MT6314 INTRO TO CNS DRUGS Flashcards
CNS DRUGS are among the most important tools for?
studying all aspects of CNS physiology.
Nearly ALL drugs with CNS effects act on?
specific receptors that modulates transmission
Unraveling the actions of drugs with known clinical efficacy led to what?
the hypotheses regarding the mechanism of disease.
Electrically excitable cell (via electrochemical process)
Neuron
Macrophages from bone marrow
Microglia
Limits penetration of substances
BBB
Found on the neuron for insulation
Myelin sheath
Wraps around the axons
Oligodendrocytes
Cell body is also known as?
Soma
Where the synaptic responses are integrated with high concentration of voltage gated sodium channels
Axon initial segment
Highly branched complex “trees”
Dendrites
Most drugs act on the CNS by?
changing ion flow through transmembrane channels of nerve cells
Two types of channels defined on the basis of the mechanism controlling their gating (Opening & closing)
Voltage Gated Channels
Ligand Gated Channels
VOLTAGE OR LIGAND: Respond to changes in membrane potential
VOLTAGE
VOLTAGE GATED ION CHANNELS are concentrated where?
INITIAL SEGMENT of the axons in nerve cells
VOLTAGE OR LIGAND: Responsible for fast action potentials
VOLTAGE
In voltage gated ion channels what channels are responsible for action potential propagation?
Sodium channels
What other parts of the neuron have voltage-sensitive ion channels for what specific elements?
Cell bodies and dendrites
potassium and calcium
What are the 2 CLASSES OF NEUROTRANSMITTER RECEPTORS?
- LIGAND-GATED ION CHANNELS OR IONOTROPIC RECEPTOS
- METABOTROPIC RECEPTORS
Types of Metabotropic receptors?
Diffusible Second Messenger Mediated Regulation
Membrane-delimited Regulation
METABOTROPIC OR LIGAND: Chemically-gated
LIGAND
What do ligand ion channels respond to?
Respond to chemical neurotransmitters (NTAs) that bind to receptor subunits of the channel
T or F: Ligand gated ion channels are sensitive to the membrane potentials
F, weakly sensitive
How many GPCRs?
7
T or F: In Metabotropic Receptors, binding results in the direct gating of a channel
F, does NOT result
Metabotropic receptors: If there is binding, what does it result to?
Binding engages the G-protein that results into production of SECOND messengers that modulates the voltage gated channels
Membrane delimited pathways mainly target what channels?
Calcium and Potassium
METABOTROPIC (Ca or K channel): Slow inhibition in postsynaptic
K
METABOTROPIC (Ca or K channel): inhibited when metabotropic is activated in post synaptic
Ca
Types of receptor channel coupling in LIGAND
GATED ion channels activation and inactivation?
- A receptor that acts directly on the channel protein
- A receptor that is coupled to the ion channel
through a G protein - A receptor coupled to a G protein that modulates
the formation of diffusible second messengers (cAMP, IP3, DAG)
ROLE OF THE ION CURRENT CARRIED BY
THE CHANNEL?
Synapse
EPSPs
IPSPs
EPSP or IPSP:
Generated by
* Opening of sodium or calcium channels
* Closing of potassium channels in some synapses
EPSP
EPSP or IPSP: Depolarizing
EPSP
EPSP or IPSP: high Na, low K
EPSP
EPSP or IPSP: Hyperpolarizing
IPSP
EPSP or IPSP: high Ca2+
EPSP
EPSP or IPSP: Generated by opening of potassium or chloride channels
IPSP
EPSP or IPSP: high K+ and Cl-
IPSP
EPSP or IPSP: low Ca2+ at presynaptic
IPSP
Some drugs exert their effect through?
direct interactions with molecular components of ion channels on axons
Examples of some drugs exert their effect through
direct interactions with molecular components of ion channels on axons?
- Carbamazepine
- Phenytoin
- Local anesthetics and some drugs used for general
anesthesia
Most drugs exert their effect mainly where?
at the synapses
Drugs may act presynaptically to alter?
- Synthesis
- Storage
- Release
- Reuptake
- Metabolism of transmitter chemicals
What interferes with the action of second messengers?
