Drugs which produce effects similar to those of adrenergic nerve stimulation or injection of epinephrine are known as sympathomimetics or Adrenergic Agonists. Before considering Adrenergic Agonists drugs, an account of the physiology of adrenergic nerves would be helpful.
Biosynthesis of Adrenergic Agonists: The varicosities (terminal swollen areas) of the adrenergic neurons are the sites of synthesis of norepinephrine. Ltyrosine, an essential amino acid, is the precursor of norepinephrine. It is taken up from the extracellular fluid and oxidized to dihydroxy phenylalanine (DOPA) with the help of L-tyrosine hydroxylase enzyme. Dopa is further converted into dopamine by dopa decarboxylase enzyme. Finally, dopamine is acted upon by dopamine beta hydroxylase and transformed into norepinephrine
In the chromaffin cells of the adrenal medulla, norepinephrine, in the presence of N-methyl transferase and S-adenosylmethionin, is changed to epinephrine.
Storage of norepinephrine: Inside the nerve ending, there are two stores of norepinephrine: granular and cytoplasmic. The granular store consists of tiny granules or vesicles which are bound by distinct membranes. Within them, norepinephrine exists partly in free state and partly in combination with ATP in a ratio of 4:1. The complex with ATP is then absorbed on a specific protein called chromogranin. The uptake of norepinephrine from the cytoplasm into granules is an active process, which can be inhibited by reserpine. There is equilibrium between the granular and cytoplasmic store, and norepinephrine can pass from the former to the latter by passive diffusion.
The cytoplasmic store consists of free norepinephrine. Most of it is formed by intraneuronal biosynthesis, but some is absorbed from extracellular fluid through the axonal membrane by an active process which can be blocked by cocaine and reserpine. The size of the cytoplasmic store is probably regulated by mitochondrial monoamine oxidase (MAO).
Release of norepinephrine: When the impulse comes, there is localized depolarization of the postganglionic nerve terminal membrane. This results in an increased Ca permeability which causes fusion of storage vesicles to the inner surface of neuronal membrane and release of norepinephrine (along with ATP and neuropeptide Y) occurs by exocytosis into the synaptic cleft.
Actions on Adrenergic Agonists: On release in the synaptic cleft, norepinephrine acts on postsynaptic adrenoceptors on the effector organ or cell and produce appropriate action depending on the type of receptors activated. A part of norepinephrine, however, acts on:
a. Presynaptic alpha-2 adrenoceptors which exert a local inhibitory effect on the terminal from which it was released.
b. Presynaptic beta-2 adrenoceptors which facilitate the release of norepinephrine from the terminal.
Thus the neuronal release of norepinephrine is regulated through these presynaptic receptors according to the need of the body. Presynaptic receptors of dopamine, histamine, prostaglandins, angiotensin-Il and enkephalin are also present on the adrenergic neurons and all of them also modulate the release of noradrenaline.
Fate of norepinephrine: 75—80% of norepinephrine released into the synaptic cleft is taken up back into nerve terminal by an active process against concentration gradient for reuse (uptake 1). This process is blocked by cocaine. Some of norepinephrine is removed from circulation at extraneuronal site (uptake 2). A small portion is excreted unchanged in urine, and another small portion combines with receptors to initiate the response. The remainder part of the neurotransmitter is metabolized by two enzymes, monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT).
A portion of norepinephrine which leaks out from granules into cytoplasm as well as that taken up by axonal transport is probably first attacked by MAO within the neuron and converted into 3,4 diliydroxymendalic acid; subsequently outside the neuron, this is acted upon by COMT to form 3-methoxy 4-hydroxy mendalic acid (VMA or vaniomendalic acid). VMA is then excreted in the urine. The norepinephrine which diffuses into circulation is first converted by COMT to normetanephrine in liver and other tissues and subsequently by extraneuronal MAO to vanilomendalic acid which is excreted in urine. In case of epinephrine, it is first converted by COMT to metanephrine and subsequently to vanilomendalic acid by MAO (Fig. 21.2).
A normal individual excretes 4—8 mg of VMA and 50—100 pg of free epinephrine and norepinephrine in 24 hours. These values are considerably raised in pheochromocytoma, a tumor of the adrenal medulla.
Mechanism of Action of Adrenergic Agonists
1. Some Adrenergic Agonists act directly on the adrenergic receptors located on the effector cells and initiate a pharmacological response such as epinephrine, norepinephrine, dopamine, isoproterenol and phenylephrine.
