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

PHARMACODYNAMICSThe 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)

PHARMACODYNAMICSPsychoactive 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)

PHARMACOKINETICSOnce 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% ***

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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)

• over 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