, pheochromocytoma, hypertensive .3 .response during abrupt withdrawal of clonidine General therapeutic uses of alpha-adrenergic blockers Essential hypertension .1 Pheochromocytoma .2 Peripheral vascular disease .3 Shock associated with severe vasospasm .4 Toxicity of alpha-agonists .5 Urinary obstruction .6 Prazosin Selective postsynaptic alpha-1 adrenoceptor blocker .1 .Used in essential hypertension, severe CHF, and Raynaud's vasospasm .2 Adverse reactions include dose-related postural hypotension (first-dose phenomenon), .3 dizziness, sodium and water retention on chronic use, tachycardia occurs much less than with the non-selective alpha blockers :Therapeutic uses of ergot alkaloids Migraine attack as ergotamine and dihydroergotamine .1 Migraine prophylaxis as methysergide .2 Postpartum hemorrhage (ergonovine and methylergonovine .3 (Senile cerebral insufficiency (dihydroergotoxine .4 5. Bromocriptine is used to suppress lactation, amenorrhoea-galactorr

ALPHA AND BETA ADRENERGIC RECEPTOR AGONISTS

RHS-366
ALPHA AND BETA ADRENERGIC RECEPTOR AGONISTS
History: A. Finklemann in 1930 stimulated the sympathetic input to rabbit intestine and found a decrease in spontaneous movements. Perfusate did the same thing to a 2nd piece of intestine. Effects mimicked by "adrenaline". B. Von Euler 1946 demonstrated that NE, not EPI is the main endogenous catecholamine in sympathetically innervated tissue. C. The study of the sympathetic nervous system is important from a clinical perspective. The SNS is involved in controlling heart rate, contractility, blood pressure, vasomotor tone, carbohydrate and fatty acid metabolism etc. Stimulation of the SNS occurs in response to physical activity, psychological stress, allergies etc. Drugs influencing the SNS are used in treatment of hypertension, shock, cardiac failure and arrhythmias, asthma and emphysema, allergies and anaphylaxis. D. There are three major catecholamines: NE, EPI, and DA naturally found in the body. EPI and NE mediate the response of the sympathoadrenal system to activation, and are also found in the CNS. DA is primarily a CNS neurotransmitter.

I. Sympathomimetic amines have 7 major classes of action A. A peripheral excitatory action: i.e. on smooth muscles of blood vessels supplying skin.

B. A peripheral inhibitory action: i.e. on smooth muscles of gut, bronchioles, and blood vessels supplying skeletal muscle. C. A cardiac excitatory action: i.e. positive chronotropic, dromotropic, and inotropic effects. D. Metabolic actions: i.e. enhanced glycogenolysis and lipolysis. E. Endocrine actions: i.e. modulation of secretion of insulin F. CNS actions: i.e. increased wakefulness and inhibition of appetite. G. Presynaptic actions: i.e. inhibition of release of NE, NPY, and ACh at autonomic nerve terminals by activation of alpha 2 receptors. Enhanced release of ACh by activation of presynaptic alpha 2 receptors on somatic motor neurons. Enhanced release of NE, and NPY by activation of Beta 2 receptors.

Classification of adrenergic receptor agonists (sympathomimetic amines) or drugs that produce sympathomimetic-like effects.

II. Pharmacology of Epinephrine

A. Epinephrine is a potent stimulator of both alpha (1 & 2) and beta (1, 2, & 3) receptors, therefore, its effects on target organs are complex.

B. Effects of EPI on blood pressure are dose dependent. 1. When given in large doses intravenously, EPI gives a rapid increase in blood pressure. As the response wanes, the mean pressure falls below normal before returning to control levels. The pressor effects are due to A) the positive inotropic effect of EPI, B) the positive chronotropic effect, and C) vasoconstriction in many vascular beds. The depressor effect is due to the activation of vasodilator beta 2 receptors in the vasculature perfusing skeletal muscle. This effect is not seen initially because it is overwhelmed by the vasoconstrictive effect of alpha 1 receptors on vascular smooth muscle at other sites, however vasoconstriction is lost as the concentration of EPI goes down, but the beta 2 mediated vasodilatory effect is retained. If you pretreat a person with an alpha adrenergic receptor blocker, one sees the so-called epinephrine reversal effect i.e. the unopposed effect of the beta 2 receptors causes a pronounced decrease in total peripheral resistance, and means blood pressure falls in response to EPI.

2. When given in small doses, there is little or no effect on the mean blood pressure because the increase in blood pressure resulting from increased heart rate and contractility is counteracted by the decrease in total peripheral resistance due to vasodilation in blood vessels perfusing skeletal muscle. You will recall that these beta 2 receptors have a lower threshold to activation than alpha 1 receptors, therefore the net effect of low doses of EPI is vasodilation.

3. When EPI causes an increase in mean arterial pressure (High doses); it activates a compensatory vagal baroreceptor mediated bradycardia which also helps to return blood pressure toward normal.

C. Effects of EPI on vascular smooth muscle are variable, resulting in a substantial redistribution of blood flow. That is, EPI causes a marked reduction of blood flow through the skin by activating its alpha 1 receptors, while simultaneously redistributing flow through the muscles by causing vasodilation there through the activation of Beta 2 receptors. This has obvious utility in survival of the organism by preparing it for fight or flight. EPI can reduce renal blood flow by 40% in doses that do not affect mean blood pressure. Effects of EPI on Cerebral Circulation. No significant constrictor action on cerebral blood vessels. If you think about it, it is a lucky thing that the blood flow to the brain is not restricted during responses to stressors.

D. Effects of EPI on Cardiac Muscle are mediated primarily by beta 1 receptors, although Beta 2 and alpha receptors are also present in the heart. As indicated before, EPI has a powerful chronotropic and inotropic effect. EPI reduces the time for systole and makes it more powerful without decreasing the duration of diastole. The latter effect occurs because EPI also increases the rate of relaxation of ventricular muscle. Cardiac output is enhanced and the work of the heart and its oxygen consumption are markedly increased. Cardiac efficiency (work done relative to oxygen consumption) is lessened! The chronotropic action of EPI is due to its ability to accelerate the slow depolarization of pacemaker cells of the SA node that takes place during diastole. Large doses may provoke cardiac arrhythmias. Large doses of EPI, or long term elevation of plasma catecholamines damages the myocardium. This may in part explain the beneficial effects of beta blockers in heart failure.