2. Other Adrenergic Agonists act indirectly by stimulating the release of norepinephrine from nerve endings such as amphetamine, ephedrine, norepinephrine, epinephrine and tyramine. The continuous use or repeated administration of indirectly acting drugs produce progressive reduction in the response due to depletion of norepinephrine from nerve terminals. This diminished response over a period of time, is called tachyphylaxis.
All adrenoceptors are G-protein coupled receptors. These have seven transmembrane ct-helical segments and show considerable molecular heterogenicity. Alpha-i receptors are coupled to phospholipase C. They produce inositol 1, 4, 5,-triphosphate (1P3) and diacylglycerol (DAC) as second messengers and raise intracellular calcium. The alpha-2 receptors are negatively coupled to adenylcyclate cyclase. So their stimulation leads to decrease in cAMP formation. All three types of beta receptors, however, stimulate adenylate cyclase. So there occurs increase in cAMP formation.
Classification of Adrenergic Agonists
i. Non-specific alpha and beta receptors Adrenergic Agonists: Epinephrine and Norepinephrine.
2. Non-specific beta-receptors Adrenergic Agonists: Isoprenaline
3. Alpha-i Adrenergic Agonists: Phenylephrine, Oxymetazoline, Xylometazoline, Naphazoline, Phenyipropanolamine, Mephentramine, Methoxamine and Metraminol.
4. Alpha-2 Adrenergic Agonists: Clonidine, Alpha-methyldopa, Guanfacine and Caunbenz
5. Beta-i receptor Adrenergic Agonists: Dobutamine, Dopexamine and Xamoterol
6. Beta-2 receptor Adrenergic Agonists: Salbutamol, Terbutaline, Orciprenaline, Soxuprine, Ritodrine, Isoetharine, Fenoterol, Nylidrine and Salmeterol.
7. DA receptor Adrenergic Agonists: Dopaeoale.
Pharmacology of Catecholamines(Adrenergic Agonists)
The term catecholamine is derived from the structure of the molecule, which consists of catechol (3, 4 dihydroxy benzene) and ethylamine side chain. Epinephrine, norepinephrine, isoproterenol and dopamine are catecholamines.
Effect on cardiovascular system: Acting on receptors, epinephrine increases the rate and force of contraction of heart and the cardiac output. Conduction across AV node is enhanced and ventricular arrhythmias may be produced.
Both epinephrine and norepinephrine produce powerful vasoconstriction of the blood vessels of the skin and mucous membrane which contain alpha-receptors. Being pure beta-receptor agonist, isoprenaline has no effect on the vasculature of these vessels. The blood vessels in the visceral organs including kidney contain mainly alpha- receptors. So epinephrine and norepinephrine cause vasoconstriction and decrease blood flow through these organs.
Isoprenaline produces no effect or may cause a week vasodilatation in these organs where beta- receptors are present. Epinephrine has a complex action on the blood vessels of skeletal muscle which contain both alpha and beta-2 receptors. Low doses of epinephrine cause dilation of blood vessels whereas large doses will induce vasoconstriction. If large doses are used first, there occurs vasoconstriction followed by vasodilatation. The former effect is mediated by alpha-receptors and later is mediated by beta-2 receptors.
Blood pressure: On intravenous administration, blood pressure rises rapidly. Since systolic blood pressure is increased more than diastolic blood pressure, pulse pressure is also increased. As the concentration of epinephrine decreases in the blood, the mean blood pressure falls below normal before returning to control level. The increase in blood pressure is due to its direct effect on heart (positive inotropic and positive chronotropic effect) and vasoconstriction of blood vessels.
Fall in blood pressure below normal is due to vasodilatation of blood vessels which is long lasting than vasoconstrictor effect. Norepinephrine increases systolic and diastolic blood pressure and total peripheral resistance. However, cardiac output is unchanged. Norepinephrine produces compensatory vagal reflex bradycardia. The coronary blood flow is enhanced by epinephrine and norepinephrine.
Effect of this Adrenergic Agonists on respiration: On intravenous administration, epinephrine produces brief apnea followed by short lived stimulation.
Effect on smooth muscles: Acting on adrenoceptors epinephrine and isoproterenol cause potent bronchodilation. Catecholamines relax smooth muscle of the gastrointestinal tract, reduce motility and contract sphincters. However, these effects are transient when catecholamines are used clinically. The effect of epinephrine on human uterus varies depending on different stages of pregnancy. During the last month of pregnancy, epinephrine inhibits uterine tone and contraction. More specific beta-receptor stimulants like albuterol and terbutaline may be useful in delaying premature labour.
