notes by dr Claudio Italiano
Today the news is that according to which in Italy in 2009 7,000 children were
born less and that the population over sixty-five is increasing. This depends on
several factors:
- reduction of births;
- reduction in mortality rates;
- disease control;
- improvement of living conditions;
- progress in medicine and prevention.
The result is an aging population, and more problems related to this condition.
On gastroepato we already talked about the problem of the frail elderly.
Here we want to talk about the cognitive disorder of the elderly, in practice of
dementia, which indicates a brain disease that involves the impairment of
cognitive functions, such as:
-
memory: in the image you can appreciate the complex circuit relation between the
various brain districts involved in the memory process.
- the reasoning,
- the language,
- the ability to orient oneself,
- to carry out very complex tasks,
- the possibility of an independent life.
- changes in personality and behavior
In the initial phases there is the deterioration of the more complex relational
functions (IADL and ADL) in which cognitive competence is greater (they are the
so-called instrumental functions, which manage finances, use the means of
transport and communication, manage the house and drugs ) and with the
progression of dementia the daily basic activities are also compromised
(personal hygiene, clothing, bath and mobility, continence).
Among the dementias, secondary ones are defined as vascular ones (ICTUS). In
these forms there is a reduction in the number of nerve cells or neurons (see
photo) and the richness of the synapses, that is, the connections between the
dendrides of the cells themselves, which transmit signals to other nerve cells
via the "synaptic buttons". At this level there are substances, called "neurotransmitters",
with an excitatory or inhibitory function, which are released and which carry
signals to the other cells with which they are interconnected.
Vice versa among primary dementias, ie those for which it is not possible to
give a scientific explanation, include Alzheimer's disease which represents 50%
of dementias, which compromises memory and other cognitive functions that
produce gradual difficulties in carrying out daily activities. from a slow
start, often completely unnoticed for a long time. After Alzheimer's disease,
Lewy's body dementia is the most common chronic degenerative disorder.
Let's see here what drugs are planned for the treatment of dementia. Let's
review them and discuss the evidence in the clinic
Buflomedil exerts an antispastic action at the level of smooth muscle cells
probably interfering with the transport mechanisms of the calcium ion. It is
also active on the hemeological factors.
Benciclan is supplied with both calcium antagonist activity and effects on brain
metabolism and antiplatelet activity.
Betahistine acts as a histamino-like drug increasing the pre-capillary flow <
Calcium antagonists, some of them appear to be specific to the cerebral
circulation. The vessel action is due to the selective blocking of the calcium
channels present on the myocell.
Cetiedil has a papaverin-like action, inhibits phosphodiesterase, sensitizes
vasal beta2 receptors to catecholamines, has calcium channel blocker action and
increases purinergic reactivity.
Ciclandelate has a direct papaverin-like action on the vessel myocell. However,
its mechanism of action seems to be more complex and also involves beta2
adrenergic receptors, and the antagonism of intracellular calcium accumulation.
Cinepazide enhances endogenous adenosine that exerts vasodilator effect.
Innarizine and Flunarizine have calcinroantagonist and antihistamine activity of
type H-1.
Hydrogenated derivatives of ergot have activity (alpha-adrenolytic, antiserotonergic and dopamine-mimetics).
Isoxsuprina stimulates the beta-adrenergic sympathetic receptors and blocks those alpha adrenergic; it also has a papaverino-like action.
Moxysilitis blocks alpha-adrenergic receptors, does not appear to have activity on other receptor types.
Nafthydrofuril has a direct spasmolytic action, local anesthetic properties and an antagonist action of serotonin and bradykinin. The drug activates the succinic dehydrogenase, an enzyme of the Krebs cycle, thus increasing oxidative metabolism and the production of ATP of the tissues. Nafthydrofuril would increase cerebral oxygen and glucose consumption.
Nicergoline, the cardiovascular effects of nicergoline are related to its
alpha-lithic activity after intravenous administration, there is an increase in
flow in the femoral and carotid arteries but the flow of vessels of the
endoabdominal viscera is not changed, if not passively.
Papaverine is an alkaloid derived from opium, but without narcotic properties.
It has a specific muscle relaxant action; in vitro determines the release of all
the smooth molecular structures, independently of the substance used to induce myocontraction. The mechanism by which this property develops is not fully known.
It works by inhibiting phosphodiesterases and then increasing intracellular
cyclic AMP levels. t, perhaps with this mechanism that the vasodilator action is
performed. Also the property observed in the brain to induce an increase in
adenosine content could be responsible for the vasodilatation demonstrated in
this district, obtained only by ex. in high doses. However, the peripheral
vasodilating action, and the resulting hypotensive effect, can mask or cancel an
increase in flow. Pentoxifillin is a xanthine with two probable pharmacodynamic
properties, vasodilation and reduction of blood viscosity. Vasodilation is
achieved by enhancing P activity and antagonism on receptors a. The drug also
possesses phospho-diesterase inhibiting activity, which causes an increase in
the cyclic AMP (cAMP) and consequent my vascular relaxation. The vasodilator
function has recently been questioned. Many mechanisms are involved in reducing
blood viscosity; the increase in erythrocyte cAMP would result in greater
deformability of the red blood cells, while the increase in platelet cAMP would
inhibit its adhesiveness and aggregation.
