Adrenergic System and Drugs

Chapter 9

Adrenergic System and Drugs 

ADRENERGIC TRANSMISSION

• Adrenergic (more precisely ‘Noradrenergic’) transmission is restricted to the sympathetic division of the ANS. There are three closely related endogenous catecholamines (CAs). 

• Noradrenaline (NA) It acts as transmitter at postganglionic sympathetic sites (except sweat glands, hair follicles and some vasodilator fibres) and in certain areas of brain. 

• Adrenaline (Adr) It is secreted by adrenal medulla and may have a transmitter role in the brain

• . Dopamine (DA) It is a major transmitter in basal ganglia, limbic system, CTZ, anterior pituitary, etc. and in a limited manner in the periphery.

Synthesis of CAs

• Catecholamines are synthesized from the amino acid phenylalanine as depicted. Tyrosine hydroxylase is the rate limiting enzyme and its inhibition by αmethyl-p-tyrosine results in depletion of CAs; this can be used in pheochromocytoma before surgery and in inoperable cases. All enzymes of CA synthesis are rather nonspecific and can act on closely related substrates, e.g., dopa decarboxylase can from 5-HT from 5-hydroxytryptophan and α methyl DA from α methyl dopa. Synthesis of NA occurs in all adrenergic neurons, while that of Adr occurs only in the adrenal medullary cells. It probably requires high concentration of glucocorticoids reaching through intrarenal portal circulation for induction of the methylating enzyme.

Storage of CAs 

• NA is stored in synaptic vesicles or ‘granules’ within the adrenergic nerve terminal. The vesicular membrane actively takes up DA from the cytoplasm and the final step of synthesis of NA takes place inside the vesicle which contains dopamine βhydroxylase. NA is then stored as a complex with ATP which is adsorbed on a protein chromogranin. In the adrenal medulla the NA thus formed within the chromaffin granules diffuses out into the cytoplasm, is methylated and Adr so formed is again taken up by a separate set of granules. The cytoplasmic pool of CAs is kept low by the enzyme monoamine oxidase (MAO) present on the outer surface of mitochondria

Release of CAs 

• The nerve impulse coupled release of CA takes place by exocytosis and all the vesicular contents (NA or Adr, ATP, dopamine β hydroxylase, chromogranin) are poured out. In case of vesicles which in addition contain peptides like enkephalin or neuropeptide Y (NPY), these cotransmitters are simultaneously released. The release is modulated by presynaptic receptors, of which α2 inhibitory control is dominant.

• The auto receptors of other cotransmitters (Y2 of NPY and P1 of ATP) also inhibit transmitter release. In addition, numerous heteroreceptors are expressed on the adrenergic neurone which either inhibit (dopaminergic, serotonergic, muscarinic and PGE2) or enhance (β2 adrenergic, angiotensin AT1 and nicotinic) NA release.

• Indirectly acting sympathomimetic amines (tyramine, etc.) also induce release of NA, but they do so by displacing NA from the nerve ending binding sites and by exchange diffusion utilizing norepinephrine transporter (NET) the carrier of uptake-1 (see below). This process is not exocytotic and does not require Ca2

Uptake of CAs 

• There is a very efficient mechanism by which NA released from the nerve terminal is recaptured. This occurs in 2 steps—

• Axonal uptake An active amine pump (NET) is present at the neuronal membrane which transports NA by a Na+ coupled mechanism. It takes up NA at a higher rate than Adr and had been labelled uptake 1. The indirectly acting sympathomimetic amines like tyramine, but not isoprenaline, also utilize this pump for entering the neurone. This uptake is the most important mechanism for terminating the postjunctional action of NA. This pump is inhibited by cocaine, desipramine and few other drugs.
• Vesicular uptake the membrane of intracellular vesicles has another amine pump the ‘vesicular monoamine transporter’ (VMAT-2), which transports CA from the cytoplasm to within the storage vesicle. The VMAT-2 transports monoamines by exchanging with H+ ions. The vesicular NA is constantly leaking out into the axoplasm and is recaptured by this mechanism. This carrier also takes up DA formed in the axoplasm for further synthesis to NA. Thus, it is very important in maintaining the NA content of the neurone. This uptake is inhibited by reserpine, resulting in depletion of CAs
• Extraneuronal uptake of CAs (uptake 2) is carried out by extra neuronal amine transporter (ENT or OCT3) and other organic cation transporters OCT1 and OCT2 into cells of other tissues. In contrast to NET this uptake transports Adr at a higher rate than NA, is not Na+ dependent and is not inhibited by cocaine but inhibited by corticosterone. It is not of physiological or pharmacological importance.

