Modul Masalah Pada Sistem Organ Saraf

Pokok Bahasan :
“INTRODUCTION TO PHARMACOLOGY OF CNS DRUGS & DRUG DELIVERY
ACROSS THE BLOOD-BRAIN BARRIER”

dr. Kinanti Narulita Dewi, M.Si, Sp.An

Email : kinantinarulita@unissula.ac.id

Departemen Farmakologi
Fakultas Kedokteran Universitas Islam Sultan Agung
Semester Genap TA 2021/2022
Capaian Pembelajaran
1. Mengetahui secara umum jenis obat yang bekerja pada sistem saraf pusat
2. Menjelaskan peran blood-brain-barrier
3. Menjelaskan faktor – faktor yang mempengaruhi obat dalam menembus
blood-brain-barrier
4. Menjelaskan transport obat melalui blood-brain-barrier
5. Mekanisme aksi kerja obat pada sistem saraf pusat
6. Menjelaskan jenis kanal ion dan reseptor obat pada sistem saraf pusat
7. Menjelaskan mekanisme down-regulation dan up-regulation reseptor obat
pada sistem saraf pusat
8. Menjelaskan jenis – jenis neurotransmitter yang berperan pada obat yang
bekerja pada sistem saraf pusat
9. Menjelaskan sintesis dan degradasi dari masing – masing neurotransmitter
 INTRODUCTION
• Drugs acting in the central nervous system (CNS) were among the first to be
discovered by primitive humans and are still the most widely used group of
pharmacologic agents.

• These include medications used to treat a wide range of neurologic and psychiatric
conditions as well as drugs that relieve pain, suppress nausea, and reduce fever,
among other symptoms. Examples include certain anticonvulsants (eg,
carbamazepine, phenytoin), local anesthetics, and some drugs used in general
anesthesia.

• Because of its unique importance, the brain is “protected” by a specialized

system of capillary endothelial cells known as the BBB. Unlike peripheral
capillaries that allow relatively free exchange of substances between cells,
the BBB limits transport through both physical (tight junctions) and
metabolic (enzymes) barriers.
BLOOD-BRAIN BARRIER
• The primary BBB is formed by
microvascular endothelial cells
with tight junctions lining the
cerebral capillaries penetrating
the brain and spinal cord of most
mammals and other organisms
with a well-developed CNS.
• The secondary BBB surrounds the
cerebral capillaries and is
composed of glial cells.
• The BBB is playing a critical role in
protecting the brain parenchyma
from blood-borne agents and
providing a signifcant obstacle to
the entry of drugs and other
exogenous compounds into the
central nervous system.
 BLOOD-BRAIN BARRIER

• The blood-brain barrier (BBB) is a protective functional separation of the

circulating blood from the extracellular fluid of the CNS that limits the
penetration of substances, including drugs.
• This separation is accomplished by the presence of tight junctions
between the capillary endothelial cells as well as a surrounding layer of
astrocyte end-feet.
• To enter the CNS, drugs must either be highly hydrophobic or engage
specific transport mechanisms.
• The second barrier is the blood–cerebrospinal fuid barrier (BCSFB), which
is formed by the epithelial cells of the choroid plexus.
 FACTORS THAT INFLUENCE THE
ABILITY OF DRUGS TO CROSS THE
BLOOD-BRAIN BARRIER
flexibility and molecular
conformation
lipophilicity and charge

size
enzymatic stability

plasma protein affinity for

binding transport carriers
 FACTORS THAT INFLUENCE THE
ABILITY OF DRUGS TO CROSS THE
BLOOD-BRAIN BARRIER
• Large polar molecules do not pass easily through the BBB.
• Small, lipid-soluble molecules, such as barbiturates, cross easily.
• Most charged molecules cross slowly.

