AUTONOMIC NERVOUS SYSTEM (ANS) PHARMACOLOGY

Introduction

• The nervous system is made up of CNS (Central Nervous System) and PNS (Peripheral nervous System). The CNS is made up of brain and spinal cord. And the PNS is made up of SNS and ANS.
• Autonomic nervous system (ANS) mostly innervates visceral organs of the body.

• Two neurons are present in the ANS pathway. One is called as preganglionic neuron and other is called as post ganglionic neuron. The junction between two neurons is called as ganglion or synapse.

Preganglionic neurons: Its cell body is present in the brain or spinal cord and its axon is elongated from inside to outside of CNS. The axon is myelinated. Actually, the cell body is present in the lateral horn of gray matter in thoracolumbar division (sympathetic). And cell body of cranio-sacral division is presence in the cranial nerves. 

 Postganglionic neurons: It is the second neuron present after the ganglia. Its cell body and dendrites are located in the autonomic ganglion. It is unmyelinated.

Ganglia: it is the junction between the preganglionic neuron and postganglionic neuron. By positioning of ganglia in to the body, they are sympathetic trunk, prevertebral (collateral) and terminal ganglia.

• ANS has two divisions: sympathetic and parasympathetic and are involved in regulation of organs/processes not under conscious control including: circulation, digestion, respiration, temperature, sweating, metabolism and some endocrine gland secretions.

Sympathetic Responses
1.    heart rate increases
2.    blood pressure increases
3.    blood is shunted to skeletal muscles
4.    blood glucose increase
5.    bronchioles dilate
6.    pupils dilate
Parasympathetic responses
1.    slows heart rate
2.    protects retina from excessive light
3.    lowers blood pressure
4.    empties the bowel and bladder
5.    increases gastrointestinal motility
6.    promotes absorption of nutrients

Figure 3: Showing neurons in the ANS pathway; their origin; innervations and neurotransmitters

ANS Neurotransmitters

**Acetylcholine

Introduction

Acetylcholine is one of many neurotransmitters in the autonomic nervous system (ANS). Acetylcholine is also the principal neurotransmitter in all autonomic ganglia. In cardiac tissue acetylcholine neurotransmission has an inhibitory effect, which lowers heart rate. However, acetylcholine also behaves as an excitatory neurotransmitter at neuromuscular junctions in skeletal muscle.

Biosynthesis, Storage, Release and Degredation

Synthesis of Ach begins from the pyruvate which is obtained from the mitochondria. Pyruvate is converted in to acetyl CoA, which is further reacted with the choline which is, enters in to the cytoplasm of axon with active transport along with the sodium ion. This acetyl CoA and choline reacted to form Ach in the presence of the enzyme, choline-acetyl transferase. Ach is chemically trimethylamine-ethylacetate. It stored in to the synaptic vesicles and in the presence of Ca⁺², the merge of the vesicle with the axoplasmic membrane occur which causes release of Ach by exocytosis. After release of Ach from the end bulb it acts up on the target receptors like nicotinic and muscarinic. Ach is metabolized by AchE enzyme presence near by the synapse. The enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline and acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function. Certain neurotoxins work by inhibiting acetylcholinesterase, thus leading to excess acetylcholine at the neuromuscular junction, causing paralysis of the muscles needed for breathing and stopping the beating of the heart.

Receptors:

There are two main classes of acetylcholine receptor (AChR), nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). They are named for the ligands used to activate the receptors.

Nicotinic: Nicotinic AChRs are ionotropic receptors permeable to sodium, potassium, and calcium ions. They are stimulated by nicotine and acetylcholine. They are of two main types, muscle type (Nm) and neuronal type (Nn). The former can be selectively blocked by curare and the latter by hexamethonium. The main location of nicotinic AChRs is on muscle end plates, autonomic ganglia (both sympathetic and parasympathetic), and in the CNS.

+ NM: They are presence on the neuromuscular junction mainly on the skeletal muscles. They cause depolarization at the muscle end plate which leads to contraction of muscle. They are pentameric having 2α, β, δ and γ or ε subunits and agonist by nicotine and PTMA and antagonist by tubocurarine.