Metabolism of CAs 

• The pathways of metabolism of CAs are depicted. Part of the NA leaking out from granules into cytoplasm as well as that taken up by axonal transport is first attacked by MAO, while that which diffuses into circulation is first acted upon by catechol-omethyl transferase (COMT) in liver and other tissues. In both cases, the alternative enzyme can subsequently act to produce vanillylmandelic acid (VMA). The major metabolites excreted in urine are VMA and 3-methoxy-4-hydroxy phenylethylene glycol (a reduced product) along with some metanephrine, normetanephrine and 3,4 dihydroxy mandelic acid. These metabolites

• are mostly conjugated with glucuronic acid or sulfate before excretion in urine. Only 25–50 μg of NA and 2–5 μg of Adr are excreted in the free form in 24 hours. However, metabolism does not play an important role in terminating the action of neuronally released CAs.

Adrenergic receptors 

• Adrenergic receptors are membrane bound G-protein coupled receptors which function primarily by increasing or decreasing the intracellular production of second messengers cAMP or IP3/DAG. In some cases, the activated G-protein itself operates K+ or Ca2+ channels or increases prostaglandin production.

• Ahlquist (1948), on the basis of two distinct rank order of potencies of adrenergic agonists, classified adrenergic receptors into two types α and β. This classification was confirmed later by the discovery of selective α and β adrenergic antagonists. Important features of α and β receptors.

• On the basis of relative organ specificity of selective agonists and antagonists the β receptors were further subdivided into β1 and β2 subtypes. Later, β3 (atypical β) receptors were described which have very low affinity for the standard β blockers. These are located on adipocytes, mediate lipolysis and induce thermogenesis. Selective β3 agonists are being developed as potential antiobesity drugs.

• In the mid 1970s the α receptors were demonstrated to be present prejunctionally as well. To differentiate these release inhibitory prejunctional α receptors, a subdivision into α1 and α2 was suggested. However, the present classification into α1 and α2 is based on pharmacological criteria (selectivity of agonists and antagonists) and not on anatomical location. Molecular cloning has further identified 3 subtypes of α1 

• Though tissue distribution of subtypes of α1 and α2 receptors has been mapped, it is not very clear cut. Sufficiently subtype selective agonists or antagonists have also not yet been developed to pharmacologically exploit the molecular heterogeneity of α1 and α2 receptors.

ADRENERGIC DRUGS (Sympathomimetics)

These are drugs with actions similar to that of Adr or of sympathetic stimulation.

Direct sympathomimetics 

• They act directly as agonists on α and/or β adrenoceptors —Adr, NA, isoprenaline (Iso), phenylephrine, methoxamine, xylometazoline, salbutamol and many others

Indirect sympathomimetics 

• They act on adrenergic neurone to release NA, which then acts on the adrenoceptors—tyramine, amphetamine

Mixed action sympathomimetics 

• They act directly as well as indirectly—ephedrine, dopamine, mephentermine

ACTIONS

• The peripheral actions of Adr in most tissues have been clearly differentiated into those mediated by α or β receptors depending on the predominant receptor type present in a given tissue. These are tabulated. The receptor subtype, wherever defined, has been mentioned in parenthesis. The actions of a particular sympathomimetic amine depend on its relative activity at different types of adrenergic receptors.

Heart 

• Adr increases heart rate by increasing the slope of slow diastolic depolarization of cells in the SA node. It also activates latent pacemakers in A-V node and Purkinje fibres; arrhythmias can occur with high doses that raise BP markedly. Raised BP reflexly depresses the SA node and unmasks the latent pacemakers. Certain anesthetics (chloroform, halothane) sensitize the heart to arrhythmic action of Adr. Idioventricular rate is increased in patients with complete heart block.

• Force of cardiac contraction is increased. Development of tension as well as relaxation are accelerated. Thus, systole is shortened more than diastole. Cardiac output and oxygen consumption of the heart are markedly enhanced.