• It is clear that the BBB is the rate-limiting factor for drug entry into
the CNS.
TRANSPORT ACROSS THE BBB
 BLOOD-BRAIN BARRIER

The second- They were developed

generation to be significantly Limiting their
antihistamines cause more polar than older crossing of the BBB.
less drowsiness antihistamines
 BLOOD-BRAIN BARRIER

l-DOPA, a precursor of
the neurotransmitter
dopamine, can enter Thus, the orally
the brain using an administered drug l-
amino acid transporter, DOPA, but not
whereas dopamine dopamine, can be used
cannot cross the BBB. to boost CNS
dopamine levels in the
treatment of
Parkinson’s disease.
 BLOOD-BRAIN BARRIER

Many nutrients (glucose and

the essential amino acids),
have specific transporters
allow them to
cross the BBB
 SITES & MECHANISMS OF DRUG ACTION
The effects of most therapeutically important
CNS drugs are exerted mainly at synapses.

Drugs may act presynaptically to alter

the synthesis, storage, release,
reuptake, or metabolism of transmitter
chemicals.

Other drugs can activate or block both pre-

and postsynaptic receptors for specific
transmitters or can interfere with the
actions of second messengers.
Sites of CNS drug action. Drugs may alter (1) the action potential in the presynaptic fiber; (2) synthesis of transmitter; (3) storage; (4)
metabolism; (5) release; (6) reuptake; (7) degradation; (8) receptor for the transmitter; or (9) receptor-induced decrease or increase in ionic
conduction. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 21–5.)
 ION CHANNELS & NEUROTRANSMITTER
RECEPTORS

The membranes of neurons contain two types of channels defined on the basis of the
mechanisms controlling their gating (opening and closing): voltage-gated and ligand-
gated channels.
ION CHANNELS & NEUROTRANSMITTER
RECEPTORS
RECEPTOR ALTERATIONS CAUSED BY CENTRAL
NERVOUS SYSTEM DRUG TREATMENT
• Receptor proteins not only regulate cell processes but are themselves
regulated.
• Receptors undergo dynamic alteration in response to changes in synaptic
neurotransmitter concentrations or in response to long-term drug
administration.
• These alterations can affect the efficiency of receptor coupling to signal
transduction pathways (desensitization or sensitization) or affect the
number of receptor proteins expressed by the neuron (down-regulation or
upregulation).
• CNS drugs that act on metabotropic or G protein–coupled receptors are
particularly noted for their alteration of receptor numbers.
RECEPTOR ALTERATIONS CAUSED BY CENTRAL
NERVOUS SYSTEM DRUG TREATMENT
• Receptor down-regulation may follow a sustained increase in
neurotransmitter release, a sustained blockade of neurotransmitter
reuptake, or longterm receptor activation by a drug. For example, long-term
administration of morphine in a patient with chronic pain can cause down-
regulation of opioid receptors in the brain and spinal cord. Receptor down-
regulation is one of the primary mechanisms of pharmacodynamic drug
tolerance.
• Receptor up-regulation is a compensatory reaction to a sustained decrease
in neurotransmission, a condition that can be caused either by a reduction in
neurotransmitter release or by long-term receptor antagonism. For
example, daily administration of haloperidol, a dopamine receptor
antagonist, in a schizophrenic patient can lead to up-regulation of D2
receptors.
 CRITERIA FOR TRANSMITTER STATUS
To be accepted as a neurotransmitter, a candidate chemical must :

(1)
(2)
be present in higher
concentration in the be released by
synaptic area than in electrical or (3)
other areas (ie, must chemical produce the same sort
be localized in stimulation via a of postsynaptic
appropriate areas) calcium-dependent response that is seen
mechanism with physiologic
activation of the
synapse
 AMINO ACID NEUROTRANSMITTERS
The amino acids of primary interest to the
pharmacologist fall into two categories :

the acidic amino acid the neutral amino acids

glutamate glycine and GABA

These compounds are present in high concentrations in the CNS

and are extremely potent modifiers of neuronal excitability
 GLUTAMIC ACID
• Most neurons in the brain are excited by glutamic acid.
• Glutamate is released into the synaptic cleft by Ca2+-dependent exocytosis.
The released glutamate acts on postsynaptic glutamate receptors and is
cleared by glutamate transporters present on surrounding glia.

