Transcript Action - كلية الطب البيطري

‫محاضرات م‪.‬م سعديه صالح مهدي الزيني‬
‫كلية الطب البيطري ‪ /‬جامعة الكوفة‬
‫فــرع الفسلجــة واألدويــة‬
‫ماجستير أدوية وسموم‬
Drugs affecting the autonomic nervous system
Drugs that produce their primary therapeutic effect by altering the function of
the autonomic nervous system. These autonomic agents act either by
stimulating portions of the ANS or by blocking the action of the ANS.
Anatomic of the CNS:
- Efferent fiber the motor portion of the ANS is he major pathway for information
transmission from the central nervous system to the involuntary effector tissue (smoth
muscle, cardiac muscle and exocrine glands.
- Enteric NS is a semiautonomous part of the ANS ,with specific function for the control of the
gastrointestinal tract.
- Afferent fibers there are sensory fibers,these are of considerable importance for the
phsiologic control of the involuntary organs but are directly influenced by only afew drugs 11-spinal roots of origin:
The parasympathetic preganglionic motor fibers originate in cranial nerve and sacral
segments of the spinal cord. The sympathetic preganglionic fibers originate in the thoracic
and lumbar segments of the cord.
2- location of ganglia:
most of sympathetic ganglia are located in two paravertebral chains that lie alonge the spinal
column. A few located on the anterior of column. Most of parasympathetic ganglia are
located in the organs innervated, more distant from the spinal cord
3- length of pre-and postganglionic fiber:
The preganglionic sympathetic fibers are short and the postganglionic fibers are long. The
opposite is true for the parasympathetic system: the preganglionic parasympathetic fibesr are
long and the postganglionic fibers are short.
4-Uninnervated receptors:
These include muscarinic receptorson the endothelium of blood vessels,the adrenoceptors on
sweat glands and adrenoceptors in blood vessels.
Sites of actions of cholinergic antagonists.
Neurotransmitter aspects of the ANS:
1-Cholinergic transmission
2- Adrenergic transmission
Cholinergic transmission:
Acetylcholine: is the primary transmitter in all autonomic ganglia and at the
parasympathetic postganglionic neuron-effecrs cell synapses.
- Synthesis and storage:
Synthesized from acetyl-CoA and cholin by the enzyme choline acetyltansferase.
this transport can be inhibited by hemicholinium. this process can be inhibited by
vesamicol.
- Ach storage into vesicles.
-Release of ACh from vesicles in the nerve ending requires the entry of calcium
through calcium channels and triggering of interaction between several proteins
associated with the vesicles and the nerve ending membrane. This interaction results in
the fusion of the vescular and nerve ending membranes, the opening of a pore to the
extracellular space, and the release of the stored transmitter. This release can be
blocked by botulinum toxin. In contrast ,the toxin in black widow spider venom
causes all the Ach stored in synaptic vesicles to empty into the synaptic gap.
- Termination of action of Ach: the action of acetylcholine is normally terminated by
metabolism to acetate and choline by the enzyme acetylcholinesterase. The products
are not excreted but are recycled in the body. Inhibition of acetylcholinesterase is an
important therapeutic effect of several drugs.
- Binding to the receptor:
Ach release from the synaptic vesicles diffuses across the synaptic space, and it binds
to either of tow postsynaptic receptors on the target cell or to presynaptic receptors in
the membrane of the neuron that released the Ach.
Synthesis and release of Ach from cholinergic neuron
Cholinergic receptors:
Cholinoceptors are molecules respond to acetylcholine, these divided into classes:
1 - muscarinic receptors: has been found for five (subtypes M1,M2,M3,M4,M5),
located on ganglia of the peripheral nervous system and on the surface of the effector
organs. M1 found on gastric cell, M2 found on cardiac cell and smooth muscle, M3
found on bladder, exocrine gland and smoth muscle.
2 - nicotinic receptors: (composed of five subunits) are located in the CNS, adrenal
medulla, autonomic ganglia and the neuromuscular junction.
Direct - action Cholinergic agonists ( parasympathomimetics)
Mimic effects of acetycholine by binding directly to cholinoceptors. These may be
classified into tow groups:
1 - Choline esters, which include acetylcholine and synthetic esters of choline such as
a- Acetylcholine
Pharmacologic effects: the action include
1- Decrease in heart rate and cardiac output.
2- Decrease in blood pressure: Ach cause vasodilation and lowering of blood pressure.
3- Smooth muscle: increase salivary secretion and motility of intestinal, urinary and uterine
smooth muscle.
4- Eye: Ach stimulating ciliary muscle contraction for near vision and in the constriction
of the pupillae sphincter muscle causing miosis.
b- carbachol has both muscarinic as well as nicotinic action, used to treat
glaucoma by causing papillary contraction and decrease in intraocular pressure
c- Bethanechol directly stimulate muscrinic receptors, causing increased
intestinal motility and used to stimulate the atonic bladder in postoperative.
