Catecholaminergic transmission

**counselor** Mon Oct 15, 2012 11:59 am

Catecholaminergic transmission

Catechol compounds are endogenous norepinephrine, epinephrine and dopamine. They are characterized by two hydroxyl in position 3 and 4 of the benzene ring

SUMMARY
The synthesis takes place from dall'aminoacido tyrosine

1) The tyrosine is hydroxylated by tyrosine hydroxylase to 3-4 dihydroxyphenylalanine (DOPA). This is the limiting step. The enzyme is activated by stimulation of adrenergic nerves.
2) The DOPA is decarboxylated to dopamine by the DOPA decarboxylase.
3) Dopamine is hydroxylated to norepinephrine by dopamine -hydroxylase. While the preceding reactions take place in the cytoplasm, the latter occurs inside the synaptic vesicles in which accumulates the cytoplasmic dopamine.
4) The synthesis of adrenaline takes place by means of feniletanolamina cytoplasmic N-methyltransferase, which has the S-adenosyl-methionine as a donor of methyl groups. The substrate of the enzyme is represented by norepinephrine which leaves the vesicles and passes into the cytoplasm, where the enzyme is localized. The enzymes are synthesized in the cell body and then migrate to the nerve endings.

STORAGE
Catecholamines present in adrenergic endings can be:
a) In small fee free in the cytoplasm
b) In a small share in free vesicles or granules
c) For the most part related to ATP within granules of ATP in a ratio 1: 4 of catecholamine.

The entrance in the vesicles of filing of catecholamine occurs by active transport by a carrier.
The catecholamines stored can also come from the extracellular space (reuptake 1).
Indirect sympathomimetic (ephedrine, tyramine and amphetamine) mobilize norepinephrine stored in vesicles, making it spread throughout the cytoplasm.
These drugs do not induce exocytosis.

LIBERATION
The annexin cytoplasmic (including the calpactina I) in the presence of Ca + + (the concentration of which increases the pulse arrives nervous for opening channels N) cause membrane fusion with the plasma and the granule exocytosis of neurotransmitter catechol.

TERMINATION OF

Takes place:
1) reuptake into nerve endings (reuptake 1)
This is the primary mechanism for the cessation of the effect.
2) Spread the gap junctional
3) extragiunzionale uptake (uptake 2)
4) metabolic transformation by MAO (mitocontriale) and COMT (cytoplasmic)

Vanillylmandelic acid is the major urinary metabolite of adrenaline and noradrenaline.
The corresponding product of the metabolism of dopamine is homovanillic acid.

Distribution of catecholamines

In addition to the SNA, norepinephrine and dopamine are widely distributed in the CNS.

Norepinephrine is mainly located in neurons that originate from:
• locus coeruleus
• lateral tegmentum
• nucleus of the solitary tract
The noradrenergic neurons play an important role in controlling the sleep-wake cycle, feeding behavior, mood.

The dopaminergic neurons are divided into three main groups:
• nigrostriatal (control muscle tone and motor coordination). Their degeneration is responsible for Parkinson's disease
• mesolimbic and mesocortical (control features emotional, psychological and cognitive)
• tuber-infundibular (control prolactin)

ADRENERGIC RECEPTORS

Are membrane receptors coupled to protein G.
Distinguish them in adrenergic receptors (for noradrenaline and adrenaline) and dopamine receptors

Adrenergic receptors 
3 receptor subtypes are known  1:
•  1A. They are located mainly in blood vessels, heart and liver
•  1B
•  1C
 1 receptors mediate the effects contratturanti on vascular smooth muscle, intestinal and genito-urinary tract. Postsynaptic receptors are G-protein coupled type Gq11, which act on the membrane phospholipids.

Have been described 3 subtypes of receptors  2
•  2A
•  2B
•  2C
The  2 adrenergic receptors inhibit the adenilatociclasi through Gi proteins. These G protein may also activate the conductance of K + channels and inhibit the Ca + +.
Are receptors in the postsynaptic localization, but mainly presynaptic.