E. Effects of EPI on Other Smooth Muscles. In general GI muscle is relaxed and resting tone and peristaltic movements are reduced. This is due to the inhibitory effect of beta 2 receptors, and possibly also due to inhibition of release of ACh by activation of inhibitory presynaptic alpha 2 receptors on cholinergic nerve terminals. The response of the uterus is variable depending on phase of the sexual cycle, state of gestation, and dose of the drug. During the last month of pregnancy, EPI inhibits uterine tone and contractions, by activating beta 2 receptors. As a result, selective beta 2 agonists are used to delay the onset of premature labor. Bronchial smooth muscle is powerfully relaxed by EPI via activation of Beta 2 receptors. Selective beta 2 agonists are used in the treatment of asthma. Epi relaxes the detrusor muscle of the bladder by activating beta receptors, and contracts the trigone and sphincter muscles due to alpha agonist effects. The result is urinary retention.

F. Metabolic effects of EPI: 1. Glycogenolysis via activation of beta 2 receptors, results in an increase in blood glucose. 2. Lipolysis via activation of beta 3 receptors, results in an increase in the concentration of free fatty acids in blood. 3. Insulin secretion is inhibited by alpha 2 receptors, and increased by beta 2 receptors, but inhibition predominates in man. 4. EPI promotes a fall in plasma K due to enhanced uptake of K into skeletal muscle via an action on Beta 2 receptors. This action has been exploited in the management of hyperkalemia.

G. Absorption and fate of EPI 1. Absorption of EPI as well as other catecholamines from GI tract is negligible due to rapid conjugation and oxidation in the intestinal mucosa of the GI tract and liver. Subcutaneous absorption slows due to vasoconstriction. Inhaled effects largely restricted to the respiratory tract in low doses. Larger doses can give systemic effects, including arrhythmias. The liver which is rich in both COMT and MAO destroys most circulating EPI. H. Toxicity and contraindications 1. EPI causes disturbing reactions such as fear, anxiety, tenseness, restlessness, headache, tremor, weakness, dizziness, etc. Hyperthyroid and hypertensive patients are particularly susceptible. 2. More serious reactions include cardiac arrhythmias, including fatal ventricular arrhythmias when EPI is given to a patient anesthetized with halogenated hydrocarbon anesthetics such as halothane. Also cerebral hemorrhage due to severe hypertension has occurred. Use of EPI in patients receiving nonselective Beta blockers is contraindicated because the unopposed actions of EPI on vascular alpha 1 receptors can lead to severe hypertension and cerebral hemorrhage. I. Therapeutic uses of EPI 1. Relief of bronchospasm 2. Relief of hypersensitivity reactions and anaphylaxis 3. To prolong the duration of action of local anesthetics. 4. As a topical haemostatic to control superficial bleeding from skin and mucosa 5. To restore cardiac rhythm in patients with cardiac arrest.

III. Pharmacology of Norepinephrine A. Cardiovascular effects of NE 1. NE is a potent agonist at alpha and Beta 1 receptors, and has little action on beta 2 receptors, therefore when given by intravenous infusion of low doses; NE causes a pronounced increase in total peripheral resistance (i.e. because there is no opposing Beta 2 mediated vasodilation). This is combined with its direct inotropic effect on the heart to cause a substantial increase in mean blood pressure, and a reflex mediated bradycardia. In contrast to EPI, pretreatment with an alpha 1 antagonist will block the pressor effects of NE, but will not cause reversal to a depressor effect. Since the effects of NE are mainly on alpha and Beta 1 receptors, indirectly acting sympathomimetics which act by releasing NE have predominantly alpha mediated and cardiac effects. B. Other responses to NE are not prominent in Man.

C. Toxicity 1. The toxic effects of NE are like those of EPI, except they are less pronounced and less frequently seen i.e. anxiety, headache, palpitations, etc. In toxic doses, can get severe hypertension. NE, like EPI is contraindicated in anesthesia with drugs that sensitize the heart to the arrhythmic effects of catecholamines such as halothane. Accidental extravasation of NE during attempted intravenous infusion can cause local anoxic necrosis and impaired circulation through the limb. In pregnant females, NE should not be used because it stimulates alpha 1 receptors in the uterus that cause contraction.

D. Therapeutic uses Currently very little therapeutic use. Sometimes used as a cardiac stimulant in cardiogenic or septicemic shock.

IV. Pharmacology of Dopamine A. Cardiovascular effects 1. At low doses DA activate D 1 receptors in renal, mesenteric, and coronary vascular beds. This leads to vasodilation. Increased flow through renal blood vessels is useful in cardiogenic and septicemic shock when perfusion of vital organs is compromised. DA activates Beta 1 receptors at higher concentrations leading to a positive inotropic effect. Total peripheral resistance is usually unchanged, although at higher concentrations DA can cause activation of alpha 1 receptors mediating vasoconstriction. B. Toxicity 1. Toxicity of high doses of DA is similar to that noted above for NE. Since the drug has an extremely short half life in plasma, DA toxicity usually disappear quickly if the administration is terminated. C. Therapeutic uses 1. Useful in treatment of severe congestive heart failure, particularly in patients with oliguria or impaired renal function. DA is also useful in the treatment of cardiogenic and septic shock in patients with reduced renal function. C. DA Agonists 1. Fenoldopam is a rapidly acting vasodilator which is used for acute control of severe hypertension. It is a D1 receptor agonist as well as an alpha 2 agonist. It does not affect alpha 1 or beta receptors. The half life of fenoldopam is 10 minutes.

V. Pharmacology of Isoproterenol A. Cardiovascular effects 1. ISO is primarily a beta receptor agonist, therefore intravenous infusion of ISO leads to a substantial reduction of total peripheral resistance. Simultaneously, ISO causes a direct inotropic and chronotropic effect on the heart. The net result is a reduction in mean pressure. B. Actions on other smooth muscles. 1. ISO relaxes almost all varieties of smooth muscle, but particularly bronchial and GI smooth muscle. Its effectiveness in asthma may also be due to inhibition of the release of histamine by activation of Beta 2 receptors. C. Metabolic effects 1. ISO is a potent lipolytic (Beta 3) and glycogenolytic (beta 2) drug. It also strongly releases insulin by activating Beta 2 receptors. D. Metabolism 1. Primarily by COMT, not MAO. Mainly in the liver. E. Toxicity 1. Like EPI, but much less pronounced. Cardiac arrhythmias can occur readily. F. Therapeutic uses 1. Used in emergencies to stimulate heart rate in patients with bradycardia or heart block. Its use in asthma and shock has been discontinued due to development of more selective sympathomimetics.