2- Alkaloids a group of naturally occurring such as muscarine, not used
thrapeutically but rather important accidental poison.
- pilocarpine therapeutic use in glaucoma choice in the emergency lowering of
intraocular pressure.
Indirect – action cholinergic agonists (anticholinesterases)
The indirect- acting cholinomimetic drugs into two major chemical classes
1- Reversible (Carbamic acid ester):
Inhibitors of acetylcholinesteras enzyme indirectly provide a cholinergic
action by prolonging the lifetime of acetycholine produce endogenously at the
cholinergic nerve endings. This accumulation of acetycholine in the synaptic
space .these drug can thus provoke a response at all cholinoceptors in the
body, including both muscarinic and nicotinic receptors of the ANS as well as
at neuromuscular junctions and in the brain. such as physostigmine and
neostigmine the drug increase intestinal and bladder motility.
2- Irreversible (phosphoric acid esters):
A number of synthetic organophosphate compounds have the capacity to
bind to acetylcholinesterase and . The resulte is long-lasting increase in Ach
at all sites where it is released. Many of these drugs are extremely toxic.
Related compound, such as parathion, are employed as insecticides.
-Ecothiophate: actions include generalized cholinergic stimulation, paralysis
of motor function causing breathing difficulties and convulsion. used for
treatment of glaucoma.
Cholinergic antagonists ( anticholinergic drug):
Called cholinergic blocker, parasympatholytics. Cholinoceptor antagonists
are readily into subclasses:
1-Basis of their spectrum action they block muscarinic and nicotinic
receptors
2-Special subgroup, the cholinesterase regenerators, are not receptor
blockers but rather are chemical antagonists of organophosphate
cholinesterase inhibitors
Cholinergic
antagonists
Antimuscarinic
M1 Selective
nonselective
Antinicotinic
Ganglion
blockers
neuromuscular
blockers
Cholinesterase
regenerators
Antimuscarinic agents (muscarinic antagonists)
muscarinic antagonists can be subdivided according to their selectivity for
M1 receptors, only a few receptor-selective antagonists ( pirenzepine,
telenzepine). All of the drugs in general are nonselective. These agents
block muscarinic receptors causing inhibition of all muscarinic function.
Atropine

A tertiary amine belladonna alkaliod, has affinity for muscarinic receptors where it
binds competitively, preventing acetylcholine from binding to these sites. Atropine
acts both centrally and peripherally.
Action
- Eye: mydriasis (dilation of the pupil) and cycloplegia (inability to focus for near
vision)
- Gastrointestinal: used an antispasmodic to reduce activity of the GI tract
- Urinary system: used to reduce hypermotility states of the urinary blodder and used
in enuresis (involuntary voiding urine) among children
- Cardiovascular: at low dose decrease cardiac rate, in higher dose of atropine, the M2
receptors on the sinoatrial node blocker, and cardiac rate increase. Blood pressure is
unaffected.
- Gland: decrease secretion of saliva gland produce a drying effect on the oral mucous
membranes ( xerostomia).
Pharmacokinetic:
Absorbed from GI, metabolized by the liver and eliminated in the urine. It
has half life of about 4 hours
Scopolamine:
Is another belladonna alkaloid has longer action and more central effect
Action : antimotion sickness, block short term memory causes sedation
Ipratropium
Used in treating asthma in patients who are unable to take adrenergic
agonists and chronic obstructive pulmonary disease.
Antinicotinic agents (nicotinic antagonists)
1- ganglion blockers:
blockers ganglionic specifically act on the nicotinic receptors of both parasympathetic
and sympathetic autonomic ganglia. Some also block the ion channels of the autonomic
ganglia. used for treatment of hypertension. hexamethonium and mecamylamin used
for this disease.
2- neuromuscular blocking drugs:
These drugs block cholinergic transmission between motor nerve endings and the
nicotinic receptors on the neuromuscular end plate of skeletal muscle, these drugs
include agonists (depolarizing) or antagonists (nondepolarizing) of Ach nicotinic
receptors at the neuromuscular junction.
1- Nondepolarizing (competitive) blockers
These drugs include tubocuarine considered to be the prototype agent in this
class, compete with Ach at the nicotinic receptor at the neuromuscular junction
without stimulating the receptors, they are called competitive blockers . These
agents have increased the safety of anesthesia, because less anesthetic is
required to produce muscle relaxation.
Mechanism of action:
a- At low doses:
these drugs intract with the nicotinic receptos to prevent the binding of
acetylcholine, prevent depolarization of the muscle cell membrane and inhibit
muscular contraction. Their action can be overcome by increase concentration of
Ach in the synaptic gap- for example by administration of cholinesterase inhibitors,
such as neostigmine.
b-At higher doses:
nondepolarizing blockers can block ion channels of the end plate. This leads to
further weakening of neuromuscular transmission and it reduces the ability of
cholinesterase inhibition to reverse.