These receptors perform various functions:
-Reduction of the release of catecholamines
-Reduction of insulin release
Inhibition of lipase activity in adipocytes
-Induced platelet aggregation
-adrenergic receptors
Have been described 3 subtypes of receptors , all coupled to Gs proteins. In skeletal muscle cells, and these proteins can stimulate the G function of Ca + + channels, in addition to stimulating the adenilatociclasi.

The  1 receptors are located primarily at the level of
• Heart (over which they have stimulating effects) and
• juxtaglomerular apparatus of the kidney (where they control the release of renin)

The receptors  2 are localized primarily on smooth muscle cells of which inhibit the contraction. Determine:
• bronchial bronchodilator
• the genitourinary muscles, with particular reference to the uterus, causing relaxation.
• to induce hepatic glycogenolysis

The receptors  3 are localized mainly in adipose tissue, where they induce lipolysis.

EFFECTS OF adrenergic stimulation EFFECTORS ON THE SNA (TABLE A)

• Eye:
iris (the pupil radial) mydriasis.
• Bronchi bronchodilation
• Heart Effect chronotropic, dromotropic, and inotropic positive batmotropo
• Blood vessels Vasoconstriction
• Decrease Stomach and intestinal tone and motility, sphincter contraction
• Urinary bladder detrusor expansion, contraction trigone and sphincter
• Male Reproductive System Cumshot
• Uterus muscle relaxation
Uterine
• Reduced mast cell release of histamine and leukotrienes
• Reduced insulin release
• Metabolic glycogenolysis and gluconeogenesis less
Stimulation triglicerido lipase

Dopamine receptors

We distinguish two families of dopamine receptors:
The D1-like (D1 and D5 include)
The D2-like (including D2, D3, D4)

The D1-like receptors are coupled to Gs proteins that stimulate adenilatociclasi
The D2-like receptors are coupled to Gi proteins, which inhibit the formation of cAMP, but also act by increasing the output currents of K + and those inhibiting input of Ca + +.

The administration of dopamine, acting on peripheral structures determines the rise of doses:
• Vasodilation, increased blood flow and renal filtration (D1 and D2 receptors that reduce the presynaptic release of norepinephrine from nerve endings and adrenaline from the adrenal medulla.
• Effect of inotropic and chronotropic positive stimulation of receptors  1
• Finally vasoconstrictor effect of  1-adrenergic receptor stimulation

Many are the central effects of dopamine (see chapters on CNS drugs).

ADRENERGIC RECEPTOR PHARMACOLOGY:

Acting sympathomimetic LIVE

 1 SELECTIVE AGONIST
Metossamina, oxymetazoline, naphazoline, tetryzoline
Phenylephrine
The latter also activates the receptors .

Pharmacodynamics
• Increase in peripheral resistance and blood pressure to stimulation of receptors  1.
• The heart rate drops to vagal reflex.

TOXICITY '
• Risk of hypertensive crisis, especially in patients who are also taking MAO inhibitors or tricyclic antidepressants
• Inflammation of the nasal mucosa to repeated use

THERAPEUTIC USES
• Nasal decongestants and ophthalmic testing (use the lowest effective dose)
• vasoconstrictors in hypotension

 2 SELECTIVE AGONIST
Clonidine, a-methyldopa, guanabenz and Guanfacine

Pharmacodynamics
• Initial increase in blood pressure by stimulation of postsynaptic receptors  2 (vasoconstriction).
• Then hypotensive effect for:
-Reduction of central sympathetic efferent (effect evoked in the medulla oblongata)
-Stimulation of peripheral presynaptic receptors  2 with inhibition of norepinephrine release

TOXICITY '
• sedation
• sexual impotence in male
• orthostatic hypotension
• Dry mouth (salivary inhibition centers)

THERAPEUTIC USES
• Treatment of hypertension (see antihypertensive drugs)
• Syndrome of abstinence from opiates and alcohol
• Treatment of hot flushes in menopause

NON-SELECTIVE AGONIST -ADRENERGIC
Stimulate both receptors  1 that the  2.

