Central Nervous System (CNS) Pharmacology

Introduction

Hiwa K. Saaed, PhDDepartment of Pharmacology & Toxicology,

College of Pharmacy, University of Sulaimani

Lecture one

Pharmacology III, 4th Year 2021-2022

TARGETS OF CNS DRUG ACTION:

u Drugs acting in the CNS were among the first to be discovered by primitive humans and are still the most widely prescribeddrugs in current use to treat a broad range of neurologic and psychiatric conditions, pain, fever, and nausea.

u In addition, many CNS-acting drugs are used without prescription to increase the sense of well-being.

u Most CNS drugs act by changing ion flow through transmembrane channels of nerve cells.

u Transmitter reuptake transporters constitute a second class of drug targets, especially for antidepressant agents.

u Inhibition of acetylcholine metabolism is the major action of the drugs currently approved for use in Alzheimer’s disease

u GABA metabolism is inhibited by an anticonvulsant agent.

2

ION CHANNELS & NEUROTRANSMITTER RECEPTORS

Two major types of Ion Channels in the brain:

u Voltage gated: regulated by changes in membrane potential.§ Axonal Na+ channels (action potential propagation) § Presynaptic Ca+2 (neurotransmitter release)

u Ligand (transmitter) gated: § Directly linked to ion channels § or Indirectly via 2nd messenger system linked to ion

channel.• Membrane bound metabotropic ion channel G protein. • Diffusible 2nd messenger metabotropic ion channel

cAMP, IP3, DAG.

3

4ION CHANNELS & NEUROTRANSMITTER RECEPTORS

from Katzung BG, editor: Basic & Clinical Pharmacology, 14th ed. McGraw-Hill, 2018: Fig. 21–2.

(A) a voltage sensor component of the protein controls the gating (broken arrow) of the channel.

(B) the neurotransmitter to the ionotropic channel receptor controls the gating (broken arrow) of the channel.

(C) shows a GPCR (metabotropic), which, when bound, activates a heterotrimeric G protein.

(D) shows the activated G protein can interact directly to modulate an ion channel

e,g, cAMP, which can interact with the ion channel or can activate a kinase that phosphorylates and modulates a channel.

(E) shows the G protein can activate an enzyme that generates a diffusible second messenger

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

u certain anticonvulsant: carbamazepine and phenytoin

u All Local anesthesia (LA)

u and some general anesthesia (GA).

5

Molecular Targets (sites) for CNS Drugs

II. Synapse:

The effects of MOST therapeutically important CNS drugs are exerted mainly at synapse by modifying some step in chemical synaptic transmission; possible mechanisms are:

u Presynaptically:

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

u Pre-post synaptic receptors: Activate or block of pre, post synaptic receptors.

6

(site 6) Serotonin and norepinephrine transporters are the targets of antidepressants, while NET and the dopamine reuptake transporter are the targets of amphetamines and cocaine.

Drugs and molecular targets in the CNS19 O

ctober 2021

7

Role of the ion current carried by the channel

↑Na+ or ↑ Ca+2 influx or ↓K+ efflux → excitation via membrane depolarization (EPSP)

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

Excitation via membrane depolarization (EPSP)8

Example of an excitatory pathwayBinding of the Ach causes depolarization of the neuron.

Inhibition via membrane hyperpolarization (IPSP)

↑Cl- or ↓ Ca+2 influx or ↑ K+ efflux → inhibition via membrane hyperpolarisation (IPSP)

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.

9

an example of an inhibitory pathwayBinding of the GABA causes hyperpolarization of the neuron.

Neurotransmitters• Acetylcholine (Ach)• Monoamines: Dopamine, NE, 5-HT• Amino acid neurotransmitters

1. Excitatory: Glutamate, Aspartate (learning and memory)

2. Inhibitory: GABA, Glycine

• Peptides: § opioids (enkephalins, endorphins), § substance-P, nociception; hunger, metabolism

• Endocanabinoids: the drug Anandamide CB1 ligand; memory, cognition and pain perception

10

CNS Transmitters and receptorsAch: • M1 excitatory (↓K+ efflux, ↑ IP3 and DAG),• M2 inhibitory (↑K+ efflux, via cAMP)• N excitatory (Na+ influx, direct coupling)

activities of above receptors modified by: 1. nicotine, 2. AchE inhibitors (tacrine) in Alzheimer’s, 3. M blockers (benzotropine) in Parkinson’s.