 +NN: These are present on autonomic ganglia, adrenal medulla and CNS. At autonomic ganglia it causes depolarization of postsynaptic neurons and propogate impulses through it. The adrenal medulla releases Adrenaline and Noradrenaline by same mechanism. And at the CNS causes excitation and inhibition depending up on the neuronal chemical. Nicotine and Di methyl phenyl piprizinium (DMPP) are agonists and hexamethonium is antagonist to them.

Associated Disiorders

**Myasthenia gravis

The disease myasthenia gravis, characterized by muscle weakness and fatigue, occurs when the body inappropriately produces antibodies against acetylcholine nicotinic receptors, and thus inhibits proper acetylcholine signal transmission. Over time, the motor end plate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine, physostigmine, or primarily pyridostigmine) are effective in treating this disorder. They allow endogenously released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in the gap junction.

Muscarinic: Muscarinic receptors are metabotropic, and affect neurons over a longer time frame. They are stimulated by muscarine and acetylcholine, and blocked by atropine. Muscarinic receptors are found in both the central nervous system and the peripheral nervous system, in heart, lungs, upper GI tract and sweat glands.

The substance known as muscarine from mushroom (amatina muscaria) is activating these type of receptors, so named as muscarinic receptors. They are G-protein coupled receptors (GPCRs). By molecular cloning they are subdivided in to M1, M2, M3, M4, and M5.

M1: It is present on the autonomic ganglia, on the gastric gland and at the certain part of the brain like hippocampus from limbic system and at the corpous straitum. It has role in gastric secretion. And histamine release.

M2: they act through Gi protein which inhibits all the functional activities. Located on the heart (SA node, AV node, atria, ventricle), on the cholinergic nerve ending and visceral smooth muscle. They inhibit Action potential resulting in hyperpolarisation of the neurons and decrease activity of SA node and conduction through AV node leads to bradycardia.
M3: it is located on the visceral smooth muscle, iris, ciliary muscle and exocrine glands. Their activity is dominated in smooth muscle.

M4: not abundant in body. They transmit neurotransmitter in certain areas of brain

M5: Derifinacin is selective antagonist and related to dopamine release.

 Muscarinic Agonists

 Direct Muscarinic Agonists:

• Choline Esters
• Alkaloids

·         Indirect Muscarinic Agonists

• Carbamates: Reversible inhibitors of cholinesterase.
• Organophosphates: Irreversible inhibitors of cholinesterase.

Effect

CVS:
The heart containing M2 type of receptors which decrease the rate of conduction in the specialized tissue of SA node, AV node and decrease force of contraction.

Many anti arrhythmic acts through the cholinergic vagal stimulation still the Ach is not given systematically (The drug given by I.V. in small doses causes decrease in BP due to vasodilatation and large doses are required to elicit bradycardia). But large doses of Ach after administration of atropine block the receptor of the Ach and free Ach direct stimulates release of catecholamine.

Ach hyperpolarizes SA node and decreases the depolarization of nodal cells. So, rate of impulse generation is decreases and lead to bradycardia.

Ach decreases conduction velocity of impulse transfer at AV node and increase force of contraction of atria and ventricle decreases.

The Blood vessels (BV) like salivary gland, some part of skin contain cholinergic nerve ending and most of the Blood vessels of the body are dilated, this is because Ach inhibit the effect of the catecholamine release and also due to release of endothelium derived relaxing factor (EDRF) Nitric Oxide (NO). NO is responsible for BV dilation.

SMOOTH MUSCLE:
It contracts the smooth muscle through the action of M3 receptor.

It increases the peristaltic movement in gut and urethra and relaxes the sphincter of the gut and evacuation of bowel is carried out through it.

In the asthmatic patient, it causes more lethal condition by constricting the bronchioles smooth muscle.

Contraction of circular muscle of iris and ciliary muscle

SKELETAL MUSCLE:
Its effect on the skeletal muscle depends on the route of administration. The intravenous injection of the Ach have no effect in the body, this is due to presence of Ach E in the plasma which null the presence of Ach in the body and also by hydrolysis. But in high dose can cause twitching and fasciculation. The effect on skeletal muscle is due to Nm type of receptor.