VI. Pharmacology of Dobutamine A. The mechanisms of action of dobutamine are complex. It is given as the racemic mixture. The l-isomer is a potent agonist at alpha 1 receptors, while the d-isomer is a potent alpha 1 antagonist. Both isomers are beta receptor agonists with greater selectivity for Beta 1 than beta 2 receptors. The net result of administration of the racemic mixture is more or less selective Beta agonist effects. B. Cardiovascular effects 1. Total peripheral resistance is not much affected, presumably by the counterbalancing effects of beta 2 agonist mediated vasodilation, and alpha 1 agonist mediated vasoconstriction. Dobutamine has a prominent inotropic effect on the heart, without much of a chronotropic effect. The explanation for this is unclear. Like other inotropic agents, dobutamine may potentially increase the size of a myocardial infarct by increasing oxygen demand. C. Toxicity is like isoproterenol, esp. arrhythmias D. Not effective orally. Given by I.V. route, however its half life in plasma is two minutes, therefore it must be given by a continuous infusion. After a few days, tolerance develops to its effects. This has led to short term use repeated intermittently. E. Therapeutic Uses 2. Used in the short term treatment of congestive heart failure or acute myocardial infarctions, because of its inotropic effect, and because it does not increase heart rate and has minimal effects on blood pressure. These effects minimize the increased oxygen demands on the failing heart muscle.

VII Pharmacology of Selective Beta 2 Agonists A. These compounds are mainly utilized for treatment of asthma. Their advantage over non-selective beta agonists is that they do not cause undesired cardiovascular effects by stimulating beta 1 receptors of the heart. B. Metaproterenol, Terbutaline, Albuterol, Pirbuterol are structural analogues of the catecholamines which have been modified so that they are not substrates of COMT and are poor substrates for MAO. These results in a longer duration of action compared to catecholamines and vary from 3 to 6 hours when administered by inhalation. C. Formoterol is a selective Beta 2 agonist with similarities to the above agents, however it has the advantages a rapid onset of action (minutes) and a long duration (12 hours). D. Salmeterol is another long acting Beta 2 agonist however it has a slow onset of action, therefore it is not useful for acute asthmatic attacks. It may also have anti-inflammatory activity. D. Ritodrine is a selective Beta 2 agonist which was developed as a uterine relaxant. It is used to delay the onset of premature labor. Other beta 2 agonists have been used for the same purpose in Europe. While these drugs can delay the onset of birth, they may not have any significant effect in reducing perinatal mortality and may increase maternal morbidity. Nifedepine ( a calcium channel blocker: NOT a beta 2 blocker) caused longer postponement of delivery, fewer maternal side effects, and fewer admissions to the neonatal intensive care unit. E. Adverse effects of Beta 2 agonists 1. Skeletal muscle tremor is the most common adverse side effect. This may be due to the presence of Beta 2 receptors in skeletal muscle, which when activated, cause twitches and tremor. Tolerance generally develops to this side effect. 2. Restlessness, apprehension, anxiety 3. Tachycardia may occur possibly secondary to beta 2 receptor mediated vasodilation. In patients with heart disease particularly, can see arrhythmias.

4. Increased glycogenolysis 5. Some recent epidemiological studies suggest that regular use of Beta 2 agonists may actually cause increased bronchial hyper reactivity and deterioration in the control of asthma. In patients requiring regular use of these drugs, strong consideration should be given to the use of additional or alternative therapies, such as use of inhaled glucocorticoids.

VIII. Pharmacology of Alpha 1 Agonists A. Phenylephrine and Methoxamine 1. Primarily directly acting vasoconstrictors by activating alpha 1 receptors. The resulting hypertension results in a prominent reflex bradycardia. They are used in the treatment of atrial tachycardia to terminate the arrhythmia by causing a reflex bradycardia. Phenylephrine is also used as a nasal decongestant and mydriatic. They are not metabolized by COMT, therefore they also have a longer duration of action than the catecholamines.

B. Mephentermine and Metaraminol 1. These drugs have two effects: a) They are directly acting alpha 1 agonists, and b) they are indirectly acting sympathomimetics i.e. they cause the release of endogenous norepinephrine. The direct effect on alpha 1 receptors mediates vasoconstriction and an increased blood pressure. The indirect effect of released NE on the heart is a positive inotropic and chronotropic action that also increases blood pressure. This results in a reflex bradycardia. Both drugs are administered intravenously. Adverse effects are due to CNS stimulation, excessive increases in blood pressure, and arrhythmias. They are used in the treatment of the hypotension which is frequently associated with spinal anesthesia. Metaraminol is also used in the termination of paroxysmal atrial tachycardia, particularly in patients with existing hypotension.

C. Midodrine 1. It is an orally effective alpha 1 agonist which is a prodrug. Its activity is due to metabolism to desglymidodrine. Sometimes used in patients with autonomic insufficiency and postural hypotension.

IX. Pharmacology of Alpha 2 Agonists A. Introduction 1. Selective alpha 2 agonists are used primarily for the treatment of hypertension. Their efficacy is somewhat surprising since many blood vessels, especially those of the skin and mucosa, contain post-synaptic alpha 2 receptors that mediate vasoconstriction. Indeed clonidine, the prototype alpha 2 agonist drug which we will consider was originally developed as a nasal decongestant because of its ability to cause vasoconstriction of blood vessels in the nasal mucosa. The capacity of alpha 2 agonists to lower blood pressure results from their CNS effect, possibly from the activation of alpha 2 receptors in the medulla that diminish centrally mediated sympathetic outflow. B. Pharmacology of Clonidine 1. Pharmacological effects a. Intravenous clonidine can cause a transient rise in blood pressure due to its ability to cause vasoconstriction via an alpha 2 agonist effect on vascular smooth muscle of skin and mucosa. This is followed by a decreased blood pressure due presumably to activation of CNS alpha 2 receptors, resulting in a decreased central outflow of impulses in the sympathetic nervous system, although this is an area of intense current research interest, and some evidence suggests that different mechanisms may be more important. Some of the antihypertensive effect of clonidine may also be due to diminished release of NE at sympathetic postganglionic nerve terminals due to activation of presynaptic alpha 2 receptors. Clonidine also stimulates parasympathetic outflow and causes slowing of the heart.

2. Pharmacokinetics a. Clonidine is well absorbed orally, and is nearly 100% bioavailability. The mean half life of the drug in plasma is about 12 hours. It is excreted in an unchanged form by the kidney, and its half life can increase dramatically in the presence of impaired renal function. A transdermal delivery system is available in which the drug is released at a constant rate for about a week. Three or four days are required to achieve steady state concentrations.

3. Adverse effects a. The major adverse effects of clonidine are dry mouth, and sedation. Other effects include bradycardia, and sexual dysfunction. About 20% of patients develop a contact dermatitis to the transdermal delivery system. In patients with long term therapy with clonidine, abrupt discontinuation is associated with development of a withdrawal syndrome and potentially life threatening hypertension.

