Tuesday, March 12, 2019

Pharmacology and toxicology II - Adrenergic

neurotransmitter

Adrenergic neurotransmission is relying on catecholamines, including dopamine,

norepinephrine and epinephrine, plus an historical compound used as drug, ???. β

Phenethylamine is important as it is part of abuse substances; noradrenaline has amine

group, while adrenaline has main groups; Isoproterenol has ???.

Catecholamine synthesis starts from tyrosine, which is a non-essential amino acid; it is

the starting point, as it is the substrate for tyrosine hydroxylase, with dopa formation,
also being the limiting step for the production of catecholamines (resulting from the high
tyrosine availability, compared to Km of the enzyme; it is different from serotonin, which
is based on tryptophan, where there’s need of a high supply to increase serotonin
production); there is aromatic amino acid ??? for production dopamine, where ???, and
norepinephrine synthesis relies on a dopamine hydroxyalse; further along, in
epinephrine neurotransmitter formation, PENMT enzyme introduces a methyl group (a
single one), for epinephrine production.

It all occurs in cytoplasm, then the catecholamine is inserted in vesicles, by the VMAT
(mono-amino transporter, non specific for catecholamines, as it transports also other
mono-amines).

Once released in the cleft, there can be degradation, by two main processes, either
MAO, introducing in noradrenaline an hydroxyl group, and COMT that introduces a
methyl group; both are important pharmacological targets, as they can be blocked in all
diseases with low catecholamine production; inhibitors of MAO-A and B (two are
present, one for norepinephrine and epinephrine both, that is type A, one for dopamine,
that is type B; the first is an old target for depression treatment, while the second is
more recently targeted for ???).

Both enzymes are active contemporaneously; there is Metanephrine production as

metabolite from COMT, which can be then a substrate for MAO, or the reverse is true;
there is at the end vanillylmandelic acid, main metabolite of catecholamines, importantly
dosed in case of pheochromocytoma (very high values).

Dopamine undergoes the same process, leading to homovanillic acid formation.

Epinephrine and norepinephrine are present in our brain;
norepinephrine is produced in the locus ceruleus, projecting to reticular formation of the
brain stem and the cortex, and it is important for vigilance and attention; if its neurons
are turned off, there is sleeping; more rostrally and ventrally there is dopaminergic
transmission, with three main projections, mesolimbic, mesocortical, from ventral-

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tegmental area, and negrostriatal projection, toward the caudal putamen; the first two
are related to pleasure stimuli (prefrontal cortex, and limbic area of the amygdala), while
the last one is affected in Parkinson disease, with functions related to movement.
An important part is the presence of receptors to recognize the transmitter and transmit
information; there are two types of receptors, α and β;

the idea there were two classes started from observations on epinephrine function,
which acts on both types; once administered, there was an increase in both systolic and
diastolic blood pressure, as well as increases in heart rate; if Phentolamine was
administered, before epinephrine was used, there was an inversion in the hypertension
effects, as Phentolamine is a blocker of α receptor, and it unmasked the β receptors;
hence, α receptor, in reference to blood pressure, are stimulators, while the β are
depressive; one drug, Phenylephrine, as well Isoproterenol, are α and β selective
agonists, respectively (one causing the hypertension, the other hypotension)

; epinephrine was active on both types of receptors (however, α receptors are located in
anatomical sites more accessible to adrenaline, and also epinephrine is more active on
the α than β, not in terms of selectivity, but in potency).

The original α and β distinction was then deepened, as α is present as α1 and α2, while
β comes as β1, β2 and β3. α1 are stimulatory receptors, acting via Gq proteins; α2 are
inhibitory, with Gi; all β receptor are acting with Gs, so stimulatory; ???; Isoproterenol is
more potent than norepinephrine and epinephrine, and on β2 receptors adrenaline is
more active than norepinephrine (hence noradrenaline has much lower affinity on β
receptors, so with its usage there is no β response, only α); β3 selective drugs are not
present.

