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.
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.
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.
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.
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.
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, β2, β3. 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.
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 |
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