Introduction to CNS pharmacology

BY Emeka P M CCP-KFU

Microanatomy
Neurons Non-neuronal:-Microglia -Microglial related macrophages -Meninges

Blood brain barrier

Blood brain barrier (BBB) Cortical microvasculature

The BBB has several functions

Protects the brain from foreign substances "in the blood that may injure the brain may injure the brain

Protects the brain from hormones and neurotransmitters in the rest of the body

Maintains a constant environment for the brain

General properties
Large molecules do not pass through the BBB easily. Low lipid (fat) soluble molecules do not penetrate into the brain. However lipid soluble molecules e.g. barbiturate drugs rapidly cross through the brain.

Molecules that have a high electrical charge are slowed

Transport of substances into the brain are dependent on:

Conc between compartments Size of molecule (MW) Flexibility and conformation of molecules Amino acid composition Lipophilicity Cellular enzymatic stability Cellular sequestration Affinity for efflux mechanisms Hydrogen bonding potentials (charge) Affinity for carrier mechanisms Effects of existing pathological conditions

Factors determining the ability of a drug to cross the blood-brain barrier

1. Lipid solubility 2. Ionization

3. Plasma protein binding

Molecular mass Transporter Active

Passive

Diffusion of substances in the brain

Paracellular (between cells) (not occur to great extent at the BBB due to tight junctions)

Transcellular (across cells) The higher the lipohilicity of a substance the greater the diffusion in the brain

Communication among neurons

Chemical synapses:- Electrotonic junctions. -Electrical field interactions. - Extracellular milieu.

Circumventricular Organs
Area postrema: vomiting centre when a toxic substance enters the bloodstream.

Vascular organ of the lamina terminalis: A chemosensory area that detects peptides and other molecules.

Pineal body: Secretes melatonin and neurosctive peptodes, associated with circadian rhythms

Strategies for drug delivery through the blood-brain barrier

Invasive -intracarotid infusion of hypertonic media. 2. Pharmacologic -liposomes -lipid-soluble pro-drugs 3. Physiologic -chimeric nutrients -chimeric peptides

Communication in CNS
Conduction of nerve impulses within a single neuron.
Communication among neurons.

 1. Voltage sensitive.

Ion Channels in Neuronal Membrane

2. Chemically activated (receptor operated).

CNS synapse
1.Axonal transport. 2.electrically excitable membrane. 3.Transmitter synthesis, storage and metabolism. 4. Transmitter uptake 5. Transmitter release 6. Postsynaptic receptors, cytoplasmic organelles, messengers, etc. 7. Presynaptic heteroreceptors 8. Presynaptic autoreceptors

Chemical synapses and other forms of neurohumoral communication

Neurotransmitters.
Neuromodulators. Neurohormones.

Identification of CNS Neurotransmitters - Criteria

Localization. Release. Synaptic mimicry:-Identity of action -Pharmacologic identity (antagonists)

Neurotransmitters in the CNS

Catecholamines:Dopamine

Neurotransmitters in the CNS

Catecholamine:Noradrenaline

Neurotransmitters in the CNS

Catecholamine:5-hydroxytryptamine, 5-HT, serotonin

Neurotransmitters in the CNS

Acetylcholine:Renshaw cells interneurons in the striatum medial septum n. hippocampus n. basalis Meynert cortex

Neurotransmitters in the CNS

GLUTAMIC ACID Excitatory for most neurons. N-methyl-D-aspartate (NMDA) receptor Learning and memory.

GABA AND GLYCINE GABA is the primary NTA mediating Inhibitory effects (IPSPs)

Neurotransmitters in the CNS

Peptides Opioid peptides Substance P Somatostatin, etc. Nitric oxide

General Characteristics of CNS Drugs

Nonspecific: effect on many different targets cells & results in diverse molecular mechanism (anesthetic gases). 2. Specific: binds to a target cell receptor, intracellular mechanism and imparts a specific therapeutic action. (psychotropic drugs).

 They are Classified into 2 major groups:According to 1. Mechanism of action. 2. Therapeutic use.

Classification of drugs acting on CNS