Physiology & pharmacology
PHARMACOLOGY
Pharmacokinetics: how the body affects the drug (ADME)
Pharmacodynamics: how the drug affects the body (the effect of a drug on receptors)
- Binding to receptors
- Biological effect
Plasma proteins are proteins which are available in the blood stream. They determine
whether a drug has a biological mode of action.
Pharmacology is mainly characterized by the
application of pharmaceuticals (= medicinal drugs) in
treatments of diseases.
Topical administration is via a particular site, so
transdermal (patch), sublingual or rectal for example.
Via sublingual administration, you put the tablet
under your tung and so it doesn’t reach the liver,
there will be no first pass effect. Buccal administration is when you add a drug in the
cheek. It wouldn’t pass the liver either.
You can never at a peptide hormone via the oral route because it will be inactivated.
So a peptide hormone like insulin should be injected for example.
Central effect: blood-brain barrier can be crossed (permeable)
Peripheral effect: blood-brain barrier cannot be crossed (impermeable)
The polarity and charge determine whether the pharmaceutical can pass these
blood-brain barriers. When you want to treat a brain disease, like Alzheimer, you
need a pharmaceutical that is able to cross the blood-brain barrier. When you have
Alzheimer, you have a leaky blood-brain barrier, so particles that would never reach
the brain, will now reach the brain and cause damage.
Membranes consist of lipids so if the pharmaceutical wants to pass the barrier, it
needs to be nonpolar and not charged.
Albumin is quantitatively the most important protein molecule in blood plasma.
Because it cannot exit blood capillaries in the healthy situation, it plays an important
role in maintaining proper osmotic pressure in blood vessels. So Albumin is an
abundant plasma protein.
1
,Active substances have a low affinity for plasma
protein but have a high affinity for receptors. When
there is a drug-plasma protein complex formed,
there is no effect from the medicinal drug. So
medicinal drugs that are bound to plasma proteins
are biologically inactive. But when this complex is
metabolized and the drug becomes free again, it will
be active again and have a therapeutic effect.
Free drug – short and strong duration of therapeutic
effect
Bound drug – prolonged duration of therapeutic
effect. There is a fraction of free drug and a fraction
of bound drug. So in this case there is a buffer
because the bound drug can be metabolized and be
free and active again and the free drug can be
bound and be inactive, so there is a buffer between
active and inactive.
The placebo effect does not involve medicinal
drugs. Your brain convinces your body that a fake
treatment is the real thing, and it thus stimulates
healing. It's about the connection between the mind and the body. About 30% of drug
treatment depends on placebo.
Digoxin is isolated from a plant called digitalis purpurea. It is used to treat heart
failure: the heart cannot sufficiently contract. Active substances are always steroids
that are bound to C3 with one or more sugar molecules.
Atropine is isolated from a plant called Atropa belladonna. Atropine is currently the
most important antagonist of the muscarinic acetylcholine receptors. Acetylcholine is
a receptor which the body uses when it gets in rest, so Atropine inhibits the
parasympathetic system.
EC: effective concentration
EC50: effective concentration to
achieve 50% of the biological effect
Emax: maximum possible effect
You need a logarithmic scale to
determine the EC50.
2
,When you use intact organs, you can
measure the effect of the medicinal drug.
When you homogenize an organ in the
blender (destroying it), you can’t measure this
anymore. You can then measure the binding
of the drug to the receptors in the organ.
There will be no physiological response, so
you don’t know if the drug has a good or bad
effect on the organ.
The number of binding sites that are free and
available to respond decreases as the
saturation of the binding sites increases, and
then the increase in binding no longer
corresponds to the increase in concentration.
Characteristic for receptor-binding experiment:
- Saturability
- Specificity
- Binding affinities
- NO DISCRIMINATION BETWEEN
AGONIST AND ANTAGONIST
An agonist has receptor affinity AND an
intrinsic biological activity. An antagonist
has receptor affinity AND NO intrinsic
biological activity. So to discriminate
between agonist and antagonist you need
to achieve a biological reaction or not.
A spontaneous transition can happen, like
metabolism. An active substance can be
made inactive or the other way around.
The EC50 of agonist A is reached earlier
than the EC50 of agonist B, so much less
of drug A is needed to achieve the 50%
effective concentration. The efficacy of A
is thus higher than B. Agonist A is called a
full agonist and B is called a partial
agonist. When B is a partial agonist, it is
thus also a partial antagonist. This partial
agonist/antagonist can reduce the efficacy
of the full agonist because the antagonist
prevents the agonist from binding.