α1 receptors are expressed in smooth muscle, mostly the vascular type, but also
genitourinary and intestinal smooth muscle, where it induces vasoconstriction (vascular
muscle), in the liver they have glycogenolytic effects (increased sugar in blood), in
intestine there is hyper-polarization and relaxation; some are also present in the heart,
but they are poorly studied and have not much effect (main effect is on β1); α2 are
classical presynaptic receptors, so they are auto-receptors (if on receptors of neurons
releasing catecholamine), or hetero-receptors (there is inhibition of ACh in
parasympathetic); stimulating the α2 there is decrease of sympathetic tone (all
sympathetic drive is reduced if there is this stimulation);

they are also present in pancreas β cells, reducing insulin secretion, and on platelets,
which favors aggregation (so thrombotic state, a major risk for cardiovascular events).
β1 receptors are present in the heart (mediating increased positive dromotropy,
chronotropy, bathmotropy, lusitropy) mediating all of the effects on the heart; they are
also preset in juxtaglomerular cells, increasing renin;

β2 receptors are present on smooth muscle, with completely opposite function

compared to the α1, inducing relaxation (also in bronchial muscles), and reducing
tension of genitourinary and GIT muscles; another site where they are present is

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skeletal muscles, increasing potassium uptake and glycogenolysis; β3 receptors are
preset in adipose tissue, mediating lipolysis, but there are no drugs specific for this type
of receptors (which could be useful for weight loosing strategies).
β receptors have larger side pockets that can accomodate Isoproterenol, accounting for
its selectivity.

Adrenergic agonists are divided in direct and indirect acting, the former acting directly
on receptors, the latter are releasing agents, uptake inhibitors, MOA inhibitors or COMT
inhibitors (they do not act directly on the receptors); there are among the direct drugs
some that are selective for the receptors subtypes, others that are non-selective (like
Ephedrine).

Adrenaline is still used, in conditions of shock and it was used as bronchodilator (not
seen anymore), with sustained blood pressure in conditions of shock; also
noradrenaline finds usage in shock and cardiac arrest; dopamine in low doses activates
the dopaminergic receptors on kidney vascular smooth muscles, while with increases
dosage, there is also action on β receptors, leading to heart effect, and, with further
increase (higher than 5mg/mL), there is strong generalized vasoconstriction mediated
with activation of all types of receptors.

Another agonist is Dobutamine (in cases of acute heart failure), used like dopamine;
Ephedrine is another drug, ???; and Metaraminol, as bronchodilator. Methoxamine,
Phenylephrine are α1 adrenergic agonists, selective agents, and are used for ???.
Clonidine, and other α2 agonists are used to treat hypertension; it can be used in
emergency as sedating drug; some local uses of α2 selective agonists are
Apraclonidine and Brimonidine (used in glaucoma, to relieve eye pressure); ???, used
in pain and spams.

Clonidine is not a pure α2 agonist, but there are Imidazoline receptors that can be
involved as well; these are in vasomotor centers of medulla oblongata, and might
contribute to the effects of the drug.

Dopamine in low doses is a purely dopaminergic agonist, at increased doses acts also
as β agonist, at higher dosage it can also activate α1 receptors.
Dobutamine, Denopamine, Xamoterol, Prenalterol are all β1 agonists; they are effective
on heart, and increase ionotropic effects in shock (only used in shock conditions, to
sustain cardiac contractility). β2 receptor agonists are active on smooth muscles, and
include adrenaline (non selective, for β1 and β2), ???; very selective is Salbutamol (also
called Albuterol); ???.

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Indirect agonists include Amphetamine, a classical sympathomimetic drug, that can
increase catecholamine in brain, as it inhibits the uptake, it blocks MAO, so it also
increase noradrenaline, and it enters the synaptic terminal in exchange with
noradrenaline, with a release which is not vesicular;

Methamphetamine, Methylphenidate (used in attention disorders, in children)

Dexmethylphenidate; Pemoline (specific for dopaminergic); also Cocaine is
sympathomimetic, but it is more active on dopamine transporters (inhibits re-uptake; it is
the basis for the pleasuring sensations given by the abuse of cocaine, as it is active in
mesolimbic area), and has no pharmacological use (it is drug of abuse).