Pre- and postsynaptic receptors for specific transmitters
Inhibits storage of cathecolamines
Reserpine
Inhibits synthesis of serotonin
Parachlorophenylalanine
Depletes monoamine synapses of transmitters by interfering with intracellular storage
Reserpine
Inhibits degradation of Acetylcholine
Anticholinesterase
Inhibits release of catecholamines
Amphetamine
2 TYPES OF NEURONAL SYSTEM IN CNS?
HIERARCHAL
NON-SPECIFIC/DIFFUSION
HIERARCHAL or NON-SPECIFIC: Contain large myelinated, rapidly conducting fibers
Hierarchal
HIERARCHAL or NON-SPECIFIC: Broadly distributed, with single cells frequently sending processes to many different parts of the brain
NON-SPECIFIC
HIERARCHAL or NON-SPECIFIC: Tangential organization
NON-SPECIFIC
Major excitatory transmitters of hierarchal system?
- Aspartate
- Glutamate
Small inhibitory interneurons transmitters in hierarchal system?
- Gamma amino butyric acid (GABA)
- Glycine
Periodic enlargements that contain transmitter vesicles
Varicosities
Where are varicosities located?
axons
Types of transmitters in Non-specific neuronal system?
- Noradrenergic Amines (NE, dopamine and serotonin)
- Peptides that act on metabotropic receptors
What part of the brain are the transmitters usually seen in a non-specific neuronal system?
compact cell group called locus caeruleus in the caudal pontine central gray matter
Marked effects on CNS functions of non-specific neuronal system?
- Attention
- Appetite
- Emotional states
CRITERIA FOR TRANSMITTER STATUS?
- Present in higher concentration in the synaptic area than in other areas (localized in appropriate areas)
- Released by electrical or chemical stimulation via a calcium-dependent mechanism
- Synaptic mimicry
* Produce the same sort of postsynaptic
response that is seen with physiologic
activation of the synapse
CHEMICALS ACCEPTED AS NTAs IN THE CNS
Acetylcholine
Dopamine
Norepinephrine
Opioid Peptides
GABA and Glycine
Glutamic Acid
Serotonin
Glycine is more numerous in the _____
cord
Glycine is inhibitory or excitatory?
Inhibitory
Increases Cl- conductance
Glycine
GABAa activation
Excitatory for most neurons
Glutamic Acid
Excitatory effects
* Activation of α1 and β1 receptors
Norepinephrine
Multiple 5 hydroxytryptamine (5-HT) receptor subtypes
Serotonin
G protein-coupled activation of K+ channels
Dopamine
D2 receptor is the main subtype of?
Dopamine
Beta-endorphins, dynorphins
Opioid Peptides
Inhibitory in pre and post synaptic
Opioid Peptides
Decrease Ca+2 conductance
Pre Opioid
Increase K+ conductance
Post Opioid
Metabotropic NTA
Serotonin
Inhibitory actions at synapses in specific neuronal systems
Dopamine
5% of neurons have receptors for this
Ach
Slow excitation
Ach
Inhibitory effects
* Activation of α2 and β2 receptors
* Increase K+ conductance
Norepinephrine
Inhibition of adenyl cyclase
Glutamic Acid
N-methyl-D-aspartate (NMDA) receptor for learning and memory
Glutamic Acid
GABA is the primary NTA mediating?
IPSPs
GABAa or GABAb: Opens Cl- conductance
A
GABAa or GABAb: Opens K+ channels
B
GABAa or GABAb: Closes Ca+2 channels
B
GABAa or GABAb: Activated by baclofen
B
GABAa or GABAb: slow component
B
GABAa or GABAb: fast component
A
Pre or Post of Opioid: Decrease Ca+2 conductance
Pre
Pre or Post of Opioid: Increase K+ conductance
Post
Increase cAMP
Dopamine
Decrease permeability to potassium
Ach
Types of Sodium Channels?
Tetrodotoxin (TTX)
Batrachotoxin (BTX)
Types of Potassium Channels?
Apamin
Charybdotoxin
Types of Calcium channels?
Omega-conotoxin
Agatoxin
Types of Ligand-gated channels?
Nicotinic ACh receptor (a-Bungarotoxin)
AMPA receptor (Philanthotoxin)
GABAa receptor (Picrotoxin)
Glycine receptor (Strychnine)
Blocks channel from the outside
TTX
Slows inactivation or shifts activation
BTX
Blocks small Calcium activated K channels
Apamin
Blocks large Calcium activated K channels
Charybdotoxin
Irreversible antagonist
Nicotine ACh receptor - a-Bungarotoxin
Blocks the channel
GABAa receptor - Picrotoxin
AMPA receptor - Philanthotoxin
Competitive antagonist
Glycine receptor - Strychnine
Receptor subtypes and corresponding agonists of ACh?