Piribedile is a synthetic piperazine derivative, first introduced into the
market as a peripheral vasodilator. Some studies have shown that the drug
inhibits the sympathetic vascular tone resulting in a reduction of vascular
resistance, while increasing the mesenteric venous tone. It would also stimulate
the metabolism at the neuronal level, with a central and peripheral dopaminergic
action.
Vincamina, is an indolyl-alkaloid isolated from Vinca minor with alkaline
structural similarity with reserpine. The drug appears to inhibit
phospho-diesterase and induce an increase in the concentration of biogenic
amines. It has vasodilatory action, responsible for the hypotention and
tachycardia demonstrated in the animal.
The various studies that have been conducted on Alzheimer's disease that is
determined by the degeneration of nerve cells in the cholinergic ways, has led
to the development of drugs capable of increasing cholinergic transmission.
As you can see at the side, the nervous transmission between two cholinergic brain
cells is represented, that is, they exploit acetylcholine for their "neurotransmission",
that is, to relate to each other. When the substance exits from the synaptic
button, that is from the first left neuron, it leads into the synaptic space.
Here receptors are present to pick up the signal represented by acetylcholine.
In the second neuron, that is, in what it receives, the neurotransmitter carries
a signal, for example, in our case, of excitation.
The purpose of therapies that move in the sense of an amplification of
cholinergic synaptic transmission, provides a series of drugs that intervene,
precisely, to try to increase the production of acetyl-choline, as precursors,
or to modulate the neurotransmission "raising the volume ", so to speak. These
drugs have been developed thanks to studies conducted on the laboratory animal,
using scopolamine, a substance that blocks the muscarinic receptor, that is,
that collects the cholinergic signal. In this way the animal became amnesic,
that is without memory, just like in the patient with Alzheimer's.
The strategies of a pharmacological intervention on the cholinergic system provide for Alzheimer's:
a) stimulants of cholinergic function.
- Acetylcholine precursors drugs:
- Colina, lecithin
- Acetyl-L-carnitine
- L-alpha-glyceryl-phosphorylcholine
- Fosfatidilcolina
- CDP-choline (cytidine-5'-diphosphocholine)
b) modulators of the secretion and storage of acetylcholine
- aminopiride
- fosfaditilserina
- piracetam
c) direct cholinergic agents.
- Colane-esterase inhibitors (I and II generation)
- Cholinergic and nicotinic cholinergic agonists
Still it must be said that in the brain aging play an important role the
catecholaminergic neurotransmitters and in particular those involved in the
dopaminergic transmission. Catecholamines are important for many functions that
also include the regulation of mood, control of alertness, of emotion. Therefore
the use of drugs that stimulate catecholaminergic transmission, such as ergolins,
which are agonists of D2 receptors, is contemplated in the patient with
cognitive disturbance. Neuropeptides can also act in this sense. The importance
of the adrenergic system in the mnemonic and cognitive processes lies in the
fact that it determines a state of alert. Some drugs such as deprenil blocking
catecholamine metabolism are successfully used in the attention and learning
mechanism.
It too plays a role in the learning process, so the presence of GABAergic
receptors has been found in the amygdala that is thought to be a structure
involved in the memory process. Some scientists have proposed an inhibition of
the GABAergic system in the patient with Alzheimer's disease, because a
dendritic system of neurons containing GABA in these subjects has been
proliferated.
Implicated in the control of mood, it does not seem to play a clear role in the
mechanisms of learning. It should be noted that there are 5HT3 receptors for
serotonin which exert an inhibition action on the release of acetylcholine which
is then facilitated by 5HT3 serotonergic antagonists.
Vasopressin: facilitates memory processes by indirect central action.
Somatostatin and ACTH play a role in the mechanisms of attention.
Beta-endorphin. It produces retrograde amnesia which is blocked by naloxone.
Therefore there are studies for Alzheimer's in this sense, using naloxone
Galanina: peptide with neuromodulatory function towards neurons containing
acetylcholine.
The excitatory amino acids are glutamic acid and aspartic acid. 30% of the CNS
synapses contain excitatory amino acids, while alterations of these are evident
in Alzheimer's disease.
They play an important role in transmitting synapses in areas of memory circuits
and participate in the genesis of long-term synaptic strengthening phenomena.
Glatamate acts on at least 4 different receptors,
They play a significant role in treating the patient with cognitive impairment.
They have the progenitor in a cyclic derivative of GABA, piracetam. They include
piracetam, oxiracetam, aniracetam and their action is complex.
They increase the release of dopamine, facilitating its acquisition; they
increase cholinergic excitatory transmission, because they antagonize the effect
of scopolamine and enhance the function of the AMPA receptor. They maintain high
levels of ATP which is an energy molecule in the cerebral ischemic tissue,
increasing the turnover of phosphatidylinositol. Studies have shown their role
in communication between the two hemispheres that is increased after
administration of piracetam and have excitation action via NMDA receptors at the
hippocampus level.
Some Neurology links chosen for you:
Il morbo di Alzheimer, la cura