CNS:

In the central nervous system, ACh has a variety of effects; as a neuromodulator upon plasticity, arousal and reward. ACh has an important role in the enhancement of sensory perceptions when we wake up and in sustaining attention. Damage to the cholinergic (acetylcholine- producing) system in the brain has been shown to be plausibly associated with the memory deficits associated with Alzheimer's disease. ACh has also been shown to promote REM sleep.

Ach can not penetrate BBB itself and exert the effect on the brain and s.cord but some cholinergic drug can penetrate the BBB like arecoline.

Drugs acting on the cholinergic system

Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine.

Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it.

	Nm	Nn	M1	M2	M3
ACh, Charbacol, AChE (Physostigmine, Galantamine, Neostigmine, Pyridostigmine)	+	+	+	+	+
Nicotine, Varenicline	+	+
Succinylcholine	+/-
Atracurium,   Vecuronium, Tubocurarine, Pancuronium	-
Epibatidine, DMPP		+
Trimethaphan, Mecamylamine, Bupropion, Dextromethorphan, Hexamethonium		-
Muscarine,    Methacholine, Oxotremorine, Bethanechol, Pilocarpine			+	+	+
Atropine, Tolterodine,            Oxybutynin			-	-	-
Vedaclidine,  Talsaclidine, Xanomeline, Ipatropium			+
Pirenzepine, Telenzepine			-
Methoctramin            Darifenacin, 4 DAMP, Darifenacin, Solifenacin Associated disorders				-	-

Clinical Uses of Cholinergic Drugs

Carbachol and Bethachol: They are only responsible for decrease in BP at low dose which affect GIT and urinary tract.

 Pilocarpine: It is diaphoretic drug and also produces salivation. It also has effect on the pupil. So it is used in the open angle glaucoma. It is used to decrease intraocular pressure. It is also used in xerostomia.

Arecoline: It acts at nicotinic receptors and it is euphoretic drug.

Adverse effects:

Cholinergic outflow shows the following symptoms:

·         SLUD: Sweating, Lacrimation, Urination, Defecation

·         Profuse diarrhea, vomiting, nausea.

·         Flushed skin.

Organophosphate Poisoning:

·         DEATH by Respiratory Suppression in the CNS is the most common cause. This is not an effect on the diaphragm, but rather is a suppression of the respiratory drive (muscarinic receptors) in the CNS.

·         2-PAM (Pralidoxime): Only effective as an antidote within the first five minutes of exposure. Acetylcholinesterase is a Serine-Protease. It binds to Acetylcholine by latching onto the NH3 group with a His residue, and hydrolyzing the ester group with a Ser residue. Organophosphates phosphorylate the cholinesterase, rendering it inactive. Within the first few minutes, this phosphorylation is reversible. 2-PAM is a strong nucleophile, and binds with the organophosphates to reverse the phosphorylation. After the first 5 or 10 minutes, aging occurs and the phosphorylation becomes irreversible. After that, 2-PAM no longer works.

·         Atropine is the treatment of choice after that.

Anticholinergic Drugs

Muscarinic receptor Antagonists

• The drug or substances bind to muscarinic receptors and produce no intrinsic activity or inhibit binding of agonist; hence called muscarinic receptor antagonists. For example: atropine, scopolamine, tropicamide etc.
• They produce similar activity but some have specificity of action on the selective tissue or organ like pirenzepine inhibits gastric acid secretion due to its selectivity towards M1 receptors.
• They are broadly classified into: Natural alkaloids (Atropine, Scopolamine, Hyoscene) and Synthetics (Ipratropium, Tiotropium, Diphenhydramine)

Nicotininc receptor Antagonists

• Ganglion blocker-Bupropion, Hexamethonium, Dextromethorphan (cough suppressant), Mecamylamine 

• Nondeplorizing skeletal muscular relaxant- Tubocurarine, doxacurium, atracurium, cisatracurium, metocurine, mivacurium, pancuronium.

• Depolarizing blocker- Succinylcholine

Mechanism of Action of Atropine
Atropine and other muscarinic antagonists competitively binds to receptors with Acetylcholine or other agonists.

