NEUROBIOLOGY ... nicotine vs. acetylcholine) ¢â‚¬¢ Dose-response curves: ¢â‚¬¢ a very low dose produces

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    • central nervous system (CNS) = brain / spinal cord

    • ~100 billion neurons

    • all thoughts / behaviors / memories result from biochemical interactions between neurons

    • Drugs that affect these processes are psychoactive drugs

    • psychoactive drugs generally modulate normal functions of the brain

  • PHARMACODYNAMICS The study of how a drug’s interactions with receptors on neurons and/or glial cells affect neurophysiology and neurotransmitter (NT) release

    “what the drug does to your body”

    • binding of the drug and/or NT to the receptor changes the functional properties of neuron

    • determined by:

    • ionic bonds of varying strength resulting from fit of 3D structure of drug within the 3D structure of receptor

    • usually reversible

  • PHARMACODYNAMICS • A receptor is a large protein embedded in cell membrane or inside cell

    • site where natural NTs (ligands / first messengers) bind

    • induces “normal” biological effects

    • usually “membrane-spanning” protein with sites for binding NTs • 7 or 12 loops of amino acids embedded in membrane • NTs / drugs fit in space between loops • binding of NT / drug “activates” receptor, usually by changing its shape

    • generally, the more receptors activated, the larger the effect

    • Release of NT / binding to receptor / receptor action can be very fast (~1 ms)

  • PHARMACODYNAMICS Psychoactive drugs generally work directly or indirectly by modulating

    receptors for endogenous NTs • Agonists

    • Full or partial agonist drugs cause synaptic activity (EPSP or IPSP) similar to the endogenous NTs

    • binding of a drug with a receptor can result in a cellular response similar or identical to NT

    • nicotine (binds with ACh receptor) • binding near NT site to facilitate NT binding (“positive allosteric modulation”) / increases affinity

    • valium binds to a site near the GABA site on the GABA receptor

    • preventing clearance of NT from the synapse • Prozac, cocaine / AChE inhibitors

    • facilitating actions of NT by any other mechanism • amphetamine

  • PHARMACODYNAMICS • Agonists (cont)

    • Inverse agonists produce an opposite synaptic response to that of endogenous NTs

    • Naloxone and naltrexone are partial inverse agonists at opioid receptors

    • Antagonists • block endogenous NT binding

    • caffeine

    Drugs can act at varying degrees of specificity / effectiveness at numerous receptors

    • almost every drug / NT binds with several subtypes of receptors • different brain areas / different effects • postsynaptic / presynaptic receptors

  • PHARMACODYNAMICS • Drugs that “fit” better at their site of action (i.e., have better “affinity”) can be more “effective” - producing larger synaptic effects at the same concentration (e.g., nicotine vs. acetylcholine)

    • Dose-response curves:

    • a very low dose produces little or no effect

    • a very high dose - no greater response can be elicited

    • Different drugs from the same “class” can have different potencies (measure of drug activity expressed in terms of the amount required to produce an effect of a given intensity)

    • caffeine less potent than amphetamine

    • aspirin less potent than morphine

    • drug interactions can alter response / effectiveness

    • different individuals respond differently

    • genetics (absorption / metabolism)

  • PHARMACODYNAMICS • Drug Tolerance:

    • state of progressively decreasing responsiveness to a drug via homeostatic regulation (biological feedback loop)

    • Metabolic tolerance

    • metabolic enzymes up-regulated (increased) by presence of drug

    • drugs eliminated more quickly

    • Cellular-adaptive / pharmacological tolerance

    • receptors on neurons are down-regulated (decreased)

    • OR reduced sensitivity of receptors

    • Behavioral conditioning

    • environmental cues paired with drug become CS

    • these cues elicit a CR opposing the effect of the drug

  • PHARMACODYNAMICS • Toxicity: harmful side effects

    • some “side effects” can be used therapeutically

    • especially drowsiness, etc.

