AGENTS ACTING
N-CHOLINERGIC RECEPTORS. NICOTINE TOXICOLOGY
(Benzohexonium,
Pirilenum, Hygronium, Pentaminum, Tubocurarini chloridum, Pipecuronii bromide
(Arduanum, Mellictinum, Dithylinum)
ADRENERGIC
RECEPTOR-ACTIVATING DRUGS. ADRENERGIC
RECEPTOR-BLOCKING DRUGS. SYMPATHOLYTIC AGENTS (Adrenalini
hydrochloridum, Noradrenalini hydrotartras, Ephedrini hydrochloridum,
Mesatonum, Naphthyzinum, Xylometasolinum, Isarinum,Salbutamolum, Fenoterolum,
Fentolaminum, Prasosinum, Anaprilinum, Atenololum, Metoprololum, Talinololum,
Reserpinum, Octadinum)
Agents acting N-cholinergic receptors. Nicotine
toxicology
As nicotine enters the
body, it is distributed quickly through the bloodstream and can cross the blood-brain barrier. On average it takes about seven seconds for the substance
to reach the brain when inhaled. The half life of nicotine in the body is
around two hours[2]. The amount of nicotine inhaled with tobacco smoke is a
fraction of the amount contained in the tobacco leaves (most of the substance
is destroyed by the heat). The amount of nicotine absorbed by the body from
smoking depends on many factors, including the type of tobacco, whether the
smoke is inhaled, and whether a filter is used. For chewing tobacco, often called dip, snuff, or snus, which is held in the
mouth between the lip and gum, the amount released into the body tends to be
much greater than smoked tobacco. Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine.
Nicotine acts on the nicotinic acetylcholine receptors. In small concentrations it increases the activity of these
receptors, among other things leading to an increased flow of adrenaline (epinephrine), a stimulating hormone. The release of adrenaline causes an increase in heart rate,
blood pressure and respiration, as well as higher glucose levels in the blood.
The sympathetic nervous
system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of
epinephrine. Acetylcholine released by preganglionic sympathetic fibers of
these nerves acts on nicotinic acetylcholine receptors, causing cell
depolarization and an influx of calcium through voltage-gated calcium channels.
Calcium triggers the exocytosis of chromaffin granules and thus the release of
epinephrine (and norepinephrine) into the bloodstream.
Cotinine is a byproduct of the metabolism of nicotine which remains
in the blood for up to 48 hours and can be used as an indicator of a person's
exposure to smoke. In high doses, nicotine will cause a blocking of the nicotinic acetylcholine receptor, which is the reason
for its toxicity and its effectiveness as an insecticide.
In addition, nicotine
increases dopamine levels in the reward circuits of the brain. Studies have shown that smoking tobacco inhibits monoamine oxidase (MAO), an enzyme responsible for breaking down monoaminergic
neurotransmitters such
as dopamine, in the brain. It is currently believed that nicotine by itself
does not inhibit the production of monoamine oxidase (MAO), but that other ingredients in inhaled tobacco smoke
are believed to be responsible for this activity. In this way, it generates
feelings of pleasure, similar to that caused by cocaine and heroin, thus causing the addiction associated with the need to
sustain high dopamine levels.
Dependence
Modern research shows that nicotine acts on the brain to produce a number of
effects. Specifically, its addictive nature has been found to show that
nicotine activates reward pathways—the circuitry within the brain that
regulates feelings of pleasure and euphoria.
Dopamine is one of the key neurotransmitters actively involved in the brain. Research shows that by
increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a
chemical with intense addictive qualities. In many studies it has been shown to
be more addictive than cocaine, and even heroin, though chronic treatment has an opposite effect on reward
thresholds. Like other physically addictive drugs, nicotine causes
down-regulation of the production of dopamine and other stimulatory
neurotransmitters as the brain attempts to compensate for artificial
stimulation. In addition, the sensitivity of nicotinic acetylcholine receptors
decreases. To compensate for this compensatory mechanism, the brain inturn
upregulates the number of receptors, convoluting its regulatory effects with
compensatory mechanisms meant to counteract other compensatory mechanisms. The
net effect, is an increase in reward pathway
sensitivity, opposite of other drugs of abuse (namely cocaine and heroin, which
reduces reward pathway sensitivity). This neuronal brain alteration persists
for months after administration ceases. Due to an increase in reward pathway
sensitivity, nicotine withdrawal is relatively mild compared to ethanol or
heroin withdrawal. Also like other highly addictive drugs, nicotine is
addictive to many animals besides humans. Mice will self-administer nicotine
and experience behavioral unpleasantries when its administration is stopped.
Gorillas have learned to smoke cigarettes by watching humans, and have similar
difficulty quitting.
Nicotinic receptors are pentamers of these subunits; i.e., each receptor
contains five subunits. Thus, there is an immense potential of variation of the
aforementioned subunits. However, some of them are more notable than others, to
be specific, (α1)2β1δε (muscle-type), (α3)2(β4)3 (ganglion-type),
(α4)2(β2)3 (CNS-type) and (α7)5 (another
CNS-type).[23] A comparison follows:
Receptor-type |
Location |
Effect |
||
Muscle-type: |
·
α-bungarotoxin ·
atracurium* |
|||
Ganglion-type: |
·
nicotine |
·
ibogaine |
||
Heteromeric
CNS-type: |
Post- and presynaptic
excitation |
·
nicotine ·
cytisine |
||
Further
CNS-type: |
·
nicotine ·
cytisine |
|||
Post- and presynaptic
excitation, mainly by increased Ca2+ permeability |
Arterioles |
Vasoconstriction, hypertension |
|
Veins |
Sympathetic |
Vasoconstriction,
increased venous return |
Heart |
Parasympathetic |
Tachycardia |
Parasympathetic |
Increased
motility and secretions |
Effects of
Nicotine on the CNS
Post-synaptic nAchR neurons are rare in CNS
(left) while pre-synaptic nAchR neurons are common (right). Main CNS effect of nicotine is to cause
release of other neurotransmitters which act on their post-synaptic receptors. Presynaptic release of acetylcholine is mimicked by
nicotine. Nicotine activates pre-synaptic nAchR;
Calcium influx depolarizes cell and causes release of glutamate which acts on
post-synaptic gluamate receptors.
A
study found that nicotine exposure in adolescent mice retards the growth of the
dopamine system, thus increasing the risk of substance abuse during adulthood [5].
There is only anecdotal evidence about abuse or addiction
with nicotine gum or nicotine patches.
Toxicology
The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 40–60 mg can be a lethal dosage for adult human beings.[6] This makes it an extremely deadly poison. It is more toxic
than many other alkaloids such as cocaine, which has a lethal dose of 1000 mg.
The carcinogenic properties of nicotine in standalone form, separate from
tobacco smoke, have not been evaluated by the IARC, and it has not been assigned to an official carcinogen
group. The currently available literature indicates that nicotine, on its own,
does not promote the development of cancer in healthy tissue and has no mutagenic properties.
Its teratogen
properties have not yet been adequately researched, and while the likelihood of
birth defects caused by nicotine is believed to be very small or nonexistent,
nicotine replacement product manufacturers recommend consultation with a
physician before using a nicotine patch or nicotine gum while pregnant or nursing. However, nicotine and the
increased cholinergic activity it causes have been shown to impede apoptosis, which is one of the methods by which the body destroys
unwanted cells (programmed cell death). Since apoptosis helps to remove mutated or damaged cells that may eventually
become cancerous, the inhibitory actions of nicotine creates a more favourable
environment for cancer to develop. Thus nicotine plays an indirect role in carcinogenesis. It
is also important to note that its addictive properties are often the primary
motivating factor for tobacco smoking, contributing to the proliferation of cancer.
At least one study has
concluded that exposure to nicotine alone, not simply as a component of
cigarette smoke, could be responsible for some of the neuropathological changes
observed in infants dying from Sudden Infant Death Syndrome (SIDS).[7]
It has been noted that
the majority of people diagnosed with schizophrenia smoke tobacco. Estimates for the number of
schizophrenics that smoke range from 75% to 90%. It was recently argued
that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine. [8] [9] More recent research has found the
reverse, that it is a risk factor without long-term benefit, used only for its
short term effects. [10]However, research on nicotine as administered through a patch
or gum is ongoing.