Action:
Not muscles are equally sensitive to blockade by competitive blockers. Small, rapidly
contracting muscles of the face and eye are most susceptible and paralyzed first,
followed by the fingers, thereafter, the limb, neck and trunk muscles are paralyzed. thin
intercostals muscles are affected and lastly the diaphragm muscles are paralyzed
Drug interaction:
a- Cholinesterase:
Drug such as neustigmine ……can overcome the action of nondepolarizing
neuromuscular lockers,but with increase dosage, cholinesterase inhibitors can cause a
depolarizing block as a result of elevated Ach concentration at the end plate membrane.
b- Halogenated hydrocarbon anesthetic:
Drugs such as halothane act t o enhance neuromuscular blocker by exerting a stabilizing
action at the neuromuscular junction.
c- Aminoglycoside antibiotics:
Drug such as gentae rmicin or tobramycin inhibit acetycholine
Release from cholinergic nerves by competing with calcium ions.
d-Calcium- channel blockess:
These agents may increase the muscular block of tubocuraine and other competitive
blockers as well as depolarizing blockers.
2- Depolarizing agents:
Mechanisme of action:The depolarizing neuromuscular
blocking drug
(succinylcholine) attaches to the nicotinic receptor
and acts like acetylcholine to depolarize the junction.
The depolarizing agent persists at high concentrations
in the synaptic cleft, remaining attached to the receptor
for a relatively longer time and providing a constant
stimulation of the receptor.
Phase-1: The depolarizing agent first causes the opening
of the sodium channel associated with the nicotinic
receptors, which results in depolarization of the
receptor.
Phase-2: This leads to transient twitching of the muscle
(fasciculation). Continued binding of the depolarizing agent
renders receptor incapable of transmitting further implses.
With time continuus depolarization gives way to gradual
repolarization as the sodium channel closes or is blockd.
This causes resistance to depolarization and a flaccid paralysis.
Action:
Succinylcholin initially produces short-lasting muscle fasciculation, followed
within a few minutes by paralysis because this drug is rapidly broken down
by plasma cholinesterase. The drug does not produce a ganglionic block
except at high doses, but it does have weak histamine-releasing action.
Therapeutic uses
Useful when rapid endotracheal intubation is required during the induction of
anesthesia and it is also employed during electroconvulsive shock treatment.
Adverse effects:
-hyperthermia malignant with halothane (reducing heat production and relaxing
muscle ton) because block release of Ca++
- apnea paralysis of diaphragm ( deficient in plasma cholinesterase)
- hyperkalemia potassium lost from within cell ( tissue damage )
Cholinesterase regenerators:
The cholinesrterase regenerators are not receptor antagonists but belong to a
Class of chemical antagonists. These molecules contain an oxime group, which
has high affinity for the phosphorus atom in organophosphate insecticides lead to
exceeds that of the enzyme active site. Used to treat patients exposed to
insecticides such as parathion
Adrenergic transmion:
Norepinephrine and epinerphrie:
Norepinephrine and epinerphrie is the transmitter, the fiber is termed adrenergic.
In the sympathetic system, norepinephrine mediates the transmission of nerve
impulses from autonomic postganglionic nerves to effector organs.
- Synthesis:
Tyrosin is transported by a Na+ linked carrier into the axoplasm of the
adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA)
by tyrosine hydroxylase, this is the rate – limiting step in the formation of
norepinephrine. DOPA is then decarboxylated by the enzyme dopadecarboxylase
to form dopamine in the cytoplasm of the presynaptic neuron. Drugs that block
synthesis eg, metyrosine.
- Storsge of norepinephrine in vesicle:
Dopamine enter vesicle by an amine transporter systme and is converted to
norepinephrine by the enzyme dopamine B-hydroxylase. Norepinephrine
protected from degradation in the vesicle. Transport dopamine into the vesicle is
inhibited by reserpine. In the adrenal medulla, norepinephrine methylated to
yield epinephrine, both of which are stored in chromaffin cells.
Release of norepinephrine:
Influx of calciume causes fusion of the vesicle with the cell membrane in a
process known as exocytosis. Release is blocked by guonethidine and
bretylium.
Binding to alpha receptors:
Norepinephrine released from the syneptic vesicles diffuses the syneptic
space and binds to either postsynaptic receptors on the effector organ or to
presyneptic receptor on the nerve ending. Adrenergic receptors use both the
cyclic adenosine monophosphate (cAMP) second-messenger system,2 and
the phosphatidylinositol cycle,3 to transduce the signal into an effect.
Removal of norepinephrine:
- diffuse out of the syneptic space and enter the general circulation.