Atropine is the antagonist of acetylcholine and other muscarinic agonists by blocking
the muscarinic receptors. Propranolol is the antagonist of adrenaline by blocking the
b-receptors. It reduces the heartbeat and the blood pressure (treatment for
hypertension).
3
, Acetylcholine (ACh) decreases blood pressure, and its
antagonist atropine increases the blood pressure.
A competitive antagonist shifts an agonist’s concentration
curve to the right without having an effect on the agonist’s
maximum effect. In competitive antagonist binding, the
antagonist and agonist will bind to the same binding site. So
the antagonist blocks the binding of the agonist to the
receptor’s agonist site. In noncompetitive antagonist binding, the
allosteric antagonist will bind to the allosteric site (different from
the agonist site) and, thereby, prevent receptor activation, even
if the agonist is bound to the receptor.
Noncompetitive antagonist
will suppress the maximum
biological response.
The curve is shift to the right
because the antagonist
reduces the potency of the
agonist.
In this picture there are 2 receptors on the smooth muscle cells
in the airways. These are 2 different receptors on the same cell. The M3 receptor
(muscarinic receptor) is sensitive for acetylcholine and the B2 receptor is sensitive for
adrenaline. Acetylcholine is released from the parasympathetic system and
adrenaline is released from the sympathetic system. When you are in rest, the
parasympathetic system is working and acetylcholine is released. Acetylcholine can
now bind to the M3 receptor and this leads to the contraction of the smooth muscle
cells via an increase in calcium. If calcium is increased, the smooth muscle cells will
contract and there will be a smaller diameter in the lungs, this means that you can
breathe less, but you are in rest, thus this is accepted. When you are active, the
sympathetic system is working and adrenaline is
released. Adrenaline can now bind to the B2
receptor and this leads to the relaxation of the
smooth muscle cells via an increase in cAMP. if
cAMP is increased, the smooth muscle cells will
relax and there will be a larger diameter in the lungs,
so this helps breathing while you're active.
Contraction: less oxygen
Relaxation: more oxygen
Functional antagonism = 2 agonists induce an opposite effect via activation of
different receptors
4
PHARMACOLOGY
Pharmacokinetics: how the body affects the drug (ADME)
Pharmacodynamics: how the drug affects the body (the effect of a drug on receptors)
- Binding to receptors
- Biological effect
Plasma proteins are proteins which are available in the blood stream. They determine
whether a drug has a biological mode of action.
Pharmacology is mainly characterized by the
application of pharmaceuticals (= medicinal drugs) in
treatments of diseases.
Topical administration is via a particular site, so
transdermal (patch), sublingual or rectal for example.
Via sublingual administration, you put the tablet
under your tung and so it doesn’t reach the liver,
there will be no first pass effect. Buccal administration is when you add a drug in the
cheek. It wouldn’t pass the liver either.
You can never at a peptide hormone via the oral route because it will be inactivated.
So a peptide hormone like insulin should be injected for example.
Central effect: blood-brain barrier can be crossed (permeable)
Peripheral effect: blood-brain barrier cannot be crossed (impermeable)
The polarity and charge determine whether the pharmaceutical can pass these
blood-brain barriers. When you want to treat a brain disease, like Alzheimer, you
need a pharmaceutical that is able to cross the blood-brain barrier. When you have
Alzheimer, you have a leaky blood-brain barrier, so particles that would never reach
the brain, will now reach the brain and cause damage.
Membranes consist of lipids so if the pharmaceutical wants to pass the barrier, it
needs to be nonpolar and not charged.
Albumin is quantitatively the most important protein molecule in blood plasma.
Because it cannot exit blood capillaries in the healthy situation, it plays an important
role in maintaining proper osmotic pressure in blood vessels. So Albumin is an
abundant plasma protein.
1
,Active substances have a low affinity for plasma
protein but have a high affinity for receptors. When
there is a drug-plasma protein complex formed,
there is no effect from the medicinal drug. So
medicinal drugs that are bound to plasma proteins
are biologically inactive. But when this complex is
metabolized and the drug becomes free again, it will
be active again and have a therapeutic effect.
Free drug – short and strong duration of therapeutic
effect
Bound drug – prolonged duration of therapeutic
effect. There is a fraction of free drug and a fraction
of bound drug. So in this case there is a buffer
because the bound drug can be metabolized and be
free and active again and the free drug can be
bound and be inactive, so there is a buffer between
active and inactive.
