Download Strategies for drug delivery through the blood

Introduction to CNS
pharmacology
Anne McKinney
Microanatomy
a) Neurons
b) Non-neuronal
-Microglia
-Microglial related macrophages
-Cells of the cerebral vasculation
-Meninges
c) Blood brain barrier
Blood brain barrier (BBB)
Cortical microvasculature
The BBB has several functions
• Protects the brain from “foreign substances”
in the blood that my 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:
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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
Penetration of drugs across BBB
Factors determining the ability of a
drug to cross the blood-brain barrier
1.
2.
3.
4.
5.
Lipid solubility
Ionization
Plasma protein binding
Molecular mass
Transporter
Passiv
e
Active
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
Transport at the BBB
4 basic mechanisms:
• Simple diffusion (low to high conc)
• Facilitated diffusion: a carrier mediated endocytosis( solute
molecules bind to specific membrane protein carrier low to high
conc
• Simple diffusion through an aqueous channel formed within
membrane
• Active transport through a protein carrier: specific binding site
that undergoes a change in affinity. Active transport requires
ATP hydrolysis and conducts movement against the
concentration gradient.
Circumventricular Organs
Several areas were BBB is weak. These areas known as
cirumventricular organs Include:
• Area postrema: “vomiting center” when a toxic substance
enters the bloodstream
• Subfornical organ important for regulation of body fluids
• Vascular organ of the lamina terminalis: A chemosensory
area that detects peptides and other molecules
• Median eminence: Regulates anterior posterior through
release of neurohormones
• Pineal body: Secretes melatonin and neurosctive peptodes,
associated with circadian rhythms
• Neurophypophysis (posterior pituitary): Releases
neurohormones like oxcytocin and vasopressin into the
blood.
Strategies for drug delivery
through the blood-brain barrier
1. Invasive
-intracarotid infusion of hypertonic media
2. Pharmacologic
-liposomes
-lipid-soluble pro-drugs
3. Physiologic
-chimeric nutrients
-chimeric peptides
Communication in CNS
1. Conduction of nerve impulses within
a single neuron
2. Communication among neurons
Ion Channels in Neuronal Membrane
1. Voltage sensitive
2. Chemically activated (receptor operated)
Types of ion channels
2. Communication among neurons
2.1
2.2
2.3
2.4
Chemical synapses
Electrotonic junctions
Electrical field (ephaptic) interactions
Extracellular milieu
CNS synapse
1.
2.
3.
4.
5.
6.
7.
8.
axonal transport
electrically excitable
membrane
transmitter synthesis,
storage and metabolism
transmitter uptake
transmitter release
postsynaptic receptors,
cytoplasmic organelles,
messengers, etc.
presynaptic heteroreceptors
presynaptic autoreceptors
2.1 Chemical synapses and other forms
of neurohumoral communication
2.1.1 Neurotransmitters
2.1.2 Neuromodulators
2.1.3 Neurohormones
Identification of CNS
Neurotransmitters - Criteria
1. Localization
2. Release
3. Synaptic mimicry
3.1 Identity of action
3.2 Pharmacologic identity (antagonists)
Neurotransmitters in the CNS
2. Catecholamines
2.1 Dopamine
Dopamine
Neurotransmitters in the CNS
2. Catecholamines
2.2 Noradrenaline
Noradrenaline
locus coeruleus
Neurotransmitters in the CNS
3. 5-hydroxytryptamine,
5-HT, serotonin
5-hydroxytryptamine
Neurotransmitters in the CNS
4. Acetylcholine
Renshaw cells
interneurons in the striatum
medial septum n.→ hippocampus
n. basalis Meynert → cortex
Neurotransmitters in the CNS
5. Peptides
Opioid peptides
Substance P
Somatostatin, etc.
6. Nitric oxide
Co-Transmission
Transmitter Peptide
Location
GABA
Hippocampal & cortical n.
Cortical neurons
Parasympathetic & cortical
Pontine neurons
Sympathetic neurons
Sympathetic neurons
Medullary & pontine n.
Locus coeruleus
Ventrotegmental neurons
Ventrotegmental neurons
Somatostatin
Cholecystokinin
Acetylcholine VIP
Substance P
Noradrenaline Somatostatin
Enkephalin
NPY
Neurotensin
Dopamine
CCK
Neurotensin
Transmitter Peptide
Location
Adrenaline
Reticular neurons
Reticular neurons
Medullary raphe
Medullary raphe
Medullary raphe
Serotonin
NPY
Neurotensin
Substance P
TRH
Enkephalin
Peptide
Peptide
Vasopressin
Oxytocin
CCK, dynorphin Hypothalamic neurons
Enkephalin
Hypothalamic neurons
Transmitter Transmitter
GABA
Glycine
Spinal cord
General Characteristics of CNS
Drugs
1. 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)
Classification of drugs
acting on CNS
1. Mechanism of action
2. Therapeutic use
Sites of drug action