Isoproterenol
It 's very powerful on the various receptor , but is almost inactive receptor .

Pharmacodynamics
-Cardiovascular
• Decreases peripheral vascular resistance
• Decreases blood pressure
• Summon positive inotropic and chronotropic
• It can lead to cardiac arrhythmias.
-Effects bronchial
• bronchodilation and
• reduced release of histamine and leukotrienes from mast cells

TOXICITY '
Major risk of arrhythmias is no longer used in therapy

Dobutamine
The molecule has a complex spectrum of action.
(-) Agonist dobutamine = 
(+) Dobutamine = antagonist 
(+) = Agonist dobutamine 
(-) = Agonist dobutamine 

Pharmacodynamics
• Marked affection positive inotropic
• Modesto positive chronotropic effect
• The peripheral resistance are little influenced
• Increased conduction velocity and automaticity (risk of arrhythmias).

THERAPEUTIC USES
Short-term treatment of heart failure after surgery.

 2 SELECTIVE AGONIST

Have bulky substituents on the amino group which increase the selectivity   2 vs 1 and reduce the affinity for the receptors . Among these:
-Metaproterenol (resistant to COMT)
-Terbutaline (resistant to COMT)
-Albuterol (resistant to COMT)
-Salmeterol and Formoterol (duration of action 12 hours)
-Fenoterol
-Ritodrine

Pharmacodynamics
Bronchi
• bronchodilation
• Reduced release of histamine and leukotrienes from mast cells
• Accelerated mucociliary function

Uterus
• Inhibition of uterine contractions.
• Compared to non-selective cause less cardiac stimulation

TOXICITY '
• Increased input of K + in skeletal muscle (tremor and hypokalemia).
• Tachycardia (is due to hypotension and residual agonist activity of receptor  1)
• Hyperglycemia
• Gradual development of tolerance

THERAPEUTIC USES
1. Bronchial Asthma
2. Threat of premature birth (the ritodrine is the
drug of choice)

Acting sympathomimetic INDIRECT

Amphetamine
It 'a sympathomimetic amine with indirect action with intense central actions
The L-isomer is more potent than d-.

After uptake into the nerve ending (via the carrier for noradrenaline) displaces norepinephrine from binding sites extravescicolari and synaptic vesicles. Norepinephrine free passes gradually into the synaptic space (not for exocytosis).

Pharmacodynamics
Cardiovascular effects
• Increase in systolic and diastolic blood pressure.
• Cala heart rate by reflex.

Central nervous system
He stimulating action at the level of the bulb, cortex and ascending reticular formation. Produces:
1. Improved performance in conditions of fatigue and sleep.
2. Elevation of mood. Appears self-confidence, initiative, and even euphoria.
3. Insomnia.
4. Mild analgesic effect and enhancement of opiate analgesia.
5. If respiration is depressed by centrally acting drugs, amphetamine increases the respiratory rate.
6. Anorectic effect. Is reduced the intake of food especially for psychomotor activation induced by the drug. Develops tolerance to anorectic.

MECHANISM ACTION CENTRAL
Even the central effects are largely due to the release of biogenic amines:
• noradrenaline (anorectic effect and increased alertness)
• dopamine (locomotor stimulation and reinforcement of action)
• 5HT (psychotic manifestation at high doses)

TOXICITY '
For intake of high doses of amphetamine can be observed:
• Restlessness and irritability.
• Insomnia
• The central stimulation is followed by fatigue and depression (even severe).
• Poisoning generate lethal convulsions, coma, cerebral hemorrhages for hypertension.
• Hallucination paranoid frequent chronic use.

Acute intoxication should be treated with:
• acidifying urine
• Sedatives benzodiazepine
• hypotensive

DRUG ABUSE
• In patients who abuse the drug is common repeated administration of amphetamine at intervals of 3-4 hours (we speak in jargon "run").
• Intravenous administration is preferred because it gives the most intense effects, you get the "rush" is characterized by feelings of intense pleasure. The "run" can last for several hours, then the person falls into a deep sleep for 15-18 hours.
• You can abuse the drug for oral administration, but with less intensity of the psychic effects.