• In glia, glutamate is converted to glutamine by glutamine synthetase,

released from the glia, taken up by the nerve terminal, and converted back
to glutamate by the enzyme glutaminase. The high concentration of
glutamate in synaptic vesicles is achieved by the vesicular glutamate
transporter (VGLUT).
 A : Glutamine is imported into the
glutamatergic neuron and converted
into glutamate by glutaminase. The
glutamate is then concentrated in
vesicles by the vesicular glutamate
transporter (VGLUT).
B : Upon release into the synapse,
glutamate can interact with AMPA and
NMDA ionotropic receptor channels
(AMPAR, NMDAR) and with
metabotropic receptors (mGluR) on
the postsynaptic cell.
C : Synaptic transmission is
terminated by active transport of the
glutamate into a neighboring glial cell
by a glutamate transporter. It is
converted into glutamine by
glutamine synthetase and transported
back into the glutamatergic axon
terminal.
Schematic diagram of a glutamate synapse.
 GABA AND GLYCINE
• Both GABA and glycine are inhibitory neurotransmitters, which are typically
released from local interneurons.

• Interneurons that release glycine are restricted to the spinal cord and brain
stem, whereas interneurons releasing GABA are present throughout the
CNS, including the spinal cord.

• It is interesting that some interneurons in the spinal cord can release both
GABA and glycine.
 GABA
• GABA receptors are divided into two main types: GABA-A and GABA-B.
• Inhibitory postsynaptic potentials in many areas of the brain have a fast and
slow component.
• The fast component is mediated by GABA-A receptors and the slow
component by GABA-B receptors.
• GABA-A receptors are ionotropic receptors and, like glycine receptors, are
pentameric structures that are selectively permeable to Cl– .
• GABA-B receptors (activated by baclofen, a centrally acting muscle
relaxant) are coupled to G proteins that either open a potassium channel
that is shared with 5-HT1A receptors, or close calcium channels.
• Drugs that influence GABA-A receptor systems : sedative-hypnotics
(barbiturates, benzodiazepines, zolpidem) & anticonvulsants (gabapentin,
tiagabine, vigabatrin).
 ACETYLCHOLINE

Acetylcholine was the first compound to be identified pharmacologically as a transmitter in the CNS.

Approximately 5% of brain neurons have receptors for acetylcholine (ACh).

Most CNS responses to ACh are mediated by a large family of G protein-coupled muscarinic M1
receptors that lead to slow excitation when activated.

Drugs affecting the activity of cholinergic systems in the brain include the acetylcholinesterase inhibitors
used in Alzheimer’s disease (eg, rivastigmine) and the muscarinic blocking agents used in parkinsonism
(eg, benztropine).
MONOAMINE NEUROTRANSMITTERS
Monoamines include the catecholamines
(dopamine and norepinephrine) and 5-
hydroxytryptamine.

The diamine neurotransmitter, histamine, has several similarities to

these monoamines. Although these compounds are present in very small
amounts in the CNS, they can be localized using extremely sensitive
histochemical methods.

These pathways are the site of action of many drugs; for example, the
CNS stimulants cocaine and amphetamine appear to act primarily at
catecholamine synapses. Cocaine blocks the reuptake of dopamine and
norepinephrine, whereas amphetamines cause presynaptic terminals to
release these transmitters.
 DOPAMINE
Dopamine exerts slow inhibitory actions
Five dopamine receptors have been
at synapses in specific neuronal
identified, and they fall into two
systems, commonly via G protein-
categories: D1-like (D1 and D5) and D2-
coupled activation of potassium
like (D2, D3, D4). All dopamine
channels (postsynaptic) or inhibition of
receptors are metabotropic.
calcium channels (presynaptic).

The D2 receptor is the main dopamine

Dopaminergic pathways include the
subtype in basal ganglia neurons, and it
nigrostriatal, mesolimbic, and
is widely distributed at the supraspinal
tuberoinfundibular tracts.
level.

