NEUROBIOLOGY central nervous system (CNS) = brain / spinal cord - - PowerPoint PPT Presentation

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
• f 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

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

PHARMACOKINETICS

Half-life = time required to eliminate 1/2 of the drug from the blood

• measured during the elimination phase
• very important for predicting optimal dose and dosing interval for

“maintenance” levels

• 1st order (most drugs):
• constant rate of elimination irrespective of plasma

concentration - half-life is constant regardless of how much drug is consumed

• ~6 half-lives to become “drug free” ***
• Zero order (alcohol, aspirin and few others)
• rate of elimination is proportional to the plasma

concentration - half- life changes depending on how much drug is consumed

Half-life = time required to eliminate 1/2 of the drug from the blood

PHARMACOKINETICS

% remaining: 1 - 50% 2 - 25% 3 - 12.5% 4 - 6.25% 5 - 3.125% 6 - 1.56% ***

14 16

PHARMACOKINETICS

• Distribution / Elimination of Drugs Following Injection
• Steady-state concentration achieved with regular-interval dosing
• 1 dose per half-life
• since only 50% is eliminated, the drug accumulates
• the amount administered each time is equal to amount

eliminated

• takes ~6 half-lives / injections for “full” saturation ***

% “saturation”: 1 - 50% 2 - 75% 3 - 87.5% 4 - 93.75% 5 - 96.875% 6 - 98.44% ***

Pediatric vs. Geriatric Psychopharmacology

• kids usually, but not always, metabolize drugs more quickly than adults
• psychiatric diagnoses in children (9-16)
• ver 1/3 had at least one psychiatric disorder
• based on adult DSM standards
• These problems seem to start early in life
• issues of drugs & the developing brain
• ketamine shows that the pediatric brain works differently
• altering pharmacology of the developing brain may have permanent

repercussions

• letting chemical / structural deficits go unchecked may be worse (?)
• Children generally metabolize drugs much more quickly (require larger

mg/kg dose)

• pediatric medicine characterized by a lot of “off-label” use

Geriatric Psychopharmacology

• General principles with elderly patients:
• metabolize drugs more slowly
• need lower dosages
• up to double the half-life
• effects intensified
• especially with the depressant drugs
• higher incidence of depression / anxiety