4. Therapeutic uses a. The major use of clonidine is in the treatment of hypertension. b. Clonidine is useful in the management of withdrawal symptoms seen in addicts after withdrawal from opiates, alcohol, and tobacco. This may be due to its ability to suppress sympathomimetic symptoms of withdrawal. c. Clonidine is useful in the diagnosis of hypertension due to pheochromocytoma. In primary hypertension, clonidine causes a marked reduction in circulating levels of norepinephrine. This is not seen if the cause of hypertension is pheochromocytoma. d. Apraclonidine and Brimonidine are structural analogues of clonidine (i.e. alpha 2 agonists) which are used topically in the treatment of glaucoma by decreasing the rate of synthesis of aqueous humor. Brimonidine also acts by enhancing the outflow of aqueous humor. Its efficacy in reducing intraocular pressure is equivalent to timolol.

C. Pharmacology of Guanfacine and Guanabenz 1. Guanfacine and guanabenz are alpha 2 receptor agonists which are also believed to lower blood pressure by activation of central sites. Their pharmacological effects and side effects are quite similar to clonidine. Guanfacine has a longer mean half life in plasma than clonidine (12-24 hrs).

X. Miscellaneous Adrenergic Agonist Drugs A. Amphetamine

1. Amphetamine is an indirectly acting sympathomimetic which causes release of NE from adrenergic nerve endings, and also blocks its reuptake into the cytoplasm of the nerve terminal. As such it has potent peripheral effects on alpha 1 & 2 receptors, and Beta 1, but not beta 2 receptors. It is also a potent CNS stimulant which is orally effective. 2. Cardiovascular effects of amphetamine include increased blood pressure, and reflex bradycardia. In larger doses see cardiac arrhythmias. 3. Other smooth muscles respond to amphetamine as they do to previously described sympathomimetics. The contractile effect on the sphincter of the urinary bladder is particularly pronounced and has been used for the treatment of incontinence. 4. Amphetamine is one of the most potent sympathomimetic amines in stimulating the CNS. The d-isomer is 3 to 4 times more potent than the l-isomer. CNS effects include increased wakefulness and alertness; decreased sense of fatigue; elevation of mood, with increased initiative, self-confidence, and ability to concentrate; elation and euphoria; depressed appetite; physical performance in athletes is improved; performance of simple mental tasks is improved, however although more work is accomplished, the number of errors increases. The most striking improvement with amphetamine occurs when performance is reduced by fatigue and lack of sleep. The behavioral effects of amphetamine depend both on the dose and the mental state or personality of the individual. Prolonged use or high doses are nearly always followed by depression and fatigue. Tolerance develops to the appetite suppressant effects rapidly. Amphetamine stimulates the respiratory center. When respiration is depressed by centrally acting drugs, amphetamine can stimulate respiration.

5. Toxicity includes: restlessness, dizziness, tremor, irritability, insomnia, confusion, assaultiveness, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or homicidal tendencies. The psychotic effects of amphetamine, including vivid hallucination and paranoid delusions, which are often mistaken for schizophrenia is the most common

serious effect, and can be elicited in any individual taking sufficient quantities of amphetamine for a long period of time. Cardiovascular effects are common and include cardiac arrhythmias, hypertension or hypotension, and circulatory collapse. GI symptoms include dry mouth, nausea, vomiting, and diarrhea. Fatal poisoning usually terminates in convulsions, stroke, and coma. Repeated use leads to the development of tolerance and psychological dependence.

6. Therapeutic uses include treatment of narcolepsy, obesity, and attention-deficit hyperactivity disorder.

7. Methamphetamine, in low doses, has prominent CNS effects like amphetamine, without significant peripheral actions. It has a high potential for abuse. It is used principally for its central effects which are more pronounced than amphetamine. Methylphenidate is a mild CNS stimulant whose pharmacological properties is essentially the same as amphetamine but which may not lead to as much motor activation. Pemoline is another CNS stimulant which has minimal cardiovascular effects. It is used in the treatment of attention-deficit hyperactivity disorder and is given once daily due to its long half-life.

B. Ephedrine 1. Ephedrine is an alkaloid isolated from the plant Ephedrine sinica. Extracts of this plant have been used in Chinese herbal medicine for at least 2000 years. Ephedrine has both

directly- and indirectly- mediated sympathomimetic effects. That is, it stimulates both alpha and beta receptors, and it causes release of NE. Ephedrine was the first sympathomimetic drug which was effective orally. Its spectrum of effects is similar to EPI, another sympathomimetic with both alpha and beta agonist effects, however it has a longer duration of effect. In addition it has CNS effects similar to amphetamine, but less intense. In the past it was used as a CNS stimulant for treatment of narcolepsy, and as a bronchodilator in asthma. More selective agents have replaced ephedrine.

C. Ethylnorepinephrine 1. It is primarily a beta agonist with some alpha agonist effects. It is administered IM or SC to cause bronchiolar dilation as well as vasoconstriction in the bronchioles, which reduces bronchial congestion. D. Oral sympathomimetics used primarily for relief of nasal congestion include phenylephrine, pseudoephedrine, and phenylpropanolamine. E. Topical sympathomimetics used primarily as nasal decongestants or mydriatics include naphazoline, tetrahydrozoline, and oxymetazoline. and xylometazoline

XI. A Summary of Therapeutic Uses of Sympathomimetics A. Uses that relate to vascular effects of sympathomimetics 1. Control of superficial hemorrhage, i.e. in facial, oropharyngeal, and nasopharyngeal surgery. EPI

2. Decongestion of mucous membranes. a. Usually get temporary relief, but it is often followed by a rebound swelling. 3. To prolong the duration of action of local anesthetics: EPI 4. in the treatment of hypotension and shock. a. Use controversial because autoregulatory phenomena usually cause intense sympathetic activation and sympathomimetics may compromise perfusion of vital organs. DA! B. Uses that relate to CNS effects of sympathomimetics 1. Narcolepsy (amphetamines) 2. Weight Reduction (amphetamines) 3. Attention deficit-hyperactivity disorder (amphetamines, methylphenidate) C. Uses for cardiac effects 1. Phenylephrine and methoxamine used in PAT by causing a reflex bradycardia. 2. Epinephrine used in emergency treatment of cardiac arrest. 3. DA is useful in the treatment of cardiogenic or septicemic shock especially in patients with compromised renal function.

D. Uses in allergic reactions

1. Epinephrine is the drug of choice to reverse the manifestations of serious acute hypersensitivity reactions due both to its cardiovascular effects and its ability to suppress release of histamine. 2. Asthma is preferentially treated with selective beta 2 agonists (Metaproterenol, terbutaline, albuterol).