- Metabolizes to o-methylated derivations by postsynaptic cell membrane
associated catechol o-methyltransferase (COMT) in the syneptic apace.
Inactive norepinephrine metabolism are excreted in the urine.
- Recaptured by uptake system that pumps the norepinephrine back into the
neuron.
Adrenergic receptors:
Adrenoceptors are divided into several subtype:
1- Alpha adreoceptors These receptors show a weak response to the synthetic
agonist isoproterenol, but they are responsive to the to the naturally
occurring catecholamines epinephrine and norepinphrine. These are located
on, blood platelets, fat cells and neurons in the brain. Alpha receptor are
subdivided into two subgroups:
a-Alpha-1 receptors:
These are present on the postsynaptic membrane of the effector organs and
mediate many of the classic effects. Activation of alpha-1 receptors initiates
a series of reactions through a G protein activation of phospholipase. These
receptors subdivided into alpha-1 A,B,C,D
b-Alpha-2 receptors:
These are located on presyneptic nerve endings and other cells, such as the B
cell of the pancreas and on some vascular smooth muscles cells. When a
sympathetic adrenergic nerve is stimulated, the released norepinephrine
traverses the synaptic cleft and interacts with the alpha-1 receptors. A
portion of the released norepinephrine (circles back) and reacts with alpha -2
receptors on the neuronal membrane. The stimulation of the alpha-2 receptor
causes feedback inhibition of the release of norepinephrine from the
stimulated adrenergic neuron. These receptors subdivided into alpha-2
A,B,C,D.
2- Beta receptors:
These are receptors, characterized by a strong response to isoproterenol with
less sensitivity to epinephrine and norepinephrine. The B-adrenoceptors can
be subdivided into three major subgroups, B-1, B-2, and B-3, based on their
affinities for adrenergic agonists and antagonists.
B-1Receptors have approximately equal affinities for epinephrine and
norepinephrine, whereas B-2 receptors have a higher affinity for epinephrine
than for norepinephrine. Thus, tissues with a predominance of B-2 receptors
(such as the vasculature of skeletal muscle) are particularly responsive to the
hormonal effects of circulating epinephrine released by the adrenal medulla.
Distribution of receptors: Adrenergically innervated organs and tissues tend to
have a predominance of one type of receptor. For example, tissues such as the
vasculature to skeletal muscle have both alpha-1 and B-2 receptors, but the
B-2 receptors predominate.
Characteristic responses mediated by adrenoceptors:
It is useful to organize the physiologic responses to adrenergic stimulation
according to receptor type, because many drugs preferentially stimulate or
block one type of receptor. As ageneralization, stimulation of alpha-1
receptors characteristically produces vasoconstriction (particularly in skin and
abdominal viscera) and an increase in total peripheral resistance and blood
pressure. Conversely, stimulation of B-1 receptors characteristically causes
cardiac stimulation, whereas stimulation of B-2 receptors produces
vasodilation (in skeletal vascular beds) and bronchiolar relaxation.

Type

Alpha-1




Alpha 2

Tissue
Actions
Most vascular smooth muscle
Pupillary dilator muscle
Pilomotor smooth muscle
Prostate
Adrenergic and cholinergic nerve
terminals
Contraction
Contraction (dilates pupil)
Erects hair
Contraction
Inhibition of transmitter
release
Platelets
Some vascular smooth muscle
Fat cells
Heart
stimulates Aggregatio
Contraction
Inhibition of lipolysis
Increases force and rate





Beta -1


Beta-2



Beta-3
Respiratory, uterine, and vascular smooth
relaxation
muscle Promotes smooth muscle
liver (human)
stimulate glycogenolysis
pancreatic B cell
stimulate insulin release
Fat cells
Activates lipolysis
Distribution of Adrenoceptor Subtypes.
Mechanism of action of the adrenergic agonists
1- Direct-acting agonists:
These drugs act directly on alpha or beta receptors, producing effects similar to those
that occur following stimulation of sympathetic nerves or release of the hormone
epinephrine from the adrenal medulla. Examples of direct-acting agonists include
2- Indirect-acting agonists:
These agents, which include amphetamine, cocaine and tyramine, may block the
uptake of norepinephrine or are taken up into the presynaptic neuron and cause the
release of norepinephrine from the cytoplasmic vesicles of the adrenergic neuron.
As with neuronal stimulation, the norepinephrine then traverses the synapse and
binds to the alph or beta receptors.
3- Mixed-action agonists:
Some agonists, such as ephedrine, pseudoephedrine and metaraminol, have the
capacity both to stimulate adrenoceptors directly and to release norepinephrine from
the adrenergic neuron.
Direct-Acting Adrenergic Agonists
Direct-acting agonists bind to adrenergic receptors without interacting with the
presynaptic neuron. As a group, these agents are widely used clinically.