Drugs that block the activity of

Drugs that increase brain dopaminergic
dopaminergic pathways include older
activity include CNS stimulants (eg,
antipsychotics (eg, chlorpromazine,
amphetamine), and commonly used
haloperidol), which may cause
antiparkinsonism drugs (eg, levodopa).
parkinsonian symptoms.
 NOREPINEPHRINE
• Most noradrenergic neurons are located in the locus coeruleus or the lateral
tegmental area of the reticular formation.
• All noradrenergic receptor subtypes are metabotropic. When applied to neurons,
norepinephrine can hyperpolarize them by increasing potassium conductance.
• Depending on the type of neuron, this effect is mediated by either α1 or β
receptors.
• Excitatory effects are produced by activation of α1 and β1 receptors. Inhibitory
effects are caused by activation of α2 and β2 receptors.
• Involve in attention and arousal.
• CNS stimulants (eg, amphetamines [used in attention deficit hyperactivity
disorder, ADHD], cocaine), monoamine oxidase inhibitors (eg, phenelzine), and
tricyclic antidepressants (eg, amitriptyline) are examples of drugs that enhance the
activity of noradrenergic pathways.
 SEROTONIN
Most serotonin (5-hydroxytryptamine; 5-HT) pathways originate from cell bodies in the
raphe or midline regions of the pons and upper brain stem; these pathways innervate
most regions of the CNS.

In most areas of the CNS, 5-HT has a strong inhibitory action.

Multiple 5-HT receptor subtypes have been identified and, with the exception
of the 5-HT3 subtype, all are metabotropic.

Both excitatory and inhibitory actions can occur on the same

neuron if appropriate receptors are present.
 SEROTONIN

5-HT has been implicated in the regulation of virtually all brain

functions, including perception, mood, anxiety, pain, sleep,
appetite, temperature, neuroendocrine control, and aggression.

Most of the agents used in the treatment of major depressive disorders affect
serotonergic pathways to some degree (eg, tricyclic antidepressants, selective
serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors).

The actions of some CNS stimulants and newer antipsychotic drugs (eg, olanzapine)
also appear to be mediated via effects on serotonergic transmission. Reserpine,
which may cause severe depression of mood, depletes vesicular stores of both
serotonin and norepinephrine in CNS neurons.
 PEPTIDE TRANSMITTERS
Peptide transmitters differ from nonpeptide transmitters : (1) the
peptides are synthesized in the cell body and transported to the nerve
ending via axonal transport, and (2) no reuptake or specific enzyme
mechanisms have been identified for terminating their actions.

Opioid peptides (beta-endorphin, met- and leu-enkephalin, and

dynorphin), which are distributed at all levels of the neuraxis. Opioid
analgesics (eg, morphine) are mediated via activation of receptors for
these endogenous peptides.

Another peptide, substance P, is a mediator of slow EPSPs in neurons

involved in nociceptive sensory pathways in the spinal cord and brain
stem.
 PEPTIDE TRANSMITTERS
• Orexins are peptides associated with sleep-wake cycling and promote
wakefulness.
• Orexin neurons also release glutamate and are thus excitatory.
• The orexin system, like the monoamine systems, projects widely
throughout the CNS to influence physiology and behavior.
• Orexin neurons exhibit firing patterns associated with wakefulness and
project to and activate monoamine and acetylcholine neurons involved in
sleep-wake cycles.
• Animals lacking orexin or its receptors have narcolepsy and disrupted sleep-
wake patterns. In addition to promoting wakefulness, the orexin system is
involved in energy homeostasis, feeding behaviors, autonomic function, and
reward
OTHER TRANSMITTERS
 HISTAMINE
• Histamine receptors are widely distributed in the brain and appear to modulate
arousal, attention, feeding behavior / appetite, and memory.
• In the CNS, histamine is exclusively made by neurons in the tuberomammillary
nucleus (TMN) in the posterior hypothalamus.
• There are four histamine receptors (H1 to H4), all of which are metabotropic.
• Centrally acting antihistamines have significant sedative and anti-motion
sickness effects.
• Antagonism of H1 receptors is a common side effect of many drugs including
some tricyclic antidepressants and antipsychotics.
 NITRIC OXIDE
• The CNS contains a substantial amount of nitric oxide synthase (NOS)
within certain classes of neurons.
• This neuronal NOS is an enzyme activated by calcium-calmodulin, and
activation of NMDA receptors, which increases intracellular calcium, results
in the generation of nitric oxide.
• Although a physiologic role for nitric oxide has been clearly established for
vascular smooth muscle, its role in synaptic transmission and synaptic
plasticity remains controversial. Perhaps the strongest case for a role of
nitric oxide in neuronal signaling in the CNS is for long-term depression of
synaptic transmission in the cerebellum.
REFERENCES