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OPIOID
Opioids are very important because they have drugs as a clinical indication is the treatment of pain
and represented a breakthrough in the evolution of pharmacology. Morphine is obviously known
for a long time, then he went in search of ever more active drugs, but not because morphine was not
active, actually attempting it has always been done, and not always successfully, is to try to separate
the analgesic activity, which is good, from the problem of tolerance and dependence, because the
morphine is a good analgesic, however, it has the disadvantage of inducing tolerance, which
involves a continuous increase of doses and dependence both physical and mental, with
development of drug addiction. The view was further expanded in the years when ' 70 was
discovered the endogenous opioid system. We have a physiologically painful sensations control
system and not just because the opioid system is a bit 'spread everywhere and are not certain about
all of its functions. So we have an endogenous control and has tried to activate the endogenous
system. This is a bit 'the story of analgesics or opioids. You know that NSAIDs have analgesic
activity and ovviamnente companies for the treatment of pain have developed protocols from the
magnitude of the pain, you can resort to a series of gradually drugs (we speak of course not just a
headache that we keep all of them, but we speak of the pains that accompany metastases in
neoplastic processes).
Let us first of all to be clear about the terminology, because the various treaties find different
terms:
-oppiati or opiates: It refers to opium derivatives and in particular to fenantrenici derivatives
which are those that possess the type of analgesic activity
-oppioidi: It is instead a broader term which includes endogenous molecules.
Given the multiplicity of substances, we try to understand how you can rank. One of the
classifications, apart from the simplified terminology that I told you about is this:
-oppioidi endogenous: are components of our body that play a variety of physiological
functions
Natural -oppioidi: those derived from opium
-oppioidi semisynthetic: in which the chemical is intervened in order to modify the structures
resulting from the nature
Synthetic -oppioidi: those that the chemical has newly synthesized.
The philosophy of the development of these drugs I have already said, that is always trying to
separate the analgesic from tossicomanigeno power.
The pathophysiology of pain sensation has advanced considerably in the latter period of time, is
a very complex sensation in which a number of components and thus new approaches seek to
identify and characterize these new components.
These are endogenous opioids:

-encefaline
-endorfine
-dinorfine
-endomorfine
-orfanina / nociceptin.
Edited by John Colapietro

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They have a particular location and then see that they have a different ability to interact with
receptors. What are these receptors? Since Kosterlitz identified in the 70 endogenous opioids,
different types of receptors have been identified, some of which, over the years, have disappeared,
because we have seen that they are only partially related to endogenous activity of the compounds.
The real three receptors, denoted by the Greek letters: -I
-delta
-kappa.
Recently, the terminology is a little 'changed and therefore are called by a code:
-MOP, critical role with regard to analgesia, but equally critical role in abuse
-KOP, indicated in the treatment of peripheral pain, because centrally generates dysphoria -
DOP, less than MOP critical both as an analgesic and as tossicomaniogeno. NOP, which it
was added when it was discovered nociceptin / orphanin.
The NOP is a GPCR that only interacts with the nociceptin / orphanin, it does not interact with
the other classical opioids and is not antagonized by naloxone. For this is a very particular
receptor.
For more info on the receptor distribution, see page. 427 of the new book.
The drugs, natural and synthetic, are diversified between them based on their ability to interact
with these classes of receptors.
These receptors are considered to be ubiquitous, but the majority of them, especially the MOP
receptor, is at the level of the street spino-thalamic and limbic system, however, are disseminated
throughout the CNS, and also at a peripheral level: the gastrointestinal tract, apparatus
genitourinary and cardiovascular apparatus.
Effects
A CNS control a number of functions:
-memory
-euphoria
-sedazione
-nausea and vomit
-analgesia, different types.
The most studied receptor is the MOP receptor, because it is the one most involved in pain
sensation, and so for that you will find many studies on the MOP receptor.
The receptors are also expressed in the periphery where they control the secretions of:
-ADH
-PRL
-Ormoni sesuali,
Then we come back to this.
Here you can see another concept, apart from the chemical composition that we will not dwell,
what the various endogenous peptides have different ability to both bond activation of the four
types of opioid receptors in the body.
The nociceptin / NOP orphanin acts on the receptor, the endomorphins, so named precisely
because they have an activity exclusively on MOP receptors, others have a rather uneven
distribution, meaning they can activate different receptors.
In summary, we have four categories of endogenous opioids: enkephalins, endorphins, dynorphins

and endomorphins. Then it was recently added nociceptin / orphanin, whose double name is linked
to a scientific fact, because at the same time two groups published the sequence and activity of this
peptide and a job was called nociceptin and another orphanin. From then on it
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was the name because these groups of researchers were able to identify this endogenous peptide
simultaneously.
These endogenous molecules differ between them as well as for the different ability to interact
with the different types of receptors, also for the chemical composition; -the enkephalin are
pentapeptides,
-the endorphins are larger,
well dynorphins-so,
-the endomorphins are tetrapeptides, then smaller.
They come from all parents:
-prodinorfina
-proencefalina
-proopiomelanocortina (POMC), from which one can also derive the MSH and ACTH through
the subsequent cleavage reactions.
The endomorphins are the most recently discovered; nociceptin / orphanin is probably the opioid
peptide of the future, so you will witness some time between the placing of several prepared to
work on this system, because the nociceptin controls a number of functions including pain and then
as the 'perfect analgesic has not yet been synthesized, and are going to be trials that pre-clinical of
drugs that have activity on the receptor for nociceptin, this means that in future years, when you
will practice the profession, you will have available drugs that act on this system.
From the series of pathophysiology studies that have been carried out in pre-clinical level, it is seen
that if we eliminate the NOP receptor in mice increases the endogenous opioid system and
therefore means that there is a greater control of pain sensation. Other experimental data have
shown that the receptor orphanin / nociceptin is involved in a number of centralized functions, in
addition to pain, memory, learning, anxiety, appetite. For example anxiety: they saw that drugs
acting on these systems have an anti-anxiety effect. Call it the opioid that will be the most likely to
develop in the near future.
Metabolism
Metbolizzati are two entities that are:
-NEP (neural-endo-peptidase or enkephalinase)
-Apn (amino peptidase N).
Of all the pepetidi endogenous opioids, enkephalins are catabolized mainly because along with
endomorphins are more involved in analgesia.
Another approach to analgesic therapy, which has been a remarkable development (ie, pain control
has always been a fundamental objective of the doctors) was to synthesize both NEP inhibitors that
APN, even though none of them reached the entry on the market. Again, when you will practice the
profession, some of these compounds will be at your disposal.
Mechanism of Action
Let's see what happens from a cellular point of view and even here obviously have flared everyone
and have studied more than anywhere else, either in vitro prepared, with both experimental animals
and of course Clinical studies also have been conducted, but the information mechanism of action
were derived from in vitro studies and the pre-clinical studies. The critical moment is the coupling
with the G protein of inhibitory type, therefore it reduces cAMP and has a series of consequences,
among which the most important ones, by a cause-effect relationship point of view is the activation
of the channels potassium with hyperpolarization and inhibition of calcium channels.
This results in inhibition of the firing, so are depressing, we pre-synaptic inhibition of the release
of several neurotransmitters, because the pre-synaptic localization is
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present on different terminals of different neurotransmitters. Do you understand the
mechanism of action which are drugs that suppress, although currently you should not say that,
but the concept of depressing you perform well the main effect.
This happens in acute, but as chronic administration involves the development of those phenomena
that we remember, of tolerance, that is habit, and drug addiction with physical and psychic
dependence, have also been studies on what are the effects cell of chronic administration of opioids,
especially morphine. So we have that in
Chronic administration of course we have the opposite: it increases the expression of
some isoforms of adenylate cyclase, PKA.
All these studies have been done in an attempt to locate the cellular mechanism of addiction and
still has not been found. However, there is this increase in the expression of certain subunits of
certain neurotransmitters such as glutamate.
Another thing that develops is the phenomenon that you remember from last year is the
desensitization of the receptor phenomenon, which would be connected to the activation of beta-
ARK and is one of the development of tolerance components.
Even chronically transcription factors are modified and are always the same, studied by everyone,
CREB, JUN, FOS, AMPA glutamate receptors. All these studies, relevant from a scientific point
of view, has not led to identify a unique therapy for the treatment of drug addiction, we probably
will get there in the future.
Tolerance is another strange fact, we have seen that operates the mechanism of receptor desensitization
and we will see that also involved the receptor internalization, all those mechanisms that have studied
pharmacology in general, which are the basis for the development of habit, of course intervene also in
the development of tolerance to opioids or habit. But the strange thing is that you can not understand,
could be due to different affinities for different type of receptor, the existence of other receptor
subtypes, but the
Tolerance does not develop to all the effects of opioids, but only for:
analgesic-effect,
-euphoriaAnd since the euphoria you feel sought by the addict, this leads to increased
doses
emetic-effect,
-Depression breath.
For the other effects tolerance it is present, but in a much less pronounced and of this you do not
understand why. Even here have done a series of studies and probably could be different receptor
subtypes involved who have different affinities, but these are just theories, the fact is that it is an
important fact because it's what we want to avoid, that is, the development of drug addiction, and
what instead seek from a therapeutic point of view, namely the analgesic effect, are both subject to
the phenomenon of habit.
I told you, molecular bases: down-regulation, changes of the concentration of endogenous
agonists (this was a very recent theory that has developed), internalisation of the receptor.
After describing the ENDOGENOUS OPIOID (NONE of which is used as a drug), let's see
what are the drugs, the effects and indications terapautiche.
We said that the drugs are divided into natural medicines, so we are the natural opioids and opium
alkaloids. Since opium latex are obtained the loaves of opium, from which we get the morphine.

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chemical classification (ie classical):
1) MORPHINE AND DERIVATIVES semi-synthesis (heroin)
2) CODEINE AND DERIVATIVES (IDROSSICODONE, oxycodone) (codeine in turn is a
derivative of opium); OF SIMILAR CODEINE (tramadol)
3) DERIVATIVES thebaine (Buprenorphine) (also thebaine in turn is a derivative of
opium)
then there are only synthetic drugs
4) METHADONE And congeners
5) meperidine And congeners
6) BENZOMORFANI (pentazocine)
7) MORFINANI (butorphanol)
8) OTHER (meptazinol, DEZOCINA)
For a clearer ranking, this ranking scompongo prof in a more schematic, which divides opioids in
NATURAL, of semi-synthesis, and SYNTHETIC.
 OPIOID NATURAL:
o Fenantrenici: morphine, codeine (or metilmorfina, a cough suppressant), thebaine
(Dimetilmorfina, no longer relevant)
o Isochinolonici: NOSCARPINA, papaverine (vasodilator)
 OPIOID semisynthetic (changes occur at the expense of mainly C3 and
C6):
o Derived from morphine: HEROIN
o Derived from CODEINE: IDROSSICODONE, oxycodone and tramadol
(The latter is a SIMILAR of CODEINE)
o Derivatives of thebaine (Buprenorphine)
 OPIOID SYNTHETIC (not structurally related to morphine, they are more
selective for MOP):
o METHADONE And congeners
o meperidine And congeners (fentanyl and remifentanil)or
BENZOMORFANI (pentazocine)

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OPIOID natural and semisynthetic
 MORPHINE
Effects
We can be distinguished in CNS effects and peripheral effects.
What happens when you take a dose of morphine in order not tossicomanigeno (because for
what you use heroin)?
CNS effects:
-analgesia
-euphoria
-Effects neurendocrini
-miosi, one of the pathognomonic signs of intoxication from -
Depression heroine of the breathing center
-Depression the cough center
-convulsioni, but only for high doses
-nausea and vomit
-Depression of secretions and motility of the gastrointestinal, uterine, respiratory and urinary tract
Of all these mentioned, almost all have side effects, while the only exploitable from a therapeutic
point of view is the analgesic effect. Therefore, morphine is the founder of opioid analgesics
natutrali.
The standard dose is around 10 mg, which is given by SC or IM route in naïve subjects (who have
not had prior exposure) and relief dl pain starts around 20 min, in some a bit 'before, others after . I
want to emphasize this with you because one of the fundamental differences that we find ourselves
between different drugs is the latency time. Do you realize that the painful sensation is highly
unpleasant, so the effect of latency time is one of the pharmacological parameters relevant to the
therapeutic effect purposes, for which it was introduced a classification of synthetic drugs based on
the duration of action .
1. The pain is made up of specific organic feel real, then the interpretation, that is, the
emotional component. Of the two components morphine acts especially on the second.
There are afferent and efferent pathways where opioid receptors are widely represented.
-via afferent, by nociceptor passes through the gray horn and spino-thalamic and arrives at
the bark bundles
-via efferent that descends from the bark and has an inhibitory function, and that goes
from the thalamus, hypothalamus, and periaqueductal gray also comes through it to the
rear gray horn.
Important thing is that reccettori of opioids are widely distributed in these pain pathways.
Most important is the distribution of opioid receptors in the dorsal horn, the periaqueductal
gray, at the intermediate level and then nuclei from locus coeruleus noradrenergic there are
fibers that have inhibitory activity and there are also type fibers serotonergic then arrive in
the dorsal body. Some drugs also acts on the opioid receptor, is expected to also act on the
noradrenergic and serotonergic transmission. It is clear that the main element is the opioid
receptor, however, there are also other components of the pain control system.

