What is? .

Is the study of medications (chemical compounds) which interact with various living
systems as:
● Molecules
● Cells
● Tissues
● Organisms
In order to produce a certain effect

Names of drugs .

Chemical (e.g Describing chemical structure

N-acetyl-p-aminophenol) Used in scientific studies

Generic Shortened version of chemical name

Used by health professionals

Brand/trade Given by a pharmaceutical companies that

make medication
 Medication and interaction with the body
When the medication it is administered it has an interaction with the body, IIt could be
by:
Pharmacokinetics
Movement and modification inside the
body
What does the body does to the
medication
1. Absorbed into circulation
2. Distributed to various tissues
3. Metabolized or broken down
4. Eliminated or excreted in urine or
fece
.
Pharmacodynamics
What medication does to the body. Also
beneficial and side effects
1. Medication binds to receptors or
specialized proteins (surface or
inside cell)
2. Signal cascade
3. Change in cell´s function
 Drug-drug interaction .

When 2 meds are administered together

Type of interaction Pharmacokinetic Pharmacodynamic

Description One med alters Meds influence each

absorption. distribution, other´s effects directly
metabolism, excretion of
another. Opposite effect of another
medication
This change the amount
available to produce Antagonist effect
desired effects

Example E.g. Two meds metabolized E. g. If you take

by same enzymes metilfenidato and
apolazam at the same time
 Drug- Receptor interaction .

What does the medications do to the body and how do they do it.
Most medications have to reach the cell and bind to a receptor. Receptors are specialized
proteins on the cell membrane and inside of the cell that can bind to a ligand and get
triggered to alter their shape activity. This gives rise to a signal cascade of intracellular
molecules to the second messengers which results in some change in the cell´s function.
 Drug- Receptor interaction .

In order that the medications have an effect, they have to reach their target cells and bind to
a receptor.

Receptors
Receptors are specialized proteins both on the cell membrane inside the cell that can bind to
a ligand and get triggered to alter their shape or activity

Cascade
This gives a rise to a signal cascade of intracellular molecules-the second messengers
which results in the cell´s function

Intracellular receptors Surface receptors

Are typically located in the cytoplasm or On the cell membrane are cell surface
nucleus of the cell and recognize small, receptors which are embedded into the
hydrophobic, meaning, water hating plasma membrane and are hydrophilic
ligands. ligands.

Once bound to their ligand, the receptor

ligand complex attaches to specific DNA
sequences that activate or inactivate
specific genes
Based on their structure and properties, cell surface receptors fall into three main types

1. Ligand gated ion channels s

Ligand gated ion channels form channels or pores that are generally closed, but they
open up once they bind a specific ligand.
They allow ions like chloride, calcium, sodium and potassium to passively flow into
the cell.
Down their gradient and triggering the signaling pathway.

2. G-protein coupled receptors / Seven pass transmembrane receptors s

They are really long proteins that have one end that sits outside the cell and then the
snake, like protein dips in and out of the cell membrane seven times and finally ends
on the inside of the cell.
The ligand binds to the end sitting outside the cell and the end of the protein that´s
within the cell activates guanine nucleotide-binding proteins or G proteins which
contain an alpha, beta and gamma subunit.
The subunit binds to a guanosine or GDP molecule and the G protein is inactivated.
When a ligand binds to the receptor, the G protein changes the shape, causing the
alpha subunit to detach and trigger other proteins in the signaling pathway.

3. Monoamine transporter s
The presynaptic membrane has transporters that need energy to take
neurochemicals back to the neuron, when there is enough in the synapse cleft and
uses it for new vesicles
This proteins uses sodium/potassium pumps
 Drug- Receptor interaction .

Every cell has a unique combination of many

diff
erent types of receptors.
In theory, each medication is specific to a
particular receptor, just like each key fits into
and opens a particular lock.
In reality, no drug is 100% specific, meaning
it could also bind to other receptors that are
similar its intended target which is why all
medications cause side effectsThe way a medication and receptor interact with each other
is ruled by two main principles:

Affinity .

How strongly a medication binds to its receptor

This is mainly determined by the strength of the chemical bond between the
two

Higher affinity - Higher potency

Amount of medication needed to elicit an effect
Medications with a high affinity, can produce an effect at a lower dose

Intrinsic activity .

After the medication binds to its receptor, it must also be able to activate
that receptor

Intensity of response .
Depends of the number of receptors

Efficacy .
Maximal effect of a response
Dose (x axis) .
Concentration of a medication in the body, which depends on the amount of a medication
given

Response (y axis) .
What happens in the body

Dose-response curve .
S shaped curve

First Curve .
At first the curve is more or less flat, that's because the concentration is to low, so not
enough receptors bind to the medication to cause a significant response

Second Curve -Graded dose-response relationship .

As the concentration increases, more receptor medication complexes form, so the response
of the medication climbs.

Third Curve- Maximum response or effect (Emax) .

All the receptors get occupied, so the curve starts to flatten out
Measure of the medication´s efficacy

EC50 .
The point where 50% of the maximum effect is produced
Mark the potency of the concentration of the medication
So the smaller EC50, the less it takes to get halfway of the maximum effect, so the more
potent that medication is

ED50 .
Is the effective dose of a medication that needs to be given to a certain population so that
50% or half of them see an effect
Entre la curva esté más pegada a la izquierda, su efecto es más potente.
En este caso, tienen la misma eficacia, pero el medicamento A tiene un efecto más potente.