    • Therapeutic Index / Ratio

    • measure of relative safety of drug:

    • ED50 - Effective dose for 50% of subjects

    • LD50 / TD50 - Lethal / Toxic dose for 50% of subjects

    • “therapeutic index” - the ratio of LD50 (or TD50) to ED50

    • small / narrow ratio is dangerous, larger is safer

    • 1000:1 safer than 10:1

  • PHARMACODYNAMICS • Placebo effects:

    •psychosomatic effect from simply being exposed to a tx • double blind studies - started in WW1 when a surgeon noticed that nurses were injecting saline instead of morphine

    • effect of drug = “pharmacological“ effect + nonspecific “expectancy” effect

    • can lead to changes in hormones, endorphins etc • Double-blind, randomized clinical trials • Also - “nocebo” effect (“noxious”) and “medical hex”

    • Antidepressants: • 28% of placebo patients improve • 50% of drug patients improve

    • placebo accounts for at least 50% of effect

    • Works best on relatively non-specific symptoms that wax/wane • depression / chronic pain


    The study of a drug’s movement through the body, including time to onset and the duration

    “what your body does to the drug”

    • ABSORPTION into the body • DISTRIBUTION throughout the body • METABOLISM detoxification / breakdown into metabolites • ELIMINATION of metabolic waste products from the body


    • how a drug gets into the body

    • to have a psychoactive effect, a drug must get to the place of action at an appropriate concentration and maintain that concentration for an adequate length of time

    Enteral (via GI tract)

    • oral (pill, liquid)

    • rectal (suppository)

    Parenteral (does not involve GI tract)

    • injection (IM, IV, subcutaneous)

    • inhaled (smoke, vapor)

    • transdermal absorption (through skin patch)

    • transmembrane absorption (through mucus membranes - snorting / gum / sublingual)





    • The Vascular System

    • Blood is entirely circulated about 1x every minute • Blood is pumped from heart through lungs for oxygen

    • Then through the body via arteries

    • nutrients, oxygen, etc leaks out of capillaries

    • “Used” then pumped back to the heart / lungs via veins

  • PHARMACOKINETICS • DISTRIBUTION throughout the body (continued)

    • Oral • drug must be soluble AND stable in stomach acid

    • slowly passes through the cells of the gastro-intestinal (GI) tract into the liver and then into the bloodstream

    • Injection, Skin & Mucous Membranes • veins > heart > lungs > heart > brain & body (in under 30 seconds)

    • little goes through the liver

    • Inhaled • lungs (large surface area - 90x human skin) > heart > brain & body (seconds)

  • PHARMACOKINETICS Once in the bloodstream, a drug must pass various barriers to get to receptors in the brain

    Only a small % of a drug at any time is bound to receptors in the brain

    Side effects often caused by the drug binding to receptors elsewhere in body

    Blood-Brain Barrier

    • Blood flow is greatest to brain (~20%)

    • Capillaries are tiny arterial blood vessels made from endothelial cells

    • Peripheral capillaries have small gaps between the endothelial cells which are large enough to allow most drugs to pass

    • via passive diffusion down the concentration gradient

    • Brain capillaries:

    • have no pores

    • are covered by a sheath of fatty glial cells

    • so - a drug has to pass through:

    • cell membranes of endothelial and glial cells

    • small, lipid-soluble molecules pass more easily

    • by definition - all psychoactive drugs

    • there is also a blood–spinal cord barrier (BSCB)

    • Placenta is not a barrier

    • drugs cross by passive diffusion

    • fetus exposed to concentrations similar to mothers


    • “biotransformation” / enzymatic breakdown

    • mostly takes place in the liver - makes molecules smaller and more water soluble (less fat soluble)

    • “first pass metabolism” – with oral administration, blood from the GI tract is drained to the liver first via the “hepatic portal system”

    • enzymes in the GI lining and liver degrade some of the drug before it ever reaches the systemic bloodstream

    • cytochrome P450

    • broken down by enzymes into metabolites that are less fat soluble

    • some metabolites are psychoactive

    • pro-drugs

    • detection of metabolites is the basi