If concentration of Ach is increased, the antagonistic effect will be overcome. But chE antagonist along with M-antagonist works in right way.       

Side Effects

Anti-Muscarinic

• Peripheral:
• Dry mouth (no salivation)
• Constipation (no anal sphincter relaxation, lost GI motility)
• Blurred Vision (no accommodation)
• Urinary retention (lost UG motility, no sphincter relaxation)
• Increased intraocular pressure (sympathetics increase intraocular pressure and parasympathetics decrease it).
• Central: Impairment of all things that ACh mediates in the CNS
• Confusion
• Memory impairment
• Hallucinations, delusions

Ganglion blockers

• Orthostatic Hypotension: block sympathetic reflex control of vasculature.
• Tachycardia: Block parasympathetic reflex control of the heart.
• GI / UG: Decreased motility, urinary retention, constipation (lost parasympathetic reflexes)
• Mouth: Xerostomia

**Adrenaline

Introduction

Epinephrine (also known as adrenaline or adrenalin) is a hormone and a neurotransmitter. Epinephrine has many functions in the body, regulating heart rate, blood vessel and air passage diameters, and metabolic shifts; epinephrine release is a crucial component of the fight-or-flight response of the sympathetic nervous system. As a hormone and neurotransmitter, epinephrine acts on nearly all body tissues. When you experience emotional stress or encounter a physically dangerous situation, your body prepares itself for prompt action by triggering your "fight-or-flight" response. This response begins in a region of your brain called the hypothalamus, which sounds the alarm and triggers increased production of adrenaline in your adrenal glands. These glands also increase the production of another hormone called cortisol. While cortisol suppresses nonessential activity and prepares your body for damage repair, adrenaline speeds up your heart rate, increases your energy supplies and raises your blood pressure.

Its actions vary by tissue type and tissue expression of adrenergic receptors. For example, high level of epinephrine causes smooth muscle relaxation in the airways but causes contraction of the smooth muscle that lines most arterioles.

Epinephrine acts by binding to a variety of adrenergic receptors. Epinephrine is a non-selective agonist of all adrenergic receptors, including the major subtypes α1, α2, β1, β2, and β3. Epinephrine's binding to these receptors triggers a number of metabolic changes. Binding to α- adrenergic receptors inhibit insulin secretion by the pancreas; stimulates glycogenolysis in the liver and muscle, and stimulates glycolysis in muscle. β- Adrenergic receptor binding triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue. Together, these effects lead to increased blood glucose and fatty acids, providing substrates for energy production within cells throughout the body.

Biosynthesis and regulation

Adrenaline is synthesized in the medulla of the adrenal gland in an enzymatic pathway that converts the amino acid tyrosine into a series of intermediates and, ultimately, adrenaline. Tyrosine is first oxidized to L- DOPA (catalysed by tyrosine hydroxylase), which is subsequently decarboxylated (catalysed by DOPA decrboxylase) to give dopamine. Oxidation of dopamine (catalysed by dopamine hydroxylase) gives norepinephrine, which is methylated to give epinephrine (catalysed by phenylethanolamine N-methyltransferase).

Adrenaline is synthesized via methylation of the primary amine of noradrenaline by phenylethanolamine N-methyltransferase (PNMT) in the cytosol of adrenergic neurons and cells of the adrenal medulla (so-called chromaffin cells). PNMT is found in the cytosol of only cells of adrenal medullary cells.

Dopamine is the first catecholamine synthesized from DOPA. In turn, norepinephrine and epinephrine are derived from further metabolic modification of dopamine. The enzyme dopamine hydroxylase requires copper as a cofactor (not shown) and DOPA decarboxylase requires PLP (not shown). The rate limiting step in catecholamine biosynthesis is hydroxylation of tyrosine.

Degradation: - Catecholamines have a half-life of a few minutes when circulating in the blood. They can be degraded either by methylation by catechol-O-methyltransferases (COMT) or by deamination by monoamine oxidases (MAO). MAOIs bind to MAO, thereby preventing it from breaking down catecholamines and other monoamines.

