NEUROBIOLOGY • 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: • ED 50 - E ffective dose for 50% of subjects • LD 50 / TD 50 - L ethal / T oxic 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
PHARMACOKINETICS 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
PHARMACOKINETICS • ABSORPTION into 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)
PHARMACOKINETICS Enteral Parenteral
PHARMACOKINETICS • DISTRIBUTION throughout the body • 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
PHARMACOKINETICS • METABOLISM • “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 basis of most drug tests • different people have different genetics for metabolism
PHARMACOKINETICS • ELIMINATION • most drugs / metabolites exit via kidneys / urine, but also lungs, bile, sweat, breast milk • Kidneys are a pair of bean-shaped organs that filter 1 L blood / min to extract 1 cc of urine / min • Usually, psychoactive drugs are too fat soluble to dissolve into the urine • must be metabolized into smaller, more water soluble molecules
PHARMACOKINETICS • Distribution / Elimination of Drugs Following Injection • “Redistribution” - after IV injection, levels of drug in the blood rise quickly and then fall quickly as drug is pumped through the body and distributed to body tissues • “Elimination” – blood levels then fall more slowly as drug is gradually metabolized by liver
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