En este caso, tienen la misma potencia pero tiene un mayor efecto el medicamento C

Depending on the effect that the ligand has in their receptor, are divided into two main
categories

Agonists .
Mimics the action of signal ligand, binding and activating a receptor
 Antagonists .
Is a medication that typically binds to a receptor without activating them niy oy decreases the
receptors ability to be activated by another agonist

Maximal Effect or Response EMax .

Maximal effect or responses an agonist can produce

# of receptors bind to agonist depends on the dose
Intrinsic activity (ability of antagonist to activate its receptors)

Full Agonists .
All available receptors bind to an agonist

Partial Agonists .
Even in a high dosis when they occupy all of the receptors, result in a smaller response
Full Agonists + Partial agonists .

If a full agonist is used at the same time with a partial agonist, they compete for the same
receptor. If we increase the dose of the full agonist, it will displace the partial agonist from
the receptor and the maximal response will still be achieved.

So the dose-response curve will shift to the right without affecting Emax, but the dose
required to achieve 50% of the maximum effect (ED50) will be increased. This allows that
the full agonist potency which is the dose of agonist needed to elicit a maximal response, will
be decreased

Competitive antagonist .
Reversibly binds to the same receptor site where an agonist binds but does not activate it
Usually bind to the receptor in a reversible way, meaning that they bind and dissociate from
it pretty fast.
So when they unbind it's more likely for one of the ligands to bind
So the inhibition caused can be overcome when more ligands are floating around
Decrease the agonist potency
Non Competitive antagonist .

Don´t bind at the same site of an agonist

They get stick on the allosteric site, so in that
way the ligand can no longer recognize as a
binding site
Won´t produce the agonist effect, no matter
how many agonists are around because the
ligand can no longer recognize de receptor
Reduce agonist efficacy, without affecting
agonist potency

Non Competitive antagonist .

1. In order to have an effect, most medications have to reach their target cells and bind
to a receptor.
2. Receptors are specialized proteins both on the cell membrane and inside the cell,
that can bind to a ligand.
3. Now that ligand could be an agonist, which is a molecule that binds and activates a
receptor. T
4. This means that the receptor changes its shape or activity and that gives rise to a
signal cascade of intracellular molecules, the second messengers which ultimately
results in some change in the cell function.

If we massively expose the receptors to their agonists, we will

get a huge downstream signal that cascades a cellular
response.
But if we continuously or persistently flood that receptor with the same agonist at the
same dose, what will happen is that the ability of the agonist to produce that response, will
drop.

Defense Mechanisms
This is actually a defense mechanism, whereby cells prevent their overstimulation by agonist

Desensitization Tolerance

Overlaps If this happens very rapidly It happens gradually

In few minutes Weeks
Can occur with the initial dose of a Repeated dosis
medication

Effects The constant exposure to an agonist, Ya no da los mismos

it will decrease the number of efectos, aunque sigue
receptors and degradate the existiendo
previous receptors
Ya no tiene efectos

Example In drug users the target receptors are

downregulated so they need a higher
dose to achieve the same high

Mechanisms of desensitization and tolerance .

Chronic exposure of agonists causes a decrease in the number of receptors. This could be a
result of:

Downregulation
Reduced synthesis of new receptors

Sequestration or internalization
Degradation of preexisting receptors through endocytosis
The cell swallows up the receptor in vesicles pinching off from the cell
membrane

Second messengers
Receptors are uncoupled from intracellular signaling pathway and
can't activate secondary messengers

Exhaustion of intermediate messenger molecules

Increase the metabolic breakdown of the medication

Example: Alcohol tolerance
Where chronic use cause the body to increase production of enzymes that breaks down
ethanol into inactive products

Non Competitive antagonist .

Refers to the movement and modification of a medication inside the

body, what the body does to the medication and how it does it.

Route of administration .

The route of administration depends on the form of the chemical preparation.

Chemical preparation
● Pill
● Solution
● Spray
● Ointment

The part of the body being treated, the medication can be administered through various
means or routes.

Such as
● Orally
● Intramuscularly
● Intravenously
● Inhaled into the lungs
● Sprayed into the nose or
nasally
● Cutaneous

Once the medication is administered,

it has to be:
1. Absorbed into the circulation
2. Distributed to various tissues
3. Metabolized or broken down
4. Eliminated or excreted in the
urine or feces
 1. Absorption

Absorption .

Is the process of moving the medication from the site of

administration into de circulation

Except intravenous administration

Medication will need to pass one or more cell membranes

Movement across the cell membrane can occur

Via passive transport, which requires no energy

Larger, water-soluble and polar medication
● Facilitated diffusion
● Passive diffusion
Via active transport, which requires energy from ATP
Small, lipid-soluble, and nonpolar medication

The rate of absorption (how quick this process occurs)

Extent of the absorption or how much of that medication reaches the bloodstream, depends
on several factors.

PH .