 

Receptors:

 In the ANS, adrenergic neurons release Noradrenaline (NA) which binds with adrenergic receptors and propogate the nerve impulses. The two main types of adrenergic receptors are α-receptors and β-receptors. These receptors further sub classified as α- α₁, α₂ and β- β₁, β_2, β_3. α₁ and β₁ mostly produces excitation and α₂ and β₂ mostly produces inhibition.

Location:

α₁: It is presence at the post junctional on effector organs like radial and sphincter muscles of iris (eye), heart, some BV (blood vessels), bronchial glands (lungs), liver, gut, skin, sex organs etc.

α₂: It is presence on the prejunctional at the nerve ending. On the brain, pancreatic β cells, fat cells, gut muscles, veins etc.

β₁: They are located at heart, salivary glands, juxtaglomerular apparatus of kidney, posterior pituitary.

 β₂: Lungs, BV, uterus, liver, eye, gut, urinary bladder, spleen, skeletal muscle, certain veins etc.

β₃: Brown adipose tissue, where there function is to generate the heat by thermogenesis. Mostly present in the children.

  

Effects

HEART 

It acts on β1 receptors of heart. It increases slope of slow diastolic depolarization of SA node. It activates SA node and latent pacemakers in AV node and purkinje fibre.

It causes arrhythmia at high dose which raise BP markedly. Raised BP reflex depresses SA node. Anaesthetics sensitize the heart to arrhythmic action of adrenaline.

Because Adrenaline force of contraction increases leads to development of tension; relaxation period also increases which shorten systole than diastole. So oxygen consumption capacity and cardiac output also increases. Conduction velocity also increases so, partial AV-block overcomes. Refractory period of all cells decreases.
Raised BP reflexes bradycardia due to stimulation of vagus by carotid sinus compression.

BLOOD VESSELS:

Main effects of adrenaline are exerted on smaller arterioles and precapillary sphincters, although veins and large arteries also respond to the drug. It constricts vessels of skin and mucus (mucous) membrane.

It dilates BV of skeletal muscles. Thus net results of this is, decrease in the peripheral resistance.

Adr can’t be given in the hypotensive state. As it is raise systolic BP by its cardiac action but it decreases diastolic action by its peripheral action.

BV contain both α1 and β2 receptors. Adr have more affinity to α1 for short period of time which causes vasoconstriction and increase in BP. After action on α1, it acts on β2 receptors for long period of time causing vasodilatation and decrease in BP. This type of response is called as biphasic response.

If a α-blocker (ergotoxin) is given, it leads to decrease in BP. Called as DALE’S vasomotor reversal.

In cerebral arteries; doesn’t have marked effect due to autoregulatory mechanism which limits the increase in cerebral blood flow.

High concentration of Adrenaline leads to pulmonary edema. This is because of elevated pulmonary capillary filtration pressure.

BLOOD PRESSURE:

It depends upon dose, route of administration and on the amine. NA increase systolic, diastolic and mean BP. It doesn’t have β2 action so no vasodilatation and peripheral resistance increase consistently due to α action.

Isoprenaline causes increase in systolic but decreases in diastolic BP. The mean BP generally falls.

Mean BP = diastolic BP + 1/3 (systolic – diastolic BP)

In normal individual BP is 120/80 mmHg, mean BP: 93.33

CO = HR * SV

CO = mean BP/ PR => Mean BP = CO * PR

If Adrenaline is given rapidly by I.V route, it increases BP proportional to dose. It causes increase in systolic pressure is greater than diastolic pressure, so pulse pressure (difference between systolic and diastolic pressure) is also increases. This occurs due to α receptor response predominant and vasoconstriction occurs also at skeletal muscle. (Increase in BP by 3 mechanism: myocardial stimulation, increase HR and vasoconstriction in most of the body.)

When Adr is given by slow I.V infusion or S.C route, it causes increase in systolic pressure due to cardiac contractile force and increase in CO but decrease in diastolic pressure due to β2 receptors of skeletal muscle causing vasodilatation. So Mean BP is decreased.