• Conduction velocity through A-V node, bundle of His, atrial and ventricular fibres is increased; partial A-V block may be overcome. Refractory period (RP) of all types of cardiac cells is reduced. All cardiac actions are predominantly β1 receptor mediated.

• When BP rises markedly, reflex bradycardia occurs due to stimulation of vagus— this is the usual response seen when NA is injected

 Blood vessels 

• Both vasoconstriction (α) and vasodilatation (β2) can occur depending on the drug, its dose and vascular bed. Constriction predominates in cutaneous, mucous membrane and renal beds. Vasoconstriction occurs through both α1 and α2 receptors. However, location of α2 (extrajunctional) receptors is such that they are activated only by circulating CAs, whereas α1 (junctional) receptors primarily mediate responses to neuronally released NA. Dilatation predominates in skeletal muscles, liver and coronaries. The direct effect on cerebral vessels is not prominent— blood flow through this bed parallels change in BP. Action is most marked on arterioles; larger arteries and veins are affected at higher doses.

BP 

• The effect depends on the amine, its dose and rate of administration

1. NA causes rise in systolic, diastolic and mean BP; it does not cause vasodilatation (no β2 action), peripheral resistance increases consistently due to α action. 
2. Isoprenaline causes rise in systolic but marked fall in diastolic BP (β1—cardiac stimulation, β2— vasodilatation). The mean BP generally falls.
3. Adr given by slow i.v. infusion or s.c. injection causes rise in systolic but fall in diastolic BP; peripheral resistance decreases because vascular β2 receptors are more sensitive than α receptors. Mean BP generally rises. Pulse pressure is increased.
4. Rapid i.e., injection of Adr (in animals) produces a marked increase in both systolic as well as diastolic BP (at high concentration α response predominates and vasoconstriction occurs even in skeletal muscles). The BP returns to normal within a few minutes and a secondary fall in mean BP follows. The mechanism is—rapid uptake and dissipation → concentration of Adr is reduced → low concentrations are not able to act on α receptors but continue to act on β2 receptors. When an α blocker has been given, only fall in BP is seen—vasomotor reversal of Dale

Respiration 

• Adr and isoprenaline, but not NA are potent bronchodilators (β2). This action is more marked when the bronchi are constricted. Adr given by aerosol additionally decongests bronchial mucosa by α action. Adr can directly stimulate respiratory centre (RC) but this action is seldom manifest at clinically used doses. Rapid i.v. injection (in animals) causes transient apnoea due to reflex inhibition of RC. Toxic doses of Adr cause pulmonary edema by shifting blood from systemic to pulmonary circuit.

Eye 

• Mydriasis occurs due to contraction of radial muscles of iris (α1), but this is minimal after topical application, because Adr penetrates cornea poorly. The intraocular tension tends to fall, especially in wide angle glaucoma

GIT 

• In isolated preparations of gut, relaxation occurs through activation of both α and β receptors. In intact animals and man peristalsis is reduced and sphincters are constricted, but the effects are brief and of no clinical import.

Bladder 

• Detrusor is relaxed (β) and trigone is constricted (α): both actions tend to hinder micturition

Uterus 

• Adr can both contract and relax uterine muscle, respectively through α and β receptors. The overall effect varies with species, hormonal and gestational status.

Splenic capsule 

• Contracts (α) and more RBCs are poured in circulation. This action is not evident in man

Skeletal muscle 

• Neuromuscular transmission is facilitated. In contrast to action on autonomic nerve endings, α receptor activation on motor nerve endings augments ACh release, probably because it is of the α1 subtype. The direct effect on muscle fibres is exerted through β2 receptors and differs according to the type of fibre. The active state is abbreviated, and less tension is developed in the slow contracting red fibres— incomplete fusion of individual responses. This along with enhanced firing of muscle spindles is responsible for the tremors produced by β2 agonists. The action on rapidly contracting white fibres is to prolong the active state and increase the tension developed.

CNS 

• Adr, in clinically used doses, does not produce any marked CNS effects because of poor penetration in brain, but restlessness, apprehension and tremor may occur. Activation of α2 receptors in the brainstem results in decreased sympathetic outflow → fall in BP and bradycardia.

Metabolic 

• Adr produces glycogenolysis → hyperglycaemia, hyperlactacidaemia (β2); lipolysis →rise in plasma free fatty acid (FFA), callogenesis (β2 + β3) and transient hyperkalemia followed by hypokalaemia due to direct action on liver, muscle and adipose tissue cells. In addition, metabolic effects result from reduction of insulin (α2) and augmentation of glucagon (β2) secretion.