At first is the PH of the environment where absorption takes place

Most of medications are either:
● Weak acids
● Weak bases
● Charged (water-soluble and polar, and cannot diffuse through cell membrane easily)
● Uncharged (lipid soluble-non polar one, which happily diffuses through the cell
membrane)

The ratio between both is determined by the pH of the environment and the strength of the
weak acid and base.
pKa
The strength is measured by pKa is the pH value when concentrations of the uncharged and
charged forms equal each other

Weakly acidic medication Weakly basic medications

Is better absorbed in acidic environment Are more likely to get absorbed in an

alkaline environment

Proximal duodenum Distal ileum

Even though the stomach is acidic, it´s not suitable for the absorption even of weak acids,
because of the mucus layer
Surface area available .

Small intestine
A good place of absorption is the small intestine, with its circular folds, villi and microvilli

Blood supply .

Other factors include the blood supply to the

absorption site and the presence of food or
other material in the gastrointestinal tract
that can either promote or inhibit the
absorption.

Steps .

After a medication is taken by mouth it gets absorbed through the walls of the small intestine

1. The medication is taken by mouth

2. It gets absorbed by the through the walls
3. Its transported into the liver via the portal vein
4. First pass metabolism
 4.1. Once the liver, hepatic enzymes work on the medication to metabolize it
4.2. Breakdown of most medications into their inactive metabolites
4.3. Converting certain prodrugs into their active metabolites, before entering the
general circulation

This however means that if a medication is taken orally, and it undergoes extensive
first-pass metabolism their concentration in the bloodstream can get so reduced that once
they reach their site of action, they can´t produce the desired effect. In that case, alternative
routes of administration should be considered, included:

● Intravenous
● Intramuscular
● Transdermal
● Sublingual
● Inhalational

What this does is that they bypass the

first pass effect, allowing that the
medication goes straight into the
systemic circulation.

Bioavailability .

Fraction of an orally administered medication that eventually reaches the circulation in it´s
unchanged form.
How much medication do you take and how much it's absorbed
 2. Distribution
Distribution .
Movement of a medication from circulation to body tissues
The rate and extent of distribution depends on several factors

Blood supply .
Medications will be more rapidly distributed to body tissues that receive large amounts of
blood supply, like the brain, liver and kidneys.

Medication will be less rapidly distributed with tissues with poor blood supply like the skin,
adipose tissue.

For any medication, it has to go through the blood brain barrier which is strictly regulated
It doesn't pass larger water soluble medications
Size and polarity .

Size and polarity of a medication

affects its distribution so in
general, smaller, hydrophobic
or lipid soluble medications
can easily cross through the lipid
bilayer cell membranes.

Plasma protein binding .

Another factor affecting distribution is the degree of plasma protein binding.

Medications travel through the bloodstream, partly bound to plasma proteins, like albumin
and partly unbound or free.
Only the unbound fraction is free to diffuse into tissues whereas medication molecules that
are bound to plasma proteins remain limited to the plasma, acting as a kind of reservoir.
That's why medications with lower plasma protein binding get distributed readily in the
tissues while medications with higher plasma protein binding take more time to free
themselves and diffuse giving them a longer duration of action.

Apparent volume of distribution .

Is used to represent how extensively a medication is

distributed throughout the body.
It is the hypothetical volume that accommodates all of
the medication in the body, if the concentration
throughout was the same as in plasma.

Recap .
 3. Metabolism
.

Is the process of converting a medication into the less or more active form, these forms are
also known as metabolites. So in most cases, metabolic reactions turn an active medication
into a less active or inactive metabolite, which is then ready to get excreted.

Some medications are administered in their inactive form, also known as a prodrug, which
needs to be metabolized into an active form within the body, before they can produce the
desired effect.
Even those medications will eventually need to go through metabolism in order to get
inactivated and excreted.

Two main phases

 ● Phase I
● Phase II
For some medications phase II may occur before phase I
For other medications only phase I or only phase II
Both phases take place primarily in the liver and for too much degree in the lungs, kidneys
and the walls for the small intestine

So let's zoom into a liver cell also known as a hepatocyte

Phase I reactions
Are typically carried out by a class of enzymes called as cytochrome P450 (CYP 450)
These enzymes hang out mainly in cell compartments like the endoplasmic reticulum and
mitochondria
They are often abbreviated as CYP followed by:
A number (family)
A letter (subfamily)
A number (form)

These enzymes convert the non-polar lipid-soluble medications into soluble medications that
are more polar, water-soluble metabolites.

Through oxidation, hydrolysis or reduction

Phase II reactions

Compound Reaction
 Methyl group Methylation

Acetyl group Acetylation

Sulfagroup Sulfatation

Glutathione Glutathionylation

Glucuronic acid Glucuronidation

These reactions create highly polar, water soluble metabolites that cannot diffuse through
cell membranes very easily, so they are trapped in the urine and eliminated by the kidneys.

There's a huge variability rate of the metabolic reactions:

Genetic variability between individuals

Poor metabolizers
Because of their genetic makeup, some people known as poor metabolizers have fewer
enzymes that work more slowly and less efficiently against certain medications.
These medications tend to build up in the body, resulting in dangerous side effects
A poor metabolizer taking a prodrug needs to be metabolized into its active form will have a
harder time seeing any effect

Rapid metabolizers
Whose enzymes metabolize and inactivate certain medications so fast that it's difficult to
achieve a high enough level of medication in the bloodstream
Will be more likely to experience side effects

The same individual may metabolize medications differently

At birth, metabolic enzyme systems are not fully developed so newborns typically have
difficulty metabolizing certain medications.
But as we age, enzymatic activity falls off again so elderly individuals cannot metabolize
medications as well.