RESPIRATION:

Adrenaline and isoprenaline are powerful bronchodilator not NA. This effect is more marked in asthma (bronchoconstriction). Adrenaline given by aerosol additionally decongests bronchial mucosa by α action and inhibition of mast cell secretion by β2 action. The mast cell secretion, autocoids causes bronchoconstriction and Adrenaline antagonized to this substances. (Bronchial asthma produced due to vagal stimulation, choline-esters, histamine or Ag-Ab interaction, bradykinin, leucotrienes or prostaglandin F2α which are antagonized by Adrenaline)

Rapid I.V infusion of Adr causes transient inhibition of respiratory center causes apnoea for some time. More dose causes pulmonary edema.

GIT:

Adr relaxes smooth muscles of the gut and reduces its motility (Due to α and β receptors).

Stomach relaxed and contraction of pyloric and ileocecal sphincter but it depends upon pre-existing tone of muscle. (If tone is high, it causes relaxation and if tone is low, it causes contraction).

UTERUS:

It can contract and relax depends upon phase of sexual cycle, state of gestation and dose.

Nonpregnant: Human-contraction        Rat- relaxation

Pregnant       : Human- relaxation         Rat- relaxation

BLADDER:

Adr relaxes detrusor muscle (β receptors) and contracts trigone and sphincter (α-agonist activity). This cause hesitation in urination and may contribute to retention of urine in bladder.

EYE:

Mydriasis is readily seen during sympathetic stimulation but not when epinephrine is instilled into conjuctival sac of normal eyes, (poorly cross the cornea).

It decreases intra-ocular pressure, the mechanism of this is not known but due to decrease production of aqueous humor and due to vasoconstriction.

OTHER SMOOTH MUSCLE:

Pilomotar muscles of hair contracts by adrenaline leads to erection of hair. Contraction of splenic capsule causes release of erythrocytes in to the peripheral circulation.

METABOLIC EFFECT:

It causes hyperglycemia, hyperlactacidemia and lipolysis.

In liver and muscle, glycogen phosphorylase is activated which causing glycogenolysis while glycogen synthetase is inhibited. Both lead to hyperglycemia and hyperlactacidemia. Also gluconeogenesis is increased.

K+ is first released from liver which leads to hyperkalaemia followed by prolonged hypokalaemia due to K+ uptake in muscle and liver itself.

In adipose tissue triglyceride lipase increases plasma free fatty acids. So, it causes increase oxygen consumption and heat production (thermogenesis), mainly by brown adipose tissue by β3 receptors.

In pancreatic islet,

β2 receptors on α cell=> increase glucagons secretion.

α2 receptors decrease cAMP=> decrease insulin release; which also leads to hyperglycemia.

CNS:

Adrenaline cannot enter in CNS due to poor permeability through BBB.

I.V or S.C route leads to excitant, vomiting, headache, apprehension, restlessness.

Adrenergic Drugs

Adrenergic nerves release norepinephrine as the neurotransmitter for the sympathetic nervous system. The sympathetic system activates and prepares the body for vigorous muscular activity, stress, and emergencies. Adrenergic drugs stimulate the adrenergic nerves directly by mimicking the action of norepinephrine or indirectly by stimulating the release of norepinephrine.

Therapeutically, these drugs are used to combat life-threatening disorders, which include acute attacks of bronchial asthma, shock, cardiac arrest, and allergic reactions. In addition these drugs are used in nasal decongestants and appetite suppressants.

Alpha1: Dopamine, Ephedrine, Epinephrine (adrenaline), Methoxamine, Methyldopa, Norepinephrine (noradrenaline), Phenylephrine 

Alpha2: Clonidine, Dopamine, Ephedrine, Ergotamine, Epinephrine, Methyldopa

Beta Adrenergic: Dobutamine, Dopamine, Ephedrine, Epinephrine, Isoprenaline (isoproterenol), Labetolol, Methyldopa, Norepinephrine (noradrenaline), Salbutamol (albuterol), Salmeterol, Terbutaline, Xalmeterol.

Clinical Significance

Adrenaline is used to treat a number of conditions including: cardiac arrest, anaphylaxis, and superficial bleeding. It has been used historically for bronchospasm and hypoglycemia, but newer treatments for these, such as salbutamol, a synthetic epinephrine derivative, and dextrose, respectively, are currently preferred.