MECHANISM OF ACTION OF REINFORCEMENT
Increased release of dopamine in the nucleus accumbens.

TOLERANCE
It istaura tolerance even for the euphoric effect, for which it tends to increase the doses

DEPENDENCE
Addiction to amphetamine is mainly psychic type
The withdrawal syndrome is characterized by:
a) anhedonia
b) lethargy
c) depression (life threatening)

THERAPEUTIC USE
Currently its use is not recommended in the treatment of obesity

Methylphenidate
It 'structurally and pharmacologically similar to amphetamine.

Ephedrine
• In addition to release norepinephrine from sympathetic neurons also activates receptors and   adrenergic receptors.
• The SNC has a similar action, but less intense than the amphetamine.
• In the past it was widely used as a bronchodilator, but its use has become obsolete in relation to central effects.

Methylenedioxymethamphetamine (Ecstasy)
E 'was synthesized at the beginning of '900 in Germany and initially used as anorectic drug.
- It has been made use of in the First World War, to combat feelings of hunger and fatigue.
- Then it was used as a medicine in psychiatry "entactogeno" to foster communication between psychiatrist and patient. This use has been abandoned in the late 70s.
- It is currently used only as a drug of abuse for recreational purposes, especially in the disco.

Pharmacodynamics
• Under the influence of Ecstasy the person feels: affable, talkative, confident, carefree, euphoric, in a state of intimacy with others.
• The rhythmic music and psychedelic lights tend to exalt the psychotropic effects of Ecstasy.
• Ecstasy is less reinforcing properties than heroin and cocaine. Ecstasy consumers tend to use other drugs of abuse.

MECHANISM OF ACTION
• Has the ability to increase the levels of serotonin and dopamine in the neuronal synapses.
• Probabilmemte the increase of serotonin determines most of the psychotropic effects of Ecstasy; dopamine contributes to such effects.

The neuron reacts to the loss of serotonin by activating its metabolism in an attempt to re-establish the internal levels.
- Are formed large amounts of free radicals in serotonergic neurons, and the cell undergoes oxidative damage.
- Hyperthermia enhances the radical reactions and neurotoxic damage.

TOXICOLOGY
Acute toxicity
It is manifested by:
• Hyperthermia and convulsions
• hypertensive crisis and tachyarrhythmias
• rhabdomyolysis
• renal failure
• liver damage
• pulmonary edema
• intravascular coagulation
• death (up to 10,000 consumers every 5 deaths / year)
The risk of toxic manifestations of Ecstasy increases to reduced metabolism of CYP2D6 deficiency
But also CYP1A2 and CYP3A4 metabolize Ecstasy

Chronic
A previous use of Ecstasy causes:
• reduced glucose uptake in various brain areas
• reduced density of serotonin transporter
• electroencephalographic changes
• memory problems
• damage to serotonergic neurons
• damage to dopaminergic neurons (Parkinson's disease)
• Musculoskeletal and heart damage in children exposed prenatally to ecstasy.

Treatment of acute poisoning:
• Gastric lavage
• Benzodiazepines for seizures
• Vasodilators for hypertensive crisis
• Antiarrhythmics for cardiac arrhythmias
• Dantrolene for hyperthermia
• Damage neurotoxic do not know how to make them regress.

USES OF sympathomimetic drugs

1) SHOCK
In cardiogenic shock can be very useful as dopamine and dobutamine because they have:
• inotropic effect, at low doses increases cardiac output without causing further vasoconstriction
• increases renal blood flow
In case of septic shock should be used before antibiotics, and drugs that correct the circulatory dysfunction (dopamine, dobutamine).
If the shock is characterized by intense hypotension will be appropriate to the use of compounds -adrenergic receptors. This may occur as a result of anesthesia or spinal injury.