Also, since most enzymatic reactions take place in the liver, a decrease in enzymatic activity,
may be due to chronic liver disease

There is also an enormous number of interactions between metabolic enzyme systems and
the things they break down.
Let's say an individual is given two medications at the same time that are metabolized by the
exact same enzyme.

That enzyme will have trouble metabolizing booths at the same time, so it will probably take
longer to break them down.

And the result will be that one or both of these medication will build up in the bloodstream
and have prolonged action

In other cases, medications, foods and even diet supplements induce or inhibit metabolic
enzyme systems, particularly the cytochrome P450.
This could be done by increasing the synthesis of enzymes or enhancing their activity so
they metabolize more quickly

Since these enzymes are involved in activating or inactivating multiple medications, inducing
or inhibiting one of them could potentially increase or decrease the activity of multiple
medications.
There are tons of possible interactions and combinations of each enzyme and medication
4. Elimination
.

It's commonly confused with excretion.

Elimination .

It's the removal of a medication from the body, this could be accomplished by metabolism
where the medication it's broken down in inactive metabolites or excretion where intact
medication is transported out of the body.

Kidneys .

This can happen through a number of ways, but the most common route is through urination.
The major function of the kidneys is to clear metabolic waste material and foreign
substances like medications by filtering the blood.

Now, if we zoom into a nephron tubule, each one is guided by cells that have two surfaces.

Apical Surface
Faces the tubular lumen

Basolateral surface
Faces the peritubular capillaries, which rung
alongside the nephron
Certain medications in the circulation could be filtered out, with other metabolic waste when
the blood goes through the glomerulus

As it filter makes his way through the proximal convoluted tubule, certain medications from
the peritubular capillaries get secreted into the tubular lumen

Polar-water-soluble medications
For this type of medications this is mainly
done actively through active secretion,
mean that they need specific carrier
proteins on the basolateral membrane of
the tubular space which use ATP for
energy

Non polar-lipid-soluble medications

Are secreted in the proximal tubule by
passive diffusion, meaning they do not require any energy by the down-concentration
gradient.

Now, as the filter travels toward the distal convoluted tubule, the level of medication grows
up inside the lumen, so the concentration is higher than in the peritubular capillary.

Non polar, lipid-soluble Polar, water-soluble

Can passively diffuse back into the Get trapped inside the tubular fluid
peritubular circulation Are eliminated by urine

The acidity of the urine affects the excretion

Most medications are either

Weak acids
Weak bases
Uncharged non-polar lipid-soluble
Charged polar-water soluble

pKa = concentration of the uncharged and charged forms, equal each other

Weak acidic medications are trapped in alkaline urine

Weak basic medications are trapped in acidic urine

Feces .
Orally administered drugs that don't get absorbed by the gastrointestinal tract, are directly
passed in feces.

Bile .
Some drugs that are absorbed in the gastrointestinal tract, enter to the enterohepatic
circulation to get to the liver and they bind to bile that is excreted back into the intestine, and
then leaves the body through the feces.

Inhaled anesthetics .
Some inhaled anesthetics are eliminated by the lungs

SmalI amounts .
Some amount of medications are excreted by
Breast milk
Sweating
Saliva
Tears

Clearance (CL)
Volume of plasma cleared of a medication per unit of time
Rate of elimination .
The rate of elimination is proportional to the concentration of that medication in the body
The unit of time in which the drug it´is eliminated, it could change, but the fraction always will
be the same

Half-life .
The rate of elimination, it also used to determine the half-life of a medication, that it is the
time required for the plasma concentration of the medication to be reduced by half

Half-life .
The exact cause of depression is unknown it exist a relation with low levels of serotonin,
norepinephrine and dopamine
Tryptophan 5HT .
Presynaptic serotonergic neurons use the
amino acid tryptophan to synthesize
serotonin which is called 5-HT

Vesicles .
Once synthesize, serotonin os stored in
small vesicles in the presynaptic neuron

Action potential .
Action potential
The action potential reaches the
presynaptic membrane

Fuse .
The vesicles fuse with the presynaptic
membrane

Synaptic cleft .
Releases serotonin to the synaptic cleft

Postsynaptic neuron 5HT2 .

Postsynaptic neuron will receive serotonin
by 5HT2
Regulates mood, feeding & reproduction
Fire off .
Postsynaptic neuron will fire off his own
potential
UNTIL they have enough serotonin on the
synaptic cleft

Signals of postsynaptic .
Postsynaptic neuron will send signals

Reset SERT .
De esta forma, la serotonina es
And presynaptic neurons with SERTs wil
regresada a la neurona presináptica, la
recap serotonin (Na, Cl, Serotonin
carga en el espacio sináptico disminuye
combination)
a la neurona postsináptica y detiene las
When they capt a K and a protein, the
señales.
doors will reset
So more serotonin can attach
Noradrenergic neurons .
Noradrenergic neurons generate
norepinephrine

Vesicles .
Norepinephrine it´s stored in vesicles

Action potential .
The action potential reaches the
presynaptic membrane

Fuse .
The vesicles fuse with the presynaptic
membrane

Synaptic cleft .
Releases serotonin to the synaptic cleft

Postsynaptic neuron (NE) .