M1 (muscarine), M2 (muscarine and bethanechol), Nicotinic (nicotine)
Receptor subtypes and corresponding agonists of dopamine?
D1 (dihydrexidine) and D2 (bromocriptine)
Receptor subtypes and corresponding agonists of GABA?
GABAa (muscimol) and GABAb (baclofen)
Receptor subtypes and corresponding agonists of glutamate?
NMDA (NMDA), AMPA (AMPA), Kainate (kainic acid and domoic acid), metabotropic (ACPD, quisqualate)
Receptor subtypes and corresponding agonists of glycine?
Taurine and b-alanine
Receptor subtypes and corresponding agonists of serotonin?
5-HT1A - eptapirone
5-HT2A - LSD
5-HT3 - 2-methyl-5-HT
5-HT4 - Cisapride
Receptor subtypes and corresponding agonists of NE?
a1 - phenylephrine
a2 - clonidine
b1 - isoproterenol, dobutamine
b2 - albuterol
Receptor subtypes and corresponding agonists of histamine?
H1 (2-histamine), H2 (dimaprit), H3 (R-a-methyl-histamine)
Receptor subtypes and corresponding agonists of opioid peptides?
Mu - bendorphin
Delta - enkephalin
Kappa - dynorphin, salvinorin A
Receptor subtypes and corresponding agonists of orexins?
OX1 (orexin A), OX2 (orexin A and B)
Receptor subtypes and corresponding agonists of tachykins?
NK1: substance P methyl ester
NK2: neurokinin A
NK3: neurokinin B
Receptor subtypes and corresponding agonists of endocannabinoids?
CB1: anandamide, 2-arachidonyglycerol
Receptor antagonist for opioid peptides?
Naltrexone
Receptor antagonist for orexins?
Suvorexant
Receptor antagonist for tachykinins?
NK1: aprepitant
NK2: saredutant
NK3: Osanetant
Receptor antagonist for endocannabinoids?
Rimonabant
Receptor antagonist for M1?
Pirenzepine and atropine
Receptor antagonist for M2?
Atropine, methoctramine
Receptor antagonist for nicotine?
dihydro-b-erythroidine
a-bungarotoxin
Receptor antagonist for D1?
phenothiazines
Receptor antagonist for D2?
Phenothiazines, butryophenones
Receptor antagonist for GABAa?
bicuculline
picrotoxin
Receptor antagonist for GABAb?
2-OH-saclofen
Receptor antagonist for NMDA?
2-amino-5-phosphonovalerate
dizocilpine
Receptor antagonist for AMPA?
NBQX
Receptor antagonist for Kainate?
ACET
Receptor antagonist for metabotropic?
MCPG
Receptor antagonist for glycine?
Strychnine
Receptor antagonist for 5-HT1A?
Metergoline, spiperone
Receptor antagonist for 5-HT2A?
Ketanserin
Receptor antagonist for 5-HT3?
Ondansetron
Receptor antagonist for 5-HT4?
Piboserod
Receptor antagonist for a1 NE?
Prazosin
Receptor antagonist for a2 NE?
Yohimbine
Receptor antagonist for b1 NE?
Atenolol, Practolol
Receptor antagonist for b2 NE?
Butoxamine
Receptor antagonist for H1 histamine?
Mepyramine
Receptor antagonist for H2 histamine?
Ranitidine
Receptor antagonist for H3 histamine?
Thioperamide
Excitatory action in ACh
Lower K, higher IP3, DAG and cation
Inhibitory action in ACh
Higher K, lower cAMP
Inhibitory action pre and post synaptically in dopamine
Pre - lower Ca
Post - higher K, lower cAMP
Inhibitory action in GABA pre and post synaptic
Pre - lower Ca
Post - higher K
Excitatory action in glutamate for NMDA, AMPA, Kainate
Higher cation conductance
Inhibitory action in Metabotropic receptors in glutamate
Lower Ca, cAMP, K
Higher IP3 and DAG
Inhibitory action in glycine
Higher Cl
Inhibitory and excitatory action in 5-HT
Inhibitory - higher K, lower cAMP
Excitatory - lower K, higher IP3/DAG/Cation
Excitatory in NE
lower K, higher IP3/DAG/cAMP
Inhibitory in NE
lower Ca/cAMP, higher K
What NE receptors includes high cAMP for inhibition in the pre synaptic membrane?
B2
Excitatory Histamine action
Higher IP3, DAG, cAMP
Tachkinins excitatory
lower K, higher IP3 and DAG