Biochemical mediation of adrenergic responses

β actions 

• The β actions are mediated through cAMP (see Fig. 4.6). Adr activates membrane bound enzyme adenylyl cyclase through a regulatory protein Gs → ATP is broken down to cAMP at the inner face. This in turn phosphorylates a number of intracellular cAMP-dependent protein kinases and initiates a series of reactions:

• In liver and muscle, glycogen phosphorylase is activated causing glycogenolysis while glycogen synthetase is inhibited. Both actions result in hyperglycaemia and hyperlactacidemia. Neoglucogenesis in liver adds to the response.

•  In adipose tissue, triglyceride lipase is activated → increased plasma free fatty acids. Increased O2 consumption and heat production result primarily by action on brown adipose tissue, which has predominant β3 receptors.

• In heart, proteins like troponin and phospholamban are phosphorylated. The former results in increased interaction with Ca2+ at the myofilaments → increased force of contraction; the latter causes sequestration of Ca2+ by sarcoplasmic reticulum → more rapid relaxation. The activated protein Gs, in addition, interacts directly with the Ca2+ channels in the membrane promoting influx of Ca2+ which reinforces the positive inotropic action exerted through cAMP.

• In the gut and bronchial muscle, relaxation (accompanied with hyperpolarization) is induced, but the intermediate steps have not been clearly delineated.

• In pancreatic islets activation of β2 receptors on α cells increases glucagon secretion, and that on β cells increases insulin secretion, both by raising intracellular cAMP. However, augmentation of insulin secretion is weak.

α actions 

• The mediation of α actions is varied and less well defined.

• In smooth muscles (including vascular) that are contracted through α1 receptors, the activated G-protein increases IP3/DAG production → mobilization of Ca2+ from intracellular organelle → activation of calmodulin dependent myosin light chain kinase → phosphorylation.
• The prejunctional α2 receptor appears to inhibit neuronal Ca2+ channels and also limit the intracellular availability of Ca2+ by decreasing cAMP production. Transmitter (NA) release is consequently diminished. Hyperpolarization through activation of K+ channels may also occur.
• In the gut, α2 receptor activation hyperpolarizes the cholinergic neurone → decreased release of ACh → reduced tone; whereas α1 receptors located directly on the smooth muscle cell increase K+ efflux → hyperpolarization → relaxation.
• n pancreatic β cells, stimulation of α2 receptors reduces the formation of cAMP → decreased insulin release.

THERAPEUTIC CLASSIFICATION OF ADRENERGIC DRUGS

Pressor agents

1. Noradrenaline 
2. Phenylephrine 
3. Ephedrine 
4. Methoxamine 
5. Dopamine 
6. Mephentermine

Cardiac stimulants

1. Adrenaline 
2. Dobutamine 
3. Isoprenaline

Bronchodilators

1. Isoprenaline 
2. Salmeterol 
3. Salbutamol 
4. Formoterol (Albuterol) 
5. Bambuterol Terbutaline

Nasal decongestants

1. Phenylephrine 
2. Naphazoline 
3. Xylometazoline 
4. Pseudoephedrine 
5. Oxymetazoline 
6. Phenyl propanolamine

CNS stimulants

1. Amphetamine 
2. Methamphetamine 
3. Dexamphetamine

Anorectics

1. Fenfluramine 
2. Sibutramine 
3. Dexfenfluramine

Uterine relaxant and vasodilators

1. Ritodrine 
2. Salbutamol 
3. Isoxsuprine 
4. Terbutaline

• Salient features of important adrenergic drugs are described below.

Dopamine (DA) 

• It is a dopamine (D1 and D2) as well as adrenergic α and β1 (but not β2) agonist. The D1 receptors in renal and mesenteric blood vessels are the most sensitive: i.v. infusion of low dose of DA dilates these vessels (by raising intracellular cAMP). This increases and Na+ excretion. Moderately high doses produce a positive inotropic (direct β1 and D1 action + that due to NA release), but little chronotropic effect on heart. Vasoconstriction (α1 action) occurs only when large doses are infused. At doses normally employed, it raises cardiac output and systolic BP with little effect on diastolic BP. It has practically no effect on nonvascular α and β receptors; does not penetrate blood-brain barrier—no CNS effects.