Epinephrine and norepinephrine relax detrusor muscle (beta-receptor) and contract the trigone and sphincter muscles (alpha- receptor) of the urinary bladder. This may lead to hesitancy in urination and retention of urine.
Epinephrine and to a lesser extent norepinephrine cause mydriasis (dilation of pupil).
Metabolic effects of this Adrenergic Agonists: Norepinephrine has least metabolic effects. Acting on beta-receptors, epinephrine and isoproterenol increase oxygen consumption; stimulate hepatic and skeletal muscle glycogenolysis and release free fatty acids from adipose tissue.
Effect on central nervous system: There is no significant effect on central nervous system in therapeutic doses. Restlessness, apprehension, headache and tremor may be seen as a secondary effects due to the profound cardiorespiratory and peripheral metabolic effects of catecholamines.
Side effects of this Adrenergic Agonists: Fear, anxiety, restlessness, throbbing headache, tremor, weakness and palpitation appear as side effects. These effects disappear with rest quiet and reassurance. Cardiac arrhythmias, hypertension, cerebral haemorrhage and acute pulmonary oedema occur with accidental overdose of catecholamines.
Preparation and Dosageof Adrenergic Agonists
1. Epinephrine (adrenaline): It is available as 1: 1000 sterile solutions in 1 ml ampules. It may be administered by subcutaneous, intramuscular or intracardiac routes. It is also available for inhalation (1% aqueous solution) purpose. It is employed with local ariaesthetics in concentrations of 1:1, 00,000 to 1:20,000 to prolong its effect.
2. Norepinephrine (noradrenaline, levarterenol): It is supplied as 1 mg/mi of levarterenol bitartrate. It is generally diluted with 1000 ml of 5% dextrose solution to give a final concentration of 4 ig/ml of levarterenol base. The solution is infused at a rate of 0.5 to 1 mi/minute.
3. Isoproterenol (isoprenaline, isuprel): It is available for parenteral use (1:5000), for inhalation (1:200; 1:100) and for sublingual (15—20 mg) administration. It may also be given by rectal route.
4. Dopamine: It is a naturally occurring catecholamine. It is the immediate precursor of the norepinephrine. Dopamine acts on alpha, beta and specific dopamine receptors. It also releases norepinephrine from storage vesicles. It produces a positive inotropic effect and increases systolic and pulse pressure. It has less prominent effect on heart rate. In low doses, it produces vasodilatation of renal and mesenteric blood vessels by acting on specific dopamine receptors. It is given by infusion at a rate of 20 ig/kg/min.
5. Dobutamine: It has structural resemblance with dopamine. It is a selective beta- 1 adrenoceptor stimulant. It increases the force of contraction without increasing the heart rate. It does not act on the dopaminergic receptors in the renal vasculature. It is administered by intravenous infusion at a rate of 2.5—10 pg/ kg/mm.
6. Dopexamine: It is an inotropic agent which stimulates cardiac dopamine and peripheral beta-2 receptors. It is given by intravenous infusion via caval catheter in the dose of 0.5—1 iig/kg/min.
Therapeutic Uses of Adrenergic Agonists
Epinephrine: Its important uses are: Allergic disorders (opposing the effects of histamine and other mediators of allergic reactions-physiological antagonist):
- Anaphylactic shock
- Urtic aria
- Hay fever
- Angioneurotic oedema
- Serum sickness
- Bronchial asthma and status asthmaticus.
- To prolong the action of infiltration anaesthesia (with local anaesthetics).
- In ophthalmology for reducing intraocular pressure in cases of simple glaucoma.
- As expedient measure in insulin hypoglycaemia.
Epinepherine hydrochloride (1:1000) or phenylephermne hydrochloride (1:100) is used to control capillary bleeding during surgical procedure on gingival tissue. The cardiovascular uses of epinephrine such as sudden cardiac arrest in healthy individuals and Stokes-Adam syndrome are limited as it can produce fatal cardiac arrhythmias. Norepinephrine: It has been used in:
- States of shock by infusion. However, it is not used for the treatment of endotoxic or haemorrhagic shock where circulating catecholamine level is already very high.