2) Hypotension
The adrenergic drugs may be appropriate to reduce the marked hypotension from spinal anesthesia or an overdose of antihypertensive.

3) Hypertension
 2 adrenergic agonists are used as centrally acting antihypertensive drugs.

4) nasal decongestion
The topical reduces systemic side effects, but also increase the risk of rebound congestion.

5) ASTHMA AND THREATENED ABORTION
Using  2 agonists selective. The use of aerosol may reduce systemic side effects.
Possible desensitization.

6) anaphylactic shock
Epinephrine is the drug of choice.

7) OBESITY '
Avoid the use of these drugs: addiction, addiction, rapid recovery of weight, residual depression.

 ADRENERGIC ANTAGONISTS

NON-SELECTIVE ANTAGONIST
Phenoxybenzamine and dibenamina
Aloalchilamine are irreversibly blocking the receptors   1 and 2.
Phentolamine and tolazalina
Are of imidazoline to blocking action on the receptors reversible   1 and 2

Are of historical interest, no longer in use InItalia because  2 receptor blockade determines:
• Increased efferent sympathetic to central effect
• Increased release of norepinephrine device for blocking autoreceptors  2.
• These effects reduce those by blocking  1.

SELECTIVE RECEPTOR ANTAGONIST  1

This class of drugs includes:

Quinazoline derivatives
The Prazosin is the prototype of these drugs.
Has affinity for the receptors  1 is about 1000 times greater than that for  2.
 1-selective compounds are:
Terazosin. Has the advantage of a duration of action of 18 hours, so it is possible one administration per day.
Doxazosin. Has T1 / 2 of 20 hours and duration of action of 36 hours.
He Trimazosina pharmacokinetic characteristics very similar to prazosin.

Derivatives of 4-aminopyridine
Indoramin. It also has direct vasodilator action. The main side effect is orthostatic hypotension

Uracil derivatives
Urapidile addition to blocking the receptors  1, also presents some agonist action on  2 and antagonist on  1.

Pharmacodynamics
• Blocking receptor  1 arterioles and veins.
• Do not affect the feedback mechanism of norepinephrine on their release
• Do not increase the frequency and cardiac output.
• It activates the renin-angiotensin system.
• Total cholesterol and LDL levels decrease. Increase HDL.

PHARMACOKINETICS
The bioavailability after oral administration is highly
Strong drug-protein binding and elimination by hepatic metabolism.
The T1 / 2 in the plasma of prazosin is 3 hours and the duration of action is 4-6 hours.
Doxazosin has half-life of 22 hours
Indoramin and urapidile have half-life of 3 and 5 hours, respectively.

TOXICITY '
1) Phenomenon of the first dose: severe orthostatic hypotension and syncope (30-90 min) after the first dose of the drug or the first combination with other antihypertensive agents.
2) Orthostatic hypotension during all therapy with  1 blockers.
3) headache and drowsiness.

THERAPEUTIC USES
1) Use as antihypertensives. These drugs are mild or moderate hypertension sufficient. May be associated with -blockers or diuretics adrenergcici
2) Congestive heart failure. They increase cardiac output by afterload reduction. Cala also the venous pressure.
3) Benign prostatic hypertrophy. Reduction of the resistance to the flow of urine in case of prostatic obstruction, for effect on the bladder and urethral sphincter
 2 SELECTIVE ANTAGONIST
Yohimbine
It 'a competitive antagonist of  2 receptors with opposite effects to those of clonidine.
Causes fact:
-Increased blood pressure
-Increased heart rate
-It 'was one of the first drugs for erectile dysfunction (uncertain effect)

 ADRENERGIC ANTAGONISTS
This is a class of drugs of large importance in the field Pharmacotherapeutic