Epinephrine
Epinephrine is one of four catecholamines - epinephrine, norepinephrine,
dopamine, and dobutamine commonly used in therapy. The first three
catecholamines occur naturally in the body as neurotransmitters; the latter is a
synthetic compound. Epinephrine is synthesized from tyrosine in the adrenal
medulla and released, along with small quantities of norepinephrine, into the
bloodstream. Epinephrine interacts with both alpha and beta receptors. At low
doses, beta effects (vasodilation) on the vascular system predominate, whereas at
high doses, alpha effects (vasoconstriction) are strongest.
Actions:
-Cardiovascular: The major actions of epinephrine are on the cardiovascular system.
Epinephrine strengthens the contractility of the myocardium (positive inotropic:
beta-1 action) and increases its rate of contraction (positive chronotropic: beta-1
action). Cardiac output therefore increases. With these effects comes increased
oxygen demands on the myocardium.
Epinephrine constricts arterioles in the skin, mucous membranes, and viscera
(alpha effects), and it dilates vessels going to the liver and skeletal muscle (beta-2
effects). Renal blood flow is decreased. Therefore, the cumulative effect is an
increase in systolic blood pressure, coupled with a slight decrease in diastolic
-Respiratory: Epinephrine causes powerful bronchodilation by acting directly on
bronchial smooth muscle (beta-2 action). This action relieves all known
allergic- or histamine-induced bronchoconstriction. Epinephrine rapidly
relieves the dyspnea and increases the volume of gases inspired and expired.
Epinephrine also inhibits the release of allergy mediators such as histamines
from mast cells.
-Hyperglycemia: Epinephrine has a significant hyperglycemic effect because of
increased glycogenolysis inthe liver (beta-2 effect), increased release of
glucagon (beta-2 effect), and a decreased release of insulin (alpha-2 effect).
-Lipolysis: Epinephrine initiates lipolysis through its agonist activity on the beta
receptors of adipose tissue.
Therapeutic uses
-Bronchospasm: Epinephrine is the drug used in the intreatment of acute asthma
and anaphylactic shock, epinephrine is the drug of choice; within a few minutes
after subcutaneous administration. Selective beta-2 agonists, such as albuterol,
are presently favored in the chronic treatment of asthma because of a longer
duration of action and minimal cardiac stimulatory effect.
-Glaucoma: In ophthalmology, a two-percent epinephrine solution may be used
topically to reduce intraocular pressure in open-angle glaucoma.
-Anaphylactic shock: Epinephrine is the drug of choice for the treatment of Type
I hypersensitivity reactions in response to allergens.
-Anesthetics: The effect of the drug is to greatly increase the duration of the local
anesthesia.
Pharmacokinetics: Epinephrine has a brief duration of action (due to rapid
degradation). epinephrine is given intravenously, subcutaneously, by
endotracheal tube, by inhalation. Oral administration is ineffective, Only
metabolites are excreted in the urine.
Adverse effects:
- CNS disturbances: adverse CNS effects that include anxiety, fear, tension,
headache, and tremor.
- Hemorrhage: The drug may induce cerebral hemorrhage as a result of a
marked elevation of blood pressure.
- Cardiac arrhythmias, Pulmonary edema
Interactions:
- Hyperthyroidism: Epinephrine may have enhanced cardio-vascular actions in
patients with hyperthyroidism.
- Cocaine: In the presence of cocaine, epinephrine produces exaggerated
cardiovascular actions. This is due to the ability of cocaine to prevent
reuptake of catecholamines into the adrenergic neuron
- Diabetes: Epinephrine increases the release of endogenous stores of glucose.
In the diabetic, dosages of insulin may have to be increased.
- Beta Blockers: These agents prevent epinephrine's effects on b- receptors,
leaving alpha-receptor stimulation unopposed. This may lead to an increase
in peripheral resistance and an increase in blood pressure.
- Inhalation anesthetics: Inhalational anesthetics sensitizethe heart to the effects
of epinephrine, which may lead to tachycardia.
Norepinephrine
Because norepinephrine is the neuromediator of adrenergic nerves, it
should theoretically stimulate all types of adrenergic receptors. In practice,
when the drug is given in therapeutic doses to humans, the Alphaadrenergic receptor is most affected.
- Cardiovascular Actions:
Vasoconstriction: Norepinephrine causes a rise in peripheral resistance
due to intense vasoconstriction (alpha-1), increase blood pressures. The
increase heart rate (inotropic) due to beta-1 stimulation
Therapeutic uses: used to treat shock, because it increases vascular
resistance and, therefore, increases blood pressure. It is never used for
asthma or in combination with local anesthetics.
 Pharmacokinetics: Norepinephrine may be given IV for rapid onset of
action. The duration of action is 1 to 2 minutes following the end of the
infusion period. It is poorly absorbed after subcutaneous injection and is
destroyed in the gut if administered orally. Metabolism is similar to that of
epinephrine.