Norepinephrine will bind to norepinephrine
receptors (NE) boosting alertness

Fire off .
Postsynaptic neuron will fire off his own
potential
UNTIL they have enough serotonin on the
synaptic cleft

Signals of postsynaptic .
Postsynaptic neuron will send signals
De esta forma, la serotonina es
Reset NET .
regresada a la neurona presináptica, la
And presynaptic neurons with NET
carga en el espacio sináptico disminuye
(norepinephrine transporters) will recap
a la neurona postsináptica y detiene las
serotonin (Na, Cl, Serotonin combination)
señales.
When they capt a K and a protein, the
doors will reset
So more serotonin can attach
Dopamine neurons .
Noradrenergic neurons generate
norepinephrine

Vesicles .
Norepinephrine it´s stored in vesicles

Action potential .
The action potential reaches the
presynaptic membrane

Fuse .
The vesicles fuse with the presynaptic
membrane

Synaptic cleft .
Releases serotonin to the synaptic cleft

Postsynaptic neuron (D) .

Dopamine will bind to dopamine receptors
(D) boosting cognitive functions,
motivation and awakeness

Fire off .
Postsynaptic neuron will fire off his own
potential
UNTIL they have enough serotonin on the
synaptic cleft

Signals of postsynaptic .
Postsynaptic neuron will send signals

Reset DAT .
De esta forma, dopamina es regresada
And presynaptic neurons with DAT
a la neurona presináptica, la carga en el
(norepinephrine transporters) will recap
espacio sináptico disminuye a la
serotonin (Na, Cl, Serotonin combination)
neurona postsináptica y detiene las
When they capt a K and a protein, the
señales.
doors will reset
So more serotonin can attach
 1. Selective Serotonin Reuptake Inhibitors
.

Serotonin
Increase the level of serotonin to alleviate the symptoms of depression
First line therapy

Mechanism .
Recordemos que SERT son los transportadores de la neurona presináptica que después de
que ya hay muchos neurotransmisores en el espacio, los capturan para resetear todo.
Si se inhiben, van a hacer que la serotonina aumente en el espacio sináptico.
Por esto, toman hasta dos semanas para hacer un efecto terapéutico.

Prevent serotonin reuptake from the synaptic cleft

Increases serotonin binding to 5HT2 receptors

Side effects .
● Anxiety
● Insomnia
● GI Distress
● Sexual Dysfunction
● Syndrome of inappropriate ADH hormones
● Suicidal ideations
● Serotonin syndrome
● It's the overstimulation of the nervous system
 SSRI

Sertraline Description Effect Other disorders

Sertraline SSRI with Small amount of DAT inhibition is Anxiety

Dopamine sufficient to cause: Psychotic
Transporter Improvement in energy, motivation, Delusional depression
(DAT) and concentration
Inhibition and The σ1 actions are not well
σ1 Binding understood:

Paroxetine SSRI with Mild anticholinergic actions: Efficacy in depression, especially at high
Muscarinic Calming, even sedating, early in doses
Anticholinergic treatment
and Weak n|orepinephrine transporter
Norepinephrin (NET) inhibitory:
e Transporter Inhibits the enzyme nitric oxide
(NET) synthase:
Inhibitory Contribute to sexual dysfunction
Actions (men)
Withdrawal reactions upon sudden
discontinuation by anticholinergic
rebound plus SERT inhibition:
Akathisia, restlessness,
gastrointestinal symptoms,
dizziness, and tingling
Inhibe CP450

Fluvoxamine SSRI with σ1 Agonist at σ1 receptors: Anxiety

Receptor Inhibe CP450 Psychosis
Binding Delusional depression
OCD
Social anxiety

Fluoxetine 5HT2C Reduced positive effect Less well matched to patients with:
Antagonists Hypersomnia, psychomotor Agitation
Insomnia
actions retardation, apathy, and fatigue Anxiety

Disinhibit release of dopamine and Anti bulimia effect in higher doses

norepinephrine
Reduce fatigue
Improve concentration

Citalopram Has a good Potential of QTc prolongation at

and a bad higher doses
enantiomer
Better-tolerated SSRIs
 Mild
antihistamine
properties that
reside in the R
enantiomer

Escitalopram Pure SERT Best-tolerated SSRI

inhibition Fewest CYP450 mediated drug
interactions
Recordemos que el cytochrome
P450 son enzimas responsables
del metabolismo de los
medicamentos y toxinas. Cuando lo
combinamos con otras drogas que
son metabolizadas por citocromo
P450 como benzodiacepinas
SSRIs reducen su rango de
eliminación y hacen que se
acumulen en el cuerpo. En este
caso, al tener pocas interacciones
con esta enzima, implica un mejor
funcionamiento.
 2. Serotonin Norepinephrine Reuptake Inhibitors
(SNRIs)
.

Serotonin and Norepinephrine

Increase the level of serotonin to alleviate the symptoms of depression
First line therapy

Mechanism .
SNRIs bind to serotonin and norepinephrine transporters (SERT and NET)
They inhibit them leading to increase levels of neurotransmitters in the synaptic cleft

Other conditions .