• Dopamine is used in patients of cardiogenic or septic shock and severe CHF wherein it increases BP and urine outflow. It is administered by i.v. infusion (0.2–1 mg/min) which is regulated by monitoring BP and rate of urine formation.

• DOPAMINE, INTROPIN, DOPACARD 200 mg in 5 ml amp.

Ephedrine 

• It is an alkaloid obtained from Ephedra vulgaris. Mainly acts indirectly but has some direct action on α and β receptors also. Repeated injections produce tachyphylaxis, primarily because the neuronal pool of NA available for displacement is small. It is resistant to MAO, therefore, effective orally. It is about 100 times less potent than Adr, but longer acting (4–6 hours). Ephedrine crosses to brain and causes stimulation, but central: peripheral activity ratio is lower than that of amphetamine.

• Ephedrine can be used for a variety of purposes, but it lacks selectivity, and efficacy is low. Use is now restricted to that in mild chronic bronchial asthma and for hypotension during spinal anaesthesia; occasionally for postural hypotension; 15–60 mg TDS.

• EPHEDRINE HCl 15, 30 mg tab; SULFIDRIN 50 mg in 1 ml inj, in ENDRINE 0.75% nasal drops.

Amphetamines 

• These are synthetic compounds having a pharmacological profile similar to ephedrine; orally active with long duration (4–6 hours). The CNS actions are more prominent; maximal selectivity is exhibited by dextroamphetamine and methamphetamine, which in the usual doses produce few peripheral effects. The central effects include alertness, increased concentration and attention span, euphoria, talkativeness, increased work capacity. Fatigue is allayed. Athletic performance is improved temporarily followed by deterioration. It is one of the drugs included in the ‘dope test’ for athletes. The reticular activating system is stimulated resulting in wakefulness and postponement of sleep deprivation induced physical disability. But this is short-lived and may be accompanied by anxiety, restlessness, tremor, dysphoria and agitation. Such use before examinations can only be condemned.

• Amphetamines stimulate respiratory centre, especially if it has been depressed. Hunger is suppressed as a result of inhibition of hypothalamic feeding centre. They also have weak anticonvulsant, analgesic and antiemetic actions: potentiate antiepileptics, analgesics and antimotion-sickness drugs. Peripheral effects on heart and BP are not significant at the usual doses (which cause only slight rise in BP), but tone of vesical sphincter is definitely increased.

• Amphetamines are drugs of abuse and are capable of producing marked psychological but little or no physical dependence. Amphetamine abusers are generally teenagers seeking thrill or kick which is obtained on rapid i.v. injection. High doses produce euphoria, marked excitement which may progress to mental confusion, delirium, hallucinations and an acute psychotic state. Peripheral component of toxicity includes vasomotor effects, palpitation, arrhythmias, vomiting, abdominal cramps and vascular collapse. Death is usually preceded by convulsions and coma.

• Repeated use is more likely to produce long lasting behavioral abnormalities; psychosis may be precipitated.

• Tolerance to central actions and toxic effects of amphetamine develops and is both pharmacokinetic as well as pharmacodynamic. Starvation due to suppression of appetite produces acidic urine; amphetamine is ionized more at acidic pH and is excreted more rapidly.

• Treatment of amphetamine toxicity includes administration of chlorpromazine which controls both central as well as peripheral α adrenergic effects. The central actions are largely mediated by release of NA in the brain. However, certain actions are probably due to DA and 5-HT release. It also inhibits neuronal uptake of DA.

Phenylephrine 

• It is a selective α1 agonist, has negligible β action. It raises BP by causing vasoconstriction. Because it has little cardiac action, reflex bradycardia is prominent. Topically it is used as a nasal decongestant and for producing mydriasis when cycloplegia is not required. Phenylephrine tends to reduce intraocular tension by constricting ciliary body blood vessels. It is also a frequent constituent of orally administered nasal decongestant preparations. Central effects are not seen with usual clinical doses.