Cholinergic pathway: Mainly interneurons throughout the cortexFunction: depend on the site, loss of cholinergic neurons in

• Cortex: Senile dementia/ Alzheimer• Lateral horn of spinal cord: (Amyotrophic lateral sclerosis) ALS• Striatum: degeneration of cholinergic & GABA –Huntington

11

Dopamine u Multiple subtypes (D1, D2, D3, D4, D5)-G-protein linked to

cAMP;

D2 receptor is the main dopamine subtype in basal ganglia neurons and its widely distributed at the supraspinal level.

u Inhibitory, via GPCR activation of potassium channels (postsynaptic) or inhibition of calcium channels (presynaptic).

u D2 Inhibitory (postsynaptic); ↑ K+ conductance; ↓ cAMP, u D2 Inhibitory (presynaptic); ↓ Ca2+ conductance

1. activities ↑ by CNS stimulants (e.g., amphetamine) and antiparkinson drugs (e.g., levodopa),

2. activities ↓ by antipsychotics (e.g., chlorpromazine).

Dopaminergic pathways: Nigrostriatal, mesolimbic, tuberoinfundibular tracts.

12

Norepinephrine

Excitatory or inhibitory, depending on receptor subtype (second messenger coupling):

1. Excitatory effects: α1 and β1 receptors 2. Inhibitory effects: α2 and β2 receptors Activities enhanced by:

• CNS stimulants, • antidepressants, • MAO inhibitors • and some anxiolytics

13

Serotonin (5-HT):

Serotonin is Inhibitory at MANY CNS site

Excitation of SOME neurons depending on the receptor subtype activity.

Serotonin receptors:

All are metabotropic EXCEPT 5-HT3 subtype (ionotropic)

Activities modified by:

u CNS stimulants,

u antidepressants,

u some anxiolytics.

14

5-HT2-vasoconstriction5-HT2B-vasodilation5-HT4- ↑GUT motility (Rx constipation in IBD)5-HT3 antagonist (ondansetron antiemetic caused by cytotoxic)

Most neurons in the brain are excited by glutamic acid via influx of cations (direct coupling and G-protein linked).

IONOTROPICu NMDA (N-methyl D-aspartate) mediate slow excitatory

responses, play a role in synaptic plasticity related to learning and memory.• is blocked by phencyclidine and ketamine (dissociative anesthesia).

• Memantine is an NMDA antagonist RX Alzheimer, dementia.

u AMPA: α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid

u Kainate

AMPA & kinate are involved in Fast excitatory transmissionMETABOTROPIC RECEPTOR u ACPD (1-Amino-1,3-dicarboxycyclopentane)

15Glutamate

GABA

is the primary neurotransmitter mediating fast IPSP in neurons in brains, it is also important in spinal cord.

u GABAA activation opens chloride channel

drugs: sedative hypnotics; barbiturates and benzodiazepine, some anticonvulsants; gabapentin, vigabatrin)

u 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.

16GABA and Glycine

Peptide transmitters

Most neuropeptide receptors are metabotropic, The best-defined peptides are:opioid peptides; β-endorphin, met-& leo-enkephalin &

dynorphinDrugs: Opioid analgesics (morphine)

Substance-P mediator of slow EPSPs-nociceptive sensory pathways in the spinal cord and brain stem

Orexins (also called hypocretins) are peptides associated with sleep-wake cycling and promote wakefulness. Others: Neurotensin, somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neuropeptide Y, and thyrotropin-releasing hormone.

17

Endocannabinoids

These are widely distributed brain lipid derivatives (eg, 2-arachidonyl-glycerol) that bind to receptors for the cannabinoids found in marijuana. They are synthesized and released postsynaptically after membrane depolarization but diffuse backward (retro-grade), acting presynaptically to decrease transmitter release, via their interaction with a specific cannabinoid receptor.Cannabinoids may affect memory, cognition, and pain perception by this mechanism.

18

Other Transmitters

Histamine receptors are widely distributed in the brain and appear to modulate arousal, appetite, and memory. Centrally acting antihistamines have significant sedative and anti-motion sickness effects. Nitric oxide (NO) is not stored but synthesized on demand. NO synthase is found in several types of neurons but the role of NO in CNS function is poorly understood.Purines§ Are cotransmitters in several types of transmitter vesicles § Receptors for ATP, adenosine, UTP, and UDP are found in the CNS. § ATP acts on metabotropic A1 receptors to inhibit calcium channels and

reduce the release of other transmitters.§ ATP also acts on P2X (ligand-gated cation channels) and P2Y

(metabotropic) receptors. These receptors are involved in memory, wakefulness, and appetite and may play roles in multiple neuropsychiatric disorders.

19