Pengantar OBAT SUSUNAN SARAF PUSAT

Noor Wijayahadi

Neurons and Synapses

Tipe Neuron

Sensoris Motoris Interneuron

SpinalCord

BrainSensoryNeuron

Neuron Sensoris• INPUT dari organ sensoris ke otak dan medula spinalis

Drawing shows a somatosensory neuron

Vision, hearing, taste and smell nerves are cranial, not spinal

SpinalCord

BrainSensoryNeuron

MotorNeuron

Neuron Motoris

• OUTPUT Dari otak dan Medula Spinalis ke otot dan kelenjar

SpinalCord

BrainSensoryNeuron

MotorNeuron

Interneuron• Membawa informasi antar neuron

• Terdapat di otak & Medula spinalis

Ion concentrations

Cell Membrane in resting state

K+

Na+ Cl-K+A-

Outside of Cell

Inside of Cell

Na+ Cl-

Membran Sell Semi-Permeable

Cell Membrane at rest

Na+ Cl-K+

Na+

Cl-K+ A-

Outside of Cell

Inside of Cell

Potassium (K+) bisa menembus membran seimbangkan konsentrasi

Sodium (Na+) & Klorida (Cl-) tidak bisa menembus

Hasil tegangan dalam sel relatif lebih negatif

- 70 mv

Bagaimana neuron otak berkomunikasi ?

Where ? SynapsesHow ? Neurotransmitters

Transporter

Jenis Neurotransmiter: 1. Amine - Acetylcholine 2. Monoamines: a. Catecholamines – Norepinephrine and Dopamine

b. Indoleamines – Serotonin3. Amino Acids – Glutamate, GABA, Glycine4. Peptides – VIP and PACAP

+ + + - - - + - - + + + + AP

++ AP-

Synapse

• Ujung axon berisi kantong NT

vesikel sinaps

SendingNeuron

SynapseAxon

Terminal

• Jenis Sinaps 1. Elektrik

2. Kemikal

Chemical v/s Electrical SynapsesElectrical Synapses

Rapid bidirectional transmission

Gap junctions

Ion current

Electrotonic transmission

Cytoplasmic continuity

Chemical SynapsesSlow unidirectional transmission

Presynaptic vesicles, active zones, postsynaptic receptors

Chemical neurotransmitters

Complex amplifying excitatory/ inhibitory signals

Synaptic cleft

Chemical Synapses• Transmission

• presynaptic

• Active zones

• Reception

•postsynaptic

Neurotransmitters• Kriteria

1. Tersedia di presynap

2. Dilepaskan bila presynap depolarisasi dan bersifat Ca2+-dependent

3. Reseptor Specific terdapat di postsynap

Beda Neurotransmitter dengan Hormon?

Neurotransmitter HormoneProximity of action

* released adjacent to target cell

* travels 20-30 nanometers

Effects are transient

Distant action

* carried through blood

* travel nanometers to meters

Long-lasting effects

• Similarities both packed into vesicles, both expelled through cells by exocytosis, both bind to specific receptors, both depolarize target membrane

Excitatory vs Inhibitory Synapses• Type I

•Excitatory•Glutamatergic•Contact dendritic spines•Large active zone

• Type II•Inhibitory•GABA-ergic•Contact cell bodies•Small active zones

Glutamate• Principle excitatory neurotransmitter in CNS• Too much glutamate excitotoxicity

– Excessive Ca2+ entry through receptors– Stroke, degenerative disease

• Two types of glutamate receptors:1. Ionotropic

2. Metabotropic

• Involved in learning & memory

GABA• Major inhibitory neurotransmitter in CNS

– Hyperpolarizes postsynaptic membrane

• Two types of GABA Receptors:– GABA-A

• Cl- channel binding Cl- conductance in presynaptic neurons

• “fast” response (1msec)• Benzodiazepines, barbiturates

– GABA-B• G-protein coupled receptor• K+ conductance• “slow” response (1sec)

Dopamine• A Nigrostrial pathway

– Controls movement

• B Mesolimbic pathway

- “pleasure pathway”

• C Mesocortical pathway

- Learning & memory

- Interacts with mesolimbic pathway to mediate euphoric effects of drugs of abuse

• D Tuberoinfundibular pathway

- Controls release of prolactin

Serotonin Receptors• 5-HT1A CNS: neuronal inhibition, behavioral effects (sleep, feeding,

thermoregulation, anxiety)

• 5-HT1B CNS: presynaptic inhibition, behavioral effects; vascular: pulmonary vasoconstriction ergotamine

• 5-HT1D CNS: locomotion; vascular: cerebral vasoconstriction

• 5-HT2A CNS: neuronal excitation, behavioral effects; smooth muscle: contraction, vasoconstriction / dilatation; platelets: aggregation α-methyl-5-HT

