1. CNS Pharmacology Dr. Hiwa K. Saaed,
Department of Pharmacology & Toxicology
College of Pharmacy
University of Sulaimani

2. CNS Pharmacology
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 agents are invaluable therapeutically, e.g., without general anesthetics, modern surgery would be impossible.
Drugs that affect the CNS can:
selectively relieve pain, reduce fever,
suppress disordered movement,
induce sleep or arousal, reduce appetite, and allay the tendency to vomit.
treat anxiety, depression, mania, or schizophrenia

3. CNS Pharmacology
In addition to their use in therapy, many drugs acting on the CNS are used without prescription to increase one's sense of well-being.
However, the excessive use of such drugs can affect lives adversely?!
when their uncontrolled, compulsive use leads to:
physical dependence on the drug
toxic side effects, including lethal overdosage.

4. Ion channels in the brain
are of two major types: Voltage & Ligand gated
Voltage gated: regulated by changes in membrane potential.
axonal Na+ channels involved in propagation of action potentials
Presynaptic Ca+2 channels that play a critical role in the release of neurotransmitters from synaptic vesicles.

5. Ion channels in the brain
II. Ligand (transmitter) gated:
Such receptors may be:
directly linked to ion channels
Indirectly by change ion channel function via second messenger system.
Membrane delimited metabotropic ion channel Gprotein
& diffusible 2nd messenger metabotropic ion channel cAMP, IP3, DAG

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7. Molecular Targets for CNS Drugs

9. Molecular Targets (sites) for CNS Drugs
I. Ion channels on axons: A SMALL no. of CNS drugs exert their effects through direct interactions with molecular components of ion channels on axons; examples
i) certain anticonvulsant e.g., carbamazepine and phenytoin,
ii) Local anesthesia (LA) and some general anesthesia (GA).

10. Molecular Targets (sites) for CNS Drugs
II. Synapse: The effects of MOST therapeutically important CNS drugs are exerted mainly at synapse; possible mechanisms are:
A. Presynaptically: drugs act presynaptically to alter the synthesis, storage, release, reuptake, or metabolism of transmitter chemicals.
B. Pre-post synaptic receptors: Other drugs- activate or block of pre-post synaptic receptors

11. Molecular Targets (sites) for CNS Drugs

12. Ion channels:
Role of the ion current carried by the channel
↑Na+ or ↑ Ca+2 influx or ↓K+ efflux → excitation via membrane depolarization (EPSP)
↑Cl- or ↓ Ca+2 influx or ↑ K+ efflux → inhibition via membrane hyperpolarization (IPSP)

13. ion current carried by potential; EPSP & IPSP
Excitatory postsynaptic potential (EPSP):
a depolarizing potential change,
i) are usually generated by the opening of Na+ or Ca+2.
ii) In some synapses similar depolarizing potentials result from the closing of K+ channels

14. ion current carried by potential:
II. Inhibitory postsynaptic potential (IPSP):
a hyperpolarizing potential change,
i) are usually generated by the opening of K+, or Cl- channels;
e.g., Activation of postsynaptic metabotropic receptor ↑ the efflux of K+.
ii) Presynaptic inhibition can occur via a ↓ Ca+2 influx elicited by activation of metabotropic receptors.

15. Neurotransmitters Ach Monoamines: Dopamine, NE, 5-HT
Amino acid neurotransmitters
Excitatory: Glutamate, Aspartate (learning and memory)
Inhibitory: GABA, Glycine
Peptides: opioids (enkephalins, endorphins), substance-P, nociception; hunger, metabolism
Endocanabinoids: the drug Anandamide CB1 ligand; memory, cognition and pain perception

16. Drugs and molecular targets in the CNS
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17. CNS Transmitters and receptors
Ach:
M1 excitatory (↓K+ efflux, via DAG),
M2 inhibitory (↑K+ efflux, via cAMP)
N excitatory (Na+ influx, direct coupling);
activities of above receptors modified by:
nicotine,
AchE inhibitors (tacrine) in Alzheimer’s,
M blockers (benzotropine) in Parkinson’s.

18. Dopamine Inhibitory, via GPCR activation of K+ channel,
multiple subtypes (D1, D2, D3, D4, D5)- G-protein linked to cAMP;
activities ↑ by CNS stimulants (e.g., amphetamine) and antiparkinson drugs (e.g., levodopa),
activities ↓ by antipsychotics (e.g., chlorpromazine).