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One of the most accepted theory is that the effect is due to inhibition of the release of
substance P and of CGRP,who they are involved in the genesis of pain sensation. This
part is great development from a research point of view of clinical and pre-clinical,
because such an important part is also played by cannabinoid receptors, which we will
discuss.
Of the various types of analgesia, spinal and supraspinal, morphine acts on
everything and the two components of pain, morphine acts primarily on the
emotional.
Therefore, morphine is a rather selective drug for MOP receptors which causes analgesia by
acting on 3 levels:
a. DORSAL HORNS OF BONE: By inhibiting, acting at presynaptic release of
SUBSTANCE P and CGRP
b. Midbrain (periaqueductal gray until the reticular bulbopontina): It reduces
the GABAergic inhibitory brake boosting the streets 5HT1 descendants and 2,
and those NA (alpha2) causing a greater closure of the GATE (Remember the
gate theory ...)
c. Limbic system: Reduces (VERY!) The affective component of pain
2. The euphoria It is one of the addict refined feeling, but with common doses (10 mg sc)
the euphoric feeling is insignificant, but still keep in mind also the psychology of the
person suffering: the fact that it no longer has pain following administration of morphine
him It makes me feel even better from the psychological point of view. So the euphoria,
however, there is not a high degree.
All those who think that the euphoria is due to the accumulation of extracellular dopamine
in certain areas of the nucleus accumbens on morphine due to inhibition of GABAergic
fibers which in turn inhibit dopaminergic those of the nucleus accumbens. This is the most
popular theory, but it is not sure that it is the only, because surely dopamine plays a very
important role, but as the addiction is a complex phenomenon, surely also involved other
mechanisms.
The fact is that all drugs that cause addiction cause an accumulation of extracellular
dopamine in the nucleus accumbens.
3. Sedation: The morphine induces sedation by inhibiting the secretion of various

neurotransmitters
(Ach, NA, Glu), this is used in anesthesiology for induction.
4. Nausea and vomit due to stimulation of the famous CTZ, which is also the seat of
activity of anti-emetics. The receptors involved are the 5HT3 and dopamine receptors,
and of course to opioid receptors.
5. Cough: Depressant.
6. Convulsions: At high doses, they have been reported. You have studied the influence
GABAergic transmission of electrical activity and thus is likely to inhibition of
GABAergic transmission.
7. The miosis acted by the contraction of the sphincter and is a pathognomonic sign of acute
intoxication from heroin, the so-called "pinpoint pupils". We also lowered intraocular
pressure.
8. neurendocrini Effects:
-Inibizione GnRH -
inibizione CRF
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-inibizione ACTH
-increase in PRL
-increased GH
-increase of ADH.
Obviously this takes on a special connotation in cases of abuse, because for small doses are
not a significant problem.
9. The respiratory depression is very important because it is the cause of cases of acute
poisoning death. The prevailing mechanism is not very clear. Even here we have been
various hypotheses proposed, according to some is linked to an alteration of the sensitivity
to CO2receptors in the respiratory center, others believe that there is a way excitatory
breathing that deprimerebbero opioids. The fact is that depression is so important that often
the cause of death from acute poisoning by opioids is their respiratory arrest.
10. Until the '50s, in the maternity wards, to women in labor, it gave tincture of opium to
determine the constipation, because in the gastro-intestinal tract level causes this effect of
constipation and an increased anal sphincter tone. Before it was believed that the effects of
morphine were exclusively at the level of the CNS, then were discovered recetttori opioid
even at the level of the gastro-intestinal system, in fact, there are drugs that act on
antidiarrheal receptors, but does not cross the BBB.
11. At biliary it contractions and spasm of the sphincter of Oddi, so in acute biliary colic is
not recommended, due to an additional obstacle to the progression of bile. For the ureter
and bladder we have increased tone.
12. The cardiovascular effects are not very relevant. There is a reduction in the consumption of
oxygen, pressure, but they are not relevant entity from a quantitative point of view.
13. A Morphine is one of the strongest histamine liberators drugs and this is another feature that
has tried to avoid in the synthetic drugs that we'll see. The vasodilation is given by
histamine and histamine also causes other functions, there is an inhibition of reflexes, there
is a certain orthostatic hypotension. There is a different sensitivity of the subject entity
histamine liberating morphine.
14. There is also a depression of immune function and this will also explain why heroin
chronic users go more easily meet to infections, apart from unhygienic environments
where they are forced to live.
Pharmacokinetics
Administration: Sc or im 10 mg (starting dose of a subject naïve), this dose is administered because
there is an extensive hepatic first-pass, amounting to 25-30%; some may be administered rectally
however uesta formulation is not so much preferred. For parenteral quickly passes the BBB.
Another mode, who are familiar with anesthesiologists, is the epidural and intraliquorale, which
may have advantages over sc and is basically an advantage duration of action, however, it can
spread to the center of breath and depress.
Metabolism: Glicuroconiugazione, are formed different glicuro-conjugates, of which one, 6, is
still active, is more fat-soluble than morphine and accumulates in the tissues. This is one of the
few exceptions that are known in pharmacology where some metabolites are able to stimulate the
receptor. The glucuronidation occurs mainly in position 6 and 3 and 3 is inactive.

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Excretion: Prevelentemente through the urinary tract, especially the 3-glucuronide, then via
the bile is negligible.
Therapeutic indications
-l'analgesia It is the only therapeutic indication of morphine (neoplastic and inflammatory
pain, ineffective for neuropathic pain).
-is recommended in cases of pulmonary edema, more to quell that the cardiovascular effects -
to cough using codeine and dextromethorphan
-anestesiologia (To induce anesthesia, although today it is preferred fentanyl, faster)
-interruzione of the withdrawal syndrome, However, when morphine is administered it is very
serious
-Parto analgesia (USA TODAY NOT MORE ', because it passes the placenta and therefore there is risk
to the
fetus, in its place using fentanyl)
Contraindications
-ridotta blood volume, risk of severe hypotension
-traumatizzati cranial, because it can increase the intracranial pressure -
Colica biliary
-ipertrofia prostate, risk of urinary retention
-asmatici, for the reduction of the respiratory center sensitivity to carbon dioxide, risk
bronchoconstriction
-Interaction with some drugs
-Severe liver disease, you can go to overdose meeting to reduced metabolizazione.
 HEROIN
It 'defined as a derivative of morphine because it is the DI-Acetyl-morphine.
It is rapidly deacetylated and remains an acetyl group, and acetyl group is highly lipophilic,
therefore the heroine crosses the BBB and then very quickly gives very quickly those feelings that
the addict research, namely the feeling of very strong euphoria, what in jargon is defined as "high".
This explains why the heroine is preferred, morphine and other drugs, for intravenous
administration (I think it goes without saying "by addicts"). Obviously heroin if it was used as an
analgesic, morphine would be better than just because we have seen that there are central
components and peripheral components, however, it can not be used for purposes analgesic for the
storage problems on the ward, or to prevent the illegal market stock from the legal market.
What he did not read the slides:
Heroin is rapidly deacetylated to 6-MAM (6-mono-acetyl-morphine) which is strongly lipophilic.
Since then:
- Highs more intense and rapid
- Marked analgesia (3 times more potent than morphine)
 CODEINE
Codeine is instead a weaker analgesic, and is the METHYL-MORPHINE.
Have you studied that owns antitussigene activities but additionally has analgesic activity although
relatively weak. This is because the liver is metabolized by CYP 2D6 in-Morphine (is therefore a
prodrug). It is converted about 10% of the total dose, and I stress about because it depends on the
individual capacity, and it is this portion that is responsible for the analgesic codeine. In fact, even
it exists in preparations in association with drugs such as paracetamol, because this obviously
having a different mechanism of action have a synergic action.
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It 'important to the discourse on the individual's ability to metabolize this because that CYP-2D6 is
a polymorphic family, so being a prodrug codeine following a high capacity for metabolisation
occurs more morphine compared to the normal form, to wild-type, and this obviously leads to a
series of toxicological problems. On the basis of the ability of metabolizing CYP-2D6, several
categories of patients can be identified and the most dangerous is the Ultrarapid metabolizer,
obviously because with a standard dose of codeine metabolizer form a UR more morphine.
There was even a note AIFA warned about this phenomenon because there was the death of a
newborn to morphine poisoning because the mother was taking normal doses of codeine was a
URmetabolizer and since transformed morphine from codeine passes into normally negligible
concentrations in breast milk, breast-feeding the child gave him high doses of morphine.
It is estimated that in Europe approximately 5.5% of the population belongs to URmetabolizer
phenotype and therefore we must be careful because these regular doses of codeine may be toxic
and above all we are careful to nursing women.
- Codeine is well absorbed orally and the effect of first pass hepatic metabolism is much
reduced.
- Individuals lacking the enzyme can operate the transformation are insensitive to the action
of the analgesic codeine
- Dose: 60 mg / dose (per os or im or sc) every 3-4 hours

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OPIOID SYNTHETIC
Functional Classification (which is the most useful):
Let's look at the functional classification, which is more important because when you request an
analgesic effect is crucial to know when the effect starts and when it ends. So based on this
classification divide the medicines:
1) Drugs in shorter duration of action than morphine:

o pethidine or meperidine (which in the US has been very successful from a
commercial point of view)
o fentanyl
o ROMIFENTANILE, Derivative of fentanyl with shorter duration of action
2) Drugs in longer duration of action than morphine:
o METHADONE It is currently the most widely used than long-term
o dextropropoxyphene It is older than methadone
 Meperidine or pethidine
Under the point of view of effectiveness, meperidine 100mg equivalent to 10mg of morphine.
Compared with morphine:
- It can be administered without any problems through all the routes (oral, im, sc) and then also
administered per os, however with morphine per os had to increase the dose
- analgesia lasts up to three hours so a little 'less than morphine
- It has the disadvantage that it can cause "serotonin syndrome"
This is predominantly assume simultaneously OF MAO INHIBITORS, then it can happen in
patients being treated for depression. This happens because the meperidine, unlike morphine, is
able to block the reuptake of serotonin and other amines, but serotonin in particular. Serotonin
syndrome is a syndrome rather serious characterized by multiple symptoms including chills,
hyperthermia, tachycardia, hallucinations, agitation, tremors and even death.
Speaking of drug interactions, you may have another interaction with inhibitors of hepatic
microsomal enzymes as opioid accumulation may occur, although this is less relevant than the
previous
- They are opioid synthesis structure piperidine or fenilpiperidinica

- bioavailability 40-60%, the beginning of action 15 minutes
- eliminated as norpethidine that longer half-life
 fentanyl (Depending on the chemical classification is a DERIVATIVE OF
- It has power many times greater

- does not release histamineAnd this is important because histamine brings a number of
consequences on the skin and circulatory
- has a very short half-life (2-3ore) with a short duration of analgesia (1-2 hours)
- but it has a fast onset of action, in a few minutes (about 5)
It is given through the streets: EV, epidural, intrathecal, transdermal (the transdermal route is very
convenient, apply a patch, which, however, we must guard and watch from a toxicological point
of view for the variability of absorption transdermally).
- the intrathecal route is exploited in combination with droperidol for neuroleptoanalgesia

- recently there are also oral formulations used for "patient controlled analgesia"

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It 'used to induce general anesthesia (sedation) as coaudivante in local anesthesia, with patch for
the treatment of pain in cancer patients.
 remifentanil (Which is a derivative of fentanyl)

Compared with morphine:
- is faster (action begins after 2 minutes) (fentanyl also the fastest)
- It is 1000 times more potent than morphine (also the most powerful fentanyl)
- short-acting (8-20 minutes) (the shortest also of fentanyl)
And 'metabolized by plasma cholinesterase, then disappear within 20 minutes.
Regarding the duration, we specify that a short duration can be both a disadvantage is a desired
feature, of course depends on the clinical situations. In fact, fentanyl, and remifentanil anesthesia is
used mainly in the field, to have an analgesic or sedative effect not to have an anesthetic effect,
because in that case we need a short duration of effect. (?!?)
 Methadone and congeners (dextropropoxyphene)

Drugs that have a duration of longer-acting morphine instead serve us for diseases with
chronic pain (for OS). These are basically two, the methadone, the most currently used, and
the older and less used now dextropropoxyphene.
But because they are sought after drugs with longer-acting morphine? What advantages? First to
last longer the analgesic effect, then for chronic pain, but also for the treatment of drug addiction
(PARENTERAL) in which the reference drug is precisely the METHADONE.
Methadone is obviously a MOP-agonists, long-acting (24 hour half-life) In fact there is danger of
accumulation, can be administered orally as well as IM or SC, is metabolized in the liver with
renal excretion but that has not much clinical relevance.
Compared to dextropropoxyphene (which is an analogue thereof) is better because:
- It has longer half-life
- dextropropoxyphene is metabolized to metabolites with longer half-life (norpropoxyphene) and
then it can become toxic, so let's say it is less easy to handle. In summary, methadone is basically
used for analgesic in chronic pain and thus to reduce the frequency of administration, and then is
used in the treatment of drug addiction.
In drug treatment it can be used both for the syndrome of abstinence from opioids and either we
take it later in the chronic treatment cessation.
The methadone dose is between 2.5mg and 15mg / 24h
Therefore methadone is a good drug, especially for its pharmacokinetic characteristics.

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PARTIAL AGONIST AND ANTAGONISTS
With this we have exhausted what are called the AGONIST PURI, because the analgesic effects
can be elicited by AGONIST PARTIAL (that also act on other receptors than MOP), which of
course we do not expect to ANTAGONISTS, who have other clinical uses . Let us consider:
partial agonists:
- tramadol famous and widely used (ANALOG OF CODEINE)
- Buprenorphine Also this fairly used (DERIVED thebaine)
- pentazocine a little 'less used
antagonists:
- naloxone
- NALTREXONE
 tramadol (From chemical classification it is a DERIVATIVE OF CODEINE) When you

turn for departments, you see that in cocktails analgesics that are made for example in patients who
have undergone surgical interventions ceased the phase of analgesia linked to the administration of
fentanyl and its derivatives in the course of anesthesia, one of the most widely used drugs
è Tramadol own.
Tramadol is a derivative of synthesis of codeine, and with regard to the pharmacodynamics of
MOP is a partial receptor agonist, but is also able to interfere with the serotonergic and
noradrenergic transmission basically with reuptake inhibition. This should be borne in mind in
their interactions. We have seen the pain pathways and we saw that there were descending
pathways that were right serotonergic and noradrenergic and it is thought that this drug acts at this
level by determining the analgesic effect.
Compared to morphine it is slightly less effective in severe or chronic pain, and is used in the
average severity of pain (now there are pain management protocols for which you know perfectly
what is the analgesic potential of different drugs and for that I will speak long co-workers of
anesthesiology).
And 'absorbed orally, half-life of 6-7ore, the maximum dose is 400mg / day.
The side effects are the same as other opioids: nausea, vomiting, seizures, sedation, dry mouth,
mild respiratory depression and mild constipation.
The real advantage over morphine is that it causes much less tolerance and dependence. So even if
one side is less effective, on the other hand it is a great medication because of addiction and
tolerance and as such is often used in analgesia protocols. Contraindications: acute intoxication
with alcohol, hypnotics, analgesics, opioids or psychotropic drugs; in patients treated with MAO
inhibitors or who have taken them within the last 14 days; in patients with epilepsy not adequately
controlled by treatment, because l Epilepsy is among the side effects; use as a complete treatment
by drugs.
 Buprenorphine (From chemical classification is a DERIVATIVE OF

thebaine)
Thebaine, 3-6-dimethyl-morphine. Once they used to, now he has been supplanted by
buprenorphine because of poor analgesic effects and significant dysphoric effects.
The Buprenorphine instead is 50 times more potent than morphine and is quite used. It 'well
absorbed sublingually, but is also available with other routes, including the transdermal

257
Pharmacodynamics: has partial agonist action on MOP, antagonism of LAD and also has agonist
activity on the NOP. The function of the LAD little we know, however, buprenorphine has mild
action dysphoric (from wiki: depressive mood disturbance in the sense accompanied by agitation
and irritability) and perhaps the LAD are the receptors involved in this action, but little is known.
Instead regarding the NOP we know they are involved in the control of nociception and pain. So
these may be other mechanisms of action.
- It 'also used in detoxification from heroin.
- Dose: 0.3 mg / dose every 6 hours.
 pentazocine (From chemical classification is a BENZOMORFANO)

It 'a partial agonist of the MOP.
Has the potential tossicomanigeno less than that of morphine
may have a dysphoric action on LAD effect
Administration routes convenient, orally and rectally, but also iv
and im What you did not read the slides:
- It can cause respiratory depression even at low doses -
Dose: 20-100mg / day
- And 'it countered by naloxone
WHO GUIDELINES: At this point I would like to tell you something about those who are the
WHO recommendations. The WHO has developed a "ladder with three steps" for the relief of
cancer pain.
1) It typically starts with NON-OPIOID
2) then it moves on to OPIOID MILD, namely CODEINE, but especially tramadol
3) and then it moves on to OPIOID SELLING, such as fentanyl, and morphine, until the
patient is not free from pain
What he did not read the slides about the WHO guides:
To calm the fear and anxiety are to be used additional medications, "adjuvants".
Drugs should be given "by the clock", or every 3-6 hours, rather than "on demand", on request.
This approach to 3 steps of administering the right medication in the right dose at the right time
is cheap and is effective in 80-90% of cases.
Now to the antagonists who are NALTREXONE, naloxone (the difference is mainly pharmacokinetic)
and nalorphine but it is an old drug, it has been completely replaced in clinical practice from
naltrexone and naloxone (the slide: nalorphine
è an antagonist also equipped with agonist action on the LAD, and partial agonist on
MOP, unlike the other two which are pure antagonists).
They were discovered because they were opioid-like molecules modified which did not cause the
same effects of opioids (drowsiness only at high doses) and that seemed to counteract the effects of
morphine.
 NALTREXONE, naloxone
If we administer them in a normal patient even at high doses they do nothing because they are pure
antagonists.
They are used, the naloxone for parenteral route and naltrexone orally, in the various phases of
heroin addiction, as we shall see later.
So naloxone is used intravenously in case of acute intoxication by opioids (RCD).
It was also used in alcoholics because it reduces the ethanol craving in alcoholics.