 Adverse effects: These are similar to those of epinephrine.
Isoproterenol
Isoproterenol is a direct-acting synthetic catecholamine that predominantly
stimulates both beta-1 and beta-2 adrenergic receptors.
Actions:
- Cardiovascular: Isoproterenol produces intense stimulation of the heart to increase
its rate and force of contraction, causing increased cardiac output.
- Pulmonary: rapid bronchodilation is produced by the drug (beta-2 action).
Therapeutic uses: Isoproterenol is now rarely used as a broncho-dilator in asthma. It
can be employed to stimulate the heart in emergency situations.
Pharmacokinetics: Isoproterenol can be absorbed systemically by the sublingual
mucosa
Dopamine
Dopamine the immediate metabolic precursor of norepinephrine, activate alpha and
beta-adrenergic receptors.
- at higher doses (alpha-1 receptors) cause vasoconstriction by activating.
- at lower doses, it stimulates beta-1 cardiac receptors.
In addition, D1 and D2 receptors occur in the blood vessels mesenteric and renal.
- D1 causes vasodilation.
- D2 receptors are found on presynaptic receptors prevent release norepinephrine.
These receptors are not affected by alpha or beta blocking drugs and are found in the
autonomic ganglia and in the CNS.
Actions:
- Cardiovascular: a stimulatory effect on the beta-1 receptors of the heart,
having both inotropic and chronotropic
- Renal and visceral: dilatation by activating D1 receptors
Therapeutic uses:
- Shock: given by continuous infusion.
- stimulating heart by beta-1 receptors to increase cardiac output, and alpha- 1
receptors on blood vessels to increase total peripheral resistance.
- increased blood flow to the kidney enhances the glomerular filtration rate
Adverse effects: nausea, hypertension, arrhythmias.
Dobutamine
Actions: a synthetic, direct-acting catecholamine that is a beta-1-receptor
agonist. It increases cardiac rate and output
Therapeutic uses: used to increase cardiac output in congestive heart failure
Adverse effects: should be used with caution in atrial fibrillation, because the
drug increases atrioventricular conduction.
Oxymetazoline
is a direct-acting synthetic adrenergic agonist that stimulates both alpha-1 and
alpha-2 adrenergic receptors.
- used locally in the eye or the nose as a vasoconstrictor and decrease
congestion. congestion.
Phenylephrine
is a direct-acting, synthetic adrenergic drug that binds to alpha receptors.
- It is a vasoconstrictor that raises blood pressures. It has no effect on the heart
itself but cause reflex bradycardia.
- used topically on the nasal mucous membranes as decongestant.
- used to raise blood pressure in hypotension
Methoxamine
is a direct-acting, synthetic adrenergic drug that binds to alpha receptors,
causing vasoconstriction. its effects on the vagus nerve by reflex increase
blood pressure
- used clinically to relieve attacks of paroxysmal supraventricular tachycardia.
- used to overcome hypotension during surgery involving halothane
anesthetics.
Adverse effects include hypertensive headache and vomiting.
Clonidine
is an alpha-2 agonist that is used in essential hypertension to lower blood
pressure because of its action in the CNS .
Metaproterenol, Albuterol, pirbuterol, and terbutaline,
Salmeterol and formoterol
Beta-2 agonist producing little effect on the heart. It produces dilation of the
bronchioles. The drug is useful as a bronchodilator in the treatment of asthma
Indirect-Acting Adrenergic Agonists
Indirect-acting adrenergic agonists cause norepinephrine release from
presynaptic terminals or inhibit the uptake of norepinephrine. These agents
do not directly affect postsynaptic receptors.
Amphetamine
The marked central stimulatory action of amphetamine is often mistaken by
drug abusers as its only action. the drug can increase blood pressure
significantly by alpha-agonist action on the vasculature as well as beta
stimulatory effects on the heart. Its peripheral actions are mediated
primarily through the blockade of norepinephrine uptake and cellular
release of stored catecholamines; thus, amphetamine is an indirect-acting
adrenergic drug. It use for treating hyperactivity in children, narcolepsy,
and appetite control. Its use in pregnancy should be avoided because of
adverse effects on development of the fetus.
Tyramine
Tyramine is not a clinically useful drug, but it is important because it is
found in fermented foods, such as ripe cheese and Chianti wine. It is a
normal by product of tyrosine metabolism.
Cocaine
Cocaine is unique among local anesthetics in having the ability to block the
Na+/K+-activated ATPase.
Sites of action of direct-, indirect-, and mixed-acting adrenergic
agonists.
Mixed-Action Adrenergic Agonists
Mixed-action drugs induce the release of norepinephrine from presynaptic
terminals, and they activate adrenergic receptors on the postsynaptic membrane.