• 5-HT2B stomach: contraction α-methyl-5-HT

• 5-HT2C CNS, choroid plexus: (CSF) secretion α-methyl-5-HT, LSD

• 5-HT3 CNS, PNS: neuronal excitation, anxiety, emesis

• 5-HT4 GIT, CNS: neuronal excitation, gastrointestinal motility

• 5-Ht5 CNS: unknown

• 5-Ht6 CNS: unknown

• 5-HT7 CNS, GIT, blood vessels: unknown

Glycine• Inhibitory neurotransmitter

– makes the post-synaptic membrane more permeable to Cl- hyperpolarizes the membrane

– glycine receptor is primarily found in the ventral spinal cord

• Strychnine

• glycine antagonist which can bind to the receptor without opening the Cl-channel

• (i.e. it inhibits inhibition)

• spinal hyperexcitability

Obat Neurofarmakologis

2 Kategori

• Obat Susunan Saraf Tepi

(Peripheral nervous system drugs)

• Obat Susunan Saraf Pusat

(Central nervous system drugs)

Mekanisme Dasar Obat Neuropharmacologis

1. Menyerupai kerja normal neurotransmitters2. Hambat / Block kerja normal zat kimia tubuh3. Modifikasi kerja sistem tubuh:

• Skeletal muscles• Cardiac muscle and output of blood• Vascular tone• Respiration• Gastric function• Uterine motility• Glandular secretion• CNS functions (heat, pain, mood, etc…)

• Neuron Function:– Neuron, synapse, response organ

• Reflex arc:– Sensory neuron, synapse, CNS, synapse, motor neuron

• Response through brain:– Sensory neuron, synapse, CNS spinal ganglia, brain,

spinal ganglia, motor neuron

Mekanisme Dasar Obat Neuropharmacologis

How Neuron Regulate Physiologic Processes

• 3 major steps in neuron action:1. Conduction of action potential

2. Release of neurotransmitter from axon

3. Binding of transmitter molecules to receptors on post-synaptic cell

Receptors could be:

Neuron

Muscle

Glandular cell

• Most neuropharmacologic agents act at synapse transmission level

• Axonal conduction NOT a common site of action

– (local anesthetics decrease axonal conduction)

• Synaptic transmission site more selective– (drugs elicit selective response)

Synaptic TransmissionFive steps in synaptic transmission are1. Synthesis of transmitter molecules2. Storage of transmitter molecules in the

vesicles3. Release of transmitter molecules by action

potential into synaptic gap4. Receptor binding (reversible)5. Termination by release of transmitter from

receptor and synaptic gap (by reuptake, enzymatic degradation, and diffusion)

Figure 12-2: Steps in Synaptic Transmission

Effects of Drugs

Drugs can

1. Enhance receptor activation• May increase effect by increasing release

– NE increases heart rate when receptors are activated

• May activate receptor BUT decrease activity– Actylcholine decreases heart rate when receptors are

activated

• Increase number of receptor molecules

2. Reduce receptor activation• Decrease response by decreasing release• Down-regulating receptor number

Effects of Drugs

1. Transmitter synthesis• Increase• Decrease• Cause synthesis of transmitter type that is more

effective than natural transmitter (higher affinity for receptor)

2. Interference with transmitter storage• Can increase storage or decrease storage in vesicles

Effects of Drugs3. Transmitter release

Promote or inhibit release– Amphetamines (CNS stimulant) increase transmitter

release– Botulinus toxin inhibits transmitter release

4. Receptor binding• Enhancement of binding (agonists)- synergism of

action- both bind to receptor• Blocking binding (antagonists)- blockage of

receptor or lowering of affinity of receptor for transmitter

4. Receptor Binding (contd…)

Neuropharmacologic drugs that act directly to the receptors can bind and• Cause activation (agonist)

– Morphine (CNS), epinephrin (cardiovasuclar system), insulin (diabetes)

• Prevent activation (antagonist)– Naloxone (overdose of morphine), antihistamine

(allergic disorder), promanol ( hypertension, angina, dysrythmiasis)

• Enhance activation (of natural transmitter) (no specific term)

– Diazepam (anxiety, seizure, muscle spasm)

Effects of Drugs

5. Termination of transmitter action– Blockade of transmitter reuptake

• increase concentration of transmitter

– Inhibition of transmitter degradation• Increase concentration of transmitter

Step in synaptic transmission

Drug action Impact on receptor activation

Synthesis of transmitter

Increased

Decreased

Synthesis of super transmitter

Increase

Decrease

Increase

Storage of transmitters Increased storage

Reduced storage

Increase

Decrease

Release of transmitters Promotion

Inhibition

Increase

Decrease

Binding to receptors Direct receptor stimulation

Mimic

Block

Increase

Increase

Decrease

Termination of transmitters

Blockade of reuptake

Prevention of breakdown

Increase

Increase

Drug Action on Synaptic Transmission

Red = Antagonist Blue = Agonists drug