- Partial or complete AV block to maintaine sufficient ventricular rate
Dopamine is useful in the treatment of:
• Shock, particularly cardiogenic or bacteremic shock
• Chronic cardiac decompensation as in congestive heart failure
Dobutamine; It is used in the treatment of heart failure associated with myocardial infarction.
Dopexamine: It is used in heart failure associated with cardiac surgery.
Pharmacology of Non-catecholamines
Although catecholamines are very powerful Adrenergic Agonists, they have certain disadvantages as under:
- They are inactive orally.
- They have a short duration of action being rapidly metabolized by MAO and COMT enzymes.
- They are generally non-selective, acting on both alpha and beta receptors.
- They do not cross blood—brain barrier.
To overcome these difficulties, a number of non-catecholamine compounds have been developed. These compounds have following properties:
- Some of them are orally effective, e.g. amphetamine, dexamphetamine.
- Some of these compounds (amphetamine, dexamphetamine, and ephedrine) cross blood—brain barrier due to lipid solubility and produce central effects.
- Some of these compounds (amphetamine and related drugs) resist degradation by MAO and COMT and have long duration of action.
- Many of the directly acting drugs of this group have receptor selectivity, e.g. phenylepherine (alpha-i agonist), clonidine (alpha-2 agonist) and salbutamol (beta-2 agonist).
Phenylepherine: It is a potent alpha- receptor agonist with very little beta-activity. It causes rise in blood pressure by causing vasoconstriction of peripheral blood vessels. As a pressor agent, drug can be given intramuscularly or intravenously in a dose of 5 mg followed by 10 mg if necessary. It is also used as mydriatic and nasal decongestant (2.5 mgI ml).
Metaraminol: It is a directly acting sympathomimetic drug with similar actions as that of norepinephrine. However, it has longer duration of action as it is not metabolized by MAO enzyme. It is used mainly as a pressor agent for maintaining blood pressure during anaesthesia, haemorrhage and other hypotensive states. It is used intramuscularly in a dose of 2—10 mg. It can also be given by slow intravenous infusion.
Methoxamine: It acts almost exclusively on alpha-receptors and has no stimulant action on heart. It increases systolic and diastolic blood pressure. Reflex bradycardia is seen. It has a prolonged action (1—1.5 hr) as not metabolized by MAO or COMT enzymes. It is used to restore or maintain blood pressure during spinal anesthesia or general anesthesia. It is given by intramuscular or intravenous route (10—20 mg/ml).
Ephedrine: It is a naturally occurring alkaloid, obtained from plants of the genus Ephedra. It mainly acts by causing the release of norepinephrine (indirect effect) and also has some direct action on alpha-receptors. So ephedrine raises arterial blood pressure. It also has CNS stimulating property. Ephedrine is mainly used as bronchodilator in asthma (15— 60 mg, given 3—4 times daily orally). It is also used as nasal decongestant (0.5% solution), mydriatic (2—5% solution) and in certain allergic disorders. Side effects are tachycardia, premature systoles, insomnia, nervousness, and emotional disturbances.
Amphetamine (dexedrine): It is an indirectly acting sympathomimetic amine. So its effect depends on the release of norepinephrine from adrenergic nerves. It has a potent CNS stimulant action. Its occasional uses are:
- Obesity (due to anorexia effect and CNS stimulant effect)
- Narcolepsy (sleep occurring in fits)
- Epilepsy to counteract sedation caused by antiepileptics
- Parkinsonism to improve mood and reduce rigidity(slight)
- Hyperkinetic children (attention deficit hyperkinetic disorder) to calm down these children
- Nocturnal enuresis in children and urinary incontinence due to its central action as well as its ability to increase tone of vesicle sphincter
- Methamphetamine is very similar to amphetamine with even higher degree of CNS stimulant property.
Selective Beta-2 Adrenoceptor Stimulants
These Adrenergic Agonists drugs are selective agonists of 2 receptors and produce relaxation of smooth muscles of bronchi, uteri, and gastrointestinal tract. Adverse effects of these Adrenergic Agonists are similar to those of isoprenaline though they are less severe. Amongst the f2 agonists, salbutamol is widely used.
Salbutamol: It has long duration of action because it is not metabolized by MAO and COMT. It is almost completely devoid of cardiovascular effects. It can be given by all routes of administration. It is used in asthma (Oral; 2—4 mg TDS and inhalation: Dose 100— 200 jig). It may be administered in a dose of 10—45 jig/mm by slow intravenous infusion to inhibit uterine contraction (tocolytic action) to prevent delivery/birth prior to 37th week of gestation (preterm delivery/birth).