Lobeline is a natural alkaloid found in
"Indian tobacco" (Lobelia inflata), "Devil's tobacco" (Lobelia tupa), "cardinal flower" (Lobelia
cardinalis), "great
lobelia" (Lobelia
siphilitica), and Hippobroma
longiflora. In its pure
form it is a white amorphous powder which is freely soluble in water.
Lobeline has been used as a smoking cessation aid,[1][2][3] and may
have application in the treatment of other drug addictions such as addiction to
amphetamines,[4][5] cocaine[6] or
alcohol.[7]
Lobeline has multiple mechanisms of action, acting as
a VMAT2 ligand,[8][9][10] which
stimulates dopamine release
to a moderate extent when administered alone, but reduces the dopamine release
caused by methamphetamine.[11][12] It also
inhibits the reuptake of dopamine and serotonin,[13] and acts
as a mixed agonist–antagonist at nicotinic
acetylcholine receptors [14][15] to which
it binds at the subunit interfaces of the extracellular domain. [16] and an
antagonist at μ-opioid
receptors.[17]
Cholinergic Antagonists
The
most common side effects of cholinergic antagonists
PHARMACOLOGY OF NEUROMUSCULAR TRANSMISSION
A.
There are two general classes of neuromuscular blocking drugs. They are the
competitive, and the depolarizing blockers. The prototype of the competitive
blockers is curare.
B.
Although the South American arrow poisons have fascinated scientists since the
1500s, the modern clinical use of curare dates to 1932 when it was first used
in patients with tetanus. Its first trial for muscular relaxation in general
anesthesia occurred in 1942.
II.
Pharmacology of Competitive Neuromuscular blockers
A.
Examples
1.
d-tubocurarine, metocurine, pancuronium
a.
Long lasting duration of blockade
2.
Vecuronium, atracurium, rocuronium
a.
Intermediate duration
3.
Mivacurium
a.
Short acting
B.
Actions on skeletal muscles:
1.
After I.V. injection, the onset of effects is rapid. Motor weakness rapidly
progresses to flaccid paralysis. Small muscles such as those of the fingers and
extraocular muscles of the eyes are effected before
those of the limbs, neck, and trunk. Subsequently, the intercostal muscles and
finally the diaphragm is paralyzed. Recovery of
function occurs in the reverse order, with the diaphragm recovering first.
Death is due to paralysis of the muscles of respiration.
C.
CNS effects
1.
Almost all contain a quaternary nitrogen therefore
they do not cross the blood brain barrier.
D.
Effects on Autonomic Ganglia
1.
Although tubocurarine
is more potent at Nm receptors than at Nn receptors of ganglia, some degree of
nicotinic receptor blockade is probably produced at autonomic ganglia and the
adrenal medulla by usual clinical doses. The net result is hypotension and
tachycardia. One also sees a decrease in the tone and motility of the GI tract.
Vecuronium, Atracurium, Rocuronium
cause considerably less ganglionic blockade.
E.
Effects on Histamine release
1.
Tubocurarine, Atracurium, and
Metocurine cause the release of histamine with resulting
hypotension, bronchospasm, and excessive bronchial and salivary secretions. Vecuronium causes less release of
histamine, while Pancuronium causes
essentially no release of histamine.
F.
Drug Interactions with Competitive Neuromuscular Blockers
1.
Synergistic potentiation
occurs with a variety of inhalation anesthetic agents such as halothane, enflurane, isoflurane.
Aminoglycoside antibiotics (...mycins) inhibit release of ACh
and thereby potentiate the Nm blockers. Tetracyclines
also produce some neuromuscular blockade, possibly by chelating Ca++.
2.
Anticholinesterases such as neostigmine,
pyridostigmine, and edrophonium will antagonize the effects of the competitive
neuromuscular blockers.
G.
Pharmacokinetics
1.
Tubocurarine and metocurine, pancuronium are excreted
primarily by the kidneys.
2.
Atracurium and Mivacurium
are metabolized by plasma esterases (accounting for briefer duration of
action).
3.
Vecuronium and Rocuronium
are metabolized by the liver.
4.
Because of their ionized structures, they are poorly absorbed orally, and are
given i.v.
H.
Toxicity
1.
Prolonged apnea:
2.
Hypotension (ganglionic blockade, inhibition of release of catecholamines from
medulla, release of histamine):
3.
Bronchospasm and increased secretions due to histamine release.
III.
Pharmacology of Depolarizing Neuromuscular Blockers
A.
Mechanisms of action and effects on skeletal muscle
1.
The depolarizing blockers succinylcholine
and decamethonium
(C-10 no longer available in the USA) block transmission by causing prolonged
depolarization of the end plate at the neuromuscular junction. This is
manifested as an initial series of twitches (fasciculations), followed by
flaccid paralysis. This is referred to as phase one blockade.
a.
Phase 1 blockade is potentiated by anticholinesterases and antagonized
by competitive blockers.
2.
If the duration of blockade is prolonged however, or if the concentration of
the blocker is excessive, then phase two blockade occurs in which the
pharmacological characteristic is that of a competitive inhibition.
a.
Phase 2 blockade is antagonized by anticholinesterases, and potentiated
by competitive blockers.
B.
Effects on the CNS
1.
Both compounds contain quaternary nitrogens and therefore do not cross the BBB.
C.
Effects on autonomic ganglia are relatively rare.
D.
Histamine is released by succinylcholine, but not by decamethonium.
E.
Drug interactions
1.
Potentiation of the neuromuscular blockade caused by the aminoglycoside antibiotics (mycins),
and tetracyclines.
2.
Do not potentiate the effects of the halogenated hydrocarbon anesthetics
(halothane et al).(Mechanism unclear).
3.
Phase 1 block potentiated by anticholinesterases and antagonized by competitive
blockers.
4.
Phase 2 block antagonized by anticholinesterases and
potentiated by competitive blockers.
5.
Lithium in therapeutic
concentrations used in the treatment of manic disorders can slow the onset and
increase the duration of action of succinylcholine.
Neuromuscular Physiology
The
neuromuscular junction consists of:
1.
a motor nerve ending with mitochondria and
acetylcholine vesicles(prejunctional)
2.
a synaptic cleft of 20-30nm in width containing
extracellular fluid .
3.
a highly folded skeletal muscle membrane(post
junctional)
4
.nicotinic cholinergic receptors located on both the presynaptis and
postsynaptic membranes.
F.
Pharmacokinetics
1.
Succinylcholine is a
structural analogue of ACh which is metabolized rapidly by plasma esterases.
Thus it has an ultrashort duration of action. Some patients who have a
prolonged response to the action of succinylcholine have a genetic deficiency
in plasma cholinesterase. Procaine type local anesthetics are also metabolized
by plasma cholinesterases, and will competitively inhibit the metabolism of
succinylcholine, resulting in a prolonged duration of action.
2.
Decamethonium is
excreted directly by the kidney.
3.
Because of their ionized structure, they are poorly absorbed orally, and are
given i.v.
Mechanism of action of competitive neuromuscular blocking drugs.
At high
doses: Nondepolarizing blockers can block the ion channels of the end
plate. This leads to further weakening of neuromuscular transmission, and it
reduces the ability of acetylcholinesterase inhibitors to reverse the actions
of nondepolarizing muscle relaxants.
Actions: Not all muscles are
equally sensitive to blockade by competitive blockers. Small, rapidly
contracting muscles of the face and eye are most susceptible and are paralyzed
first, followed by the fingers. Thereafter, the limbs, neck, and trunk muscles
are paralyzed. Then the intercostal muscles are affected, and lastly, the
diaphragm muscles are paralyzed. Those agents (for example, tubocurarine,
mivacurium, and atracurium), which release histamine, can produce a fall
in blood pressure, flushing, and bronchoconstriction.
Therapeutic uses: These blockers
are used therapeutically as adjuvant drugs in anesthesia during surgery to
relax skeletal muscle. These agents are also used to facilitate intubation as
well as during orthopedic surgery.
Pharmacokinetics: All
neuromuscular blocking agents are injected intravenously, because their uptake
via oral absorption is minimal.
G.
Toxicity
1.