Ephedrine and pseudoephedrine
Ephedrineand and pseudoephedrine are plant alkaloids, that are now made
synthetically. These drugs are mixed-action adrenergic agents. They not only
release stored norepinephrine from nerve endings but also directly stimulate both
alpha and beta receptors. Ephedrine and pseudoephedrine are not catechols and are
poor substrates for COMT (catechol O-methyltransferase) and MAO (adenosine
monophosphate); thus, these drugs have a long duration of action.
Pharmacokinetics: excellent absorption orally and penetrate into the CNS.
Ephedrine is eliminated largely unchanged in the urine, and pseudoephedrine
incomplete hepatic metabolism before elimination in the urine.
Side effect: Ephedrine raises blood pressures by vasoconstriction and cardiac
stimulation.
Therapeutic uses:
- Ephedrine used in chronic treatment of asthma to prevent attacks.
- Ephedrine improves motor function in myasthenia gravis. with
anticholinesterases.
-Ephedrine stimulation of the CNS produce increases alertness, decreases fatigue,
and prevents sleep and improves athletic performance.
-Pseudoephedrine is primarily used to treat nasal and sinus congestion or
congestion of the eustachian tubes.
Adrenergic Antagonists (blockers or sympatholytic)
The adrenergic antagonists bind to adrenoceptors but do not trigger the usual
receptor-mediated intracellular effects. These drugs act by either reversibly or
irreversible attaching to the receptor, thus preventing its activation by
endogenous catecholamines. These are classified according to affinities for
alpha or beta receptors.
Alpha Adrenergic Blocking Agents
blockade of these receptors reduces the sympathetic tone of the blood vessels,
This induces a reflex tachycardia resulting from the lowered blood pressure.
Phenoxybenzamine
is nonselective, noncompetitive, irreversible), linking to both alpha-1
postsynaptic and Alpha-2 presynaptic receptors. The actions about 24 hours
after a single administration.
Actions:
a- Cardiovascular effects: By blocking alpha receptors, prevents vasoconstriction.
Decrease blood pressure but increase cardiac output by reflex tachycardia due to
decreased peripheral resistance, inhibitory alpha- 2 receptors in the heart
b- Epinephrine reversal: All alpha adrenergic blockers reverse the alpha agonist
actions of epinephrine the vasoconstrictive action of epinephrine is interrupted
but vasodilation of other vascular caused by stimulates beta receptors on the
heart is not blocked .Therefore, the systemic blood pressure decreases in
response to epinephrine given in the presence of phenoxybenzamine.
Therapeutic uses:
- used in the treatment of pheochromocytoma, before surgery removal to
prevent the hypertensive.
- effective in treating Raynaud's disease.
- Autonomic hyperreflexia .
Adverse effects: can cause hypotension, nasal stuffiness, nausea, and
vomiting.
Phentolamine
competitive block of alpha-1 and alpha-2 receptors. The drug's action lasts for
4 hours side effect cause tachycardia, arrhythmias and anginal pain. Used for
diagnosis of pheochromocytoma.
Prazosin, terazosin, doxazosin, alfuzosin, and tamsulosin
are selective competitive blockers of the alpha-1 receptor. The first three drugs
are
- useful in the treatment of hypertension .
-Tamsulosin and alfuzosin are indicated for the treatment of prostatic
hyperplasia.
-Metabolism leads to inactive products that are excreted in the urine except for
those of
-doxazosin, which appear in the feces. Doxazosin is the longest acting of these
drugs.
- Cardiovascular effects: decrease peripheral vascular resistance and lower
arterial blood pressure
Therapeutic uses:
- hypotensive response that can result in syncope ( first-dose) effect, may be
minimized by adjusting the first dose to 1/3 or 1/4 of the normal dose.
- Prostatic hypertrophy decreases tone in the smooth muscle of the bladder
neck and prostate and improves urine flow.
Adverse effects: dizziness, a lack of energy, nasal congestion, headache,
drowsiness,
and orthostatic Due to retain sodium and fluid used along with a diuretic.
Yohimbine
is a selective competitive alpha- 2 blocker. It is found as a component of the
bark of the yohimbe tree.
Uses: as a sexual stimulant and used to relieve vasoconstriction associated
with Raynaud's disease.
Beta- Adrenergic Blocking Agents
beta blockers are competitive antagonists, divided into nonselective (beta-1 beta2 receptors) and cardioselective beta-1 receptors. These drugs also differ in
- intrinsic sympathomimetic activity,
- CNS effects
- pharmacokinetics.
Although all beta blockers lower blood pressure in hypertension without
postural hypotension, because the alpha adrenoceptors remain functional.
Uses: angina, cardiac arrhythmias, myocardial infarction, congestive heart failure,
hyperthyroidism, and glaucoma and prophylaxis of migraine (headaches).
Propranolol ( ideral )
nonselective beta antagonist, blocks ( beta-1 and beta-2) receptors.