• Dose: 2–5 mg i.m., 0.1–0.5 mg slow i.v. inj, 30–60 μg/min i.v. infusion; 5–10 mg oral; 0.25–0.5% nasal instillation; 5–10% topically in eye;

• FRENIN 10 mg in 1 ml inj; DECOLD PLUS 5 mg with paracetamol 400 mg + chlorpheniramine 2 mg + caffeine 15 mg tab., FENOX 0.25% with naphazoline 0.025% nasal drops, DROSYN 10% eye drops, in DROSYN-T, TROPACP 5% with tropicamide 0.8% eye drops.

Methoxamine 

• Another selective α1 agonist with no β actions (has weak β blocking action). Resembles phenylephrine very closely.

Mephentermine 

• It produces both cardiac stimulation and vasoconstriction by directly activating α and β adrenergic receptors as well as by releasing NA. Cardiac output, systolic and diastolic BP are increased. The direct positive chronotropic effect on heart is generally counter balanced by vagal stimulation due to rise in mean BP.

• Mephentermine is not a substrate for either MAO or COMT: active orally with longer duration of action (2–6 hr). It crosses blood-brain barrier to some extent—may produce excitatory effects at higher doses. It is used to prevent and treat hypotension due to spinal anaesthesia and surgical procedures, shock in myocardial infarction and other hypotensive states.

SELECTIVE β2 STIMULANTS

• These include, salbutamol, terbutaline, salmeterol, formoterol and ritodrine. They cause bronchodilatation, vasodilatation and uterine relaxation, without producing significant cardiac stimulation. β2 selectivity is only relative. Salbutamol has β2:β1 action ratio of about 10. They are primarily used in bronchial asthma. Other uses are:

1. As uterine relaxant to delay premature labour. Ritodrine is the preferred drug (see p. 323)
2. In hyperkalaemic familial periodic paralysis— β2 agonists benefit by enhancing K+ uptake into muscles → lowering plasma K+ levels.

• The most important side effect is muscle tremor; tachycardia and arrhythmias are less likely

Isoxsuprine 

• It is an orally effective long-acting selective β receptor stimulant which has direct smooth muscle relaxant property as well. It has been used as uterine relaxant for threatened abortion and dysmenorrhea, but efficacy is poor. Beneficial effects in peripheral and cerebral vascular diseases are disappointing. Side effects: nausea, tachycardia, flushing, hypotension, dizziness, tremor

NASAL DECONGESTANTS

• These are α agonists which on topical application as dilute solution (0.05–0.1%) produce local vasoconstriction. The imidazoline compounds— naphazoline, xylometazoline and oxymetazoline are relatively selective α2 agonist (like clonidine). They have a longer duration of action (12 hours) than ephedrine. After-congestion is claimed to be less than that with ephedrine or phenylephrine. They may cause initial stinging sensation (specially naphazoline). Regular use of these agents for long periods should be avoided because mucosal ciliary function is impaired: atrophic rhinitis and anosmia can occur due to persistent vasoconstriction. They can be absorbed from the nose and produce systemic effects—CNS depression and rise in BP. These drugs should be used cautiously in hypertensives and in those receiving MAO inhibitors.

Pseudophedrine 

• A stereoisomer of ephedrine; causes vasoconstriction, especially in mucosae and skin, but has fewer CNS and cardiac effect and is a poor bronchodilator (little β2 agonistic activity). It has been used orally as a decongestant of upper respiratory tract, nose and eustachian tubes. Combined with antihistaminics, mucolytics, antitussives and analgesics, it is believed to afford symptomatic relief in common cold, allergic rhinitis, blocked eustachian tubes and upper respiratory tract infections. However, no selective action on these vascular beds has been demonstrated; rise in BP can occur, especially in hypertensives.

Phenylpropanolamine (PPA) 

• Chemically and pharmacologically similar to ephedrine; causes vasoconstriction and has some amphetamine like CNS effects. It is included in a large number of oral cold/decongestant combination remedies; in USA it was used as an appetite suppressant as well. Many reports associating PPA use (for weight loss) with hemorrhagic stroke among women appeared in the USA. A case control study “Hemorrhagic Stroke Project” was undertaken, which found that though overall data showed only a marginally increased risk in men and women (whether used for weight loss or for cold), there was a strong association when 3-day exposure preceding stroke was considered. Also, there have been concerns regarding its potential to precipitate behavioral/psychiatric disturbances. The FDA concluded that indications for which PPA is used donot warrant the excess risk (though marginal) and recommended discontinuation of PPA containing products. In UK, Canada and Japan warnings have been issued and labelling changed. In India PPA containing formulations are available over the counter, but the recommended daily dose does not exceed 100 mg (which is lower than the dosage used in USA). Dose: 25–50 mg TDS. 