258
What is the symptom triad of acute intoxication by opioids?
- Coma
- bradypnea
- Miosis tightened, the so-called tip pupils pin
There can also be hypothermia, hypotension, and if we hypoxia is severe mydriasis
rather than miosis.
What do you do? The life-saving medicine (if busier PS, especially at night, you can see that
there is a certain frequency of acute intoxication) is just as naloxone, administered 0.4 mg EV,
sometimes you have to repeat the treatment.
FROM HEROIN ADDICTION
Drug addiction can also occur with other opioids, but is much more modest.
EFFECTS:
- CENTRAL: Analgesia, euphoria, inhibiting the release of GnRH and CRH, miosis,
respiratory depression, convulsions, nausea, vomiting;
- PERIPHERALVasodilation, reduction of gastric secretion, constipation, contraction of the
sphincter of Oddi, reducing the tone of the pelvic muscles.
Heroin generates TOLERANCE, dependence and withdrawal syndrome.
The dependence is both physical and mental, and is manifested by remarkable craving.
The TOLERANCE concerns: euphoria, analgesia, respiratory depression and emetic. It is linked
to: down-regulating receptor, internalization and degradation of receptors, adenylate cyclase
increased expression of c-Fos and c-Jun, changes in the concentration of endogenous agonists, on
rec effect. AMPA glutamate.
The withdrawal syndrome appears a few hours after the last administration of heroin for EV (this
is less marked for the opioids used as analgesics for OS) and is manifested by:
Hyperalgesia, NERVOUSNESS, AGGRESSION, depersonalization, widespread myalgia,
tremors, seizures (back pain), NAUSEA, ABDOMINAL CRAMPS, runny nose, watery eyes.
THERAPY: 80 mg of methadone per gram of heroin.

It follows a weaning protocol A SCALAR (is reduced by 5 mg every 3 days), and is associated
with a psychological support therapy, monitoring pcs with urinalysis until it reaches the state
"drug-free".
After administering NALTREXONE for OS for "prophylaxis" (because if the patient takes heroine
does not warn those who are "pleasing" symptoms). Alternatively you can use:
CLONIDINE, Buprenorphine, naloxone.
It is also being tested a vaccine.
PHARMACOGENOMICS addiction: alterations: rec. opioid, P-gp, CYP, metabolizing enzymes

of neurotransmitters, BDNF.

259
Effects of the sympathetic and parasympathetic autonomic nervous system on organs and systems. (Table
11.2 p 190-191) The uro-genital tract can be modulated both by the activity of the sympathetic
parasympathetic.
- The detrusor muscle of the bladder possesses receptors 2 which, when stimulated, causing its
relaxation and M3 receptors that mediate instead its contraction. So the administration of
Cholinomimetics cause an increase in urinary flow, while the administration of drugs anatagonisti
receptor muscarinic receptors give a decreased urinary flow.
- On ureters and bladder trine there are receptors 1 that mediate their contraction and M3
receptors that mediate relaxation.
As for the activity of the eye muscles:

- The sphincter muscle of the pupil can give miosis, that is, constriction of the pupil, for stimulation
of M3 muscarinic subtypes.
- The iris can give radial muscle contraction or with M3 antagonists or agonists of the receptor a1
- The ciliary muscle controls the the crystalline state: slight relaxation with receptor
stimulation 2 and contraction stimulation of M3 receptors
With regard to the action on the salivary glands and the lacrimal gland, the secretion is obtained by
administration of cholinomimetics drugs that stimulate the M3 receptors
In the adrenal medulla the regulation of secretion of adrenaline and noradrenaline can be obtained
by stimulating with the nicotinic acetylcholine receptor N (a3) 2 (b4) 3.
A very important concept, which always depends on the neuroanatomical and neurochemical evidence
character and that has the pharmacological implications, is that the autonomic nervous system, in its
two sympathetic and parasympathetic components, has a mutual control system.
The sympathetic system is activated when seeking to modulate the activity of its antagonist is the
parasympathetic system. In fact we know that the sympathetic and parasympathetic always exert
opposite actions: one stimulates and inhibits the other. When trying to stimulate an organ must block
the antagonist.
[From Figure 11.5 p 188] In other words we can say that at the level of a post-ganglionic sympathetic
termination is liberated adrenaline that acts at the target organ level, but from this same region originate
side fibers which lead to level of post-ganglionic parasympathetic fiber. The antagonist of the system
block can be performed via the hetero-receptors. The receptors can in fact stand out:
- autoreceptors if they are inhibited by the same neurotransmitter that is produced in the
termination on which the receptors are present
- heteroreceptors if they are receptors of other nerve endings.
What happens in this mutual control system is that when a synapse activates the sympathetic nervous
system is released noradrenaline. This neurotransmitter from a side realizes a negative feedback system
going to bind to autoreceptors and inhibiting its further liberation; on the other side by the post-synaptic
sympathetic fibers originate collaterals that release norepinephrine which binds to heteroreceptors on
post-synaptic fiber parasympathetic exerting, in general, an inhibitory effect.
In addition to the fiber post-ganglionic sympathetic is also present a adrenergic receptor that is not
sensitive to norepinephrine released by post-ganglionic sympathetic fiber, but is sensitive to adrenaline
released by the adrenal gland. Quest'adrenalina, which is activated under conditions of stress or
pharmacological stimulation condition (for example, when it is assumed that nicotine stimulates the
release of catecholamines), goes into circulation, activates the receptor at the level of post-synaptic
sympathetic termination and exerts action inciting or reinforcing activity of the sympathetic.
The same applies when you activate the parasympathetic: cholinergic termination has a potential to also
inhibit noradrenergic termination. So the post-synaptic sympathetic termination will heteroreceptors of
muscarinic acetylcholine that bind and inhibit the activation of the sympathetic. On post-synaptic
parasympathetic fibers are still present autoreceptors acetylcholine that we distinguish in muscarinic receptors
and nicotinic receptors. When acetylcholine binds to muscarinic receptors car exerts an inhibitory effect, when
it binds to nicotinic receptors it has a
reinforcing action. 260
antianginal
Background
In the previous lesson it was explained NO and many of antianginal drugs are
nitrates capable of donating NO.
Already in 1857 a drug, amyl nitrite, can relieve pain retrosternal typically
defined as angina pectoris, we were later introduced to other drugs all still be
able to donate NO has been identified.
Only since the end of last century it started to be used to treat angina pectoris
other classes of drugs such as calcium channel blockers and beta-blockers.
angina Definition
Angina pectoris is a disease characterized by symptoms from this point of view
retrosternal pain that takes your breath and which usually radiates to the
shoulder, left upper limb, neck, and jaw epigastrium.
A fundamental characteristic of angina pectoris is the transitory nature (as
opposed to myocardial infarction), then it is a transient coronary ischemia.
It speaks generally of three types of angina, and why it is important to
distinguish different will be the classes of drugs to use.
Of course, these are generalizations, there are never any clear separation,
however, still need to understand how to treat the patient. We distinguish:
1) STABLE ANGINA or STRESS: the most frequent (about 80% of cases of

angina), it is a disease correlated to coronary atherosclerosis, caused by an
increase in cardiac work due to physical exertion (for this called angina
stress) or emotional stimuli.
2) Prinzmetal's angina or vasospastic: it has instead at rest and is due to

coronary vasospasm, so we can already see that different drugs will be used than
the previous type of angina.
3) ANGINA UNSTABLE: also here will be different medications to be used

because it is a type correlated to the rupture of an atheromatous plaque from
which they can give rise to thrombi capable of causing coronary occlusion, so we
will use thrombolytic and antiplatelet drugs which however do not serve in
other types of angina.
Some texts distinguish angina typical and atypical angina, the atypical is that
Prinzmetal, typical distinguishes itself in stable angina and
261
unstable angina, stable angina is that stress, unstable angina is characterized
by plaque rupture.
Whatever type of angina, this disease occurs when there is an imbalance

between oxygen demand by the myocardium and the ability of the blood
stream to provide this oxygen.
The imbalance can be caused by:

1) Insufficient blood supply
2) Excessive oxygen demand by the myocardium which can be determined by
an increased heart rate, a 'increased contractility, an increase in ventricular
volume or an increase in blood pressure. So we can act:
1) is trying to reduce oxygen demand by the myocardium (ex blockers that
if we are often the first choice but also some calcium channel blockers act
in this way).
2) both by increasing the blood supply going to use especially of vasodilators

(nitrates and calcium channel blockers, as we will see depending on the action
level prevailing in the arterial or venous level we will prefer certain drugs over
others, generally nitrates act especially at the venous level while calcium
antagonists especially arterial level), increase the regional myocardial blood
flow also other drugs such former statins and antithrombotics.
In general, therefore the therapy will be different depending on the patient

ANGINA OF EFFORT: Increase coronary blood flow and reduce the work of
the myocardium
Prinzmetal's or variant angina: limiting coronary spasm so vasodilators
UNSTABLE ANGINA: antithrombotic and antiplatelet agents rather than the
antianginal drugs
Classification of antianginal drugs

  Nitrates: nitroglycerin, isosorbide mononitrate
  ACTIVATOR POTASSIUM CHANNEL: nicorandil
 FOOTBALL channel blockers verapamil, diltiazem, nicardipine,
 felodipine, amlodipine etc
  B-blockers: propranolol, metoprolol, atenolol
  INHIBITORS OF THE CURRENT If: ivabradine
  ACE inhibitors: captopril, lisinopril, enalapril etc
  3-KAT inhibitors: trimetazidine
 Statins: pravastatin, simvastatin, etc.
262
 nitrates
The nitrates are the oldest class of anti-anginal drugs, today are no longer a
first choice except in special situations such as emergencies when using
sublingual sublingual allowing an immediate effect (ex nitroglycerin the effect
has a time latency 2-3 minutes).
MECHANISM OF ACTION: Prodrugs are able to release NO to

è able to activate the enzyme soluble guanylate cyclase which
increases GMPciclico.
IL GMPciclico active GMPciclico-dependent proteins such as the PKG (but also
phosphodiesterase, phosphatase and some membrane) channels going to reduce
the intracellular calcium levels, resulting in decreased kinase phosphorylation
of myosin light chain MLCK (phosphorylation which is calciodipendente) and
relaxation smooth muscle.
The NO2 groups that are present in the chemical structure of the nitro-
derivatives are those that will release the NO, the nitroglycerin is metabolized
by eliminating a group at a time.
pharmacological effects
 CARDIOVASCULAR EFFECTS
1. Vasodilation especially VENOUS level with decrease of ventricular

end-diastolic pressure and therefore the preload.
2. Vasodilation in the ARTERIOLES BIG level (especially in large
arteriolar vessels, does not take place in the arteriolar vessels with a
diameter less than 100 micron) with reduction of ventricular systolic
pressure and therefore afterload.
3. Vasodilation at the level CORONARY (most evident in patients with
variant angina)
We therefore reduction in blood pressure with reflex tachycardia.
The prevailing action at the venous level and large arterioles is probably linked to
the fact that in these vessels are enzymes capable of releasing NO from nitro
compounds.
 EFFECTS LEVEL OF OTHER AGENCIES AND EQUIPMENT
miolitico effect at the level of the bronchial tubes, gall bladder, bladder,
uterus, not
263
clinically exploitable because it occurs at high doses when already
there are cardiovascular effects.
  EFFECTS LEVEL PLATELET

are important, we decrease platelet aggregation

  OTHER EFFECTS
The nitrite ion interacts with the hemoglobin ferrous ion and form
methemoglobin, which has a very low affinity for oxygen, but this effect
can be exploited in the case of cyanide poisoning, cyanide in fact binds to
the heme group of hemoglobin and it can be displaced from nitro
compounds. In addition to the hemodynamic effects, nitrates also have
direct anti-ischemic effects (defined MAKING ISCHEMIC) phenomenon
may be due directly all'NO but probably also linked to the formation of
nitroso-thiol groups (thiol groups are linked) that would be mediators of
other actions the nitro compounds. In this context, after administration
 of nitrates have:
1. Increased resistance to ischemic events
2. Reduced ECG changes in cases of percutaneous angioplasty
3. Impaired endothelial dysfunction by ischemia / reperfusion
To summarize the most important effects are:

Decreasing the preload with less venous return and reduced wall stress.
Improved intake of oxygen to the myocardium.
Afterload reduction with reduced systolic blood pressure, reduce stress
and increase systolic aortic compliance.
CLASSIFICATION:
1. chemical classification into nitrites and nitrates which differ by the
number of nitrogen oxidation (nitrates are those most commonly
used)
2. based on length of action:

Nitrated derivatives short-acting: Ex nitroglycerin sublingual; isosorbide
dinitrate sublingually; amyl nitrite inhalation. Nitroderivatives long
duration of action: ex nitroglycerin for oral slow release, in the form of
transdermal patches, in the form of an ointment or a slow-release form
for absorption through the mucosa of the mouth (are several formulations
that have been developed); isosorbide dinitrate oral; isosorbide
mononitrate orally.
3. according to the power, which depends on the metabolism.

