Intro to CNS Drugs (NOT DONE)

What protects the brain from foreign substances but also can affect the effectiveness of CNS drugs?

The Blood Brain Barrier

What is the BBB made of?

• Tight endothelial junctions

• Basement Membrane

• Receptors

• proteins

• Pericytes

• Astrocytes

What does the BBB keep out?

• Ionized compounds

• Large Compounds

To cross the BBB a drug/molecule needs to be what?

• Small

• Lipid soluble

• Poorly protein-bound

• Non-ionized at the pH of cerebral spinal fluid (7.3)

What can cause increased solubility of the brain?

• Inflammation

• Site of Tumors

• Neonates

• Specific areas have increased solubility

  • Ex: 4th Ventricle

What receptors/proteins regulate the BBB by limiting the passage of molecules?

1. Solute carrier proteins

   1. Carry essential molecules (glucose/vitamins) across the BBB

2. Receptor-mediated transcytosis

   1. Transport important hormones (insulin/leptin)

   2. Transcytosis=transport of biological molecules

3. ATP-binding cassette (ABC) transporters

   1. Move substances in both directions across BBB

   2. P-glycoproteins and MDR1 are subtypes of this transporter

What is ABCB1?

• The gene that encodes for P-glycoprotein, aka MDR1

Some drugs ____ or _____ p-glycoprotein

Inhibit/Induce

What is the difference between active/inactive P-glycoprotein?

• Active

  • a protein in cell membranes that acts as an energy-dependent efflux pump, exporting a wide variety of substances like drugs, toxins, and xenobiotics out of cells

• Inactive

  • More drugs cross the BBB

CNS drugs activate/inactivate specific _______

Neurons

What are the 6 CNS transmitters?

• Glutamate

• GABA

• Dopamine

• 5HT

• Ach

• NE

Describe the function of Glutamate as a CNS transmitter

• Primarily excitatory

• Causes Na+ influx into postsynaptic neurons (causes signal)

Describe the function of GABA as a CNS transmitter?

• Inhibitory postsynaptic

• Influx of Cl- into postsynpatic neurons

  • Polarizes neuron (prevents signal)

Describe the function of Dopamine as a CNS transmitter?

• Excitatory/Inhibitory

• Emotion, reward system, motor control

Describe the function of 5-HT (serotonin) as a CNS transmitter?

• Excitatory/Inhibitory

• Feeding behavior, body temp, sleep

Describe the function of Ach as a CNS transmitter?

• Excitatory

• Arousal, memory, learning, movement

Describe the function of NE as a CNS transmitter?

• Excitatory

• Arousal, mood, cardiovascular region

T/F: Side effects are common to CNS drugs

True, most receptors are present throughout the brain, so by trying to treat one part you can trigger all parts

The ______ pathway of neurons is responsible for perception and localization of pain, and then sending that to the brain

Ascending

Harmful stimuli are first detected by specialized free nerve endings called __________

Nociceptors

Once a nociceptor is stimulated, the harmful stimulus is changed to an electric signal that is transmitted from the nociceptor to the brain via peripheral ______ nerves

afferent

Which neurotransmitter is used to inhibit postganglionic neurons and inhibit peripheral nerves and dorsal horn pain?

Serotonin

What are Analgesics?

Drugs that relieve pain

What are the 3 ways that we use anesthetics?

1. Topically

2. Injection into tissue

3. Injected into space

How do local anesthetics function?

• Reversible competitive inhibitors of Neuronal Na+ Channels

  • Decrease polarization via blocking Na+ channels

    • Results in the blocking of the A.P initiation

      • Results in the blockage of nociception conduction (blocks pain signal so it doesn’t reach the brain)

T/F: Local anesthetics induce unconsciousness

False

What are the different ways that local/topical anesthetics can be used?

1. As a sole analgesic

2. To improve anesthetic quality

3. Contribute to multimodal analgesia

4. Decrease the amount of required opioids

Local anesthetics are sometimes combined with ________ or an _________ to increase the duration of activity by preventing the drug from exiting the desired area of analgesia.

• Epinephrine

• Alpha-2-Agonist

Nerves vary in __________ to local anesthetics

Susceptibility

What are some factors that can affect a nerve’s susceptibility to local anesthetics?

• Diameter of nerve

  • A small diameter is blocked more easily than large one

• Sensory vs Motor (more resistant to blockage)

• Touch/proprioception is less affected

Toxicity of Local Anesthetics are partly determined by ________ within cardiocytes and cells of the central nervous system.

Accumulation

What are some adverse effects of Local Anesthetics?

• Tissue ischemia/necrosis

  • Caused by Decreased blood flow

    • Caused by Epinephrine or Alpha-2-Agonist

• Systemic injections of high doses can cause

  • Seizures

  • Respiratory Depression

  • Hypotension

  • Cardiac Arrest

• Cardiovascular depression

• Allergic reactions

• Ion trapping in pregnant animals

What are the Pharmacokinetics of Local Anesthetics?

1. High/Low protein bound

2. Metabolized where?

3. Acidic/basic?

1. Highly protein bound

2. Metabolized in liver

3. Weak bases

   1. Trapped in low pH areas