ANORECTIC AGENTS

• Because of adverse central effects, the use of amphetamines to suppress appetite cannot be justified. A number of related drugs have been developed which inhibit feeding centre (like amphetamine) but have little/no CNS stimulant action or abuse liability. All of them act by inhibiting the reuptake of NA/DA or 5-HT, enhancing monoaminergic transmission in the brain. Accordingly, they may be grouped into:

• The noradrenergic agents primarily affect the appetite centre, while the serotonergic ones primarily affect the satiety centre. The noradrenergic agents activate hypothalamic adrenergic/ dopaminergic receptors and have residual stimulatory effects; interfere with sleep. None is marketed in India (PPA is included only in decongestant formulations)

Sibutramine 

• This recently introduced antiobesity drug inhibits the reuptake of both NA as well as 5-HT but does not have clinically useful antidepressant property. It suppresses appetite in a manner similar to fenfluramine and appears to stimulate thermogenesis by indirectly activating β3 system in adipose tissue. It can cause loss of 3–9 kg weight, but many subjects regain the same when therapy is discontinued. Side effects include dry mouth, constipation, anxiety, insomnia, mood swings, chest pain and a mild increase in BP and HR. A number of serious adverse reaction reports including cardiovascular events and deaths have been received by the USFDA and drug committees in Europe. An ongoing study is assessing its impact on long-term morbidity and mortality.

THERAPEUTIC USES

Vascular Uses

• Hypotensive states (shock, spinal anaesthesia, hypotensive drugs) One of the pressor agents can be used along with volume replacement for neurogenic and hemorrhagic shock; also, as an expedient measure to maintain cerebral circulation for other varieties of shock. They should not be used in secondary shock when reflex vasoconstriction is already marked. Use in cardiogenic shock is tricky, because attempts to raise BP may also increase cardiac work. Slow i.v. infusion of dopamine/dobutamine is more appropriate in this situation; use of NA is practically obsolete. Adr 0.5 mg injected promptly i.m. is the drug of choice in anaphylactic shock. It not only raises BP but counteracts bronchospasm/ laryngeal edema that may accompany. Because of the rapidity and profile of action Adr is the only life saving measure. Oral ephedrine has been used to treat postural hypotension due to autonomic neuropathy (diabetes, parkinsonism, idiopathic) or advanced age. However, it is not satisfactory because it cannot mimic selective NA release that occurs only on standing. Elastic stockings and use of fludrocortisone to expand plasma volume are more helpful.

• Along with local anaesthetics Adr 1 in 200,000 to 1 in 100,000 for infiltration, nerve block and spinal anaesthesia. Duration of anaesthesia is prolonged and systemic toxicity of local anesthetic is reduced. Local bleeding is minimized.

• Control of local bleeding from skin and mucous membranes, e.g., epistaxis compresses of Adr 1 in 10,000, phenylephrine/ephedrine 1% soaked in cotton can control arteriolar and capillary bleeding. NA 8 mg in 100–200 ml saline put in stomach through a tube can control bleeding from gastric erosions and stress ulcers.

• Nasal decongestant in colds, rhinitis, sinusitis, blocked nose or eustachian tube—one of the α-agonists is used as nasal drops. Shrinkage of mucosa provides relief, but after-congestion, atrophy of mucosa on prolonged use are still a problem. The imidazolines should be used in lower concentrations in infants and young children, because they are more sensitive to central effects of these drugs. Nasal decongestants should be used very cautiously in hypertensive patients and in elderly males. Pseudoephedrine, PPA, and phenylephrine have been used orally as decongestants, but effective doses will constrict other blood vessels as well and cause rise in BP. However, they do not produce after-congestion.
• Peripheral vascular diseases like Buerger’s disease, Raynaud’s phenomena, diabetic vascular insufficiency, gangrene, frost bite, ischemic ulcers, night leg cramps, cerebral vascular inadequacy: vasodilators including isoxsuprine have been used, but are far from satisfactory in most cases, because often the capacity of the affected vessels to dilate is severely limited, and ischemia itself is a potent vasodilator.