Anxiety
Neuropathic pain (peripheral neuropathy)
Peripheral neuropathy
Urinary incontinence

NET .
NET inhibition increases dopamine in the prefrontal cortex

Side effects .
● Insomnia
● Nausea
● Sexual dysfunction

Because of the increase levels of norepinephrine it can cause

● High blood pressure
● Sweating
● Headaches
● Suicidal ideations
 SSRI

Name Description Effect Other disorders

Duloxetine More potent Relieve unipolar depression in the Efficacy in the treatment of cognitive
SERT than absence of pain, but it also relieves symptoms of depression that are
NET pain in the absence of depression prominent in geriatric depression
Liver damage
Incontinencia urinaria
Neuropathic pain
Fibromyalgia

Venlafaxine More inhibition Two side effects: sweating and Used for several anxiety disorders
of NET than elevated blood pressure. Panic disorders
SERT PTSD
Inhibit CP450 OCD

Desvenlafaxine It's an active Active metabolite

metabolite of Greater NET inhibition relative to
venlafaxine SERT inhibition compared to
More inhibition venlafaxine
of NET than
SERT in
contrast to
venlafaxine

3. Tricyclic Antidepressants (TCAs)

.

Increase the levels of serotonin and norepinephrine to alleviate symptoms of depression

They are divided in Tertiary (non-selective) and Secondary (selective)
Effective treatment of depression
Not first line therapy (Severe side effects)
Used when no response to other antidepressants

Other indications
Phobic disorders
Chronic neuropathic pain
Migraine prophylaxis
 Tertiary TCAs Secondary TCAs

SERT and NET Only NET

Amitriptyline Desipramine
Imipramine (nocturnal enuresis) Nortriptyline
Clomipramine (OCD)

Side effects

Histamine H1 Receptors Sedation

Muscarinic Receptors Atropine side effects

Dry mouth
Tachycardia
Urinary retention
Confusion
Hallucinations

Alpha 1 Receptors Orthostatic hypotension

Cardiotoxic Arritmias
Prolonged QT interval
Convylsion
Coma

P450 Inhibit Cytochrome P450 enzymes

4. Monoamine Oxidase MAOIs

 .

Each of these presynaptic neurons has small reuptake proteins, which pump the
neurotransmitters from the synaptic cleft back into presynaptic neurons

Once inside the neuron, a class of enzymes called monoamine oxidase will break down
some of these neurotransmitters and keep them in vesicles to be reused in the next time of
liberation.

Monoamine Oxidase A Monoamine Oxidase B

Serotonin Dopamine
Norepinephrine
Dopamine

MAOIs
Increase the levels of all neurotransmitters related with depression
Not first line therapy due to their side effects (second or third line therapy)
Special in atypical depression

Non Selective Selective

Isocarboxazid Selegiline
Phenelzine Rasagiline
Tranylcypromine

Inhibit monoamine oxidase A Only inhibit

Inhibit monoamine oxidase B Monoamine oxidase B

Serotonin Dopamine
Norepinephrine More common to treat Parkinson disease
Dopamine

Side Effects .

● Serotonin syndrome
● Hypertensive crisis

5. Atypical antidepressants
.

Specially used in major depressive disorder

Are reserved for individuals that respond to other antidepressants
Common medications
Mirtazapine
Vortioxetine
Trazodone
Nefazodone
Vilazodone
Bupropion

Mirtazapine .

Is a serotonin antagonist which might seem counterintuitive

There are different types of of 5GT2 receptors and mirtazapine blocks
5HT2A: Allows the release of dopamine in the prefrontal cortex and improves sleep
5HT3A: Reduces nausea and vomiting
Histamine H1 Receptors: Lead to sedation and weight gain

So more serotonin can bind to 5HT1A receptors which have a stronger link to depression

Vortioxetine .

Vilazodone is a partial agonist

Vortioxetine is a full agonist
 .
Are mainly used to treat schizophrenia and other psychotic condition

Categories .
First generation “Typical antipsychotics” Act on D2 receptors
Second generation “Atypical antipsychotics”

Dopamine

Even though the exact cause of schizophrenia is still unknown, evidence suggests that it's
related to dopamine.

Within the brain, dopamine is found in four main dopamine pathways

Mesolimbic pathway Motivation and desire

Mesocortical pathway Regulates emotions

 Nigrostriatal pathway Contain motor neurons that bypass the
medullary pyramids to control involuntary
movements and coordination

Tuberoinfundibular Releases dopamine to limit the secretion of

prolactin

Other regions .

● Chemoreceptor trigger zone

Initiate the vomiting reflex
● Medullary periventricular pathway
Regulates eating behavior

In schizophrenia .