E. Uses in ophthalmology 1. Sympathomimetics cause mydriasis i.e. phenylephrine and epi. These two drugs also cause a reduction in intraocular pressure in wide angle glaucoma. F. Uses in obstetrics 1. Beta 2 agonist (Ritodrine) blocks onset of premature labor by inhibiting contractility of uterus G. Nasal decongestion

Uptake of catecholamines:
1) Neuronal Uptake: Adrenergic neurons have a high capacity of actively taking up noradrenaline from the extracellular fluid to the cytoplasm resulting in a fall of the transmitter concentration at the receptor sites. This neuronal uptake process or Uptake 1 is both stereo- and structure selective. It has a higher affinity for L-than for D-forms, and for noradrenaline twice as much as for adrenaline. Uptake1 is probably the most important mechanism in terminating the action of neuronally released noradrenaline. Drugs that inhibit uptake-1 potentiate the response to sympathetic stimulation and to exogenously administered noradrenaline and adrenaline. Such drugs include cocaine, guanethidine and tricyclic antidepressants as desipramine 2) Granular uptake: The noradrenaline taken up into the cytoplasmic pool may also be actively transported into the storage vesicles or granules, a process described as granular uptake. Inhibitors of uptake1, have little effect on this process whereas resepine has little effect on uptake1 but is a potent inhibitor of granular uptake 3) Extraneuronal uptake: Some peripheral tissues as cardiac muscle and smooth muscle of the intestine and blood vessels may also take up circulating catecholamines especially when their concentration becomes relatively high. This extraneuronal uptake or uptake2 has different characteristics from uptake1 and is suggested to play a role in inactivating circulating catecholamines

ADRENOCEPTOR ANTAGONISTS RHS-366

Alpha-Adrenoceptor Antagonists (AlphaBlockers)
General Pharmacology These drugs block the effect of sympathetic nerves on blood vessels by binding to alphaadrenoceptors located on the vascular smooth muscle. Most of these drugs acts as competitive antagonists to the binding of norepinephrine that is released by sympathetic nerves synapsing on smooth muscle. Therefore, sometimes these drugs are referred to as sympatholytics because they antagonize sympathetic activity. Some alpha-blockers are non-competitive (e.g., phenoxybenzamine), which greatly prolongs their action. Vascular smooth muscle has two primary types of alpha-adrenoceptors: alpha1 (a1) and alpha2 (a2). The a1-adrenoceptors are located on the vascular smooth muscle. In contrast, a2-adrenoceptors are located on the sympathetic nerve terminals as well as on vascular smooth muscle. Smooth muscle (postjunctional) a1 and a2-adrenoceptors are linked to a Gq-protein, which activates smooth muscle contraction through the IP3 signal transduction pathway. Prejunctional a2-adrenoceptors located on the sympathetic nerve terminals serve as a negative feedback mechanism for norepinephrine release. a1-adrenoceptor antagonists cause vasodilation by blocking the binding of norepinephrine to the smooth muscle receptors. Non-selective a1 and a2-adrenoceptor antagonists block postjunctional a1 and a2-adrenoceptors, which causes vasodilation; however, the blocking of prejunctional a2-adrenoceptors leads to increased release of norepinephrine, which attenuates the effectiveness of the a1 and a2-postjunctional adrenoceptor blockade.

Furthermore, blocking a2-prejunctional adrenoceptors in the heart can lead to increases in heart rate and contractility due to the enhanced release of norepinephrine that binds to beta1-adrenoceptors. Alpha-blockers dilate both arteries and veins because both vessel types are innervated by sympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in the arterial resistance vessels. Because most blood vessels have some degree of sympathetic tone under basal conditions, these drugs are effective dilators. They are even more effective under conditions of elevated sympathetic activity (e.g., during stress) or during pathologic increases in circulating catecholamines caused by an adrenal gland tumor (pheochromocytoma). Therapeutic Uses Alpha-blockers, especially a1-adrenoceptor antagonists, are useful in the treatment of primary hypertension, although their use is not as widespread as other antihypertensive drugs. The non-selective antagonists are usually reserve for use in hypertensive emergencies caused by a pheochromocytoma. This hypertensive condition, which is most commonly caused by an adrenal gland tumor that secretes large amounts of catecholamines, can be managed by non-selective alpha-blockers (in conjunction with beta-blockade to blunt the reflex tachycardia) until the tumor can be surgically removed. Specific Drugs Newer alpha-blockers used in treating hypertension are relatively selective a1-adrenoceptor antagonists (e.g., prazosin, terazosin, doxazosin, trimazosin), whereas some older drugs are non-selective antagonists (e.g., phentolamine, phenoxybenzamine). (Go to www.rxlist.com for specific drug information) Side Effects and Contraindications The most common side effects are related directly to alpha-adrenoceptor blockade. These side effects include dizziness, orthostatic hypotension (due to loss of reflex vasoconstriction upon standing), nasal congestion (due to dilation of nasal mucosal arterioles), headache, and reflex tachycardia (especially with non-selective alphablockers). Fluid retention is also a problem that can be rectified by use of a diuretic in

conjunction with the alpha-blocker. Alpha blockers have not been shown to be beneficial in heart failure or angina, and should not be used in these conditions.

BETA ADRENOCEPTOR ANTAGONISTS

Pharmacology Beta blockers block the action of endogenous catecholamines (epinephrine (adrenaline) and norepinephrine (noradrenaline) in particular), on -adrenergic receptors, part of the sympathetic nervous system which mediates the "fight or flight" response. There are three known types of beta receptor, designated 1, 2 and 3. 1-Adrenergic receptors are located mainly in the heart and in the kidneys. 2-Adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. 3-receptors are located in fat cells. -Receptor antagonism Stimulation of 1 receptors by epinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity. Stimulation of 1 receptors on the kidney causes renin release. Stimulation of 2 receptors induces smooth muscle relaxation (resulting in vasodilation and bronchodilation amongst other actions), induces tremor in skeletal muscle, and increases glycogenolysis in the liver and skeletal muscle. Stimulation of 3 receptors induces lipolysis. Beta blockers inhibit these normal epinephrine-mediated sympathetic actions, but have minimal effect on resting subjects. That is, they reduce the effect of excitement/physical exertion on heart rate and force of contraction, dilation of blood vessels and opening of bronchi, and also reduce tremor and breakdown of glycogen. It is therefore expected that non-selective beta blockers have an antihypertensive effect. The antihypertensive mechanism appears to involve: reduction in cardiac output (due to

negative chronotropic and inotropic effects), reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity. Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand. The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade. Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin angiotensin aldosterone system with a resultant decrease in blood pressure due to decreased sodium and water retention. Intrinsic sympathomimetic activity Some beta blockers (e.g. oxprenolol and pindolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low level agonist activity at the adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy. Agents with ISA are not used in post-myocardial infarction as they have not been demonstrated to be beneficial. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia.[3] 1-Receptor antagonism Some beta blockers (e.g. labetalol and carvedilol) exhibit mixed antagonism of both - and 1-adrenergic receptors, which provides additional arteriolar vasodilating action. Other effects Beta blockers decrease nocturnal melatonin release, perhaps partly accounting for sleep disturbance caused by some agents.[4] Beta blockers protect against social anxiety:

"Improvement of physical symptoms has been demonstrated with beta-blockers such as propranolol; however, these effects are limited to the social anxiety experienced in performance situations." [5] Beta blockers can impair the relaxation of bronchial muscle (mediated by beta-2) and so should be avoided by asthmatics. Clinical use Large differences exist in the pharmacology of agents within the class, thus not all beta blockers are used for all indications listed below. Indications for beta blockers include:

Hypertension Angina Mitral valve prolapse Cardiac arrhythmia Congestive heart failure Myocardial infarction Glaucoma Migraine prophylaxis Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism Essential tremor Phaeochromocytoma, in conjunction with -blocker

Congestive heart failure Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition, studies in the late 1990s showed their positive effects on morbidity and mortality in congestive heart failure.[6] [7] [8] Bisoprolol, carvedilol and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure. The beta blockers are a benefit due to the reduction of the heart rate which will lower the myocardial energy expenditure. This is turns prolongs the diastolic filling and lengthens coronary perfusion.[9] Beta blockers have also been a benefit to improving the ejection fraction of the heart despite an initial reduction in it.

Trials have shown that Beta blockers reduce the absolute risk of death by 4.5% over a 13 month period. As well as reducing the risk of mortality, the number of hospital visits and hospitalizations were also reduced in the trials. Anxiety and performance enhancement Some people, particularly musicians, use beta blockers to avoid stage fright and tremor during public performance and auditions. The physiological symptoms of the fight/flight response associated with performance anxiety and panic (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand. Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration. [10] Since they lower heart rate and reduce tremor, beta blockers have been used by some Olympic marksmen to enhance performance, though beta blockers are banned by the International Olympic Committee (IOC).[11] Although they have no recognisable benefit to most sports, it is acknowledged that they are beneficial to sports such as archery and shooting. Adverse effects Adverse drug reactions (ADRs) associated with the use of beta blockers include: nausea, diarrhea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, abnormal vision, decreased concentration, hallucinations, insomnia, nightmares, clinical depression, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed 1/-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema.[3] Central nervous system (CNS) adverse effects (hallucinations, insomnia, nightmares, depression) are more common in agents with greater lipid solubility, which are able to cross the blood-brain barrier into the CNS. Similarly, CNS adverse effects are less common in agents with greater aqueous solubility. Adverse effects associated with 2-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common

with 1-selective (often termed "cardioselective") agents, however receptor selectivity diminishes at higher doses. Beta blockade, especially of the beta-1 receptor at the macula densa inhibits renin release, thus decreasing the release of aldosterone. This causes hyponatremia and hyperkalemia. A 2007 study revealed that diuretics and beta-blockers used for hypertension increase a patient's risk of developing diabetes whilst ACE inhibitors and Angiotensin II receptor antagonists (Angiotensin Receptor Blockers) actually decrease the risk of diabetes.[12] Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics and beta-blockers as first-line treatment of hypertension due to the risk of diabetes.[13] Beta blockers must not be used in the treatment of cocaine, amphetamine, or other alpha adrenergic stimulant overdose. The blockade of only beta receptors increases hypertension, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha adrenergic system stimulation unopposed. [14] The appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant abuse are vasodilators like nitroglycerin, diuretics like furosemide and alpha blockers like phentolamine.

Examples of beta blockers Dichloroisoprenaline, the first beta blocker. Non-selective agents

Alprenolol Carteolol Levobunolol Mepindolol Metipranolol Nadolol

Oxprenolol Penbutolol Pindolol Propranolol Sotalol Timolol

1-Selective agents

Acebutolol Atenolol Betaxolol Bisoprolol[16] Esmolol Metoprolol Nebivolol

Mixed 1/-adrenergic antagonists

Carvedilol Celiprolol Labetalol

2-Selective agents

Butaxamine (weak -adrenergic agonist activity

Side Effects / Health Consequences

Low Blood Pressure Slow Heart Rate Impaired Circulation Loss of Sleep

Heart Failure Asthma Depression Sexual Dysfunction Nausea Headaches Dizziness Muscle Cramps

Pharmacological differences

Agents with intrinsic sympathomimetic action (ISA) o Acebutolol, carteolol, celiprolol, mepindolol, oxprenolol, pindolol Agents with greater aqueous solubility o Atenolol, celiprolol, nadolol, sotalol Agents with membrane stabilising activity o Acebutolol, betaxolol, pindolol, propranolol Agents with antioxidant effect o Carvedilol o Nebivolol

Indication differences

Agents specifically indicated for cardiac arrhythmia o Esmolol, sotalol Agents specifically indicated for congestive heart failure o Bisoprolol, carvedilol, sustained-release metoprolol, nebivolol Agents specifically indicated for glaucoma o Betaxolol, carteolol, levobunolol, metipranolol, timolol Agents specifically indicated for myocardial infarction o Atenolol, metoprolol, propranolol Agents specifically indicated for migraine prophylaxis o Timolol, propranolol

Propranolol is the only agent indicated for control of tremor, portal hypertension and esophageal variceal bleeding, and used in conjunction with -blocker therapy in phaeochromocytoma

Neuromuscular-blocking drugs Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine (ACh) synthesis or release, or by acting postsynaptically at the acetylcholine receptor. While there are drugs that act presynaptically (such as botulin toxin and tetrodotoxin), the clinically-relevant drugs work postsynaptically. Clinically, neuromuscular block is used as an adjunct to anesthesia to induce paralysis, so that surgery, especially intra-abdominal and intra-thoracic surgeries, can be carried out with fewer complications. Because neuromuscular block may paralyze muscles required for breathing, mechanical ventilation should be available to maintain adequate respiration.

Classification These drugs fall into two groups: Non-depolarizing blocking agents: These agents constitute the majority of the clinicallyrelevant neuromuscular blockers. They act by blocking the binding of ACh to its receptors, and in some cases, they also directly block the ionotropic activity of the ACh receptors Depolarizing blocking agents: These agents act by depolarizing the plasma membrane of the skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistant to further stimulation by ACh.