Cardiac uses

• Cardiac arrest (drowning, electrocution, Stokes-Adams syndrome and other causes) Adr may be used to stimulate the heart; i.v. administration is justified in this setting with external cardiac massage.

• Partial or complete A-V block Isoprenaline may be used as temporary measure to maintain sufficient ventricular rate.

• Congestive heart failure (CHF) Adrenergic inotropic drugs are not useful in the routine treatment of CHF. However, controlled short term i.v. infusion of DA/dobutamine can tide over acute cardiac decompensation during myocardial infarction, cardiac surgery and in resistant CHF.

• Bronchial asthma Adrenergic drugs, especially β2 stimulants are the primary drugs for relief of reversible airway obstruction.

• Allergic disorders Adr is a physiological antagonist of histamine which is an important mediator of many acute hypersensitivity reactions. It affords quick relief in urticaria, angioedema; is lifesaving in laryngeal edema and anaphylaxis. It is ineffective in delayed, retarded and other types of allergies, because histamine is not involved.

• Mydriatic Phenylephrine is used to facilitate fundus examination; cycloplegia is not required. It tends to reduce intraocular tension in wide angle glaucoma. The ester prodrug of Adr dipivefrine is a second choice/adjuvant drug for open angle glaucoma.

 Central uses 

1. Hyperkinetic children (minimal brain dysfunction, attention deficit hyperkinetic disorder): Amphetamines have an apparently paradoxical effect to calm down hyperkinetic children. This disorder is recognized as the mildest grade of mental retardation or a reduction in the ability to concentrate, i.e., the span of time for which attention can be focused on a subject is abbreviated. Amphetamines by increasing attention span improve behavior and performance in studies; tolerance to this effect does not develop. However, growth retardation may occur due to reduction in appetite. The risk-benefit ratio of such therapy needs to be considered in individual patients.
2. Narcolepsy Narcolepsy is sleep occurring in fits and is adequately controlled by amphetamines. Development of tolerance, abuse and behavioral abnormalities are the calculated risks of such therapy. Imipramine like drugs is generally tried first.
3. Epilepsy Amphetamines are occasionally used as adjuvants and to counteract sedation caused by antiepileptics.
4. Parkinsonism Amphetamines improve mood and reduce rigidity (slightly) but do not benefit tremor. They are occasionally used as adjuvants in parkinsonism.
5. Obesity The anorectic drugs can help the obese to tolerate a reducing diet for short periods, but do not improve the long-term outlook. Their use (for 2–3 months) may be considered in severe obesity, but not for cosmetic reasons in mild to moderate obesity. In the absence of dietary restriction none of them has any significant weight reducing effect, and lifestyle modification is required to maintain weight loss. Tolerance develops to the anorectic action of all available drugs. Most subjects tend to regain weight after the slimming regimen is over. Currently, sibutramine is being used, though its long-term safety is not established.

The newer approaches being developed for control of obesity are:

• Orlistat An inhibitor of gastric and pancreatic lipase; it interferes with digestion and absorption of dietary triglycerides. Absorption of cholesterol and fat-soluble vitamins is also impaired. It has facilitated weight loss in clinical trials. Fluid motions, steatorrhoea, abdominal pain, nausea, flatulence and vitamin deficiency are the side effects.

• Olestra is a sucrose polyester which can be used as a cooking medium in place of fat but is neither digested nor absorbed. Its acceptability is inconsistent.

• Leptin (the endogenous slimming peptide) analogues, neuropeptide Y antagonists and β3 adrenergic agonists are under investigation as antiobesity drugs.

• Rimonabant A selective cannabinoid (CB-1) receptor antagonist that blocks hunger promoting action of cannabis has been found in clinical trials to decrease appetite and help weight reduction by the obese. Neusea is a side effect. Rimonabant has also been tried to help smoking cessation

Nocturnal enuresis in children and urinary incontinence 

• Amphetamine affords benefit both by its central action as well as by increasing tone of vesical sphincter.

Uterine relaxant 

• Isoxsuprine has been used in threatened abortion and dysmenorrhoea, but efficacy is doubtful. Selective β2 stimulants, specially ritodrine, infused i.v. have been successfully used to postpone labour but maternal morbidity and mortality may be increased due to their cardiac and metabolic actions and incidents of pulmonary edema

Insulin hypoglycaemia 

• Adr may be used as an expedient measure, but glucose should be given as soon as possible.