Terbutaline: It is chemically related to orciprenaline but has more selective action on 2 receptors. It is used as a bronchodilator in asthma (Oral: 2.5 to 5 mg BD or TDS). Important side effects are nervousness, tremor, palpitation, drowsiness, nausea and vomiting. It is contraindicated in patients with hyperthyroidism and hypertension.
Salmeterol is a long acting (12 hours) 13, adrenergic agonist. It is weaker agonist than salbutamol. Its onset of action is slow. It is used in the prevention of asthmatic attacks, especially the nocturnal ones and those induced by exercise. Its dose is 1—2 puffs (25 jig per puff) every 12 hours.
Isoetharine (30—40 mg/day), rimiterol (200 jig inhalation) and fenoterol (100—200 jig inhalation) are other 13, selective agonists, which are used for the treatment of acute episodes of bronchoconstriction.
Ritodrine is a 132 selective agonist which is administered in doses of 50 jag/mm i.v. infusion:mn obstetrics as tocolytic agent.
Reproterol (0.5—1 mg by aerosol inhalation) is used in intermittent episodes and for prophylaxis in exercise- induced bronchospasm.
• Cocaine: It is a local anaesthetic with a sympathomimetic action. It acts by inhibiting the neuronal reuptake of norepinephrine. It readily enters the brain and possesses potent CNS effects. It is widely abused (addicting) drug.
• Tyramine: It is found in many food products such as cheese, beer and wine. It has indirect sympathomimetic action. It is readily metabolized by MAO enzyme. Some of the food drug interactions are due to tyramine content of food.
Points for Dental Students
1. Concern often arises regarding the use of vasoconstrictor in patients with hypertension and heart disease. Vasoconstrictors enhance the depth and duration of local anesthesia, thus reduces the anesthetic dose and potential toxicity. If caution is used to avoid intravascular injection, lidocaine with 1:100,000 epinephrine (limited to a total of 0.036mg epinephrine) can be used safely in those with controlled hypertension and stable coronary heart disease, arrhythmia, or congestive heart failure. Precaution should be taken with patients to tricyclic antidepressants and non-selective beta blockers, since these drugs may potentiate the effect of epinephrine.
2. Pressor agents may be required to maintain blood pressure during dental surgery. So a dental student must learn their pharmacodynamic and pharmacokinetic properties for safe use.
3. Adverse effects of marty drugs are due to their action on adrenergic receptors (ct or 3). So it is important to learn the basic principles of this system. It will be useful to understand the side effects and minimize them.
4. Do not use terbutaline powder for inhalation in asthmatic patients because it may harm tooth enamel and cause tooth erosion due to its <5.5 pH.
- Adrenergic Agonists are drugs which produce effects similar to those of adrenergic nerve stimulation or injection of epinephririe.
- Norepinephrine is synthesized in the varicosities of the adrenergic neuron. Inside the nerve ending, there are two stores of norepinephrine.
- Norepinephrirte and epinephrine are metabolized by catechol-O-methyl transferase and monoamine oxidase enzymes and excreted in urine as vanilomendalic acid.
- Some Adrenergic Agonists (catecholamines) act directly on the adrenergic receptors located on the effector cells and initiate pharmacological response while others (non-catecholamines) act indirectly by stimulating the release of norepinephrine from nerve endings. Some may act by both the mechanisms.
- Important uses of epinephrine are anaphylactic shock, urticaria, angioneurotic oedema, serum sickness, bronchial asthma, status asthmaticus and to prolong the action of infiltration anaesthesia.
- Norepinephrine may be used in states of shock and partial or complete heart block.
- Dopamine is used in the treatment of shock and congestive heart failure.
- Dobutamine is employed in the treatment of heart failure associated with myocardial infarction by i.v. infusion.
- Dopexamine stimulates cardiac dopamine and peripheral beta-2 receptors. It is used in heart failure associated with cardiac surgery.
- Other pressor agents are phenylepherine, metraminol, and methoxamine. Phenylepherine is also used as mydriatic and nasal decongestant.
- Ephedrine is used in bronchial asthma, as nasal decongestant, mydriatic and in certain allergic disorders.
- Salbutamol, terbutailne, isoetharine and salmeterol are selective agonists of beta2 receptors and produce relaxation of smooth muscles of bronchi, uteri, and gut. Amongst them, salbutamol is widely used in asthma and to inhibit uterine contraction.