19. Dopamine
D2 receptor is the main dopamine subtype in basal ganglia neurons and its widely distributed at the supraspinal level.
Dopaminergic pathways:
Nigrostriatal,
mesolimbic,
tuberoinfundibular tracts

20. Norepinephrine
Excitatory or inhibitory, depending on receptor subtype (second messenger coupling):
Excitatory effects: α1 and β1 receptors
Inhibitory effects: α2 and β2 receptors
Activities enhanced by:
CNS stimulants,
antidepressants,
MAO inhibitors
and some anxiolytics

21. Serotonin (5-HT):
Serotonin is inhibitory at MANY CNS site but can cause excitation of SOME neurons depending on the receptor subtype activity.
All are metabotropic except 5-HT3 subtype (ionotropic),
Activities modified by:
CNS stimulants,
antidepressants,
some anxiolytics.

22. Glutamate
Most neurons in the brain are excited by glutamic acid via influx of cations (direct coupling and G- protein linked).
NMDA (N-methyl D-aspartate)
AMPA: α-amino-3-hydroxy-5-methylisoxazole-4- propionic acid
Kainate
ACPD: Metabotropic receptor
Ionotropic

23. Glutaminergic pathway
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24. Glutamate
NMDA mediate slow excitatory responses and also play a role in synaptic plasticity related to learning and memory.
NMDA is blocked by phencyclidine and ketamine (dissociative anesthesia).
Memantine is an NMDA antagonist RX Alzheimer, dementia.
AMPA and Kinate are involved in Fast excitatory transmission

25. GABA and Glycine
GABA is the primary neurotransmitter mediating fast IPSP in neurons in brains, it is also important in spinal cord.
GABAA activation opens chloride channel
drugs: sedative hypnotics; barbiturates and benzodiazepine, some anticonvulsants; gabapentin, vigabatrin)

26. GABA & GLYCINE
GABAB; GPCR either open K+ channel or close Ca+2 channel Slow IPSP (Drug: Baclofen)
Glycine: More numerous in the cord than in the brain. Blocked by strychnine, a spinal convulsant

27. GABAA Receptor Complex
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Talking Points
Similar to other nonbenzodiazepine hypnotics (Ambien=Zolpidem and Sonata=Zaleplon), LUNESTA (eszopiclone) is believed to exert its hypnotic effects through its interaction with pentameric GABA-A receptor complexes.
GABA is the major inhibitory neurotransmitter of the mammalian Central Nervous System (40% of Central Nervous System neurons are estimated to be gabaergic) and is thought to play the pivotal role within the sleep inducing and maintenance systems.
GABA-A receptors are heterogeneous, i.e. comprised of different subtypes, largely based on the alpha unit (-1, -2,… - -6)
Different subtypes are located in different anatomical locations of the Central Nervous System and are involved in different unique neurophysiologic functions.
Currently available nonbenzodiazepines are alpha-1 super-selective. They produce sedation, but may also produce amnesia in some patients because alpha-1 subtype receptors are so widely distributed throughout the brain and are not specific to the Central Nervous System sleep/wake systems.
LUNESTA (eszopiclone) is believed to have unique, balanced activity at a-1 and a-3 GABA-A receptor subtypes. Alpha-3 subtypes are associated with brainstem arousal nuclei and are considered instrumental in mediating the inhibitory “off-signal” from the hypothalamic sleep control center projection neurons. This highly specific off-signal is the key event allowing for sleep onset and maintenance to proceed. The alpha-3 activity may allow LUNESTA (eszopiclone) to mediate sleep without amnesia by facilitating control of the hypothalamic sleep “on-switch.” The clinical significance of this pre-clinical data continues to be investigated.
BZD binding
GABA

28. Peptide transmitters present in higher concentration in the synaptic,
Many peptide have been identified in the CNS and some meet most or all of the criteria for acceptance as neurotransmitter:
present in higher concentration in the synaptic,
Released by electrical or chemical stimulation via Ca+2 dependent mechanism,
produce the same sort of postsynaptic response that is seen with physiologic activation of the synapse.

29. Peptide transmitters Opioid Peptides & Substance-P
The best defined peptides are:
opioid peptides; β-endorphin,
met-& leo-enkephalin &dynorphin
Drugs: Opioid analgesics (morphine)
Substance-P mediator of slow EPSPs-nociceptive sensory pathways in the spinal cord and brain stem

30. Endocannabinoids
These are brain lipid derivatives (e.g., 2- arachidonyl glycerol) Bind to cannabinoids** receptors
They are synthesized and release post synaptically after membrane depolarization
But travel backward acting presynaptically (retrograde) to decrease transmitter release
**cannabinoids found in marijuana