Non-depolarizing blocking agents All of these agents act as competitive antagonists against acetylcholine at the site of postsynaptic acetylcholine receptors. Tubocurarine, found in curare of the South American plant genus Strychnos, is the prototypical non-depolarizing neuromuscular blocker. It has a slow onset (>5 min) and a long duration of action (1-2 hours). Side effects include hypotension, which is partially explained by its effect of increasing histamine release, a vasodilator,as well as its effect of blocking autonomic ganglia. It is excreted in the urine. This drug needs to block about 70-80% of the Ach receptors for neuromuscular conduction to fail, and hence, for effective blockade to occur. At this stage, end-plate potentials (EPPs) can still be detected, but are too small the reach the threshold potential needed for activation of muscle fiber contraction.

Depolarizing blocking agents Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine. However, these agents are more resistant to degradation by acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers. This differs from acetylcholine, which is rapidly degraded and only transiently depolarizes the muscle. There are two phases to the depolarizing block. During phase I ( depolarizing phase), they cause muscular fasciculations (muscle twitches) while they are depolarizing the muscle fibers. Eventually, after sufficient depolarization has occurred, phase II ( desensitizing phase) sets in and the muscle is no longer responsive to acetylcholine released by the motoneurons. At this point, full neuromuscular block has been achieved. The prototypical depolarizing blocking drug is succinylcholine (suxamethonium). It is the only such drug used clinically. It has a rapid onset (30 seconds) but very short duration of action (5-10 minutes) because of hydrolysis by various cholinesterases. Succinylcholine was originally known as diacetylcholine because structurally it is composed of two

acetylcholine molecules joined with a methyl group. Decamethonium is sometimes, but rarely, used in clinical practice.

Comparison of drugs The main difference is in the reversal of these two types of neuromuscular-blocking drugs.

Non-depolarizing blockers are reversed by acetylcholinesterase inhibitor drugs. Since they are competitive antagonists at the ACh receptor so can be reversed by increases in ACh. The depolarizing blockers already have ACh-like actions, so these agents will have prolonged effect under the influence of acetylcholinesterase inhibitors. The administration of depolarizing blockers will initially exhibit fasciculations (a sudden twitch just before paralysis occurs). This is due to the depolarization of the muscle. Also, post-operative pain is associated with depolarizing blockers.

The tetanic fade is the failure of muscles to maintain a fused tetany at sufficiently-high frequencies of electrical stimulation.

Non-depolarizing blockers will have this effect on patients. Depolarizing blockers will not.

Adverse effects Since these drugs may cause paralysis of the diaphragm, mechanical ventilation should be at hand to provide respiration. Additionally, these drugs may exhibit cardiovascular effects, since they are not fully selective for the nicotinic receptor and hence may have effects on muscarinic receptors.If nicotonic receptors of the autonomic ganglia or adrenal medulla are blocked, these drugs may cause autonomic symptoms. Additionally, neuromuscular blockers may facilitate histamine release, which causes hypotension, flushing, and tachycardia.

potassium from muscle fibers. This puts the patient at risk for life-threatening complications, such as hyperkalemia and cardiac arrhythmias. Certain drugs such as aminoglycoside antibiotics and polymyxin and some fluoroquinolones
In depolarizing the musculature, suxamethonium may trigger a transient release of large amounts of

nglionic Transmission

imary Pathway Most autonomic ganglions (Para and Sym) work in the following way. The pre-ganglionic nerve terminal relea ACh which activates a nicotinic receptor (Rc) on the autonomic ganglia, producing a fast excitatory potential, stimulating transmission through the post-ganglionic nerve terminal.

HEXAMETHONIUM or C6 is the prototype nicotinic Rc antagonist that blocks ganglionic transmission. It does in a competitive fashion meaning that if you give a cholinesterase inhibitor, you can build up the level of ACh in the presence of hexamethonuim and override its blockade.

Secondary Pathway Found in certain ganglia such as the SA node

ACh released from a pre-ganglionic nerve ending, acts on a nicotinic Rc, produces a fast excitatory potential, is blocked by HEXAMETHONIUM, just as in the primary pathway. **But, there are also slow excitatory and slow inhibitory potentials being produced.

The slow excitatory pot. arises when ACh that is released from the pre-ganglionic terminal activates a muscari 1 (M1) Rc on the ganglia. This can be blocked be the specific M1 Rc antagonist PIRENZEPINE. PIRENZEPINE may eventually be introduced for the treatment of peptic ulcer. The slow excitatory potential ca also be blocked by the non-specific muscarinic antagonist ATROPINE, which blocks the transmission of ACh a all muscarinic Rc sites.

The slow inhibitory potential arises from the pre-ganglionic release of ACh acting on the muscarinic 2 (M2) Rc a SIF cell (small intensely fluorescent) or interneuron. There is dopamine in the interneuron which, when released, activates a dopaminergic Rc on the ganglia to produce the slow inhibitory potential. The slow inhibito potential is important because the drug METACLOPRAMIDE that blocks the inhibitory action of dopamine on t ganglia leading to activation of the post-ganglionic nerve terminal. This drug is used in the treatment of gastric atony

There is a difference between the gastric atony therapeutic drugs METACLOPRAMIDE and the muscarinic Rc agonist BETHANECHOL. BETHANECHOL stimulates intestinal motility, but also stimulates HCl secretion. For some unknown reason, METACLOPRAMIDE does not stimulate acid secretion when it stimulates intestinal motility. Therefore, METACLOPRAMIDE is a good choice for treatment of patients with peptic ulcers and with gastric atony.

Summary: To achieve complete blockade of the ganglia, you would need HEXAMETHONIUM to block the act of ACh at the nicotinic Rc and ATROPINE to block the action of ACh at the muscarinic 1 and 2 Rc.

anglionic Stimulants NICOTINE--low dose stimulant

Activates nicotinic Rc on autonomic ganglia, stimulating transmission through both parasympathetic and sympathetic ganglia. It does so only in low doses, because in high doses, it causes ganglionic blockade by desensitization of the ganglionic Rc. Because it can cause desensitization of Rcs, it is considered a very dangerous drug. For example, if the Rcs at the neuromuscular junction are desensitized, respiration will become impaired. Also, desensitization of the Rcs in the medulla oblongata impairs respiration centrally.

NICOTINE is considered a non-selective nicotinic Rc agonist because it binds a variety of nicotinic receptors. will activate nicotinic Rcs at motor end plates (causing muscle fasciculations), on the adrenal medulla (causin Epi and NE release), and in the CNS.

