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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