264
OWNERSHIP 'OF THE MOST' IMPORTANT nitrates:
1. ORGANIC NITRATES
They classify themselves according to the power, we have in fact:

High power Compounds: NITROGLYCERIN (glyceryl trinitrate) and
Pentaerythryl-TETRA-NITRATE
low power Compounds: Isosorbide dinitrate and MONONITRATE. The
former are more powerful, because the NO is released through the aldehyde
DEHYDROGENASE MITOCHONDRIAL, seconds instead are metabolized
by GLUTATHIONE REDUCTASE LIVER.
Finally, the majority of organic nitrates may liberate NO exclusively in the
presence of free thiol groups and enzymes with active site, this because it
was seen that the production of NO is directly proportional to the
concentration of same, and has un'andamento sigmoidal nitrates compared
to the concentration of thiols.
 NITROGLYCERIN: used mainly for emergencies sublingually,
peak plasma within 4 minutes of sublingual administration, half-life
 of 1-3 minutes.
The dinitrates metabolites have vasodilating potency 10 times smaller
but longer half-life (40 minutes)


 Isosorbide dinitrate: maximum peak concentration within 6 minutes
after sublingual administration.The metabolites isosorbide 2-
mononitrate and isosorbide 5-mononitrate have longer half-lives, are
responsible for the therapeutic effects and can be administered as such.
They are the only ones to be used in case of stable angina because it
improves the prognosis and decreases the frequency of angina attacks.


 Isosorbide mononitrate: in fact, is to all intents and purposes a drug
available in tablets, characterized by a low first pass metabolism, excellent
oral bioavailability, half-life and duration of action longer than isosorbide
dinitrate.
2. Amyl nitrite: Highly volatile liquid that is obsolete because unpleasant

odor and the very short duration of action, now is used only for
experimental purposes.
3. NITRITES ORGANIC: also used ONLY for experimental purposes.
4. Nitroprusside: Used in emergency, in a protected environment, because
sensitive to light and temperature. Release NO regardless of the pH with
an unclear mechanism.
265
Pharmacokinetics
These drugs must be metabolized to release NO and this
metabolization takes place essentially by 2 enzymes:
1. The hepatic glutathione reductase (mainly for low power nitrates) that
quickly turns the organic nitrate denitrati metabolites and the nitrites
into more water-soluble nitrites; all these metabolites are less active at
the level vessel (NITRATES LOW POWER).
2. The mitochondrial aldehyde dehydrogenase which it is mainly involved
in the metabolism of nitroglycerin and other medications (Nitrate
HIGH POWER).
It must be said that if we use very high doses of nitroglycerin can have
saturated aldehyde dehydrogenase and metabolism will be dependent also by
glutathione reductase.
A: Following oral administration the bioavailability is quite low due to first

pass metabolism, so much so that these drugs are mainly used for alternative
routes of administration such as:
  Via sublingual.
 Oral route (in this case you avoid the first pass metabolism) available
 late formulations.
  Transdermal patches.
 Intravenous which is used for the treatment of severe heart failure (this
indication on that later) rather than for angina.
D: The half-life of organic nitrates unchanged and about 2-8 minutes

E: RENAL, denitrati and form of conjugated metabolites
glucuronide.
INDICATIONS: angina pectoris (sublingual in case of acute attack or before a

physical effort, as a preventive measure), heart failure (transdermal long-
acting) and for the treatment of hypertensive emergencies.
SIDE EFFECTS: They depend essentially on the vasodilatation

 HEADACHE in almost all patients, for dilation of meningeal arteries, so
much so that in the past they used a mechanical constriction of these
arteries fasciandosi the head, is attenuated with the continuation of the
 treatment.
  FLUSHING FACE again lessens with lengthy processing.
 Postural hypotension linked to reduced venous return to the heart, can
also assume a character of particular gravity, especially if it is also
assumed ethyl alcohol
266
 Methemoglobinemia due to the reaction of the nitrite ion with the
 hemoglobin ferrous ion, can give tissue hypoxia and aggravate angina.
 Cutaneous eruptions infrequent and linked to hypersensitivity.
INTERACTIONS: It is important to remember that the action of nitrates can

affect the action of other drugs, in particular there is an interaction with the
phosphodiesterase inhibitors are drugs that enzymes responsible for the
conversion of GMPciclico guanosine monophosphate. These drugs are used
for erectile dysfunction, were initially developed as antianginal, it turned out
that in fact there are several isoforms of phosphodiesterase otherwise
expressed, for example, between heart and corpora cavernosa (there speak
better Prof. Di Renzo).
If they are inhibited phosphodiesterase, the GMPciclico, which increases as
a result of the action of the nitrates, is not metabolized and the hypotensive
effect increases up to be able to also cause the patient's death.
The association between these drugs and nitrates is therefore contraindicated,
You can use nitrates only after 4emivite assumption of phosphodiesterase
inhibitors (so you have to wait 24 hours in the case of sildenafil or vardenafil
and tadalafil 80 hours if it is a longer half-life).
RESISTANCE: As seen some side effects decrease with the continued

treatment, in fact for nitrates there is a tolerance problem that not only affects
the side effects but also the pharmacological effects.
The chronic use of nitro-derivatives results in a significant attenuation of
their effects (for this nitrates are no longer of first choice except in
emergencies).
It is not clear how they occur tolerance and there are many hypotheses, it is
probably a multifactorial phenomenon genesis. We know some factors that
could be involved:
1) Inability of smooth muscle cells to generate NO starting from the nitro

compounds, by reduction or malfunction of metabolizing enzymes such as
glutathione reductase and the mitochondrial aldehyde dehydrogenase.
2) depletion from the cells of the sulfhydryl groups with non-formation of the
"nitrosothiols", which as we have seen they are involved in the pharmacological
activity of the nitro-derivatives, then another mechanism could be precisely the
lack of these thiol groups of cysteines or level.
3) it could be also involved the oxidation of cysteines to form disulfide bridges

that do not make it more available thiol groups for the formation of
nitrosothiols. These cysteines are oxidized by ion ONOO- whose
267
production is stimulated by treatment with NO. This ROS damages
ALDEHYDE DEHYDROGENASE MITOCHONDRIAL, is also active outside
the mitochondria where it is going to cause a cross-talk with the NADPH
oxidase vascular, stimulating even more the production of ONOO- same.
4) Increase of catecholamines and activation of the renin-angiotensin system by

reflex.
5) Increase of blood volume caused by nitrates that balances the beneficial

effects due to the reduction of the myocardial sull'ischemia pre- and afterload.
Given these assumptions to eliminate or reduce the tolerance phenomenon we

can use different strategies:
1) administering antioxidant drugs including especially the N-acetylcysteine

that, in addition to being an antioxidant, it also acts as a donor of sulfidrici
group.
(N-acetylcysteine the meet very often in the study of this examination, for
example, as an antidote in acetaminophen poisoning, as a mucolytic and as a
substance used to reduce the toxicity of certain antineoplastic agents such as
cyclophosphamide).
2) administering donor substances sulfidrici groups.
3) administering ACE inhibitors or ARBs to block the renin-angiotensin

system.
4) administering diuretics.
But since none of these drugs is sufficient to decrease the tolerance, the strategy
preferred by doctors, as it proved to be the most effective and also avoids the
administration of other substances, is the interruption of therapy for 8-12
hours.
For example, if we are dealing with a patient with effort angina that makes use
of a transdermal nitroglycerin ask them to remove the patch at night when it is
assumed that does not make special efforts, but if, for example, is a person who
works at night treatment should be interrupted during the day, then depending
on the needs of the patient will stop the administration of nitro compounds in 8-
12 hours in which the subject is less active.
(A student's question: the interruption can be done in all types of angina?
Answer: because it serves to reduce the phenomenon of tolerance).

268
 ACTIVATOR OF CHANNELS OF THE K +
nicorandil
MECHANISM OF ACTION: Acts with two mechanisms of action:
1) It is able to donate NO
2) It is able to activate the potassium channels (this however causes a
vasodilatation effect, because it causes hyperpolarization MOBILE)
According to some jobs Nirocandil is also able to block the entry of calcium
through the calcium channels of type L.
The Nicorandil has a powerful effect vasodilation of both arterial venous

levels with reduction in both the pre- and afterload.
It is usedhowever, as a second choice in patients who remain symptomatic
despite optimal treatment with other drugs, typically is used in patients who
are waiting for a surgery or angioplasty (i pcs non-responders to the classical
therapy are candidates for surgical intervention). Theside effects They are
similar to those of nitro compounds with headache, dizziness and redness but
an advantage with respect to the nitro compounds is that not tolerance. It
should not be used together with sulfonylureas because they block the
channels of the ATP dependent K +, and should not be used together with the
PDE-5 inhibitors for the marked orthostatic hypotension.
2+
 Ca RIVALS
See below under "DRUGS TO DISPLAY DIFFERENT IN
CARDIOVASCULAR DISEASE"
 β-BLOCKERS
See below under "DRUGS TO DISPLAY DIFFERENT IN
CARDIOVASCULAR DISEASE"
 If CURRENT INHIBITORS
L 'ivabradine, seek to shiftare metabolism towards a condition of lower
myocardial oxygen consumption, avoiding the oxidation of fatty acids, and
acting (specific feature of ivabradine) at the level of a pluriionica current if said
current (current FUNNY , Colantuoni docet) present at NSA level; thus inhibits
the automatism of the NSA without variations ino and dromo-tropism and
without variation of blood pressure, the anti-anginal effect is related negative
chronotropic action. For its effects can be used
269
also as antiarrhythmic. It is used as a second choice in people who do not
respond to first line anti-anginal therapy (beta-blockers).
And 'it metabolized by CYP3A4.
SIDE EFFECTS: Visual disturbances (appearance of "flashing lights")
transients, dizziness, cardiac block first degree, extrasystoles. E
'contraindicated in pieces with heart block, bradycardia, myocardial
infarction, atrial fibrillation, acute myocardial insufficiency, renal and
hepatic impairment.
 INHIBITORS 3-KAT
A drug that acts instead predominantly on metabolic shift is trimetazidine,
responsible for inhibition of 3 ketoacil coenzyme A resulting in glucose
oxidation which involves the use of a smaller number of oxygen molecules; It is
also used as prophylaxis of episodes of stable angina. Side effects of the already
charged with heartburn, episodes of weakness and kidney damage.
Contraindications in pieces with CNS disorders such as dizziness, tinnitus and
visual disturbances. Prescribed as an adjunct in pieces with stable angina
unresponsive to standard treatments.
 ACE INHIBITORS
SEE antihypertensive
 OTHER DRUGS
Other drug is ranolazine which always acts shiftando myocardial metabolism
towards a reduced oxygen consumption and which is used as adjunctive therapy
in pcs suffering from exertional anginado not respond to first-line therapy. It
inhibits the entry of Na + currents induced in hypoxia, preventing the overload
of Ca2 +, decreasing the diastolic wall tension and the consequent extrinsic
compression of the coronary.
Side effects dizziness, headache, nausea and vomiting, constipation,
drowsiness CNS anxiety and insomnia, vision problems, muscle cramps,
dysuria, hematuria, and peripheral edema.
Interactions with drugs metabolized by CYP3A4 and CYP2D6 (being
cytochromes responsible for its metabolism) and with drugs that prolong
the QT interval or in patients who have this alteration.
Other next-generation alternative drug perhexiline still not marketed in

Europe but only in Germany; inhibits carnitine palmitoyl transferase-1 with
consequent mitochondrial oxidation of glucose and
270
lower oxygen consumption for equal molecules of ATP as an energy
substrate available to the myocardium. Its use, however, is still limited by a
narrow therapeutic index and the inter- and intra-individual variability.
RATIONAL USE OF DRUGS IN THERAPY

SUMMARY: We can use drugs
-aumentano the availability of oxygen, favoring its distribution in the cardiac
level (beta-blockers and calcium antagonists) straight determine vasodilation,
calcium channel blockers
-riducono the oxygen demand (drugs I line: calcium channel blockers and beta
blockers that reduce the FC and myocardial contraction. Still, nitrates that
reduce the preload and calcium antagonists that reduce afterload.)
For the treatment of acute episodes using nitroglycerin in the first instance for
intravenous drugs and then I line as calcium channel blockers and beta-
blockers; in the case of previous heart failure or myocardial infarction using
beta blockers; in without heart failure cases they can be used both; if there is
hypertension, vasospasm The choice is calcium channel blockers. If these drugs
do not work or are not suitable for pcs in particular conditions are used drugs
of II line in monotherapy or in combination therapy (more frequently). Among
them if there are hemodynamic changes (relative to the FC control) is used
amalazina, but if they are absent using ivabradine. ed: it could be the other,
the recording was not clear-
Exemplifying further: if we have a heart attack with ST-segment depression in
the first instance we use nitroglycerin and acetyl salicylic acid as antiplatelet and
then beta-blockers and calcium channel blockers. If you have a heart attack
with ST-segment elevation in that case we use a non-anginal therapy, but we
must try to remove the atheromatous plaque and prevent thrombus formation
and will use opioid analgesics on the pain pathways, fibrinolytic, or will resort to
coronary angioplasty.
-For we exertional angina nitrates, calcium channel blockers, beta-blockers;
-for variable angina can only be used nitrates and calcium antagonists, beta-
blockers for the possible effect of vasoconstriction;
- For unstable angina have recourse to a totally different therapy with
antiplatelet agents such as acetylsalicylic acid, clopridrogel (?) Abcisumat (?),
And then optionally can be used antianginal drugs, but in a second phase,
because we must first remove the clot or prevent it from having the thrombus
formation.