NICOTINES effects on a new smoker

Cardiovascular similar to a sympatho-adrenal activation (fight or flight) Initial effect - increase in BP: Increase total peripheral resistance (TPR) due to increase in sympathetic tone of arterioles Increase cardiac output (CO) due to increase in sympathetic tone in venules Increase ventricular contraction - remember only sym innervation to ventricles Remember that arterioles, venules and ventricle are only innervated by the sympathetic system Secondary effect - decrease in BP: the release of NE and Epi by the adrenal medulla the action of Epi on 2 Rcs in skeletal muscle beds, causing dilation.

Tertiary effect - increase in BP: The Epi then acts on the arteriole smooth muscle 1 Rcs, the ventricle and SA node 1 Rcs and the vein Rcs to produce constriction and, therefore, increase BP. ***HR in response to nicotine is unpredictable***

Respiration
Activates chemoreceptors to increase respiration

Stimulates the medulla oblongata centrally to increase respiration

Gastrointestinal tract
increase in GI motility and in HCl secretion Parasympathetic has dominant tone in G.I. tract

Central actions

Causes nausea and/or vomiting when acting at the chemoreceptor trigger zone (doesnt have to cross BBB to activate trigger zone) Causes release of antidiuretic hormone, causes water retention

Dangers of NICOTINE:
Ganglionic blocker at high doses cause paralysis of respiratory muscles and inhibition of the medulla oblongata, leading to respiratory distress Absorbed across skin, placenta, blood brain barrier, and gets into nursing mothers milk easily. In the case of an overdose, treatments include syrup of ipecac and activated charcoal to absorb the nicotine.

Ch

administered IV at high doses along with an AChE inhibitor can cause ganglionic stimulation at low doses, ACh has trouble getting to nicotinic receptors on autonomic ganglion but no trouble reaching the muscarinic receptors on smooth muscle.

MPP (dimethylphenylpiperazinium ion)

Only stimulates ganglionic transmission. It does NOT cause Rc desensitization, therefore, it does not cause ganglion blockade at high doses.

Specific for nicotinic Rc on autonomic ganglia and at the adrenal medulla. It does not act at the neuromuscular junct

Cardiovascular effects basically same as nicotine increase TPR increase ventricular contraction increase venous return increase blood pressure reflex bradycardia in response to elevation of blood pressure this is the difference between DMPP and NICOTINE effects parasym tone is dominant at SA node, so parasym outflow to that site is increased to achieve the reflex bradycar stimulates transmission through the vagus by increasing the release of ACh to SA node

 baroceptors sense high BP so two things happen to give the overall effect of decreased HR: 1) Increase Para activity @ SA node slowing HR, 2) Decrease Sym tone with high BP Adrenal Medulla - acts to stimulate Epi and NE release (same as NICOTINE) resulting in a slight decrease in BP wh Epi hits the skeletal muscle beds and 2 Rc, followed by and increase in BP when NE and Epi hit the 1 and 1 Rc a over the body

anglionic Blocking Drugs

cological actions will depend on which division of the autonomic nervous sys dominates in controlling an organ function.

Parasym dominates at SA node therefore use of a ganglionic blocker will lead to tachycardia by removing the inhibit tone. Magnitude of response to the drug will depend on tone at the time of administration Giving a standing person a ganglionic blocker will cause them to faint because you are blocking the dominating sympathetic innervation to the veins that return blood to the heart. Giving a reclined person the same drug will have a much smaller effect because the sym innervation on the veins is much less in a reclined individual.

Blockers abolish autonomic reflexes, impairing ones ability to maintain homeostasis (cant sweat, salivate, or mainta BP). For example, because parasym innervation dominates in pupil constriction, taking a ganglionic blocker will bloc parasympathetics causing pupils not to constrict in bright sunlight.

ominating systems
TPR arteriolar smooth muscle Venous return cardiac output Ventricular Sweat glands

mpathetic

Parasympathetic

SA node dominating parasym innervation, when blocked, usually causes tachycardia, but it can sometimes cause bradycardia. Bradycardia results when an individual has an elevated heart rate at the time the ganglionic blocker is given. This occurs because at elevated heart rates, the sym tone is greater than the parasym tone; therefore, the ganglionic blocker blocks the dominating sym tone, resulting in a decrease in heart rate. Pupil size ganglionic blocker causes mydriasis Accomodation blocker causes the individual to only be able to see objects that are distant GI motility and HCl secretion a blocker will decrease HCl secretion and slow GI motility PROPANTHELINE and METHANTHELINE (both anti-muscarinic drugs) are ganglionic blockers with ATROPINE-like action and are used in the treatment of peptic ulcer (not too useful because histamine is th

 oth Para & Sym in sexual function. Ganglionic blocker will cause impotence because para=erection and sym=ejaculation

major cause of HCl release, and drugs that specifically block the H 2 histamine Rc are now available fewe unwanted side effects) Bladder function ganglionic blocker causes urinary retention Salivation blocker causes dry mouth

cal uses of ganglionic blockers because of side-effects, their use is extremely limited

acute dissecting aortic aneurysm to decrease blood pressure and to decrease blood flow to the site of the tear by blocking sympathetics hypertensive crises advantageous to block autonomic reflexes

Specific ganglionic blockers

HEXAMETHONIUM C6 1)positively charged 2)long duration of action 3) not well-absorbed therefore wont cross blood brain barrier so it will not cause central side-effects 4) rarely used today MECAMYLAMINE 1) long duration 2) differs from HEXAMETHONIUM in that it is not charged so it is absorbed better, but it will cross the blood brain barrier and cause central side effects TRIMETHAPHAN 1) positively charged 2) used more than the other two blockers because short duration of action 3) must be given IV (orally inactivates) 4) lowers blood pressure by causing ganglionic blockade and by releasing histamine which causes vasodilation 5) someone with asthma will not want TRIMETHAPHAN because it will aggrevate the condition so HEXAMETHONIUM would be better choice.

e effects
Constipation Orthostatic hypotension Tachycardia

Photophobia Blurred vision Impotence Dry mouth Increased body temp. cant sweat when hot Delay gastric emptying important if taking another drug simultaneously that must get into the duodenum to be absorbed. The drug that must be absorbed in the duodenum would have delayed action since it is stuck in the stomach and may also build up to toxic level in the stomach. Tolerance develops when treating hypertension. The blockers withdraw sym stim to the arterioles so less NE is released onto the 1 Rc of arterioles. This causes the Rcs to increase in number to compensate for the decrease NE. As the number increases, the drug loses its effectiveness. Tolerance also may develop because the slow excitatory Rc M1 may take over transmission as the fast excitator pot is being blocked.