Belong to this class of drugs
• non-selective antagonists against receptors   1 and 2 adrenergic receptors (propranolol, alprenolol, nadolol)
•  1-selective antagonists (metoprolol, esmolol, atenolol, bisoprolol)
• antagonists with intrinsic sympathomimetic activity (ISA) or partial agonists. These include the pindolol and oxprenolol (non-selective) and the acebutolol ( 1-selective)
-adrenergic antagonist with vasodilating activities incidental. For example, the labetatolo is also  2 agonist and antagonist    receptor antagonist carvedilol is    It also has antioxidant and antiapoptotic.
Pharmacodynamics

-Cardiovascular System
At the level of the heart these drugs cause:
• Reduction of heart rate and reduce the force of contraction.
• Reducing the rate of atrio-ventricular
• Reduction of cardiac automaticity.
• The cardiac output decreases, especially under stress.
• Partial agonists changed very little cardiac function at rest

A level vessel is observed:
• Increase in peripheral resistance after administration of non-selective antagonists  (removal of the control  2).
• In case of prolonged administration peripheral vascular resistance returned to normal. Decreases, however, whether the antagonists with ISA or have residual vasodilator action.

The antihypertensive effect of these drugs appears to be the result of the following effects:
• reduction in cardiac output
• reduced release of renin
•  2 receptor blockade neurons that facilitate the release of norepinephrine
• reduction in peripheral vascular resistance for some antagonists

-adrenergic antagonists decrease the working capacity for action on cardiac receptors  1 and  2 vascular skeletal muscle.
In patients with angina pectoris increases exercise tolerance for reduced oxygen consumption of the heart.

Bronchi-
Antagonists that block receptor  2 on bronchial smooth muscle can produce bronchoconstriction. The effect is observed especially in subjects with asthma or chronic obstructive pulmonary disease

-Metabolic Effects
• Drugs that block the receptor  2 reduces glycogenolysis and then the recovery from hypoglycemia.
• Caution in diabetic subjects.
• It reduces the production of unsaturated fatty acids.
• Increase in triglycerides and VLDL, and decreased HDL after administration of non-selective  blockers.

PHARMACOKINETICS
Antagonists such as propanolol lyophilic present compared to the more hydrophilic (eg metoprolol):
• Increased hepatic metabolism
• short half-life
• low bioavailability
•-bound drug-protein
• crossing the BBB.

TOXICITY '
• bradyarrhythmia (increased risk for association with calcium channel blockers or cardiac glycosides).
• Decreased exercise tolerance
• Risk of precipitating heart failure in patients with impaired cardiac function.
• Feeling of coldness.
• Abrupt discontinuation of  blocker can cause attacks of angina and cardiac arrhythmias.
• Bronchoconstriction (non-selective antagonists).
• Insomnia and depression.
• Risk of hypoglycemia in diabetics.

THERAPEUTIC USES
• Treatment of 'hypertension.
• Hypertrophic cardiomyopathy, a disease characterized by high end-diastolic pressure and obstructive outflow of blood
• Treatment of angina pectoris on effort, not in the vasospastic
• Treatment of supraventricular and ventricular arrhythmias
• Secondary prevention of myocardial infarction. After acute myocardial infarction reduces the risk of subsequent heart attacks and reduce mortality
• Heart failure: in recent years has emerged this indication, apparently paradoxical. For this indication, however the dosages of -blockers are considerably lower than for other indications. The effect appears to be due to reduced oxygen consumption and protection from arrhythmogenic effects of catecholamines.
• Migraine: propranolol and timolol are FDA approved for migraine prevention
• Hyperthyroidism and thyrotoxicosis: reduce symptoms related to adrenergic hyperactivity
• In glaucoma reduce the secretion of aqueous humor and facilitate drainage.

The selective  1 are preferred definitely in patients with bronchospasm, diabetes peripheral vascular disease, hyperlipidemia.

DRUGS ACTING on dopamine receptors

-Dopamine is used in cardiogenic shock in which heart failure is associated with hypotension and reduced renal for fusion.

Dopamine-receptor antagonists are used as anti-Parkinson drugs such as antipsychotics and

D2-antagonists are used as anti-emetic drugs

Dopamine antagonists are the subject of discussion among CNS drugs.