Prolonged apnea
2.
Malignant hyperthermia
can occur when patients are receiving halothane and succinylcholine. It is one
of the main causes of death due to anesthesia.
a.
In vitro tests are available to evaluate susceptibility to malignant
hyperthermia and results in a prediction of susceptible, normal, or equivocal.
Malignant hyperthermia is treated by rapid cooling, inhalation of O2,
and treatment with Dantrolene. This drug blocks release of Ca++ from the
sarcoplasmic reticulum and reduces muscle tone and heat production.
3.
During prolonged depolarization, muscle cells may lose significant quantities
of K+. In patients in whom there has been extensive injury to soft tissues the
efflus of K+ following continued administration of succinylcholine can be life
threatening due to hyperkalemia.
a.
Administration of succinylcholine is contraindicated or very dangerous because
of life threatening hyperkalemia in such conditions as burns, trauma, spinal
cord injuries with paraplegia or quadriplegia, and muscular dystrophies. In
these cases, competitive neuromuscular blockers should be used.
IV.
Therapeutic Uses of Neuromuscular Blockers
A.
Mainly as adjuvants to surgical anesthesia to cause muscle relaxation.
B.
In orthopedics to facilitate correction of dislocations and alignment of
fractures.
C.
To facilitate endotracheal intubation
D.
To prevent trauma in electroconvulsive shock therapy
E.
In treatment of severe cases of tetanus
I.
Ganglionic Neurotransmission
A.
The primary event at autonomic ganglia is the rapid depolarization of
postsynaptic Nn receptors by ACh. The duration of this event is on the order of
milliseconds. This effect is blocked by hexamethonium.
B.
The next event seen is the development of an IPSP which also lasts only
milliseconds. The IPSP is blocked by both
atropine, and by alpha adrenergic blockers. This evidence suggests that a
preganglionic cholinergic nerve terminal in the ganglion acts on M2 receptors
to activate a catecholaminergic interneuron (probably containing dopamine)
which then synapses on the postganglionic neuron.
C.
The next event is the development of the late EPSP. This event lasts on the
order of 30-60 seconds. It is blocked by atropine and appears to be due to the
activation of M1 receptors.
D.
Finally one sees the late
slow EPSP, which persists for several minutes. This appears to be due to the
action of multiple peptides including VIP, SP, NPY, Enkephalin, etc.
E.
It should be emphasized that the secondary events of ganglionic transmission
modulate the primary depolarization, by making it more or less likely to occur.
This is so because these secondary events either facilitate or inhibit the
processes of spatial and temporal summation of subthreshold depolarizing
stimuli. The relative importance of secondary pathways and receptors also
appear to differ between different parasympathetic and sympathetic ganglia.
Remember that conventional Nn receptor antagonists can inhibit ganglionic
transmission completely, but muscarinic antagonists, alpha adrenergic
antagonists, and peptidergic antagonists can not do so.
II.
Ganglionic Stimulating Drugs
A. Nicotine
is an alkaloid isolated from the leaves of tobacco, Nicotiana tabacum in 1828.
Its pharmacological actions are complex and often unpredictable because 1) its
effects are on both sympathetic and parasympathetic ganglia,
and 2) because stimulation is frequently followed by depolarization blockade.
The drug also can stimulate and desensitize receptors. The ultimate response of
any one system thus represents the summation of several different and opposing
effects of nicotine. For example, heart rate can be increased by excitation of
sympathetic or inhibition of parasympathetic ganglia. Conversely, heart
rate can be decreased
by excitation of parasympathetic or inhibition of sympathetic ganglia. Nicotine
also 1) stimulates release of Epi from the adrenal medulla, 2) excites
cardiorespiratory reflexes by a direct effect on the chemoreceptors of the
carotid and aortic bodies, 3) excites cardiovascular responses secondary to
evoked blood pressure changes mediated by baroreceptors, and 4) stimulates and
blocks CNS cholinergic pathways in the medulla influencing heart rate.
2.
Nicotine also stimulates the nicotinic receptors of muscle (Nm), and this is
followed rapidly by depolarization blockade.
3.
Nicotine stimulates sensory receptors including mechanoreceptors,
thermoreceptors, and pain receptors.
5.
Nicotine is readily absorbed from the respiratory tract, oral membranes, and
skin. Since nicotine is a strong base it is highly ionized in the stomach and
hence poorly absorbed from the stomach. It is metabolized primarily in the
liver, but also in the lung and kidney. Both nicotine and its metabolites are
rapidly excreted by the kidney. Nicotine is excreted in the milk of lactating
mothers who smoke.
6.
Poisoning occurs from exposure to insecticides containing nicotine, or in
children by accidental ingestion of tobacco products. Death may result within a
few minutes from respiratory failure. For therapy, vomiting should be induced
with syrup of ipecac, or gastric lavage performed. Activated charcoal is then
passed into the stomach to bind free nicotine.
B.
Other ganglionic stimulants
1.
Tetramethyl ammonium (TMA)
and dimethylphenyl piperazinium (DMPP)
are also ganglionic stimulants. They differ from nicotine primarily in the fact
that stimulation is not followed by ganglionic depolarization blockade.
III.
Ganglionic blocking drugs
Ganglionic
Blockers
Ganglionic
blockers specifically act on the nicotinic receptors of both parasympathetic
and sympathetic autonomic ganglia. Some also block the ion channels of the
autonomic ganglia. These drugs show no selectivity toward the parasympathetic
or sympathetic ganglia and are not effective as neuromuscular antagonists.
Thus, these drugs block the entire output of the autonomic nervous system at
the nicotinic receptor. Except for nicotine, the other drugs mentioned in this
category are nondepolarizing, competitive antagonists. The responses observed
are complex and unpredictable, making it impossible to achieve selective
actions. Therefore, ganglionic blockade is rarely used therapeutically.
However, ganglionic blockers often serve as tools in experimental pharmacology.
|
A.
The available ganglionic blockers in the U.S.A. are trimethaphan and mecamylamine. They are competitive
antagonists. Trimethaphan has a positive charge, while mecamylamine does not,
therefore trimethaphan is given intravenously and acts peripherally, while
mecamylamine can be given orally, but crosses the blood-brain barrier.
Trimethaphan is rapidly excreted in unchanged form by the kidney. Mecamylamine
is excreted by kidney much more slowly. Other ganglionic blockers that you may
hear about include hexamethonium
and pentolinium, but
they are no longer in clinical use in the U.S.
B.
Pharmacological properties of ganglionic blockers can often be predicted by
knowing which division of the ANS exerts dominant control of various organs ie
SITE PREDOMINANT TONE EFFECT OF GANGLIONIC BLOCKADE
Blood vessels |
Sympathetic |
Vasodilation, hypotension |
Sweat glands |
Sympathetic |
Anhidrosis |
Heart |
Parasympathetic |
Tachycardia |
Iris |
Parasympathetic |
Mydriasis |
GI tract |
Parasympathetic |
Reduced tone and motility |
Bladder |
Parasympathetic |
Urinary retention |
Salivary Gland |
Parasympathetic |
Xerostomia (reduced secretions) |
1.
The importance of existing sympathetic tone in determining the extent to which
blood pressure is reduced by ganglionic blockers is illustrated by the fact
that they may have little or no effect when the patient is recumbent, but cause
orthostatic hypotension when shifting to the standing state, because standing
activates sympathetic reflexes to prevent pooling of blood in the feet. Since
these reflexes are blocked postural hypotension is a major problem in
ambulatory patients. In the old days, these compounds were in fact used for the
treatment of hypertension, but they were abandoned as more selective treatment
became available, which did not cause so many side effects. Some of the more
severe side effects include marked hypotension, constipation, fainting,
paralytic ileus, and urinary retention. For mecamylamine, which crosses the
blood-brain barrier, large doses can cause tremors, mental confusion, seizures,
mania or depression. The only remaining use of ganglionic blockers in
hypertension is for the initial control of blood pressure in patients with
acute dissecting aortic aneurysm. An additional use of these compounds is in
the production of controlled hypotension during surgery in order to minimize
hemmorhage in the operative field, and to facilitate surgery on blood vessels.