The placebo effect does not involve medicinal
drugs. Your brain convinces your body that a fake
treatment is the real thing, and it thus stimulates
healing. It's about the connection between the mind and the body. About 30% of drug
treatment depends on placebo.
Digoxin is isolated from a plant called digitalis purpurea. It is used to treat heart
failure: the heart cannot sufficiently contract. Active substances are always steroids
that are bound to C3 with one or more sugar molecules.
Atropine is isolated from a plant called Atropa belladonna. Atropine is currently the
most important antagonist of the muscarinic acetylcholine receptors. Acetylcholine is
a receptor which the body uses when it gets in rest, so Atropine inhibits the
parasympathetic system.
EC: effective concentration
EC50: effective concentration to
achieve 50% of the biological effect
Emax: maximum possible effect
You need a logarithmic scale to
determine the EC50.
2
,When you use intact organs, you can
measure the effect of the medicinal drug.
When you homogenize an organ in the
blender (destroying it), you can’t measure this
anymore. You can then measure the binding
of the drug to the receptors in the organ.
There will be no physiological response, so
you don’t know if the drug has a good or bad
effect on the organ.
The number of binding sites that are free and
available to respond decreases as the
saturation of the binding sites increases, and
then the increase in binding no longer
corresponds to the increase in concentration.
Characteristic for receptor-binding experiment:
- Saturability
- Specificity
- Binding affinities
- NO DISCRIMINATION BETWEEN
AGONIST AND ANTAGONIST
An agonist has receptor affinity AND an
intrinsic biological activity. An antagonist
has receptor affinity AND NO intrinsic
biological activity. So to discriminate
between agonist and antagonist you need
to achieve a biological reaction or not.
A spontaneous transition can happen, like
metabolism. An active substance can be
made inactive or the other way around.
The EC50 of agonist A is reached earlier
than the EC50 of agonist B, so much less
of drug A is needed to achieve the 50%
effective concentration. The efficacy of A
is thus higher than B. Agonist A is called a
full agonist and B is called a partial
agonist. When B is a partial agonist, it is
thus also a partial antagonist. This partial
agonist/antagonist can reduce the efficacy
of the full agonist because the antagonist
prevents the agonist from binding.
Atropine is the antagonist of acetylcholine and other muscarinic agonists by blocking
the muscarinic receptors. Propranolol is the antagonist of adrenaline by blocking the
b-receptors. It reduces the heartbeat and the blood pressure (treatment for
hypertension).
3
, Acetylcholine (ACh) decreases blood pressure, and its
antagonist atropine increases the blood pressure.
A competitive antagonist shifts an agonist’s concentration
curve to the right without having an effect on the agonist’s
maximum effect. In competitive antagonist binding, the
antagonist and agonist will bind to the same binding site. So
the antagonist blocks the binding of the agonist to the
receptor’s agonist site. In noncompetitive antagonist binding, the
allosteric antagonist will bind to the allosteric site (different from
the agonist site) and, thereby, prevent receptor activation, even
if the agonist is bound to the receptor.
Noncompetitive antagonist
will suppress the maximum
biological response.
The curve is shift to the right
because the antagonist
reduces the potency of the
agonist.
In this picture there are 2 receptors on the smooth muscle cells
in the airways. These are 2 different receptors on the same cell. The M3 receptor
(muscarinic receptor) is sensitive for acetylcholine and the B2 receptor is sensitive for
adrenaline. Acetylcholine is released from the parasympathetic system and
adrenaline is released from the sympathetic system. When you are in rest, the
parasympathetic system is working and acetylcholine is released. Acetylcholine can
now bind to the M3 receptor and this leads to the contraction of the smooth muscle
cells via an increase in calcium. If calcium is increased, the smooth muscle cells will
contract and there will be a smaller diameter in the lungs, this means that you can
breathe less, but you are in rest, thus this is accepted. When you are active, the
sympathetic system is working and adrenaline is
released. Adrenaline can now bind to the B2
receptor and this leads to the relaxation of the
smooth muscle cells via an increase in cAMP. if
cAMP is increased, the smooth muscle cells will
relax and there will be a larger diameter in the lungs,
so this helps breathing while you're active.
Contraction: less oxygen
Relaxation: more oxygen
Functional antagonism = 2 agonists induce an opposite effect via activation of
different receptors
4