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DRUGS ANTIARRHYTHMICS
The anti-arrhythmic drugs They are obviously of drugs against arrhythmias. To understand what are the
first arrhythmias remember what it means in Italian rhythm sequence in a specific order and regular
events. In arrhythmias normal heart rhythm is disturbed. If we look like a normal beating heart and a
fibrillating heart we see that the surface of the heart fibrillating completely lose the order and
synchronicity of the beat and gives us the impression of a "d 'flutter'.
È particularly important to clarify the classification of arrhythmias. From a pharmacological point of view,
the first thing we need to point out is that we have to distinguish between bradiritmie (the 'essential element
is the slowing of heart rate) and tachyarrhythmias. The bradiritmie are no pharmacological interest, except
to the extent that in rare cases we use atropine. So we will deal mainly tachyarrhythmias. As part of
tachyarrhythmias do further subdivision according to the seat in which the arrhythmia is to be realized:
-Aritmie atrial or supraventricular
ventricular -Aritmie
-Aritmie nodal.
Why is it so important to make this distinction? Essentially for hemodynamic consequences. We begin
to see what may be the consequences of an arrhythmia. The consequences of an arrhythmia may
involve:
relatively trivial -situazioni for which the patient has a subjective feeling for the altered cardiac rhythm
(palpitations)
dramatic -situazioni which are typical of ventricular arrhythmias (ventricular fibrillation) in which the
patient presents with pulseless and consequently imminent danger of death.
So at least part of the argument of antiarrhythmic drugs will cover the d 'emergency medicine. That said, taking
into account that we have a broad spectrum of different hemodynamic consequences of arrhythmias, ask
ourselves if we can expect a different behavior depending on the place of origin of arrhythmia.
Supraventricular arrhythmias:
If we have to supraventricular arrhythmia origin and lose the rhythm of the atrial contribution, it will
happen that we lose the atrial contribution to ventricular filling. So imagine having a fibrillating atrium, an
atrium in which lost the capacity to contract, pumping blood all 'inside of the ventricle, the consequence
will be that the contribution in ventricular filling guaranteed by the atria is lost. At this point the
hemodynamic consequence will be different depending on the patient's characteristics observed:
-if the patient is in an acceptable cardiac compensation situation (ventricular reserve), can
compensate for the absence of atrial contribution and consequently there will be only as a
manifestation of symptoms of the disorder palpitation for the patient, but the hemodynamic situation
is preserved.
- if we are faced with a patient in which the atrial contribution to ventricular filling is fundamental, because
we are in the situation where if we lose the amount of blood that is pushed by 'hall we have a decrease in
preload (hemodynamic situation compromised), then we will have a fall of the output, which may be
symptomatic.
272
So in the case of supraventricular arrhythmias, the risk is that we find a decrease in the range of patients
who have an impaired cardiac situation.
Ventricular arrhythmias:
In the event that we are faced with a major ventricular arrhythmia to lose the level of the heart pump
function, which totally due to the ventricle. This will apply not only to fibrillation but also for ventricular
tachycardias and consequently very simplistically we could say that from hemodynamically ventricular
arrhythmias pose extremely most significant risks to patient survival.
Then in front of an arrhythmia, we have two different treatment options with regard to supraventricular
arrhythmias:
-The first option is to restore sinus rhythm. In this case we speak of cardioversion. The cardioversion may
be electrical or pharmacological. So cardioversion is to restore sinus rhythm.
- The second possibility is to keep the situation of arrhythmia and wait for this arrhythmia is resolved
spontaneously.
In the case of ventricular arrhythmias it is required to restore sinus rhythm.
recapitulate:
When we approach the study of arrhythmias, the first distinction to make is between supraventricular
arrhythmias and ventricular arrhythmias. In the case of ventricular lose the pumping of the heart
contribution, this brings us to a patient that can be observed in the absence of conditions of wrist or in any
case a patient to extreme risk of survival. So in these circumstances I have to restore sinus rhythm. So I
have to make a cardioversion, either electrical or pharmacological.
But in the case of supraventricular arrhythmias I can find in front of an offset patient, so with a good
cardiac reserve. In this case the loss of atrial contribution interests me up at some point and less
complication I can wait. Waiting means that I have to bring down the ventricular rate. In fact between
atrium and ventricle c 'it is in the middle of the atrioventricular node, what I will do is to increase the
refractoriness of the atrioventricular node and prevent the ventricle follow the atrium in its high frequency.
If the patient is not in a good hemodynamic condition, what I try to do is to restore sinus rhythm.
To understand how we can achieve these goals we must first try to understand what are the points of
pharmacological attack. We should therefore understand the ways in which they originate arrhythmias.
Returning for a moment to the physiology of the heart, we must ask ourselves how the heart muscle can
contract neatly in a rhythmic fashion. The fundamental reason is that the myocardium is a syncytial tissue.
Fabric syncytial implies that the cardiomyocytes are connected not only anatomically but also functionally
thanks to the 'existence of Gap Junction, which is why a d' action potential propagates from a cardiomyocyte
to the next. This propagation is directional because the moment in which a cardiomicita is energized then
enters at a later stage of refractoriness. So what happens is that the d 'action potential arrives,

273
RETURN:
That said, what happens when we are in an arrhythmia? It happens that in an arrhythmia or rather in a
situation that predisposes to the development of arrhythmias, there is some region of the myocardium
which is for some reason inexcitable when it comes d 'action potential. So it happens that when the d
'action potential, skip the inexcitable area and skip to the next segment. But in the meantime this
inexcitable area may have exceeded the refractory period. That is, there may be a small piece of the
myocardium which has a refractory a bit 'longer and lose it later.
So after the d 'action potential has bypassed this area and excites subsequent zone it is found that the area
that had been blown finds inexcitable. Since the only element that gives directionality to the propagation of
the cardiac action potential is the refractoriness, if this area is now not excitable c 'it is nothing that prevents
that the d' action potential is propagated in a retrograde and invade in the opposite direction compared to
that physiological. This is the basis of the return phenomenon. In fact, the return phenomenon is nothing
more than a retrograde propagation of d 'cardiac action potential. It is made possible by different
mechanisms. One of these that we have just described is the possibility that a portion of the myocardium
more or less extended found himself in refractory conditions when the surrounding areas have been excited.
Now the d 'action potential can go back, excites the area before inexcitable, this area of course is
depolarized and itself becomes possible source of an' action potential can propagate. This potential will
propagate in areas that are excitable and if those same areas that have resulted in the retrograde conduction
are returned excitable then we could observe a anterograde propagation. It is to create a sort of vicious
circle in which the d 'action potential back, invades the previously refractory zone and now excitable, this
zone in turn is energized and generates a d' action potential that is propagated in the surrounding areas and
reverts she inexcitable. When he recovered it will be invaded again by the potential.
That said, we can say that we have imagined the return as a two-dimensional situation, but in reality we know
that the heart wall has a certain thickness so we have to imagine it like a vortex.
We have said that because it can generate a return is essential that in the moment in which the successive
zones to that inexcitable are to be excited, the one that has been skipped has not recovered from the
excitability (refractoriness). But it is said that this is always the case, because I might have a refractory
overlap between two different areas. That is more precisely because they generate the return is essential that
you do not overlap kinds of refractoriness between the area skipped and the next, because
274
otherwise it will not be realized that condition said previously for the return, namely that the skipped area is
returned excitable. If you want with this behavior it is still extremely unlikely to generate the return taking
into account that it is quite prolonged phase of cardiomicita refractory.
But there is another mechanism that we should consider, that we have to consider that not necessarily
excitement of inexcitable area is due to 'start, as first cause, just the return of d' action potential. Because
there may be a trigger. In summary it is possible that when you are generating the arrhythmia, in the very
first moment when the starting area inexcitable was skipped, I have only refractory periods are quite separate
to allow the return, but nevertheless you can generate an arrhythmia because I have a trigger, an d 'abnormal
action potential, premature, which is to be generated. This premature potential excite me the area before
inexcitable regardless of the return of the potential d action by the successive zones.
Other recapitulate of all the mechanism of the return:

In conclusion we can say that the basic mechanism of arrhythmias is the return. Return means that there are
regions of the myocardium, which can be very small or even larger, in which I have a retrograde
propagation of d 'action potential and therefore this recirculates between zones of the surrounding
myocardium in a sort of vicious circle in which the potential d 'action back, rieccita areas not previously
excited and hence excites subsequent ones so as to keep car. Because this mechanism to work it is
necessary that the area which is initially skipped, because in the refractory period, and then "starting point"
of the arrhythmia returns to be excitable when the successive zones are energized. In fact, if it were still in
the refractory period, however, it would not be excitable (would overlap the refractory periods). Now as the
d 'cardiac action potential is quite long (hundreds of ms) in this case it is easy that there is overlap and
therefore is highly unlikely to generate an arrhythmia, is possible but unlikely.
Nevertheless, the return can be generated because, beyond that we are in conditions of repolarization and
refractoriness, in the area that was skipped we the generation of an 'abnormal action potential, a trigger, a
pathological potential (red in the picture). It is a delayed after depolarization or early after depolarizaton.
First, after depolarization depolarization means after the initial depolarization of cardiomicita, so no more
than a d 'abnormal action potential.

275
These after depolarization can be divided into:
-Early after depolarization (EAD), which in turn is divided into plateau late EAD EAD or whether they take
place respectively in phase 2 or 3 of the potential
-delayed after depolarization (DAD) when they take place in phase 4 (rest potential) then the
cardiomocita had already ripolarizzato.
So very often the re-entry mechanisms are triggered by an after depolarization, that is a d 'abnormal action
potential that generates a pathological cardiomicita. This premature potential, abnormal, can be divided into
early (early) if in place in the phase of refractoriness or repolarization or may be late (delayed) if in place
after the cardiomicita has ripolarizzato. On the basis of what we have said, we begin to understand that the
drug treatment may be usable or to prevent the indentation, then the retrograde propagation, or to prevent
the trigger, or both.
Now for the classification falls into two groups:
- Macro falls or falls macroscopic

- Micro indents or recesses in microscopic.
The ones we've seen before are basically micro falls because it concerned the regional heterogeneity.
But we can also have macro return (which is often anatomical) and are those that are related to the
presence of abnormal conduction pathways all 'inside of the heart. So we have the possibility d 'action
potential to propagate in a backward, as seen previously, not because there is a lack of homogeneity of
the myocardium but because there are abnormal conduction pathways. The speech is of course still the
same except that we have to climb on much larger dimensions.
Example of macro anatomical back: Wolff Parkinson White Syndrome. In this syndrome, in addition to
having the normal path of propagation of d 'cardiac action potential along the bundle of His, we have the
presence of an abnormal beam which connects the atria with the ventricles. So it can happen two
different possibilities and therefore two different types of this syndrome:
1) It can happen that we have the anterograde propagation of d 'cardiac action potential along the
normal routes (ie NAV-BEAM OF HIS-depolarization VENTRICLES). The d 'action potential at
this point in the normal heart should simply propagate into the ventricles and make them contract. In
the heart that has the abnormal beam instead go back and go to invade the hall. Once returned to
'depolarize the atrium of course, it generates a d' action potential which is not what physiological
who must simply propagate, then goes on to invade the conduction system and again can be
propagated. So we have a situation back on a scale that now affects the entire heart.
2) There may be the anterograde propagation along the beam and the abnormal retrograde propagation
along the bundle of His.
So in these two cases, we will have two different possibilities of the syndrome with two different
modes of propagation of the indentation.
We can also distinguish between functional and anatomical fall. The functional falls are due to
the refractoriness of the distribution abnormalities in the myocardium, while the anatomical falls
are due to the presence of pathological conduction bundles.
Not for macro strength falls and falls anatomical are synonyms, as well as micro returns and indents
functional. In fact I can have the production of a macro return, which for example through the whole
ventricle, even with a source of heterogeneity (ie functional). Can I have therefore a ventricular
tachycardia with throughout the entire ventricle that is interested in returning but there are

276
abnormal beams (not c 'is an anatomical basis), but it is fully functional. Then I'll have a macro
return on a functional basis. I can understand that it is a macro returning from 'ECG. Indeed latter
'will show a considerable extent, this means that I have a great myocardial mass that is contracting.
If you are in a micro-entry conditions (as can happen in ventricular fibrillation) have very few
regions of the myocardium that are made for each other (heart "d 'wings' beat). Dall 'ECG
understand that the mass that contracts with each depolarization is small, in fact the ECG trace will
be very small in amplitude.
TWIST OF PUNTA
C 'is another type of arrhythmia that we need to talk about why it is extremely important in pharmacology,
because we find it for other types of drugs such as toxicity, namely torsades de pointes. Many drugs can
present it as a side effect. Clearly, the drug is not the only type of torsades de pointes, there are other types
such as those from channelopathies. It is called torsades de pointes for the characteristic cardiac electrical
axis behavior. L 'axis has its definite direction we can glean going to study the ECG in various derivations.
If instead we are going to study the cardiac electrical axis behavior during the torsades de pointes, we note
that the cardiac electrical axis rotates, moves.
Even this type of arrhythmia is an arrhythmia by inhomogeneity of refractoriness characterized by a

prolonged QT interval. In fact we measure the QT interval in some way the duration of the refractory
because it represents the time of repolarization. So when you stretch the QT interval means that it is
stretched refractoriness. This means that when the normal potential d 'cardiac action (originated in the NSA,
propagated by NAV and BEAM OF HIS), if I have a QT lengthening drug-induced, for example, there is the
risk that the ventricular cardiomicita is still refractory . At this point we must remember one thing about the
physiology of the order of excitement infarction. It is a precise order. In other words, when it comes d 'action
potentials from the atria via the conduction beam, is not that all portions of the ventricular myocardium are
contracted simultaneously, but there is a definite order in which the different regions of the myocardium are
energized (shown with studies carried out in the 70s espiantando still beating hearts from deceased subjects,
taken to the laboratory and a large number of electrodes on different portions of the ventricular myocardium
and it is seen the 'temporal order of excitation) have been applied. This means that I have some portions of
the myocardium that are normally energized for the first, of the portions that are energized to second, others
for third and so on up to the nth portion. If I have a prolonged QT interval sufficient to generate the
arrhythmia, it happens that comes d 'action potential and will be skipped (because it is refractory) the area
which first should be excited. Meanwhile, the next zone that has passed the refractoriness is normally
excited. Given that the first area has been skipped, when it comes the potential d 'next action is returned to
being excitable and therefore will now be stimulated but that now will be skipped will be the next zone
(which is now refractory), and so forth. This means that we have different regions of the myocardium that
are skipped according to a precise order to each d 'action potential and all this explains why the electric
wheel axle. So why is it so dangerous quest 'arrhythmia? It is dangerous because it degenerates and becomes
ventricular fibrillation. Meanwhile, the next zone that has passed the refractoriness is normally excited.
Given that the first area has been skipped, when it comes the potential d 'next action is returned to being
excitable and therefore will now be stimulated but that now will be skipped will be the next zone (which is
now refractory), and so forth. This means that we have different regions of the myocardium that are skipped
according to a precise order to each d 'action potential and all this explains why the electric wheel axle. So
why is it so dangerous quest 'arrhythmia? It is dangerous because it degenerates and becomes ventricular
fibrillation. Meanwhile, the next zone that has passed the refractoriness is normally excited. Given that the
first area has been skipped, when it comes the potential d 'next action is returned to being excitable and
therefore will now be stimulated but that now will be skipped will be the next zone (which is now
refractory), and so forth. This means that we have different regions of the myocardium that are skipped
according to a precise order to each d 'action potential and all this explains why the electric wheel axle. So
why is it so dangerous quest 'arrhythmia? It is dangerous because it degenerates and becomes ventricular
fibrillation. when it comes d 'next action potential is returned to being excitable and therefore will now be
stimulated but that now will be skipped will be the next zone (which is now refractory), and so forth. This
means that we have different regions of the myocardium that are skipped according to a precise order to
each d 'action potential and all this explains why the electric wheel axle. So why is it so dangerous quest
'arrhythmia? It is dangerous because it degenerates and becomes ventricular fibrillation. when it comes d
'next action potential is returned to being excitable and therefore will now be stimulated but that now will be
skipped will be the next zone (which is now refractory), and so forth. This means that we have different
regions of the myocardium that are skipped according to a precise order to each d 'action potential and all
this explains why the electric wheel axle. So why is it so dangerous quest 'arrhythmia? It is dangerous
because it degenerates and becomes ventricular fibrillation. So why is it so dangerous quest 'arrhythmia? It
is dangerous because it degenerates and becomes ventricular fibrillation. So why is it so dangerous quest
'arrhythmia? It is dangerous because it degenerates and becomes ventricular fibrillation.
Therapeutic strategies:
Now let's see what types of pharmacological interventions can imagine to put in place if we want to treat
arrhythmias. We have several options and we will see that often with various medications have a
superposition of different effects. However, we can distinguish between various possibilities:

277
- Make it impossible to return. It means increasing the homogeneity of the refractory in the
myocardium that initially the inhomogeneities. So if I want to get an antiarrhythmic effect I can
operate upstream. If the myocardium has areas with refractory longest and most of the areas with
the shortest refractory, you can cancel these differences lengthening the refractory so that I carry all
the same level and am unlikely to occur or arrhythmia propagation.
- I avoid that the d 'action potential that reaches back in return in retrograde way the myocardium
that was skipped. Then implement of pharmacologic interventions that slow down the cardiac
conduction with the aim of preventing the retrograde propagation.
Beside these two fundamental mechanisms, then c 'it is a direct mechanism on after depolarization.
So you can intervene to prevent the triggers that will be realized which are the ones that determine
the appearance of arrhythmia.
Before going further, it is important to another concept of therapeutic strategies. Arrhythmias the
can observe the moment are in place, so I already have a patient with an arrhythmia and in which
are subject to the considerations made at the beginning. That is, the patient can have symptoms such
as palpitations, shortness of breath, or may even be in a dramatic situation like lying on the ground
and pulseless (clearly here will require an urgent intervention, cardioversion). Of course there may
be conditions that predispose to 'arrhythmias, such as the presence of inhomogeneities, the
appearance of after depolaritazion. So you can imagine doing another type of pharmacological
intervention, ie prophylaxis. That is theoretically antiarrhythmic drugs can I use them for
cardioversion but also for prophylaxis.
summing up: There is no doubt that if c 'is an arrhythmia in the course, I have to put in place of
pharmacological or non-pharmacological interventions for cardioversion or to minimize the
consequences of arrhythmias. If you are faced with a patient who is at risk of arrhythmias, it can be
for example a patient who has had a myocardial infarction, a patient decompensated, in all these
types of entities can implement prophylaxis. However it prophylaxis is not always advisable or at
least not all drugs are recommended for prophylaxis because they can be dangerous.
Targets of antiarrhythmic drugs:
Once you understand the strategies of intervention to counter arrhythmias, you have to identify the
molecular targets that will be the targets of antiarrhythmic drugs. Going to treat arrhythmia means going
to treat a generation and an abnormal propagation of a potential d 'cardiac action and therefore must
consider what are the mechanisms of the cardiac action potential generation. Clearly these other
mechanisms are not the ion channels and transporters. So antiarrhythmic drugs will certainly be drugs
acting on ion channels involved in the genesis of the d 'cardiac action potential.

278
Potential d 'cardiac action:
We know from physiology that the d 'action potential is not equal throughout the myocardium, but we have
potential d' cardiac action that generate and propagate with different mechanisms in different areas of the
myocardium. To the argument that we must do, the fundamental distinction has to be made between the
generation mechanisms of d 'cardiac action potential level nodal (NSA and NAV) and generation
mechanisms of d' action potential at the level of myocardial contractility. At the level of the nodal d 'action
potential it will have a more rounded shape, in the working myocardium level (contractile infarction, atrial
and ventricular) but also in the conduction system (bundle of His andPurkinje fibers)There will be an
extremely steeper upstroke. This diversity is due to the fact that while the d 'cardiac action potential in the
contractive myocardium is dominated by' opening of the voltage dependent sodium channels, to the NSA
and NAV level is dominated by 'the opening of voltage-gated calcium channels. The latter are significantly
much slower than the Na + channels.
nodal Fabric:
We see in the specific ion channels involved in the generation of 'cardiac action potential at the nodal level.
The trigger is given to us by a conductance which is called If, a non-specific cationic conductance, the so-
called funny current (If). The funny current has the characteristic of being opened in response to
'hyperpolarization, ie when the myocardium repolarizes at some point reaches the voltage value that triggers
the opening of the funny current. Being a nonspecific cation current prevails entrance cation and then
depolarize. This depolarization triggered by the funny current brings up a first-class calcium channel. It is of
the T type voltage gated calcium channels. Like all channels, calcium channels are channels that can be
regulated by ligand and can be regulated by voltage. We are interested in the latter which are classified
depending on the extent of depolarization required to open them. So we distinguish:
-channels HVA: are open from high depolarization. The prototype is the L channel that is of calcium
channel blockers target.
-channels LVA: are open from low depolarization. The prototype is the T-type channel
So returning to the funny current, this determines a small depolarization that is sufficient to open the
channels T. L 'opening of the channel T even more depolarized, with respect to the funny current alone,
reaching more positive potential values and such as to reach the threshold for the opening of the HVA
channels of type L.
IN SUMMARY we have this sequence:
  
hyperpolarization funny current opening of T-type channel opening the L-type channel
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In all this sodium channels it is not really. Later we repolarization thanks to potassium channels and then
the cycle begins again. It is extremely important that there is an involvement of the Na + channels because
it helps us understand what will be the selective drug targets to touch the NSA and the NAV. These
targets are obviously the calcium and basically those of type L. The channels calcium antagonists, which
are antihypertensive drugs, we also find them as antiarrhythmic drugs and may interfere with the
depolarization at nodal level of both the NSA that the NAV.
C 'is also another pharmacological intervention mechanism on the action potential at the nodal level
which is that of the neurotransmitter regulation of the funny current (with Ach parasympathetic vagal and
sympathetic with noradrenaline). These two regulate the type of funny current in an absolutely opposite,
in the sense that:
- Ach moves towards increasingly negative values of potential of the funny current aperture, making
it less likely because it must descend more than the potential during the repolarization. As a result
slows the heart rate.
- Norepinephrine is so funny that the current is open to more positive values of the potential,
making it more likely and therefore the heart rate increases.
We can interfere with the activity of depolarization of the sinoatrial node and atrioventricular going to
interfere on the regulation of these two neurotransmitters. If I want to get a type of heart rate-lowering
effect for a tachyarrhythmia I'll have to go and touch the adrenergic component and then c is a second
class of drugs to go and touch the d 'action potential at the nodal level, or beta blockers. In this case we
will have an indirect pharmacological intervention on the funny part.
There is also a possibility of direct pharmacological intervention on the funny current with a drug called
ivabradine. But it is important to know that it is NOT a drug approved as an anti-arrhythmic but it is only
approved as antianginal.
Action potential in the contractile tissue:

We have several phases (fase0, phase 1, phase 2, phase 3 and phase 4). In these phases we observe the
activation of different ionic channels:
 Phase 0: Observe the activation of voltage dependent sodium channels, responsible precisely
dell'upstroke. It dominates the contribution of the voltage-gated sodium channels in particular
SCN5A Nav subtype. There will antiarrhythmic drugs that will act on the channel Nav making it
less likely the opening.

280
 Phase 1: Rapid repolarization, there are always drugs that act at this level. he sees involved
two subtypes of K ITO channels: ITO and ITO slow fast KV 1.4 KV 4. 2-3 (it is not
particularly essential to learn these little numbers).

 Phase 2: Plateau phase. They open the L-type Ca channels they do enter and trigger the opening of
intracellular Ca deposits with consequent depolarization; inter alia these channels feed into the filling of
storage vessels for the next systole. At this point opening of the conductances for the K: Ca some made
by using the K channels calcium- dependent; others are the currents IKS (slow) encoded by the KV 7
channels or KvLQT1. Then in phase 2 the depolarization is balanced by the activation of K channels,
whereby the membrane potential remains relatively stable: a certain proportion exits and enters a certain
altitude. The plateau ends when there is inactivation of L calcium channel that dominates the leakage of
potassium and heart repolarizes.

 Phase 3: Repolarization. It begins when there is inactivation of the channels L football since I'm
inactivating channels and the rise of cytosolic calcium after a while 'time close. This will completely
unbalance the relationship between the cations entering - he always goes less calcium - and the ones that
 come out - because the K comes out. Now dominate the HERG K channels that encode the current
IKR (fast). Obviously, when we say currents "s" and "r" refers to the kinetic characteristics of the
current: s = slow (KNCQ channels), r = rapid (HERG channels) and not at the moment in which open
channels during the potential d ' action. HERG is the channel that will be played throughout the
history of refractoriness and the duration of the action potential.

 Step 4: Corresponds to diastole. It is involved in a particular class of potassium channels: inward
rectifier that adjust the cardiac action potential on rest values and keep it stable.
If we want to step on repolarization, the refractory, we may take action on potassium channels and then we
will have antiarrhythmic drugs acting on potassium channels and we could act on the calcium channels. So
the famous calcium antagonists, in addition to functioning level in the nodal tissue, also work at the level of
myocardial contractile
CLASSIFICATION OF DRUGS ANTI-arrhythmic

A first classification of antiarrhythmic drugs is called who composed. It is the classification of
Vaughan-Williams and is a classification of pharmacodynamic order. Distinguishes antiarrhythmic
drugs based on d 'action. In fact, we have:
Class 1: Drugs that block sodium channels
Class 2: beta blockers
Class 3: Drugs that prolong the duration of the d 'cardiac action potential and will act on those involved in
the conductances of potassium repolarization
Class 4They are calcium channel blockers.
This classification has a big problem which is to be too reductive. We will see that studying the different
drugs, we have for example the drug X affects only the sodium channel and does nothing about other
channels, that is, in other words we will have a large overlap of the d 'mechanisms for the various drugs.
Then there was a second proposal to the antiarrhythmic classification which is the so-called Sicilian Gambit
(page 1138 of the book). It is a very complex classification. the various anti-arrhythmic drugs and in high
various targets are reported (ion channels, receptors, pumps), the clinical effects and the effects on 'ECG for
each drug. For each molecule relative slots are filled.
(Prof. specification that is not so important for the study because it is too complex but the final
iteration because summarizes the main pharmacological effects).

281
Before delving into drugs that dominate each of these channels, I would remind another important phenomenon:
it is true that this morphology of the cardiac action potential is like a little 'everywhere in the heart nodal not, but
there are small differences, mainly concerning the duration of the plateau phase, which is much shorter than in the
atria while it is longer in the conduction system (thus bundle of His and Purkinje fibers) and in the ventricles;
This, as we shall see, will have important practical implications.
The effects of each antiarrhythmic drug on ECG can be summarized into 3 categories:
- QRS Widening: The QRS complex corresponds to ventricular depolarization (ventricular contraction),
so I expect to have the enlargement of QRS whenever there is a slowing of ventricular depolarization; In
other words, if I go to touch sodium channels in stage 0, I will have this enlargement because it takes
longer to depolarize the ventricles (the last year sbob: I'm doing something that makes it more difficult
for sodium channels to open ).
- QT interval elongation: QT interval represents the time required for the ventricle repolarise, so
when we see a lengthening of the QT interval, we are facing the fact that we are slowing
repolarization or, in other words, we are extending the refractory period. (HERG as controls

repolarization, if a molecule that blocks HERG lengthened QT interval)
- PR interval Elongation: The PR interval represents the atrioventricular conduction, then drugs that
act on the AV node lengthen the stretch PR.
So if you know the mechanism of action of a drug, you can expect its effect on the track.
In fact, you will find books on another parameter, that is, the Vmax or Vo ie the time required for
maximum depolarization, so if we drugs (class I) that slow Vo, are merely slowing the run of the
fibers.
Now we will look at the various classes of Vaughan-Williams, going to consider their drug targets.
Class I - Channels Nav

Class I is represented by drugs that act on sodium channels, in particular, there is the voltage-gated sodium
channels - employees. These channels, in fact, are enclosed in Nav family, where are numbered
consecutively: 1.1, 1.2 and so on. These numbers correspond to a different tissue distribution and, since we
are talking about antiarrhythmic drugs of class I VW, we are interested in the channels present in the heart,
ie Nav 1.3 and Nav 1.5 above.
These ion channels are made by a large α-subunit, which contains the basic elements that serve to channel to
operate. This subunit is made up of 4 domains, which can be numbered with DI, DII, DIII and DIV, each of
them organized in 6 transmembrane segments (S1 to S6) which are connected to each other by loops. There
are two important points to consider:
o The entrance pore = Is the structure that passes the sodium ions and is made from small loop within that
connect the S5-S6 segments of the 4 domains.
o The voltage sensor = It is the part of the ion channel that "feels" the depolarization and is located in S4.
The binding site of antiarrhythmic drugs resides on the S6 segment of domain IV, that is one of the
segments participating in the construction of the pore, and NOT binds to the S4 voltage sensor. "No one will
be so bad to ask of such residues make up this site" but in any case they have in common with the binding
site of anti-epileptic and local anesthetics (see below).
In addition to the subunit α, we can find the subunit β or ancillary, which help the subunits α reaches the
cell membrane and interfere with the sensitivity of the subunit α-voltage, but does not contain useful
elements for the operation of channels, all located on the subunit α .

282
Nav channel currents
This is an extreme schematization of an experiment Patch clamp electrophysiology called, in which

electrodes are placed within the cells and measure the changes in voltage or current variations; in this case
we will note the current variations because we are to change the voltage to allow the opening or closing of
the channel.
In the upper trace is the stimulus that we apply, and then the voltage variation, while the bottom trace is
the current, then the ions that enter, cardiomyocyte.
NB In electrophysiology, by convention, all tracks ranging downwards are currents that enter cells, while
all the currents that come out from the cell damage tracks towards the other.
Just depolarizzo (the upper trace salt), the yellow track descends rapidly down because current enters and
this means that the sodium channel is the channel to give a suitable phase 0 as that of ventricular
cardiomyocyte (rapid depolarization); in fact we also see that the current decreases very rapidly: this
phenomenon rapid reduction of the current in the presence of depolarization is called INACTIVATION.
Wanting to better define the inactivation of the ion channel is the phenomenon in which the channel loses
its ability to conduct ions continue to be present in spite of the depolarizing stimulus; In fact, looking at the
yellow track, we note that in a few msec the sodium current is turned off almost completely. For a long
time it was thought that sodium channels were totally inactivated, that is, after the depolarization was no
longer possible to pass any sodium current, but recently it has been understood that this is not true as there
is a current called Sodium-persistent.
It indicates the chart: if you put the zero at the point where begins the yellow line is known, after the ascent
from the bottom peak, as the current actually stabilizes at plateau at a point not far from zero, but which is
not zero precisely because it is a small but persistent sodium current after inactivation. We must remember,
however, that much of the current carried by sodium channels is lost immediately due to inactivation, so
the persistent component (which remains in time) is very small and we find the plateau; not surprisingly,
there are mutations of sodium channels which may give a long QT syndrome which is explained by an
increase of the sodium-persistent current.
There are therefore two different components of the sodium current:

1. rapidly inactivating
2. Slowly inactivating
Schematically the extreme, although this is a bit 'sketchy, we can say that a Class I antiarrhythmic drugs
act mainly on the rapidly inactivating component.
On slowly inactivating current (or persistent) act other drugs such as ranolazine (Ranexa is the trade name),
who have already met with anti-anginal drugs, which for the moment is not approved for arrhythmias but
only for angina pectoris (ed he says that he nominated for completeness but not normally ranks among the
antiarrhythmics).
283
The inactivation phenomenon of Nav is in voltage-dependent time: the more depolarized is the cell, the
more channels are inactivated. This speech has 2 faces in regard to both the depolarization which is
obtained by stimulating the channels, both the resting potential:
- If you make a depolarization starting from a very negative potential, they will have more channels that
open and also very strong depolarizations (as in this case) will very rapidly inactivate the channels.
- If one starts from a potential more positive rest, there will be far fewer available channels, so if the
cardiomyocyte is already partially depolarized, then many channels will already be inactivated because
it is not only perceived the voltage that is induced with stimulation but also the voltage at rest (resting
potential). Conceptually, this is very important because very often the pathological cardiomyocyte is a
cardiomyocyte depolarized, as happens in the case of ischemic heart in which the cardiomyocytes have
little ATP, for which the pump Na / K ATPase does not work and the cell depolarizes with the wide
inactivation fast sodium channel.
You have to imagine that there is some sort of balance between the stimulated and shaped the inactivated
form of the channel, and this balance is all the more moved to the inactivated form is the more
depolarized cell, without considering why the cell is depolarized.
This happens because the ion channel can be found in various states, exemplified by the state diagram of the
ion channel.
C OR THE
The state diagram allows me to hypothesize that the ion channel exists in 3 different conformations:

- Conformation closed: The channel does current pass because it is not sufficiently depolarized condition of
rest.
- Conformation open: The channel, being in depolarization, opens and passes ions.
- Conformation inactive: The channel does not pass ions, even if there is a depolarizing stimulus. Once
entered in the inactive state (after it has been opened), obviously there does not remain forever but
recovers from inactivation for which will return to the closed state, by employing a certain period of
time.
There are obviously intermediate conformations but, for the purposes of drug talk, we are interested in
only these three states. In addition, from the diagram it shows the possibility of change of state through the
equilibrium arrows.
Inactivation and Theory of cumulative use and state dependent blockade

This discussion applies to antiarrhythmic drugs and their operations through the use of the block Theory and
state employee, a theory that among the authors also presents Katzung. Before clarifying this theory,
however, we need an important concept, which is the cumulative inactivation. We have seen before that you
need a certain amount of time to go from inactivated to the closed state and, conceptually, I can have two
different situations:
   
1. Here comes the first action potential opens the channel the channel is inactive passes a certain period of time the

channel is closed It comes a second action potential.
If the depolarization rate is low, all ion channels (virtually) have time to recover from
inactivation. This happens in the normal heart.
2. In case of tachycardia (and thus also of a heart arrhythmia) will come a time in which the interval
between depolarizations 2 is so short that not all channels are able to recover from inactivation, whereby
284
when it arrives the second depolarization does not find the same amount of available channels that
was the first, and then to each depolarization increases more and more the amount of inactivated
channels until an equilibrium is reached (note different from the balance of normal heart). This
means that, in addition to the variation of channels recruited according to the resting potential in
which begins the depolarization (concept defined before), there is also the fact that the arrhythmia
itself increases the percentage of inactivated channels.
If we compare a normal heart with a heart arrhythmia, probably the percentage of inactivated sodium
channels is higher in heart arrhythmia, and this is the key to the operation of the antiarrhythmic agents of
Class I.
The theory of the use of block and state employee It states that the capacity of antiarrhythmic drugs to
block a voltage-dependent channel, in the specific case Nav, depends on the frequency with which this
channel is open and the state in which the channel is located. The Class I antiarrhythmic drugs work best
on the channel inactivated because they give me a user and was dependent on the block; Clinically this
translates into a better locking in the heart arrhythmic because they block the Nav in a more pronounced
when they are in the open state or inactivated state.
The idea behind this theory is a trivial pharmacodynamic concept: each drug to function binds to a target (in
this case antiarrhythmic - Nav drug) and the affinity of antiarrhythmic drugs for the Nav varies according to
the state in which the sodium channel is located: the anti-arrhythmic drug binds avidly to the channel which
is located in the open state or inactivated but not ever binds to the channel which is located in the closed
state. If the affinity is different, it means that the number of anti-arrhythmic drug molecules that I am tied to

the Nav is not the same for the closed channel, inactivated or opened STATE DEPENDENCY.
The state in which the ion channel is located depends on the use that is made of this ion channel. "Use"
means how many times the ion channel is opened: if it arrives depolarization, it is clear that you will have
the transition from closed state to open, so I will have more open ion channels and, given that my anti-
arrhythmic drug has a state-dependence , it will find more channels that can block; if the anti-arrhythmic
drug binds better to the inactive state, it will find many inactivated more channels as much as I would have
previously opened channels (you must first open the channels to let them pass to the inactivated state), also

because with increasing pacing rate grows also the amount of inactivated channels USE DEPENDENCE.
[From sbob last year: the more frequently the greater channel is opened is the probability that a
Class 1 drugs the block].
Obviously, both will have antiarrhythmic drugs who prefer the open state both drugs who prefer the
inactivated state (some even both) and each of them will work better as many are the channels
285
present in the state that they prefer, but in any case, the arrhythmia is a pathological state which matches
with the presence of many channels present in the open state / inactivated, it is treatable with these drugs.
This is a concept very utilitarian because it tells us that they are "smart" drugs as they act only when the
channels are in the wrong state, or even in a normal subject could lead to the suppression of excitability at
rest.
The concept of using block and was addicted is not a concept that is limited only to the class of Class I
antiarrhythmic drugs, but found in other two major classes of drugs: anti-epileptic drugs (or one of the
classes of them), because epilepsy is a bit 'arrhythmia of the neuron, and local anesthetics.
To support this theory, we can say:
- Lidocaine (Class Ib antiarrhythmic prototype) is also an important local anesthetic.
- Phenytoin (old class Ib antiarrhythmic no longer used as such) is an antiepileptic.
The isoforms of Nav channels have slightly different affinities for the various classes of drugs, for
example the cerebral Nav has a slightly greater affinity for the antiepileptic Nav while the heart's got to
the antiarrhythmics.
This slide shows us that if you use an anti-arrhythmic class I, I move the voltage dependence of inactivation
curve of the channel. To understand this concept, we need to consider why a Class A drugs
The bind to inactivated channels in the form, Ie a form which normally does not pass Na ions, and
are nonetheless able to improve the condition of arrhythmia. This occurs because when the anti-
arrhythmic drug binds to inactivated channel, stabilizes it and the likelihood that the channel
distance from the inactivated form the closed shape becomes lower, so the time it takes steps from

the inactivated state to the closed state increases This results in the movement of the voltage
dependence of inactivation.

286
The tendency of an ion channel to inactivation depends on the voltage: the more depolarized it is the ion
channel, so it is more likely that this channel is inactive (eg. Ischemia). The yellow curve on the graph
represents the percentage of inactivated channels as a function of voltage: grows as much as the voltage
(depolarizzo), the greater is the percentage of inactivated channels until all channels will inactivate.
When you give a class I antiarrhythmic drug, the curve shifts to the left so with smaller depolarizations, I
idle channels of a higher percentage. [Prof. repeats again but I am attaching the part of sbob last year I think
is clearer on this point, even if the professor will explain a bit 'better later in sbob: if I put an antiarrhythmic
on sodium channels it will be necessary, because it has the inactivation recovery and return channel is
available, I will need the potential to become much more negative than normally happens.
Let me explain: I told you before that inactivation is voltage-dependent - as many as more depolarizzo
ion channels are inactivated; When the same way ripolarizzo recovery will always voltage-dependent:
the more negative the potential becomes all the more channels recover from inactivation.
If I'm giving a class 1 antiarrhythmic this voltage dependence of the recovery moves towards more
negative values, which means that I have to wait for the potential to become much more negative because
the return channel to be available and then re-opened.]
In the previous lesson we saw that often occur of after-depolarization, which depend on Na and Ca channels
that open, so it is necessary that there is a certain amount of channels available to continue this
depolarization: with the passage of time voltage changes, because the cell is ripolarizzando, for which the
normal cardiomyocyte progressively increases the number of inactivated sodium channels; passes more time
and membrane voltage becomes more negative way then what allows these channels to recover from
inactivation and reactivation of return available.
In normal cardiomyocyte the red dot corresponds to 25% of Na channels available for a second activation,
since the potential is not entirely negative as the one at rest but allows part of the channels to recover. If I
administer the drug class antiarrhythmic I saw that the same potential I have more inactivated channels, I
will not have 25% of the available channels but I'll have a lot less, and if I want to have 25% of the available
channels, I'll go down with potential lower (ed more negative), so as to return almost to the resting potential;
then with Class I antiarrhythmic I also have an effect on the after-depolarization, because more channels are
idle, the less will continue depolarization. So, summing up, I will have two effects:
- Slow recovery from inactivation
- Moving the voltage dependence to more negative values (sull'after depolarization effect)
[The teacher answers a question and took the opportunity to give an explanation on the theory of the use
of block and was addicted]. The Class I antiarrhythmic drugs are divided into three subfamilies:

287
 Ia = Locks the sodium channel in the open state, that is, a channel that has been depolarized. In this
case, the "state dependence" is the channel block in the open state while the "use dependence" derives
 from the fact that the channels are opened more so the more there are frequent depolarizations.
 Ib = Locks the sodium channel in the inactivated state. In this case, the "state dependence" is the
channel block in the inactivated state while the "use dependence" is the cumulative inactivation, or the
depolarization at rest. They are the classic anti-arrhythmic drugs in the post-infarction state (lidocaine).
 Ic = Coexist the two mechanisms. They coexist even the use of mechanisms and state dependence.
So I have two different modes of operation and was employed:

- STATE DEPENDENCY: Lock open / inactivated
- USE DEPENDENCE: Repeated opening of the channel / cumulative inactivation
The final effect is always the same: the antiarrhythmic drug works better in the heart arrhythmia that in
normal heart because it is possible that they are the above conditions.
Detachment of the drug

The drug comes off when, of course,
leaves the state in which the channel was
more akin to the drug, and thus, since
sooner or later, the channel is closed
(although it takes more time because of
the effect of the drug on channel, as
mentioned above), there will come a time
when the antiarrhythmic will detach.
The time for the drug detachment from
the ion channel is quantified with a
numerical constant that takes the name
of τ (τ is conceptually the same studied
in pharmacokinetics). The phenomenon
of
detachment follows an exponential trend, quantifiable with a constant K, or its reciprocal τ. Taking the
concept of pharmacokinetics, τ is the time required for the antiarrhythmic drug dissociates from 63% of the
channels.
The Class I antiarrhythmic drugs have different τ and, based on this difference, it is divided into the same
three classes seen before:
 Ia = τ 1-10 sec
 Ib = τ <1sec
 Ic = τ> 10sec
The τ has an important practical implication:

In blue it is shown the portion of the action potential in which to force the anti-arrhythmic drug must
remain linked to the channel, being the open channel, and then then inactive in the initial phase; in red we
are the extra time (extra-time) all'antiaritmico need to break away from the channel, when in fact it is
already ripolarizzato cardiomyocyte.
The behavior is different depending on whether we consider the atrium or the ventricle:
SINUS RHYTHM

288
It is different for the red component, namely τ, but for the blue component, ie the duration of the
depolarization. The time the antiarrhythmic drug employs tied the canal is longer in atrial cardiomyocyte,
because in the ventricular action potential is longer. So the action potential is longer in the ventricles rather
than in the courts.
This is found in sinus rhythm, when I say that what little antiarrhythmic drug that binds went on all the time
to break away, so I will not have any effect of cumulative inactivation.
arrhythmic HEART
Nell'aritmia the frequency increases so that the time between an action potential and the next becomes
shorter and, if we consider for example a very short τ (the drug comes off immediately) as in the case of Ib
drugs, we will :

289
- In the atria = the action potential is so short that the τ can not cover the time between an action
potential and the next and then the drug is detached before the next action potential arrivals, because
the short τ is not compensated by a long action potential, so all channels will be able to recover and
lose affinity for the drug;
- In the ventricles = being the action potential longer, while being always high heart rate as in the atria
(we are talking of a heart tachycardia), are unable to compensate for the short τ and, therefore, when it
comes the second potential d 'action, there will still be an antiarrhythmic drug fee tied to the ion channel
and is just so that you can have an antiarrhythmic action, otherwise each time you lose the cumulative
effect of inactivation and the drug administered able to block just the little that freezes when the action
potential reaches, but that would only be a temporary blockade.
For this reason the short τ drugs are not used on atrial tachyarrhythmias but they work very well on
the ventricle. So lidocaine, for example, you can not be used or in atrial fibrillation or atrial flutter in
but you can use in ventricular tachyarrhythmias.
In atrial tachyarrhythmias using only those long-τ, because only in this case you can not make up for the
short duration of the action potential and ensure that, upon arrival of the second potential, there is a
portion of the drug bound to the channel; then quinidine (class Ia) can be used in atrial tachyarrhythmias,
as well as flecainide (class Ic).
But if we consider a very long τ there will be a different condition. [This last part on the long τ was only
treated in sbob last year for which I enclose here]:
What happens with very long tau? The tau long means that the time in which the antiarrhythmic remains
tied to the channel may be long enough to be annoying even to sinus rhythm, so when you do a drug with
long tau I need to watch ability to have an impact on the sinus rhythm fundamentally cardiac
sull'inotropismo it will decrease the amount of sodium that enters existing conditions in sinus rhythm.
But in arrhythmia: since there tau which compensates me that the duration of atrial action potential is very
short, these antiarrhythmic drugs work just as well in the atrium and ventricle.

290
CTHE ORRENTI K+ Pharmacodynamic INVOLVED IN SOME CLASS ANTIARRHYTHMICS I (IAE THEC)
Taking up the concept with which he had finished the previous lesson, the professor begins to introduce the new
topic.
As part of the Class I antiarrhythmic, there are certain medications that recognize different targets from the Na
channel+; the most popular target among these is represented by some classes of K channels+. In the image
adjacent is possible to ascertain the presence of several of the K current+ which vary depending on the phase of the
cardiac action potential:

THEto: initial transient current, responsible for the rapid initial
 repolarization phase; 
It is not a particularly important target of
antiarrhythmic drugs.
 +
THEks (slow delayed rectifying K ): together with stream I nextkr It is
an important drug target, where by the term "r" (rapid) and "s" (slow)
 refers kinetics of inactivation; this will then be a K current+ to
to the
inactivation
slow and the channel which conveys such ionic movement will KCNQ1 or Kv7.1 (the wording "LQT1",
visible in the image, refers to the fact that mutations of that channel cause one of the forms long QT
 syndrome).

THEkr: It is one of the K current+ to rapid inactivation, conveyed by so-called HERG current. [The professor
stresses that this current has already been appointed in the context of pharmacology I with regard to the
toxicity of first-generation antihistamines, since the I blockkr It leads to the QTlungo syndrome and torsades de
 pointes]. is a current rapidly activating, inactivating quickly and with strong rectification (outgoing currents
It
conveys).
 THEk1 (K+ inwardly rectifying, Kir): Matches the Inward Rectifier current, responsible for maintaining the
resting potential.
Among all the ionic currents specified, one interested from the block by Class I antiarrhythmic drugs of class III
and is the HERG current; therefore, the effects exercised by those drugs on the duration of the action potential is
playing right on Ikr current, activated in phase 3 of the cardiac action potential (repolarization cardiomyocyte). In
fact, the effect that is obtained by inducing the HERG current block is the extension of the duration of the cardiac
action potential repolarization by lengthening the time, with a consequent lengthening of the QT interval.