Trimethaphan can be used in the treatment of autonomic hyperreflexia. This
syndrome is commonly seen in patients with injuries of the spinal cord in whom
minimal provocation (ie distended bladder) can elicit profound sympathoadrenal
discharge.
Adrenergic receptor-activating
drugs. Adrenergic
receptor-blocking drugs. Sympatholytic agents
The adrenergic drugs affect receptors
that are stimulated by norepinephrine or epinephrine.
Some adrenergic drugs act directly on the adrenergic receptor (adrenoceptor) by
activating it and are said to be sympathomimetic. Others block the action of
the neurotransmitters at the receptors (sympatholytics), whereas still other
drugs affect adrenergic function by interrupting the release of norepinephrine
from adrenergic neurons.
The Adrenergic
Neuron
Adrenergic neurons release norepinephrine as the
primary neurotransmitter. These neurons are found in the central nervous system
(CNS) and also in the sympathetic nervous system, where they serve as links
between ganglia and the effector organs. The adrenergic neurons and receptors,
located either presynaptically on the neuron or postsynaptically on the
effector organ, are the sites of action of the adrenergic drugs.
A.
Neurotransmission at adrenergic neurons
Neurotransmission in adrenergic neurons closely
resembles that already described for the cholinergic neurons, except that
norepinephrine is the neurotransmitter instead of acetylcholine. Neurotransmission
takes place at numerous bead-like enlargements called varicosities. The process
involves five steps:synthesis, storage, release, and receptor binding of
norepinephrine, followed by removal of the neurotransmitter from the synaptic
gap.
Synthesis and release of
norepinephrine from the adrenergic neuron. (MAO = monoamine oxidase.)
Potential
fates of recaptured norepinephrine: Once norepinephrine reenters the cytoplasm
of the adrenergic neuron, it may be taken up into adrenergic vesicles via the
amine transporter system and be sequestered for release by another action
potential, or it may persist in a protected pool. Alternatively, norepinephrine
can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria.
The inactive products of norepinephrine metabolism are excreted in the urine as
vanillylmandelic acid, metanephrine, and normetanephrine.
B.
Adrenergic receptors (adrenoceptors)
In the
sympathetic nervous system, several classes of adrenoceptors can be
distinguished pharmacologically. Two families of receptors, designated α
and β, were initially identified on the basis of
their responses to the adrenergic agonists epinephrine, norepinephrine, and
isoproterenol. The use of specific blocking drugs and the cloning of genes have
revealed the molecular identities of a number of receptor subtypes. These
proteins belong to a multigene family. Alterations in the primary structure of
the receptors influence their affinity for various agents.
α1 and α2 Receptors: The
α-adrenoceptors show a weak response to the synthetic agonist
isoproterenol, but they are responsive to the naturally occurring
catecholamines epinephrine and norepinephrine (Figure 6.4). For α
receptors, the rank order of potency is epinephrine ≥ norepinephrine
>> isoproterenol. The α-adrenoceptors are subdivided into two
subgroups, α1 and α2, based on their affinities for α agonists
and blocking drugs. For example, the α1 receptors have a higher affinity
for phenylephrine than do the α2 receptors. Conversely, the drug clonidine
selectively binds to α2 receptors and has less effect on α1
receptors.
α1
Receptors: These receptors are present on the postsynaptic membrane of the
effector organs and mediate many of the classic effects—originally designated
as α-adrenergic—involving constriction of smooth muscle. Activation of
α1 receptors initiates a series of reactions through a G protein activation
of phospholipase C, resulting in the generation of inositol-1,4,5-trisphosphate
(IP3) and diacylglycerol (DAG) from phosphatidylinositol. IP3 initiates the
release of Ca2+ from the endoplasmic reticulum into the cytosol, and DAG turns
on other proteins within the cell.
α2 Receptors: These receptors, located primarily on
presynaptic nerve endings and on other cells, such as the β cell of the
pancreas, and on certain vascular smooth muscle cells, control adrenergic
neuromediator and insulin output, respectively. When a sympathetic adrenergic
nerve is stimulated, the released norepinephrine traverses the synaptic cleft
and interacts with the α1 receptors. A portion of the released
norepinephrine “circles back” and reacts with α2 receptors on the neuronal
membrane (see Figure 6.5). The stimulation of the α2 receptor causes
feedback inhibition of the ongoing release of norepinephrine from the
stimulated adrenergic neuron. This inhibitory action decreases further output
from the adrenergic neuron and serves as a local modulating mechanism for
reducing sympathetic neuromediator output when there is high sympathetic
activity. [Note: In this instance these receptors are acting as inhibitory
autoreceptors.] α2 Receptors are also found on
presynpatic parasympathetic neurons. Norepinephrine released from a presynaptic
sympathetic neuron can diffuse to and interact with these receptors, inhibiting
acetylcholine release [Note: In these instances these receptors are behaving as
inhibitory heteroreceptors.] This is another local modulating mechanism to
control autonomic activity in a given area. In contrast to α1 receptors,
the effects of binding at α2 receptors are mediated by inhibition of
adenylyl cyclase and a fall in the levels of intracellular cAMP.
Further subdivisions: The α1 and α2 receptors are further
divided into α1A, α1B, α1C, and
α1D and into α2A, α2B, α2C, and α2D. This extended
classification is necessary for understanding the selectivity of some drugs.
For example, tamsulosin is a selective α1A antagonist that is used to
treat benign prostate hyperplasia. The drug is clinically useful because it
targets α1A receptors found primarily in the urinary tract and prostate
gland.
History:
A. Finklemann
in 1930 stimulated the sympathetic input to rabbit intestine and found a
decrease in spontaneous movements. Perfusate did the same thing to a 2nd piece
of intestine. Effects mimicked by "adrenaline". B. Von Euler 1946
demonstrated that NE, not EPI is the main endogenous catecholamine in
sympathetically innervated tissue. C. The study of the sympathetic nervous
system is important from a clinical perspective. The SNS is involved in
controlling heart rate, contractility, blood pressure, vasomotor tone,
carbohydrate and fatty acid metabolism etc. Stimulation of the SNS occurs in
response to physical activity, psychological stress, allergies etc. Drugs
influencing the SNS are used in treatment of hypertension, shock, cardiac
failure and arrhythmias, asthma and emphysema, allergies and anaphylaxis. D.
There are three major catecholamines: NE, EPI, and DA naturally found in the
body. EPI and NE mediate the response of the sympathoadrenal system to
activation, and are also found in the CNS. DA is primarily a CNS
neurotransmitter.
I. Sympathomimetic amines have 7 major classes of action
A. A peripheral excitatory action: ie on
smooth muscles of blood vessels supplying skin.
B. A peripheral inhibitory action: ie on
smooth muscles of gut, bronchioles, and blood vessels supplying skeletal
muscle.
C. A cardiac excitatory action: ie
positive chronotropic, dromotropic, and inotropic effects.
D. Metabolic actions: ie enhanced
glycogenolysis and lipolysis.
E. Endocrine actions: ie modulation of
secretion of insulin
F. CNS actions: ie increased wakefulness
and inhibition of appetite.
G.
Presynaptic actions: ie inhibition of release of NE, NPY, and ACh at autonomic
nerve terminals by activation of alpha 2 receptors. Enhanced release of ACh by
activation of presynaptic alpha 2 receptors on somatic motor neurons.
Enhanced release of NE, and NPY by activation of Beta 2 receptors.
Classification of
adrenergic receptor agonists:
II. Pharmacology of Epinephrine A.
Epinephrine is a potent stimulator of both alpha (1 & 2) and beta (1,2,
& 3) receptors, therefore, its effects on target organs is complex.
B. Effects of EPI on blood
pressure are dose dependent. 1. When given in large doses
intravenously, EPI gives a rapid increase in blood pressure. As the response
wanes, the mean pressure falls below normal before returning to control levels.
The pressor effects are due to A) the positive inotropic effect of EPI, B) the
positive chronotropic effect, and C) vasoconstriction in many vascular beds.