Cardiac Arrest

Adrenaline is used as a drug to treat cardiac arrest and other cardiac dysrhythmias resulting in diminished or absent cardiac output. Its actions are to increase peripheral resistance via α1receptor-dependent vasoconstriction and to increase cardiac output via its binding to β1 receptors.

Anaphylaxis

Due to its vasoconstrictive effects, adrenaline is the drug of choice for treating anaphylaxis. Allergy patients undergoing immunotherapy may receive an adrenaline rinse before the allergen extract is administered, thus reducing the immune response to the administered allergen.

Asthma

Adrenaline is also used as a bronchodilator for asthma if specific β2 agonists are unavailable or ineffective.[7] When given by the subcutaneous or intramuscular routes for asthma, an appropriate dose is 300-500 mcg.

In local anesthetics

Adrenaline is added to injectable forms of a number of local anaesthetics, such as bupivacaine and lidocaine, as a vasoconstrictor to slow the absorption and, therefore, prolong the action of the anesthetic agent. Due to epinephrine's vasoconstricting abilities, the use of epinephrine in localized anaesthetics also helps to diminish the total blood loss the patient sustains during minor surgical procedures. Some of the adverse effects of local anesthetic use, such as apprehension, tachycardia, and tremor, may be caused by adrenaline.

Adverse effects

Adverse reactions to adrenaline include palpitations, tachycardia, arrhythmia, anxiety, panic attack, headache, tremor, hypertension, and acute pulmonary edema.

Contraindications: MAO Inhibitors, Cocaine, Tri-cyclics. These all potentiate NE, thus don't give catecholamines

Anti-Adrenergic Drugs
Anti-adrenergic agents are those which act on adrenergic receptors and block their activity. It reduces sympathetic out flow and antagonised them.

α Blockers

These are agents which antagonised α receptors and decreases sympathetic activity. Alpha blockers are classified as Non Equilibrium and Equilibrium types:

Non-equilibrium type-Phenoxybenzamine.

Equilibrium type is further classified into Non selective and Selective

Non selective: ergotamine, ergotoxine, tolazoline, chlorpromazine.

Selective: α₁ selective: prazosin, doxazocin; α₂ selective: yohimbine.

• Principal Effects:
• Decreased TPR, decreased blood pressure (primary effect)
• Tachycardia (reflex)
• Increased release of renin (reflex)
• Side Effects:
• Miosis
• Decreased adrenergic sweating
• Stuffy nose
• Increased insulin release
• Impaired ejaculation

β Blockers

These are the agents which block the β-receptors present in the body. β-receptor antagonists are classified as, Nonselective and Selective.

Non selective (β₁ and β₂):

·         Membrane stabilizing activity without intrinsic sympathomimetic activity: Propranolol, Timolol, Sotalol.

·         Membrane stabilizing activity with intrinsic sympathomimetic activity: Pindolol.

·         With additional α blocking activity: Labetalol, Carvedilol.

Selective: β₁ selective: Atenolol, Metoprolol, Acebutolol, Esmolol; β₂ selective: Butoxamine.

• Principle Effects:
• They decrease the inotropic state of the heart ------> decrease oxygen demand of the myocardium. Useful in treating angina pectoris.
• They decrease blood pressure:
• They increase TPR and decrease cardiac output, but the net effect is to decrease blood pressure.
• They decrease renin secretion in the kidney, which also helps to decrease blood pressure.
• They decrease AV conduction in the heart, and are useful in treating arrhythmias.
• Side-effects:
• Rebound Tachycardia can result if the drug is withdrawn quickly, due to denervation supersensitivity (i.e. up-regulation of beta1-receptors after using the drug for a while).
• Insulin release is blocked in pancreas ------> possible hyperglycemia, which can be a problem with Diabetics.
• Can also lead to hypercholesterolemia.

• ·Contraindications: Asthma is an absolute contraindication, for non-selective beta-blockers. You don't want to block the bronchodilatory effects of beta2-receptors.

You can possibly use beta1-selective (cardioselective) antagonists with asthmatics, but even these drugs still have some beta2-activity (even if minimal).