Altered levels of dopamine mainly affect the mesolimbic and mesocortical pathway

Mesolimbic Mesocortical

High levels of dopamine Low levels of dopamine

Cause positive symptoms such as Cause negative symptoms
Delusions Lack of motivation
Hallucinations Social withdrawal
Disorganized thought Flat affect
 Glutamate

NMDA (N-methyl-D-aspartate) subtype of glutamate receptor is hypofunctional at critical

synapses in the prefrontal cortex
Hypothetically due to the neurodevelopmental abnormalities in schizophrenia
Dysfunction of glutamate synapses at a specific site:
GABA interneurons in the prefrontal cortex
Causes glutamate neurons that they innervate downstream to become “disinhibited” and
thus hyperactive
Deficits in the enzyme that makes their own neurotransmitter GABA

https://www.youtube.com/watch?v=ufeyjUc_RGA

Serotonin

The serotonin theory of psychosis proposes that hyperactivity/imbalance of serotonin activity,

particularly at serotonin 5HT2A receptors, can result in psychosis.
Hypothetically due to the neurodevelopmental abnormalities in Schizophrenia
Imbalance in excitatory 5HT2A receptor stimulation of those glutamate pyramidal neurons
discussed above, which directly innervate VTA/ mesostriatal integrated hub dopamine
neurons and visual cortex neurons.

Treatment
Targeting mesolimbic/mesostriatal dopamine D2 receptors .
 1. Typical antipsychotics
.

When it comes treating schizophrenia some typical antipsychotics like:

Higher potency Low potency (Have a stronger sedating

effects)

● Haloperidol ● Thioridazine
● Trifluoperazine ● Chlorpromazine
● Fluphenazine ● Thiothixene

Pathways damaged in schizophrenia .

Ok esto es prácticamente qué pasa si bloqueas a D2 con los typical antipsychotics

Are more likely to cause these side effects

Mesolimbic pathway ● Block dopamine D2 receptors

● Alleviate positive symptoms of schizophrenia
Debe estar baja en
dopamina

Mesocortical ● Block dopamine receptors

Pathway ● Block dopamine receptors in mesocortical pathway
● Might worsen the negative effects
Debe de estar alta
en dopamina

Tuberoinfundibular Stimulation of prolactin

pathway ● Oligomenorrhea (oli)
● Galactorrhea (gala)
● Gynecomastia (gyne)

Nigrostriatal pathway Extrapyramidal symptoms

● Pesudo Parkinson
● Muscular rigidity
● Bradikinesia (Slow movements)
● Akinesia (loss of movement)
● Akathisia (motor restlessness)
● Dystonia (Involuntary twisting contractions)
● Tardive dyskinesia

Trigger zone Blocking dopamine receptors in the chemoreceptor trigger zone

decrease nausea and vomiting
 H1-Histamine Sedative effect

Alpha 1 Receptor Orthostatic hypotension

inhibition

Muscarinic receptor Anticholinergic side effects

inhibition Dry mouth
Blurred vision
Urinary retention
Constipation

Blocking D2 and Apathetic, anhedonic, and lacking motivation, interest, or joy from
motivation social interactions.
“Neuroleptic-induced deficit syndrome”
Treatment includes reducing the dose of the D2 blocker or
switching to a D2 blocker that is better tolerated

Psychiatric indications .

● Psychosis
● Delirium
● Bipolar disorder
● Obsessive compulsive disorder
● Tourette syndrome
● Huntington disease

Typical antipsychotics are more likely to cause side effects vs atypical

Extrapyramidal symptoms usually disappear once the medication is stopped

Chlorpromazine 1st agent with D2 antagonist

Exploit sedation

Haloperidol Most potent D2 antagonist

Less sedating

Sulpiride Cause motor side effects

Prolactine elevation
Lower doses: Efficacy for negative symptoms

Amisulpride More selective for mesolimbic/mesostriatal DA

Efficacy for the negative symptoms and for depression
 2. Atypical antipsychotics
.

Based on dopamine theory

They block dopamine D2 receptors in Mesolimbic that alleviate positive symptoms

Based on serotonin theory

Block serotonin 5-HT2A receptors
Decrease dopamine release
When atypical antipsychotic block them, dopaminergic neurons have no inhibitory signals, so
dopamine release actually increases in mesocortical pathway
Alleviate negative symptoms in schizophrenia

OHH eleva uno y baja otra

Atypical antipsychotics .

Clozapine
Olanzapine
Quetiapine
Paliperidone
Risperidone
Lurasidone
Ziprasidone
Aripiprazole (partially stimulates D2 and 5HT1)

Indications .

Bipolar disorder
OCd
Anxiety
Depression
Tourette Syndrome
Mania
Antidepressant actions in bipolar and unipolar depression
Anxiolytic action
Agitation in dementia

Side Effects .

Tuberoinfundibular pathway ● Stimulation of prolactin

● Oligomenorrhea
 ● Galactorrhea
● Gynecomastia

Nigrostriatal pathway Extrapyramidal symptoms

Acute
● Dystonia
● Akathisia
● Pseudoparkinsonismo

Tardive
● Tardive dyskinesia

H1-Histamine Sedative effect

Alpha 1 Receptor inhibition Orthostatic hypotension

Muscarinic receptor inhibition Anticholinergic side effects

Dry mouth
Blurred vision
Urinary retention
Constipation

Metabolic Syndrome Weight gain

Diabetes
Dyslipidemia
Cardiovascular risk

Clozapine Effective when other drugs for psychosis fail

Reduce the risk of suicide
Occupies fewer D2 receptors
Awakening return to a near normal level of cognitive, interpersonal
and vocational functioning
Little motor symptoms
Not elevated prolactin
Could cause neutropenia
Increased risk of seizures and myocarditis
Very sedating

