Therapeutic Classification of Adrenergic Drugs

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Chapter: Essential pharmacology : Adrenergic System and Drugs

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


THERAPEUTIC CLASSIFICATION OF ADRENERGIC DRUGS

 

    1. Pressor agents

 

Noradrenaline        Phenylephrine

Ephedrine              Methoxamine

Dopamine             Mephentermine

 

      2. Cardiac stimulants

 

Adrenaline

Dobutamine

Isoprenaline

 

        3. Bronchodilators

 

Isoprenaline       Salmeterol

Salbutamol          Formoterol

(Albuterol)           Bambuterol

 

Terbutaline

 

   4.  Nasal decongestants

 

Phenylephrine, Naphazoline, Xylometazoline, Pseudoephedrine

Oxymetazoline,         Phenyl propanolamine

 

      5. CNS stimulants

 

Amphetamine

Methamphetamine

Dexamphetamine

 

   6. Anorectics

 

Fenfluramine, Sibutramine, Dexfenfluramine

 

    7. Uterine relaxant and vasodilators

 

Ritodrine        Salbutamol

Isoxsuprine    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 g.f.r. 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 bloodbrain 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.

 

Dobutamine

 

A derivative of DA, but not a D1 or D2 receptor agonist. Though it acts on both α and β adrenergic receptors, the only prominent action of clinically employed doses (2–8 μg/kg/ min i.v. infusion) is increased force of cardiac contraction and output, without significant change in heart rate, peripheral resistance and BP. As such, it has been considered to be a relatively selective β1 agonist. It is used as an inotropic agent in pump failure accompanying myocardial infarction, cardiac surgery, and for short term management of severe congestive heart failure. It is less arrhythmogenic than Adr.

 

CRDIJECT 50 mg/4 ml and 250 mg per 20 ml amp, DOBUTREX, DOBUSTAT 250 mg vial.

 

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 shortlived and may be accompanied by anxiety, restlessness, tremor, dysphoria and agitation. Such use before examinations can only be condemned.

 

Amphetamines stimulate respiratory centre, specially 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 anti-motion 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 behavioural 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 5HT release. It also inhibits neuronal uptake of DA.

 

Amphetamine: 5–15 mg oral;    BENZEDRINE 5 mg tab.

Dexamphetamine:  5–10  mg  (children  2.5–5  mg)  oral;

DEXEDRINE 5 mg tab.

Methamphetamine: 5–10 mg oral: METHEDRINE 5 mg tab.

 

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 nephazoline 0.025% nasal drops, DROSYN 10% eye drops, in DROSYNT, 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. Occasionally used as a pressor agent.

Dose: 10–20 mg i.m.; 3–5 mg slow i.v. inj.

 

VASOXINE 20 mg/ml inj.

 

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 bloodbrain 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.

Dose: 10–20 mg oral/i.m., also by slow i.v. infusion. MEPHENTINE 10 mg tab, 15 mg in 1 ml amp, 3 mg/ml in 10 ml vial.

 

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:

As uterine relaxant to delay premature labour. Ritodrine is the preferred drug;

         

        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 dysmenorrhoea, but efficacy is poor. Beneficial effects in peripheral and cerebral vascular diseases are disappointing.

Side effects: nausea, tachycardia, flushing, hypotension, dizziness, tremor.

Dose: 5–10 mg oral, i.m. 4–6 hourly, DUVADILAN 10 mg tab, 40 mg SR cap, 10 mg/2 ml inj.

 

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.

 

Xylometazoline: 0.05–0.1% topical in nose; OTRIVIN 0.05% (pediatric), 0.1% nasal drops.

 

Oxymetazoline: 0.025–0.05% topical in nose; NASIVION, SINAREST 0.025% (pediatric), 0.05% nasal drops. Naphazoline: 0.1% topical in nose; PRIVINE 0.1% nasal drops.

 

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.

 

Dose: 30–60 mg TDS.

 

SUDAFED 60 mg tab, 30 mg/5 ml syrup; in SINAREST 60 mg with chlorpheniramine 2 mg + caffeine 30 mg + paracetamol 500 mg tab; in CHESTON 30 mg with chlorpheniramine 2 mg + bromhexine 4 mg per tab/5 ml syr; in ACTICOLD 60 mg with chlorpheniramine 4 mg + paracetamol 500 mg tab; in CODYLEX 60 mg with chlorpheniramine 4 mg + ibuprofen 400 mg tab.

 

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 haemorrhagic stroke among women appeared in the USA. A case control study “Haemorrhagic 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;

 

In ACTIFED 25 mg with triprolidine 2.5 mg tab; in ESKOLD 50 mg with diphenylpyraline 5 mg spansule; in FLUCOLD 25 mg with chlorpheniramine 2 mg + paracetamol 500 mg tab.

 

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 5HT, enhancing monoaminergic transmission in the brain. Accordingly they may be grouped into:

 

Noradrenergic agents: Phentermine, phenylpropanolamine (PPA), diethylpropion, mazindol.

 

Serotonergic agents: Fenfluramine, dexfenfluramine.

 

Noradrenergic/serotonergic agent:     Sibutramine.

 

 

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).

 

Fenfluramine and dexfenfluramine reduce food seeking behaviour by enhancing serotonergic transmission in the hypothalamus. However, tolerance to the anorectic action develops in 2–3 months. They have tranquillising rather than stimulant property, and were extensively used by slimming centres.

 

In the late 1990s ecocardiographic abnormalities, valvular defects, pulmonary hypertension and sudden deaths were related to the use of a combined preparation of fenfluramine + phentermine. Similar valvular lesions are known to occur in carcinoid. The USFDA recommended discontinuation of fenfluramine, dexfenfluramine and their combinations. These are now banned in India and most other countries.

 

Sibutramine

 

This recently introduced antiobesity drug inhibits the reuptake of both NA as well as 5HT, 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 longterm morbidity and mortality.

 

Dose: Start with 10 mg OD, increase to 15 mg OD if tolerated. OBESTAT, SIBUTREX 5 mg, 10 mg caps.

 

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