The depressor effect is due to the activation of vasodilator beta 2 receptors
in the vasculature perfusing skeletal muscle. This effect is not seen initially
because it is overwhelmed by the vasoconstrictive effect of alpha 1 receptors
on vascular smooth muscle at other sites, however vasoconstriction is lost as
the concentration of EPI goes down, but the beta 2 mediated vasodilatory effect
is retained. If you pretreat a person with an alpha adrenergic receptor
blocker, one sees the so-called epinephrine reversal effect ie the unopposed
effect of the beta 2 receptors causes a pronounced decrease in total peripheral
resistance, and mean blood pressure falls in response to EPI.
2. When given in small doses, there is
little or no effect on the mean blood pressure because the increase in blood
pressure resulting from increased heart rate and contractility is counteracted
by the decrease in total peripheral resistance due to vasodilation in blood
vessels perfusing skeletal muscle. You will recall that these beta 2 receptors
have a lower threshold to activation than alpha 1 receptors, therefore the net
effect of low doses of EPI is
vasodilation.
3. When EPI causes an increase in mean
arterial pressure (High doses), it activates a compensatory vagal baroreceptor
mediated bradycardia which also helps to return blood pressure toward normal.
C. Effects of EPI on vascular
smooth muscle is variable, resulting in a substantial redistribution
of blood flow. That is, EPI causes a marked reduction of blood flow through the
skin by activating its alpha 1 receptors, while simultaneously redistributing
flow through the muscles by causing vasodilation there through the activation
of Beta 2 receptors. This has obvious utility in survival of the organism by
preparing it for fight or flight. EPI can reduce renal blood flow by 40% in
doses that do not effect mean blood pressure. Effects of EPI on Cerebral
Circulation. No significant constrictor action on cerebral blood
vessels. If you think about it, it is a lucky thing that the blood flow to the
brain is not restricted during responses to stressors.
D. Effects of EPI on Cardiac
Muscle are mediated primarily by beta 1 receptors, although Beta 2 and
alpha receptors are also present in the heart. As indicated before, EPI has a
powerful chronotropic and inotropic effect. EPI reduces the time for systole
and makes it more powerful without decreasing the duration of diastole. The latter effect occurs because EPI also increases
the rate of relaxation of ventricular muscle.
Cardiac output is enhanced and the work of the heart and its oxygen
consumption are markedly increased. Cardiac efficiency (work done relative to
oxygen consumption) is lessened! The
chronotropic action of EPI is due to its ability to accelerate the slow
depolarization of pacemaker cells of the SA node that takes place during
diastole. Large doses may provoke cardiac arrhythmias. Large doses of EPI, or
long term elevation of plasma catecholamines damages the myocardium. This may
in part explain the beneficial effects of beta blockers in heart failure.
E. Effects of EPI on Other
Smooth Muscles. In general GI muscle is relaxed, and resting
tone and peristaltic movements are reduced. This is due to the inhibitory
effect of beta 2 receptors, and possibly also due to inhibition of release of
ACh by activation of inhibitory presynaptic alpha 2 receptors on cholinergic
nerve terminals. The response of the uterus is variable depending on
phase of the sexual cycle, state of gestation, and dose of the drug. During the
last month of pregnancy, EPI inhibits uterine tone and contractions, by
activating beta 2 receptors. As a result, selective beta 2 agonists are used to
delay the onset of premature labor. Bronchial smooth muscle is powerfully
relaxed by EPI via activation of Beta 2 receptors. Selective beta 2 agonists
are used in the treatment of asthma. Epi relaxes the detrusor muscle of the
bladder by activating beta receptors, and contracts the trigone and sphincter
muscles due to alpha agonist effects. the result is urinary retention.
F. Metabolic effects of
EPI:
1. Glycogenolysis via activation of beta
2 receptors, results in an increase in blood glucose.
2. Lipolysis via activation of beta 3
receptors, results in an increase in the concentration of free fatty acids in
blood.
3. Insulin secretion is inhibited by
alpha 2 receptors, and increased by beta 2 receptors, but inhibition
predominates in man.
4. EPI promotes a fall in plasma K due
to enhanced uptake of K into skeletal muscle via an action on Beta 2
receptors. This action has been
exploited in the management of hyperkalemia.
G. Absorption and fate of EPI
1. Absorption of EPI as well as other
catecholamines from GI tract is negligible due to rapid conjugation and
oxidation in the intestinal mucosa of the GI tract and liver. Subcutaneous
absorption slow due to vasoconstriction. Inhaled effects largely restricted to
the respiratory tract in low doses. Larger doses can give systemic effects,
including arrhythmias. The liver which is rich in both COMT and MAO destroys
most circulating EPI.
H.
Toxicity and contraindications
1.
EPI causes disturbing reactions such as fear, anxiety, tenseness, restlessness,
headache, tremor , weakness, dizziness, etc. Hyperthyroid, and hypertensive
patients are particularly susceptible.
2.
More serious reactions include cardiac arrhythmias, including fatal ventricular
arrhythmias when EPI is given to a patient anesthetized with halogenated
hydrocarbon anesthetics such as halothane. Also cerebral hemmorhage due to
severe hypertension has occurred. Use of EPI in patients receiving nonselective
Beta blockers is contraindicated because the unopposed actions of EPI on
vascular alpha 1 receptors can lead to severe hypertension and cerebral
hemmorhage.
I. Therapeutic uses of EPI
1. Relief of bronchospasm
2. Relief of hypersensitivity reactions
and anaphylaxis
3. To prolong the duration of action of
local anesthetics.
4. As a topical hemostatic to control
superficial bleeding from skin and mucosae
5. To restore cardiac rhythm in patients
with cardiac arrest.
III. Pharmacology of
Norepinephrine A. Cardiovascular
effects of NE
1.
NE is a potent agonist at alpha and Beta 1 receptors, and has little action
on beta 2 receptors, therefore when given by intravenous infusion of low
doses, NE causes a pronounced increase in total peripheral resistance (i.e.
because there is no opposing Beta 2
mediated vasodilation). This is combined with its direct inotropic effect on
the heart to cause a substantial increase in mean blood pressure, and a
reflexly mediated bradycardia. In contrast to EPI, pretreatment with an alpha 1
antagonist will block the pressor effects of NE, but will not cause reversal to
a depressor effect. Since the effects of NE are mainly on alpha and Beta 1
receptors, indirectly acting sympathomimetics which act by releasing NE have
predominantly alpha mediated and cardiac effects.
B.
Other responses to NE are not prominent in Man.
C.
Toxicity
1. The toxic effects of NE are like
those of EPI, except they ar less pronounced and less frequently seen ie
anxiety, headache, palpitations, etc. In toxic doses, can get severe
hypertension. NE, like EPI is contraindicated in anesthesia with drugs that
sensitize the heart to the arrhythmic effects of catecholamines such as
halothane. Accidental extravasation of NE during attempted intravenous infusion
can cause local anoxic necrosis and impaired circulation through the limb. In
pregnant females, NE should not be used because it stimulates alpha 1 receptors
in the uterus that cause contraction.
D. Therapeutic uses
1. Currently very little therapeutic
use. Sometimes used as a cardiac stimulant in cardiogenic or septicemic shock.
IV. Pharmacology of Dopamine
A.
Cardiovascular effects
1.
At low doses DA activate D 1 receptors in renal, mesenteric, and coronary
vascular beds. This leads to vasodilation. Increased flow through renal blood
vessels is useful in cardiogenic and septicemic shock when perfusion of vital
organs is compromised. DA activates Beta 1 receptors at higher concentrations
leading to a positive inotropic effect. Total peripheral resistance is usually
unchanged, although at higher concentrations DA can cause activation of alpha 1
receptors mediating vasoconstriction.
B.
Toxicity
1.
Toxicity of high doses of DA is similar to that noted above for NE. Since the
drug has an extremely short half life in plasma, DA toxicity usually disappear
quickly if the administration is terminated.
C.
Therapeutic uses
1.
Useful in treatment of severe congestive heart failure, particularly in
patients with oliguria or impaired renal function. DA is also useful in the treatment of cardiogenic and septic shock
in patients with reduced renal function.
C. DA Agonists
1. Fenoldopam
is a rapidly acting vasodilator which is used for acute control of severe
hypertension. It is a D1 receptor
agonist as well as an alpha 2 agonist.
It does not effect alpha 1 or beta receptors. The half life of fenoldopam is 10 minutes.
V. Pharmacology of
Isoproterenol
A.