Actions:
- Cardiovascular: Propranolol diminishes cardiac output, having both negative
inotropic and chronotropic effects. It directly depresses sinoatrial and
atrioventricular activity, and decreased consumption of oxygen these effects are
useful in the treatment of angina
- Peripheral vasoconstriction: Blockade of beta receptors prevents beta-2
mediated vasodilation. The reduction in cardiac output leads to decreased blood
pressure and reduced blood flow to the periphery.
- Bronchoconstriction: Blocking beta-2 receptors causes contraction of the
bronchiolar smooth muscle (asthma).
- Increased Na+ retention: Reduced blood pressure causes a decrease in renal
perfusion, resulting in an increase in Na+ retention, (combined with a diuretic).
- Disturbances in glucose metabolism: beta blockade leads to decreased
glycogenolysis ( not to be given in case of insulin-dependent diabetic)
- Blocked action of isoproterenol: block the actions of isoproterenol and beta
blocker of epinephrine but norepinephrine
Therapeutic effects:
- Hypertension: lowers blood pressure in hypertension by Decreased cardiac
output and inhibition of renin release from the kidney
- Glaucoma: used in chronic treatment (timolol) neither affects the ability of the eye
to focus for near vision nor change pupil size,
- Migraine: in chronic migraine, the mechanism may depend on the blockade of
catecholamine-induced vasodilation in the brain vasculature.
- Hyperthyroidism: In acute hyperthyroidism (thyroid storm), prevent cardiac
arrhythmias.
- Angina pectoris: useful in the chronic management of stable angina, decreases the
oxygen requirement of heart muscle and reducing the chest pain
- Myocardial infarction: prophylactic use in myocardial infarction reduces infarct
size and hastens recovery. The mechanism for these effects may be a blocking of
the actions of circulating catecholamines, which would increase the oxygen
demand, also reduces the incidence of sudden arrhythmic death after myocardial
infarction.
Adverse effects:
Bronchoconstriction: asthma.
Arrhythmias: Treatment with β-blockers must never be stopped quickly
because of the risk of precipitating cardiac arrhythmias, which may be
severe.
Sexual impairment: Because sexual function in the male occurs through alpha
adrenergic activation, beta blockers do not affect normal ejaculation or the
internal bladder sphincter function.
Drug interactions: Drugs that interfere with the metabolism of propranolol,
such as cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its
antihypertensive effects. Conversely, those that stimulate its metabolism,
such as barbiturates, phenytoin, and rifampin, can decrease its effects.
Timolol and nadolol: Nonselective beta antagonists
Timolol used in chronic glaucoma and occasionally, hypertension.
Acebutolol, atenolol, metoprolol, and esmolol: Selective beta-1 antagonists
- eliminate the unwanted bronchoconstrictor effect (beta-2 effect) in asthma.
- Cardioselective beta -1 blockers, at low doses (50-100) times than bera-2
blockers
- These drugs lower blood pressure in diabetic hypertensive patients.
- Esmolol has a very short lifetime due to metabolism of an ester linkage. It is
only given intravenously if required during surgery
Pindolol and acebutolol: Antagonists with partial agonist activity
Actions:
Cardiovascular: have intrinsic sympathomimetic activity (ISA). These partial
agonists stimulate the beta receptor, yet they inhibit stimulation by the more
potent catecholamines, epinephrine and norepinephrine.
-These are effective in hypertensive patients with moderate bradycardia, because
decrease effect on heard rate and cardiac output is less pronounced
- Carbohydrate metabolism is less affected (valuable in the treatment of
diabetics)
- Not used as antiarrhythmic agents
Labetalol and carvedilol: Antagonists of both alpha- and beta adrenoceptors
Actions: reversible blocke alpha and beta receptors. used in treating the elderly or
black hypertensive patients for whom increased peripheral vascular resistance is
undesirable. They do not alter serum lipid or blood glucose levels. [Note: In
general, black hypertensive patients are not well controlled with β-blockers.] and
used in pregnancy-induced hypertension.
Adverse effects: Orthostatic hypotension and dizziness
Drugs Affecting Neurotransmitter Release or Uptake
They effects indirectly on the adrenergic neuron by causing the release of
neurotransmitter from storage vesicles or alter the uptake of the
neurotransmitter into the adrenergic nerve.
Reserpine
Plant alkaloid, blocks the amines transport system Mg2+/adenosine
triphosphate (ATP) from the cytoplasm into storage vesicles, has a slow
onset, a long duration
of action, and effects that persist for many days. Decrease blood pressure.
Guanethidine
blocks the release of stored norepinephrine as well as displaces
norepinephrine
from storage vesicles (thus producing a transient increase in blood pressure).
Side effect: causes orthostatic hypotension and interferes with male sexual
function.
Cocaine
Although cocaine inhibits norepinephrine uptake, it is an adrenergic agonist.