Olanzapine Antagonist
Both 5HT2A and D2 receptors
The next most effective agent
Higher risk for metabolic side effects
Efficacy in unipolar and bipolar depression
 Quetiapine 5HT2A and D2 receptors agonist
Different pharmacological properties especially at different doses
Psychosis
Hypnotic for insomnia
Depression
Anxiety
Parkinson disease

Risperidone Uses in schizophrenia/maintenance and bipolar mania/maintenance

Treatment of irritability: Autistic disorder
Agitation and psychosis:dementia
Reduced motor side effects at lower doses, it raises prolactin level even
at low doses

Paliperidone The active metabolite of risperidone

Not hepatically metabolized
More tolerable, with less sedation, less orthostasis, and fewer motor
side effects

Aripiprazole D2/5HT1A partial agonist

Low motor side effects, mostly akathisia, and actually reduces prolactin
Treating schizophrenia/maintenance, agitation and bipolar
mania/maintenance
Autism related irritability and Tourette síndrome
Adjunctive treatment to SSRIs/SNRIs for major depressive disorder

Brexpiprazole More potent 5HT2A antagonism, 5HT1A partial agonism and a1

antagonism
Reduce its propensity to cause motor side effects and akathisia
Antidepressant actions, treatment of agitation in dementia
Combined with the SSRI sertraline for the treatment of PTSD.

Benzodiazepines .

Acts as a central nervous system depressant

Act as a central nervous system depressant

Uses .
Relieve anxiety
Seizure disorders (trastornos convulsivos)
Hypnotic for insomnia
Anesthetic
Withdrawal syndrome (síndrome de abstinencia)

They act by enhancing GABA when it binds to their receptor

What happens with anxiety? .

On anxiety happens two things:

1. Over Excitatory neurons
When one neuron is stimulates, it will release excitatory neurotransmitters which
bind to receptors on the next neuron
This causes the neuron to depolarize and release its own excitatory neurotransmitter
2. GABA
Let pass Cl to the neuron to hyperpolarize and be less responsive to stimuli

So in anxiety we have or too much excitation or too little inhibition

Benzodiazepines .

● Try to decrease excitatory signals enhancing the effect of inhibitory neurons

● They are composed of a benzene ring that consists of six carbon atoms fused to a
diazepine ring.
● It's made by five carbon atoms and two nitrogen atoms
● Based on the duration of action, they can be roughly divided into acting benzos

Receptors BZ in GABA .
These medications target the BZ site of
GABAA receptors. When both
benzodiazepine and GABA bind to their separate sites on the receptor, benzodiazepines
increase the frequency of Cl- channels opening, thereby increasing the influx of Cl- ions.

As a result, high intracellular concentrations of Cl- ions cause membrane hyperpolarization,

which means it’s much more difficult for neurons to depolarize and fire off an action potential.

Chart of benzodiazepines .

Now, let’s draw a chart of the dose-dependent effects of

benzodiazepines.

Low doses of benzodiazepines

Cause sedation, disinhibition, and anxiolysis

Increases of benzodiazepines
Causes hypnosis and anesthesia.

Long term treatment .

Alright, so benzodiazepines are indicated when the neurons get “super excited” and we
want to calm them down like in anxiety disorders, or during a panic attack.

It’s important to note that preferred medications for the long-term treatment of panic attacks
are selective serotonin reuptake inhibitors, or short SSRIs, due to abuse potential,
dependence, and tolerance of benzodiazepines.

Anticonvulsants .
Are very effective anticonvulsants
Treatment for status epilepticus (when a person have over 5 minutes of ongoing seizures or
multiple seizures)

Anesthesia .
This works because we want to depress the function of the patient's nervous system

Insomnia .
Works with insomnia but they decrease REM sleep
Also they can be used to treat night terrors

Withdrawal symptoms .
Since alcohol and barbiturates also work by targeting GABAA receptors, benzodiazepines
can be used to manage their withdrawal symptoms by decreasing their severity.

DiazePAM .
Can also be used as the second-line treatment for eclampsia, which is a life-threatening
complication of pregnancy that is associated with seizures.
Convulsiones en una mujer embarazada
Side effects .
They are more selective than barbiturates, these side effects are less severe.

● Drowsiness (somnolencia)
● Decrease in concentration
● Problem solving abilities
● Reaction time
● Paradoxical stimulation in certain part of the brain leading to fast speech,
excitement and restlessness
● Anterograde amnesia
● Caution with elferly because they can cause ataxia and precipitation falls

Metabolized .
Most of these medications are metabolized in the liver by CYP450 enzymes into
active metabolites; therefore they should be avoided in individuals with liver
impairment.

Tolerance .
When used chronically, a person can develop tolerance to benzodiazepines, and their
effectiveness decreases, which means that they’ll need to increase the dose to get the
same effects. This is problematic because benzodiazepines are habit forming and could
lead to addiction.

Short acting benzodiazepines

Moreover, short-acting benzodiazepines are associated with a higher addiction

potential since they have a shorter half life!

Chronic use .
Chronic use also leads to dependence, which means, when the medication is discontinued,
the person experiences withdrawal symptoms like

● Insomnia
● Anxiety
● Seizures.

Contraindicaciones .
● Miastenia gravis
● Insuficiencia respiratoria
● Glaucoma
● Hígado insuficiente
● Not in pregnancy and in breastfeeding