Tissue	Receptor Subtype	Agonists	Antagonists
Heart	beta1	NE, EP, dobutamine, xamoterol	atenolol, metoprolol.
Adipose tissue	beta1, beta 3?
Vascular Smooth Muscle	beta 2	EP, salbutamol, terbutaline, salmeterol	butoxamine
Airway Smooth Muscle	beta 2	terbutaline, salbutamol, salmeterol and zinterol,	butoxamine
Smooth muscle contraction	alpha 1	NE, EP, phenylephrine, oxymetazoline)	prazosin, doxazocin
Inhibition of transmitter release Hypotension, anaesthesia, Vasoconstriction	alpha 2	clenbuterol, alpha-methylnoradrenaline, dexmedetomidine, and mivazerol, clonidine, clenbuterol	yohimbine, idazoxan, atipamezole, efaroxan, and rauwolscine

 Table 2: Showing the Tissues of the body, Receptors and the Drugs Acting on Adrenergic Systems

Adrenaline	Acetylcholine	Atropine
Heart: β1 receptors ↑ HR, ↑ force of contraction, ↑ CO (SA node) ↑ BP-followed by ↓ due to feed back regulation. Av node-↑ conduction velocity. Reflex bradycardia- carotid sinus compression.	Heart: M2 receptors ↓ Force of contraction. SA node- hyperpolarization (bradycardia) Av node- ↑ RP, ↑ PR interval Delayed conduction.	Heart: M2- blockade—block in vagal effect. Tachycardia. I.m/s.c- initial bradycardia—M1-R-autoreceptor. Av node- ↓ RP, ↓ PR interval ↑ Conduction velocity.
Blood vessels: α- more affinity-short time-vasoconstirction-↑ BP β- less affinity-prolong time-vasodilation- ↓ BP Bipolar response Reversal of it: Dale’s vasomotor reversal.	Blood vessels: Very less BV innervated with cholinergic transmission (salivary gland, some part of skin) EDRF- NO- vasodilation- ↓ BP.	Blood vessels: Tachycardia and VMC- ↑ BP. Due to feed back regulation- ↓ BP.
CNS: α2 – autoreceptors Not cross- BBB. Not powerful CNS stimulant Restlessness, apprehension, headache and tremor.	CNS: Fewer drugs penetrate- BBB. If directly given-stimulation-followed by- depression.	CNS: High dose- medulla (stimulation)-vagal, vasomotor, VMC. Depression- vestibular excitation-antimotion sickness. As a anti-parkinsonian drug Effect- irritation,restlessness, hallucination, delirium, amnesia. -respiration dep-coma.
Glands: Insulin secretion ↓ - β cells-  α2 receptors Glucagons secretion ↑- α cells- β receptors. Saliva- scanty mucus secretion Sweat-↓ Lacrimal secretion-↓	Glands: ↑ secretion of sweat and saliva - ↑ Ca+2	Glands: ↓ secretion by blocade of Ach receptors Dryness mouth-↓ secretion. ↓ gastric secretion (Anti-ulcer) ↑ Temp- ↓ sweat
Smooth muscles: Bronchial mus- bronchodilation by- β2 - iinhibition of mast cell secretion and α- effect on mucosa. Gut-relaxes-↓ motility- sphincter contracts. Urinary bladder- detrusor muscle-relax ( β) and trigone- contract ( α)- hesitation in urination.	Smooth muscles: Bronchoconstriction- lethal in asthma. Gut- ↑ peristalsis- relaxes sphincter in gut. contraction	Smooth muscles: Relaxes-bronchodilation-histamine, eicosanoids… Gut- ↓ motility. Relaxation of ureter and bladder.
Eye: Mydriasis (not given from conjuctiva) ↓ intra-ocular pressure	Eye: Contraction-circular muscle Contraction-ciliary muscle- ↓ i.o.p	Eye: Mydriasis-relaxation of iris And cyclopegia- relaxation or paralysis of ciliary muscle- paralysis accommodation of lens- ↑ FL

Table 3: Differences between effects of Acetylcholine, Adrenaline, Atropine

Figure 4: Showing the Sympathetic and Parasympathetic innervations of the body