Cardiovascular effects
1.
ISO is primarily a beta receptor agonist, therefore intravenous infusion of ISO
leads to a substantial reduction of total peripheral resistance.
Simultaneously, ISO causes a direct inotropic and chronotropic effect on the
heart. The net result is a reduction in mean pressure.
B.
Actions on other smooth muscles.
1.
ISO relaxes almost all varieties of smooth muscle, but particularly bronchial
and GI smooth muscle. Its effectiveness in asthma may also be due to inhibition
of the release of histamine by activation of Beta 2 receptors.
C.
Metabolic effects
1.
ISO is a potent lipolytic (Beta 3) and glycogenolytic (beta 2) drug. It also
strongly releases insulin by activating Beta 2 receptors.
D.
Metabolism
1.
Primarily by COMT, not MAO. Mainly in the liver.
E.
Toxicity
1.
Like EPI, but much less pronounced. Cardiac arrhythmias can occur readily.
F.
Therapeutic uses
1.
Used in emergencies to stimulate heart rate in patients with bradycardia or
heart block. Its use in asthma and shock has been discontinued due to
development of more selective sympathomimetics.
VI. Pharmacology of
Dobutamine
A.
The mechanisms of action of dobutamine are complex. It is given as the racemic
mixture. The l-isomer is a potent agonist at alpha 1 receptors, while the
d-isomer is a potent alpha 1 antagonist. Both isomers are beta receptor
agonists with greater selectivity for Beta 1 than beta 2 receptors. The net
result of administration of the racemic mixture is more or less selective Beta
agonist effects.
B.
Cardiovascular effects
1.
Total peripheral resistance is not much effected, presumably by the
counterbalancing effects of beta 2 agonist mediated vasodilation, and alpha 1
agonist mediated vasoconstriction. Dobutamine has a prominent inotropic
effect on the heart, without much of a chronotropic effect.
The explanation for this is unclear. Like other inotropic agents, dobutamine
may potentially increase the size of a myocardial infarct by increasing oxygen
demand.
C.
Toxicity is like isoproterenol, esp. arrhythmias
D.
Not effective orally. Given by I.V. route, however its half life in plasma is
two minutes, therefore it must be given by a continuous infusion. After a few
days, tolerance develops to its effects. This has led to short term use
repeated intermittently.
E.
Therapeutic Uses
2.
Used in the short term treatment of congestive heart failure or acute
myocardial infarctions, because of its inotropic effect, and because it does
not increase heart rate and has minimal effects on blood pressure. These
effects minimize the increased oxygen demands on the failing heart muscle.
VII Pharmacology of Selective Beta 2 Agonists
A. These compounds are mainly utilized
for treatment of asthma. Their advantage over non-selective beta agonists, is
that they do not cause undesired cardiovascular effects by stimulating beta 1
receptors of the heart.
B. Metaproterenol, Terbutaline,
Albuterol, Pirbuterol are structural analogues of the
catecholamines which have been modified so that they are not substrates of COMT
and are poor substrates for MAO. This results in a longer duration of action
compared to catecholamines and varies from 3 to 6 hours when administered by
inhalation.
C.
Formoterol is a selective
Beta 2 agonist with similarities to the above agents, however it has the
advantages a rapid onset of action (minutes) and a long duration (12 hours).
D.
Salmeterol is another long
acting Beta 2 agonist however it has a slow onset of action, therefore it is
not useful for acute asthmatic attacks. It may also have anti-inflammatory
activity.
D.
Ritodrine is a selective Beta 2 agonist which was developed as
a uterine relaxant. It is used to delay the onset of premature labor. Other
beta 2 agonists have been used for the same purpose in Europe. While these
drugs can delay the onset of birth, they may not have any significant effect in
reducing perinatal mortality and may increase maternal morbidity. Nifedepine ( a calcium channel blocker:
NOT a beta 2 blocker) caused longer postponement of delivery, fewer maternal
side effects, and fewer admissions to the neonatal intensive care unit.
E. Adverse effects of Beta 2 agonists
1. Skeletal muscle tremor is the most
common adverse side effect. This may be due to the presence of Beta 2 receptors
in skeletal muscle, which when activated, cause twitches and tremor. Tolerance
generally develops to this side effect.
2. Restlessness, apprehension, anxiety
3. Tachycardia may occur possibly
secondary to beta 2 receptor mediated vasodilation. In patients with heart
disease particularly, can see arrhythmias.
4. Increased glycogenolysis
5. Some recent epidemiological studies
suggest that regular use of Beta 2 agonists may actually cause
increased bronchial hyperreactivity and deterioration in the control of asthma.
In patients requiring regular use of these drugs, strong consideration should
be given to the use of additional or alternative therapies, such as use of
inhaled glucocorticoids.
VIII. Pharmacology of
Alpha 1 Agonists
A. Phenylephrine and Methoxamine
1. Primarily directly acting
vasoconstrictors by activating alpha 1 receptors. The resulting hypertension
results in a prominent reflex bradycardia. They are used in the treatment of
atrial tachycardia to terminate the arrhythmia by causing a reflex bradycardia.
Phenylephrine is also used as a nasal decongestant and mydriatic. They are not
metabolized by COMT, therefore they also have a longer duration of action than
the catecholamines.
B.
Mephentermine and Metaraminol
1.
These drugs have two effects: a) They are directly acting alpha 1 agonists, and
b) they are indirectly acting sympathomimetics ie they cause the release of
endogenous norepinephrine. The direct effect on alpha 1 receptors mediates
vasoconstriction and an increased blood pressure. The indirect effect of
released NE on the heart is a positive inotropic and chronotropic action that
also increases blood pressure. This results in a reflex bradycardia. Both drugs
are administered intravenously. Adverse effects are due to CNS stimulation,
excessive increases in blood pressure, and arrhythmias. They are used in the
treatment of the hypotension which is frequently associated with spinal
anesthesia. Metaraminol is also used in the termination of paroxysmal atrial
tachycardia, particularly in patients with existing hypotension.
C. Midodrine1. It is an orally effective alpha 1 agonist
which is a prodrug. Its activity is due to metabolism to
desglymidodrine. Sometimes used in
patients with autonomic insufficiency and postural hypotension.
IX. Pharmacology of Alpha
2 Agonists
A. Introduction
1.
Selective alpha 2 agonists are used primarily for the treatment of hypertension.
Their efficacy is somewhat surprising since many blood vessels, especially
those of the skin and mucosa, contain post-synaptic alpha 2 receptors that
mediate vasoconstriction. Indeed clonidine, the prototype alpha 2 agonist drug
which we will consider was originally developed as a nasal decongestant because
of its ability to cause vasoconstriction of blood vessels in the nasal mucosa.
The capacity of alpha 2 agonists to lower blood pressure results from their CNS
effect, possibly from the activation of alpha 2 receptors in the medulla
that diminish centrally mediated sympathetic outflow.
B. Pharmacology of Clonidine
1. Pharmacological effects
a. Intravenous clonidine can cause a
transient rise in blood pressure due to its ability to cause vasoconstriction
via an alpha 2 agonist effect on vascular smooth muscle of skin and mucosa.
This is followed by a decreased blood pressure due presumably to activation of
CNS alpha 2 receptors, resulting in a decreased central outflow of impulses in
the sympathetic nervous system, although this is an area of intense current
research interest, and some evidence suggests that different mechanisms may be
more important. Some of the antihypertensive effect of clonidine may also be
due to diminished release of NE at sympathetic postganglionic nerve terminals
due to activation of presynaptic alpha 2 receptors. Clonidine also stimulates
parasympathetic outflow and causes slowing of the heart.
2. Pharmacokinetics
a. Clonidine is well absorbed orally,
and is nearly 100% bioavailable. The mean half life of the drug in plasma is
about 12 hours. It is excreted in an unchanged form by the kidney, and its half
life can increase dramatically in the presence of impaired renal function. A
transdermal delivery system is available in which the drug is released at a
constant rate for about a week. Three or four days are required to achieve
steady state concentrations.
3. Adverse effects
a. The major adverse effects of
clonidine are dry mouth, and sedation. Other effects include bradycardia, and
sexual disfunction. About 20% of patients develop a contact dermatitis to the
transdermal delivery system. In patients with long term therapy with clonidine,
abrupt discontinuation is associated with development of a withdrawal syndrome
and potentially life threatening hypertension.