291

DEPENDENCE USING REVERSE. At this point, following the same logical reasoning adopted in respect of
Na channels+It becomes immediately wonder whether the current HERG blockade induced by some
antiarrhythmics class I is a state and use dependent block of HERG the current block is neither state nor use
dependent. The direct consequence to this statement is that the magnitude of HERG block will be correlated in a
 manner  of available channels, so if many channels will be available to open, I'll
proportional only to the amount
 However, since the HERG current rapidly inactivating, arrival arrhythmia an important share of
have a better efficacy and vice versa.
K channels+ will quickly become inactive and therefore unavailable to the activity of the drug: paradoxically,
 it is in an arrhythmic heart.
the HERG current is more susceptible to blockade induced dall'antiaritmico NOT in the heart arrhythmia, than
 
[A boy asks the professor to repeat the concept, carry the repetition of the explanation: "So,
when we saw a moment ago was the lock and use dependent on the Na channels +I told you that this is something that we
like: we understand that when the heart is arrhythmic, that uses a lot of the Na channel+, The Na channel+It has blocked
more and therefore I have a selective pharmacological effect for arrhythmic heart. But, unfortunately, for the K
channels+HERG, the opposite happens: the current block is not significant in the heart arrhythmia and even if we wanted
to compare the susceptibility of the heart arrhythmia and heart not arrhythmic, heart arrhythmia is no longer blocked the
arrhythmic heart. How do you explain this strange thing? It is explained taking into account that the channel block has
not been dependent and, if it is not, be able to lock the channel in proportion to the number of channels that can be
opened. This means that, if there is an inactivation process that decreases the number of active channels in the membrane,
 happens during
then the apparent block that I may keep the administration dell'antiaritmico will be smaller. Clear? What
arrhythmia? It happens that the heart is depolarized and since HERG is strongly inactivating current,
! The use of reverse addiction is not a state reverse addiction: the drug does not bind to the closed form
channel (as one might mistakenly think); simply, it will not have any difference, in terms of affinity, in
preferring one of the states in which the channel can come to lie.
Obviously, this statement follows that the pharmacological inactivation of HERG current will also occur to sinus
rhythm: the administration of a drug such capabilities in a patient who does not present arrhythmia, as in the case
of prophylaxis (in which the patient is at risk arrhythmia, but still has sinus rhythm), exposes to the risk of QT
prolongation and, consequently, of torsades de pointes (arrhythmia that can degenerate into ventricular
fibrillation).
This important problem does not present a solution: at the time when a drug will be administered with these
characteristics (egCHINIDINA), It must take into account that a proportion of patients will present the long QT
syndrome.
summing up: The Ia and especially class Ic drugs also determine an appreciable block of HERG current, thereby
resulting in a lengthening of cardiac repolarization. While this elongation contributes antiarrhythmic action making
more homogeneous the myocardium in its refractory period, on the other hand, outside of the context of an
arrhythmia, expose the patient to the risk of torsades de pointes; drugs belonging to the two classes will therefore
be rather dangerous.
USO THE TONTIARITMICI IN PROPHYLAXIS
Considering the danger of anti-arrhythmic, as well as additional factors, their use in prophylactic therapy is
controversial. For this reason, in fact, the class A drugs I are not administered in prophylaxis, or better, than in
the past in which to use them in prophylaxis was common practice, it now tries to avoid their use in patients who
do not present arrhythmias, to avoid the considerable risks (long QTtorsades de pointesventricular
fibrillation).
What is to be administered to a patient at risk of developing an arrhythmia and, therefore, as T ERAPIA
PROFILATTICA, I'm:
- Ca2+antagonists
- blockers
- Amiodarone
292
SPECIFICITÀ OF FARMACI CLASS THE
The classification of antiarrhythmic drugs into three groups is essentially based on the following
characteristics: the status of the channel for which exhibit higher affinity in determining the block, the effect of
the drug on the duration of the action potential and the particularities of .
BLOCKING screen CHANNEL DDURATION OF PDTO PArticular 

T
H
E INTERMEDIATE: 1-
STATE TOperto significant lengthening of repolarization
TO 10SEC
T They have no significant effect on repolarization, but may even
H
E
STATE THENATTIVATO determine a slight reduction of its duration (due to the massive block from SHORT: <1SEC
B
they exercised against TheNa, With consequent blocking of the depolarization)
T Slight effect on the duration of repolarization, justified by the fact that the block
H
E STATE TOopen E
of the K + channel it is largely offset by the considerable LONG:> 10SEC
C THENATTIVATO slowing depolarization
 
CLASSIFICATION
Class Ib Class Ic
Class I:
 THEIDOCAINA
 FLECAINIDE
 CHINIDINA  MEXILETINA
 PROPAFENONE
 PROCAINAMIDE  TOCAINIDE
 ISNCAINIDE
 DIISOPIRAMIDE  FENITOINA
 MORICIZINA
CLASS OF DRUGS THETO
1.CHINIDINA: CLASS OF DRUGS THETO
The quinidine is an "old" drug, considerable one of the first anti-

arrhythmic used. From a structural point of view is the D-
stereoisomer of quinine (already studied in the treatment of
malaria), but does not possess any antimalarial activity.
electrophysiological Effects:
Typical features of class Ia drugs:
  
Lock channels in the open state
  
 intermediate
  
Elongation of the action potential Cardiac due to:
- slowing of repolarizationQT prolongation
- slowing down of the depolarization due to the blockade of Na + channels+Prolongation of the QRS

of the myocardiumreduced entry of Ca2+ and decreased
Negative inotropic effect: Reduced depolarization 
 2+
release of Ca from storesreduced contractility
 
It inhibits the currents IKr (Phase III)
293
sull'SNA Effects: In addition to the effects of the drug on the action potential determined by block quinidine
exercise in respect of the Na channel+, The drug is able to exert actions at the level of the autonomic
nervous system:
- simpaticolitica Activities: Due to the activity1-blocker of quinidine (actually the drug is able to
antagonize the receptor2But the effect on '1is certainly more pronounced); such inhibition
It follows orthostatic hypotension
- parasimpaticolitica Activities: Due to
[I quote the professor in this point, considering that the foregoing is a
blocking action on the vagus nerve; this effect
personal interpretation of the following (min: 45.07): "When do
has a greater importance than simpaticolitica
quinidine, the effect of the NAV block in the conduction of the atrio-
activity considering that it leads to a reduction ventricular signals will decreased and therefore, theoretically, quinidine
of the atrio-ventricular refractoriness. The should not prevent the ventricle does not follow atrial rhythm. That is, if
administration of quinidine, therefore, should I do quinidine to a patient which has an atrial fibrillation, should I lose
hinder the role of "filter" physiologically something in terms of atrioventricular block "]
played by NAV against the momentum created
in
NSA, with the result that the ventricle will follow the atrial rhythm; Nevertheless, quinidine is also able to
inhibit CavL behaving, in fact, as a calcium channel antagonist and determining, and then, a block of the atrio-
ventricular conduction. The parasimpaticolitico effect of the NAV level is partly balanced by the action on the
L-type Calcium channels: this explains why the Quinidine has been used for a long time in the treatment of
supraventricular arrhythmias.
In view of its ability to block the vagal transmission on the NAV and simultaneously inhibit the channels
CavL, quinidine is a considerable "dirty drug."
Pharmacokinetics: The quinidine is administered OS, it undergoes hepatic metabolism by CYP3A4; a

metabolite is active. Eliminated by the kidneys mainly in unchanged form
Indications: At the moment a drug is poorly used instead compared to the past, in which the Quinidine was
widely used in the treatment of supraventricular arrhythmias, and in particular, for cardioversion arrhythmias of
atrial fibrillation or flutter.
Side effects:

 
Gastrointestinal toxicity: Despite the parasimpaticolitica action, quinidine causes diarrhea

 Central toxicity (Quinine already met during the study) "Cinconismo": poisoning that occurs with headache,
dizziness, tinnitus and visual disturbances

 
dermatological effectsRush urticarial

 
Thrombocytopenia and hemolytic anemia

 
orthostatic hypotension

 
LUPUS-LIKE Syndrome

cardiovascular toxicityIt is an absolutely anticipated event that a significant fraction of patients treated with
quinidine flagship developments twist (due to QT prolongation). In addition, in consideration of its ability to
 its negative inotropic effect, quinidine can precipitate failure in pieces that
slow depolarization and therefore
have a limited cardiac reserve.
Interactions:[The professor recommended to remember the good pharmacokinetic interactions, as relevant]

The main interactions of quinidine are basically two:
1. E 'an inhibitor of CYP2D6, Cytochrome, as well as being involved in the metabolism of codeine, is
responsible for the metabolism of propafenone. Particular attention therefore should be taken in the event that
you want to combine the two antiarrhythmic.
2. E 'an inhibitor of P-glycoprotein, Un'ATPasi able to extrude drugs and that is expressed both in the intestine
(resulting in a reduction in the bioavailability), both at the renal level (participating excretion
294
tubular drug); its inhibition, therefore, will determine the block elimination of drugs that depend on it. In
particular, in the context of cardiac patients, particular attention should be placed on the eradication of
Digoxin (whereas the association between quinidine and digoxin may cause an increase in circulating
levels of the latter drug, with a consequent increased risk of manifestation of digitalis toxicity).
2.PROCAINAMIDE: CLASS OF DRUGS THETO

The second member of this family and procainamide (Class Ia)
Procainamide is an important drug, perhaps even more than quinidine.

The electrophysiological characteristics are always the same, can change the value of τ, which here is worth 1.8
sec, whereas before it was worth 3, but for the rest of the drug is similar to quinidine:
 Lock the channel in the open state

 τ intermediate
 QT prolongation
 It inhibits the currents IKr (Phase III)
Pharmacokinetics: Let us remember only the specific aspects: YES administered by VIA EV SLOW, there is a
metabolite, the 'N-acetyl, which lengthens the QT interval but does not have effect on the phase 0. Why do we
care? Let's go a little 'back, pharmacogenomics, which allowed us to learn that there is an individual variation in
the ability to metabolize drugs. The procainamide is metabolised to N-acetyl from 'NAT enzyme (N-
acetyltransferase), polymorphic enzyme. So exist acetylators FAST and slow acetylators. QUICK acetylators are
those that convert much procainamide to N-acetyl; This means that these patients present high levels of the
metabolite and will be more at risk of the general population, or slow acetylators of the population of developing
long QT syndrome.
sull'SNA Effects: What we see instead the slope of AUTONOMIC? We see that the antimuscarinic activity is
limited and the drug is devoid of α activity1-blocker, and procainamide it has minor effects on SNA
compared to quinidine, and this is definitely positive.
Indications: Is a drug, as said earlier, quite used today, in fact is used in arrhythmias in patients who have not
an impairment of the ventricular function, ie in good compensation patients. Initial treatment using pieces of
stable and sustained monomorphic ventricular tachycardia
Choice of drug: Every year, when I hold lectures on antiarrhythmics, some of you asked me "are many, those who
use?" Then I brought the slides, but you have to be seen as very timid. Let me explain: These slides are trying to
show the drug to be used, or more uisati drugs, at a date indication, referring to the guidelines. REPEAT: born of
your questions, to your issues and not on my desire to invade an area that certainly is not mine, being the
'arrhythmology a specialized cardiology.
Side effects: Let's look at the side effects of this procainamide:
 Hypotension from ganglionic blocking;

 Long QT syndrome;
 procainamide is one of the classic examples of drugs that can give a syndrome similar to lupus erythematosus
SYSTEMIC (ANA appear!), with the features that you see in the slide. Before

295

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OPIOID

These are endogenous opioids:

Edited by John Colapietro

In summary, we have four categories of endogenous opioids: enkephalins, endorphins, dynorphins

Edited by John Colapietro

Edited by John Colapietro

Edited by John Colapietro

3. Sedation: The morphine induces sedation by inhibiting the secretion of various

Edited by John Colapietro

Edited by John Colapietro

1) Drugs in shorter duration of action than morphine:

- They are opioid synthesis structure piperidine or fenilpiperidinica

 fentanyl (Depending on the chemical classification is a DERIVATIVE OF

- It has power many times greater

- the intrathecal route is exploited in combination with droperidol for neuroleptoanalgesia

Edited by John Colapietro

 remifentanil (Which is a derivative of fentanyl)

 Methadone and congeners (dextropropoxyphene)

Edited by John Colapietro

 tramadol (From chemical classification it is a DERIVATIVE OF CODEINE) When you

 Buprenorphine (From chemical classification is a DERIVATIVE OF

Edited by John Colapietro

 pentazocine (From chemical classification is a BENZOMORFANO)

Edited by John Colapietro

FROM HEROIN ADDICTION

THERAPY: 80 mg of methadone per gram of heroin.

PHARMACOGENOMICS addiction: alterations: rec. opioid, P-gp, CYP, metabolizing enzymes

Edited by John Colapietro

As for the activity of the eye muscles:

1) STABLE ANGINA or STRESS: the most frequent (about 80% of cases of

2) Prinzmetal's angina or vasospastic: it has instead at rest and is due to

3) ANGINA UNSTABLE: also here will be different medications to be used

Whatever type of angina, this disease occurs when there is an imbalance

The imbalance can be caused by:

2) both by increasing the blood supply going to use especially of vasodilators

In general, therefore the therapy will be different depending on the patient

Classification of antianginal drugs

MECHANISM OF ACTION: Prodrugs are able to release NO to

1. Vasodilation especially VENOUS level with decrease of ventricular

 EFFECTS LEVEL OF OTHER AGENCIES AND EQUIPMENT

  EFFECTS LEVEL PLATELET

To summarize the most important effects are:

2. based on length of action:

3. according to the power, which depends on the metabolism.

Edited by John Colapietro

They classify themselves according to the power, we have in fact:

2. Amyl nitrite: Highly volatile liquid that is obsolete because unpleasant

A: Following oral administration the bioavailability is quite low due to first

D: The half-life of organic nitrates unchanged and about 2-8 minutes

INDICATIONS: angina pectoris (sublingual in case of acute attack or before a

SIDE EFFECTS: They depend essentially on the vasodilatation

INTERACTIONS: It is important to remember that the action of nitrates can

RESISTANCE: As seen some side effects decrease with the continued

1) Inability of smooth muscle cells to generate NO starting from the nitro

3) it could be also involved the oxidation of cysteines to form disulfide bridges

4) Increase of catecholamines and activation of the renin-angiotensin system by

5) Increase of blood volume caused by nitrates that balances the beneficial

Given these assumptions to eliminate or reduce the tolerance phenomenon we

1) administering antioxidant drugs including especially the N-acetylcysteine

2) administering donor substances sulfidrici groups.

3) administering ACE inhibitors or ARBs to block the renin-angiotensin

Edited by John Colapietro

The Nicorandil has a powerful effect vasodilation of both arterial venous