4. Therapeutic uses
a. The major use of clonidine is in the
treatment of hypertension.
b. Clonidine is useful in the management
of withdrawal symptoms seen in addicts after withdrawal from opiates, alcohol,
and tobacco. This may be due to its ability to suppress sympathomimetic
symptoms of withdrawal.
c. Clonidine is useful in the diagnosis
of hypertension due to pheochromocytoma. In primary hypertension, clonidine
causes a marked reduction in circulating levels of norepinephrine. This is not
seen if the cause of hypertension is pheochromocytoma.
d. Apraclonidine
and Brimonidine are structural
analogues of clonidine (ie alpha 2 agonists) which are used topically in the
treatment of glaucoma by decreasing the rate of synthesis of aqueous
humor. Brimonidine also acts by
enhancing the outflow of aqueous humor.
Its efficacy in reducing intraocular pressure is equivalent to timolol.
C. Pharmacology of
Guanfacine and Guanabenz
1.
Guanfacine and guanabenz are alpha 2 receptor agonists which are also believed
to lower blood pressure by activation of central sites. Their pharmacological
effects and side effects are quite similar to clonidine. Guanfacine has a
longer mean half life in plasma than clonidine (12-24 hrs).
X. Miscellaneous
Adrenergic Agonist Drugs A. Amphetamine
1.
Amphetamine is an indirectly acting sympathomimetic which causes release of NE
from adrenergic nerve endings, and also blocks its reuptake into the cytoplasm
of the nerve terminal. As such it has potent peripheral effects on alpha 1
& 2 receptors, and Beta 1, but not beta 2 receptors. It is also a potent CNS stimulant which is
orally effective.
2.
Cardiovascular effects of amphetamine include increased blood pressure, and
reflex bradycardia. In larger doses see cardiac arrhythmias.
3.
Other smooth muscles respond to amphetamine as they do to previously described
sympathomimetics. The contractile effect on the sphincter of the urinary
bladder is particularly pronounced and has been used for the treatment of
incontinence.
4.
Amphetamine is one of the most potent sympathomimetic amines in stimulating the
CNS. The d-isomer is 3 to 4 times more potent than the l-isomer. CNS effects
include increased wakefulness and alertness; decreased sense of fatigue;
elevation of mood, with increased initiative, self-confidence, and ability to
concentrate; elation and euphoria; depressed appetite; physical performance in
athletes is improved; performance of simple mental tasks is improved, however
although more work is accomplished, the number of errors increases. The most
striking improvement with amphetamine occurs when performance is reduced by
fatigue and lack of sleep. The behavioral effects of amphetamine depend both on
the dose and the mental state or personality of the individual. Prolonged use or high doses are nearly always
followed by depression and fatigue.
Tolerance develops to the appetite suppressant effects rapidly. Amphetamine stimulates the respiratory
center. When respiration is depressed by centrally acting drugs, amphetamine
can stimulate respiration.
5.
Toxicity includes: restlessness, dizziness, tremor, irritability, insomnia,
confusion, assaultiveness, anxiety, delirium, paranoid hallucinations, panic
states, and suicidal or homicidal tendencies. The psychotic effects of
amphetamine, including vivid hallucination and paranoid delusions, which are
often mistaken for schizophrenia is the most common serious effect, and can be
elicited in any individual taking sufficient quantities of amphetamine for a
long period of time. Cardiovascular effects are common and include cardiac
arrhythmias, hypertension or hypotension, and circulatory collapse. GI symptoms
include dry mouth, nausea, vomiting, and diarrhea. Fatal poisoning usually
terminates in convulsions, stroke, and coma. Repeated use leads to the
development of tolerance and psychological dependence.
6.
Therapeutic uses include treatment of narcolepsy, obesity, and
attention-deficit hyperactivity disorder.
7.
Methamphetamine, in low doses, has prominent CNS effects like
amphetamine, without significant peripheral actions. It has a high potential
for abuse. It is used principally for its central effects which are more
pronounced than amphetamine. Methylphenidate
is a mild CNS stimulant whose pharmacological properties is essentially the
same as amphetamine but which may not lead to as much motor activation. Pemoline
is another CNS stimulant which has minimal cardiovascular effects. It is used
in the treatment of attention-deficit hyperactivity disorder and is given once
daily due to its long half-life.
B. Ephedrine
1. Ephedrine is an alkaloid isolated
from the plant Ephedra sinica. Extracts of this plant have been used in Chinese
herbal medicine for atleast 2000 years. Ephedrine has both directly- and
indirectly- mediated sympathomimetic effects. That is, it stimulates both
alpha and beta receptors, and it causes release of NE. Ephedrine was the first
sympathomimetic drug which was effective orally. Its spectrum of effects is
similar to EPI, another sympathomimetic with both alpha and beta agonist
effects, however it has a longer duration of effect. In addition it has CNS
effects similar to amphetamine, but less intense. In the past it was used as a
CNS stimulant for treatment of narcolepsy, and as a bronchodilator in asthma.
More selective agents have replaced ephedrine.
C.
Ethylnorepinephrine
1.
It is primarily a beta agonist with some alpha agonist effects. It is
administered IM or SC to cause bronchiolar dilation as well as vasoconstriction
in the bronchioles, which reduces bronchial congestion.
D.
Oral sympathomimetics used primarily for relief of nasal congestion
include phenylephrine, pseudoephedrine, and phenylpropanolamine.
E.
Topical sympathomimetics used primarily as nasal decongestants or
mydriatics include naphazoline, tetrahydrozoline, oxymetazoline.,and xylometazoline
XI. A Summary of
Therapeutic Uses of Sympathomimetics
A. Uses that relate to vascular effects of sympathomimetics
1. Control of superficial hemmorhage, ie
in facial, oropharyngeal, and nasopharyngeal surgery. EPI
2. Decongestion of mucous membranes.
a. Usually get temporary relief, but it
is often followed by a rebound swelling.
3. To prolong the duration of action of
local anesthetics: EPI
a. Use controversial because
autoregulatory phenomena usually cause intense sympathetic activation, and
sympathomimetics may compromise perfusion of vital organs. DA!
B. Uses that relate to CNS effects of
sympathomimetics
1. Narcolepsy (amphetamines)
2. Weight Reduction (amphetamines)
3. Attention deficit-hyperactivity
disorder (amphetamines, methylphenidate)
C. Uses for cardiac effects
1. Phenylephrine and methoxamine used in
PAT by causing a reflex bradycardia.
2. Epinephrine used in emergency treatment
of cardiac arrest.
3.
DA is useful in the treatment of cardiogenic or septicemic shock
especially in patients with compromised renal function.
D. Uses in allergic reactions
1. Epinephrine is the drug of choice to
reverse the manifestations of serious acute hypersensitivity reactions due both
to its cardiovascular effects and its ability to suppress release of histamine.
2. Asthma is preferentially treated with
selective beta 2 agonists (Metaproterenol, terbutaline, albuterol).
E. Uses in ophthalmology
1. Sympathomimetics cause mydriasis ie
phenylephrine and epi. These two drugs also cause a reduction in intraocular
pressure in wide angle glaucoma.
F. Uses in obstetrics
1. Beta 2 agonist (Ritodrine) blocks
onset of premature labor by inhibiting contractility of uterus
G. Nasal decongestion
Adrenoblockers,
Sympatholytics agents
All beta-blockers (BBs) except esmolol
and sotalol are approved for treatment of hypertension and one or more of
following indications: angina pectoris, myocardial Infarction, ventricular
arrhythmia, migraine prophylaxis, heart failure and perioperative hypertension.
Only sotalol
delays ventricular repolarization and is effective for maintenance of sinus
rhythm in patients with chronic atrial fibrilation. Esmolol has short half-life and is given for
hypertensive (perioperative) urgency and for atrial arrhythmias after cardiac
surgery.
Beta-blockers act by blocking the action of
catecholamines at adrenergic receptors throughout the circulatory system and
other organs. BBs major effect is to slow the heart rate and reduce force of
contraction. BBs via inhibition
of receptors at justaglomerular cells
inhibit renin release.
Beta-blockers may
be classified based on their ancillary pharmacological properties.
Cardioselective agents have high affinity for cardiac β 1 and
less affinity for bronchial and vascular β2 receptors compared
with non-selective agents and this reduces (but does not abolish) β 2
receptor-mediated side effects. However, with increasing doses cardiac
selectivity disappears. Lipid-soluble agents cross the blood-brain barrier more
readily and are associated with a higher incidence of central side effects.
Some beta-blockers have intrinsic sympathomimetic activity –
ISA (i.e., they stimulate β
receptors when background sympathetic nervous activity is low and block them
when background sympathetic nervous activity is high). Therefore, theoretically
BBs with ISA are less likely to cause bradycardia, bronchospasm, peripheral
vasoconstriction, to reduce cardiac output, and to increase lipids. BBs with
ISA are less frequently used in the treatment of hypertension.
Beta Blocker |
Relative Cardiac Selectivity |
Intrinsic Sympathomimetic Activity |
Daily Dosing Frequency |
Lipid Solubility |
b1
+ a1 |
Acebutolol SECTRAL |
++ |
+ |
2 |
Moderate |
- |
Atenolol TENORMIN |
++ |
- |
1 |
Low |
- |
Betaxolol KERIONE |
++ |
- |
1 |
Low |
- |
Bisoprolol ZEBETA |
++ |
- |
1 |
Low |
- |
Carteolol CARTROL |
- |
++ |
1 |
Low |
- |
Carvedilol COREG |
- |
- |
2 |
High |
+ |
Esmolol BREVIBLOC |
+ |
- |
i.v. |
Moderate |
- |
Labetalol TRANDATE NORMODYNE |
- |
- |
2 |
Moderate |
+ |
Metoprolol LOPRESSOR |
+ |
- |
1 or 2 |
Mod. / High |
- |
Nadolol CORGARD |
- |
- |
1 |
Low |
- |
Penbutol LEVATOL |
- |
+ |
1 |
High |
- |
Pindolol VISKEN |
|
+++ |
2 |
Moderate |
- |
Propranolol INDERAL |
- |
- |
2 |
High |
- |
Timolol BLOCADREN |
- |
- |
2 |
Low / Mod. |
- |
Lipophilic
beta blockers may enter CNS more extensively and readily which may lead to
increased CNS side effects. Labetalol and carvedilol have both β1-
and α1-blocking properties, and decrease heart rate and
peripheral vascular resistance. Both agents possess the side effects common for
both classes of drug. Beta-blockers tend to be less effective in the elderly
and in black hypertensives. To reduce side effects in hypertensive patients it
is recommended to use a beta-blocker with high cardioselectivity, low lipid solubility
and long half-life that allows once daily dosing.
Adverse effects:
BBs slow the rate of conduction at
the atrio-ventricular node and are contraindicated in patients with second- and
third-degree heart block. Sinus bradycardia is common and treatment should be
stopped if patient is symptomatic or heart rate falls below 40 b/min. Because
of blockade of pulmonary ß2 receptors, even small doses of BBs
can cause bronchospasm (less common with cardioselective agents), and all
beta-blockers are contraindicated in asthma. Blockade of ß receptors in
the peripheral circulation causes vasoconstriction and may induce particularly
in patients with peripheral circulatory insufficiency adverse affects such as
cold extremities, Raynaud’s phenomenon, and intermittent claudication.
Nevertheless, they are reasonably tolerated in patient with mild peripheral
vascular disease. Lipid-soluble agents can cause central nervous system side
effects of insomnia, nightmares and fatigue. Exercise capacity may be reduced by
BBs and patients may experience tiredness and fatigue. BBs
can worsen glucose intolerance and hyperlipidemia and in diabetic
patients mask signs of hypoglycemia. However, diabetic hypertensive patients
with previous MI should not be denied BB because of concerns about metabolic
side effects.
Alpha-1 adrenergic receptor blockers ( …. OSIN )
Prazosin [MINIPRESS] Terazosin [HYTRIN]
Doxazosin [CARDURA]
Alfuzosin
[UROXATRAL] Tamsulosin [FLOMAX]
The
β1-adrenoceptor blockers produce vasodilatation by blocking the
action of norepinephrine at post-synaptic β1 receptors in
arteries and veins. This results in a fall in peripheral resistance, without a
compensatory rise in cardiac output. Doxazosin, terazosin, and, less commonly,
prazosin are used as oral agents in the treatment of hypertension. They are
relatively more selective for a1b - and a1d-receptors
which are involved in vascular smooth muscle contraction. Alfuzosin and tamsulosin are used for
symptomatic treatment of begin prostatic hyperplasia (BPH), since compared to
other oral α1-blockers, they have less antihypertensive effects
and are relatively more selective as antagonists at the α1a subtype,
the primary subtype located in the prostate.
Based on ALLHAT study data, alpha blockers are not longer
considered first-line drug for treatment of hypertension. They are drugs of
choice for treatment of hypertensive patient with BPH. Adverse effects include
first dose hypotension, dizziness, lethargy, fatigue, palpitation, syncope,
peripheral edema and incontinence.
Adverse
Reactions: The adverse effects of beta-blockers are generally mild and
temporary; they usually occur at the onset of therapy and diminish over time.
Most adverse reactions of beta-blockers are extensions of their therapeutic
effects. Bradycardia and hypotension are rarely serious and can be reversed
with IV atropine, if necessary. AV block, secondary to depressed conduction at
the AV node, might necessitate sympathomimetic and/or pressor therapy or the
use of a temporary pacemaker. Congestive heart failure is more likely to occur
in patients with preexisting left ventricular dysfunction and usually will
respond to discontinuation of beta-blocker therapy.
Adverse
CNS effects include dizziness, fatigue, and depression. Although much less
common with hydrophilic beta-blockers, CNS depression can occur, resulting in
mental disorders, fatigue, and, in some cases, vivid dreams. Diarrhea and
nausea/vomiting are the most common GI adverse effects during therapy with
beta-blockers. Bronchospasm and dyspnea are more likely to occur with
nonselective beta-blockers or with high doses of cardioselective agents because
the beta selectivity of the drug is lost. Patients with preexisting
bronchospastic disease are at greater risk.
Both
hypoglycemia and hyperglycemia can occur during beta-blocker therapy.
Beta-blockers can interfere with glycogenolysis to cause hyperglycemia and can
also mask signs of hypoglycemia. Beta-blockers should be used cautiously in
brittle diabetics.
beta-blockers
have little effect on total cholesterol and plasma LDLs, but have been shown to
increase triglycerides and decrease plasma HDLs. The role that the
characteristics of cardioselectivity and intrinsic sympathomimetic activity of
beta-blockers play in these effects are more controversial. In a recent
meta-analysis, it was shown that agents with intrinsic sympathomimetic activity
or cardioselectivity tend to have less effect on triglycerides and HDLs. Agents
with both characteristics tended to reduce total cholesterol and LDLs.
Adverse
reactions from ophthalmic beta-blockers are usually limited to their ocular
effects, such as transient burning, stinging, and blurred vision however, these
preparations can be absorbed causing systemic adverse reactions, similar to
oral or parenteral beta-blockers. Ophthalmic betaxolol appears to cause less
systemic effects compared to ophthalmic timolol and levobunolol.
Comparison of agonists,
antagonists, and partial agonists of β adrenoceptors.
Despite
the current knowledge of the diversity and function of beta-receptors within
the human body, much remains to be learned about some of their regulatory roles
in physiologic homeostasis. Although the variety of beta-receptor antagonists
that are currently available is plentiful, the pharmacologic uses for
beta-receptor antagonists is likely to continue to grow.
1.
http://www.youtube.com/watch?v=797WAV3kZhQ&playnext=1&list=PL83879046C561EB07&index=5
2.
http://www.youtube.com/watch?v=fPzjU6YRsf4&feature=related
3.
http://www.youtube.com/watch?v=TaAvhG2SInM&playnext=1&list=PLE304A951086EE624&index=50
4.
http://www.apchute.com/moa.htm
5.
http://www.youtube.com/watch?v=ejq99wLEMTw&playnext=1&list=PL4DE83C6B1D56C4E4&index=5