Brain Facts

100 Known Neurotransmitters

Less than 20 are “Really” Understood

Come in different categories

• Agonist & Antagonist
• Partial Agonists & Inverse Agonists

One Piece of Brain

The Size of a Grain of Sand - 100,000 neurons - 2,000,000 axons and 1,000,000,000 (B) synapses

In the Entire Brain. . .

100,000,000,000 (B) neurons - Each connected to 1,000 synapses = 100,000,000,000,000 (T) synaptic Connections

In the Brain Each Second. . .

100,000,000,000,000 (T) Connections with an average of 1000 signals cross each synapse = Ten Quadrillion Operations per second

In the Brain Each Second. . .

Each of those 10 Quadrillion Signals - Modulated by 1500 proteins of one or more neurotransmitters

Two More Brain Facts

1. No two neurons are separated by more than six steps!
2. And each neuron is serviced by 10 glial cells

Neuron Organization

• Dendrite→Nucleus (Cell Body)→Axon
• Memory Trick: D-N-A

Terminal Button of Vesicles

Neurotransmitters inside the vesical move to bottom of the terminal button and then the neurotransmitters are released to the cleft.

RI (reupintaker): Man-made cork closes the male transmitter

When too many transmitters are released into the cleft – you die ie: there are enzymes breakdown transmitters

What happens after Neurotransmitter (NT) is released?

• Bind

• Re-uptake via Transporter

• Degrade

Terminal Button Components & Roles – Listed# on figure above:

1 Drugs serves as neurotransmitter precursor l-DOPA (treats Parkinson)

2 Drug inhibits neurotransmitter synthesis

• Aspirin
• NSAIDS

3 Drug prevents storage of neurotransmitter in vesicles

• Tetrabenazine (Xenazine®) (treats Huntington’s)
• NEW: Valbenazine/Ingrezza®
• MOA: VMT2 Inhibitor
• Tardive Dyskinesia & Tourette’s

4 Drugs stimulates release of neurotransmitter

• Amphetamines
• Lacto-venom

5 Drugs inhibits release of neurotransmitter

• Botulinum Toxin (Bo-tox)

6 & 7 - Drugs stimulate or block post-synaptic receptors - ½ of all meds work at #6 & #7

• Agonists: Ropinirole
• Antagonists: Thorazine®, Haldol® & SDAs (Serotonin-Dopamine Antagonists)

8 Drugs stimulates auto-receptors; inhibits release of neurotransmitter

• Clonidine
• Guanfacine
• Intuniv®

9 Drugs block auto-receptors and increases release of neurotransmitters

• Mirtazapine form of Benedril (insomnia, depressed, not sleeping-get them to sleep first)
• Remeron®

10 Drug inhibits neurotransmitter degradation

• Monoamine Oxidase Inhibitors (Phenelzine/Nardil®)
• Acetylcholinesterase Inhibitors (Donepezil/Aricept®)

11. Drug blocks reuptake -1/3 of all drugs work here

• SSRIs, Prozac, SNRIs, Venlafaxine

Pharmacokinetics - What the Body does to the Drug

A-D-M-E – Absorption, Distribution, Metabolism, Elimination

Absorption – Bioavailability

Distribution

Metabolism – Biotransformation in the liver (Parenteral Around Liver: does not biotransform: IM, IV, Inhale, Transdermal, suppository) - Metabolite (altered version of chemical compound) – Cydachrome 450 CYP 450 (3A4, 2D6, 2C9) Enzyme in liver functionalization breaks down drugs- Use Cheek swab to check for liver enzymes - Breaks down the most drugs - 3A4 - breaks down most psychotropic drugs - 2D6 (Caucasians have most of this enzyme) - Family, Sub-Family, Specific Isoenzyme - Certain drugs can make more enzymes or less enzymes– Prodrug-when one takes it, it is inactive and in liver turns into active drug: ex: codine (prototypic drug) turns into active morphine. Asprin, Respiradone, Tomoxafin-for cancer

Elimination – Half Life & Steady State - The shorter the half-life the harder it is to withdraw off of an antidepressant e.g. Paxil Only applies to antidepressants

Pharmacodynamics - What the Drug does to the Body

Receptors – protein molecules with 1 or more binding sites, located on cell membranes

1. Agonist (enhance)

2. Partial Agonist (diminish)

3. Antagonist (block)

4. Inverse Igonist (opposite)

5. Indirect Agonist

• Affinity (Binding)
• Intrinsic Activity (receptor only exists for this activity and when it receives it

Potency & Efficacy

Dose Response Curve

• ED50 vs LD50

Therapeutic Index – how safe is the drug

Placebos

Placebos vs Nocebos

Placebo come from Latin “I will please”

Originally used to refer to both pleasant and harmful effects of treatment

45% of prescribers admit using placebos

Nocebo comes from Latin “I will harm”

Term emerged in the 1980

Untoward effects of an inert treatment

Pure vs. Impure Placebos

Pure

“Sugar Pills”

Saline Injections

Impure Placebos

Off-label uses of medications; antibiotics to treat a virus

Lab Tests/Physical Exams for assurances

Inactive Medical Devices

Surgeries (e.g., small incision in knee with no work done)

Placebo Response Factors

Pill Color

Red = stimulants/pain relief

Blue = depressants/sleep aids

Type of Treatment

Surgery > Injection > Capsules > Tablets

Pill Size

Bigger Pills = Better Placebo Effect

Bigger Price = Better Placebo Effect = Longer Lasting Placebo Effects

Evidenced-Based Placebo

Placebos may account for 75% of antidepressant effectiveness.

Active placebos may account for the remaining 25%.– Have perceptible side effects that do not contribute to clinical effectiveness

Neurotransmitters (NTs) focused on in Psychopharmacology

Serotonin (5-HT) - Mood

Dopamine (DA) - Reward

Norepinephrine (NE) – Motivation/Vigilance

Acetylcholine (ACh) - Memory

Histamine (H1) - Sedation

GABA – Cognition & Inhibition

Glutamate: Excitation & Master switch of Brain, can turn on virtually all CNS neurons!

Serotonin (5-HT)

Originally called Intermine, then named Serotonin restores chronic platelets in the blood and then affects the mood

• 90% - in digestive system   8% - in blood   2% - in brain (mood)

• 5mg-10mg in body for 40 million cells

Regulation of

• Mood
• Appetite
• Apathy
• Sleep
• Pain
• Panic
• Suicidal Ideation
• My interocular pressure
• Fluoxetine (Prozac®), January 1988

5-HT is released from platelets in response to vascular injury

• Promotes vasoconstriction

SSRIs inhibit uptake of serotonin into platelets

• Reduced ability to form clots and increases risk of bleeding

IMPORTANT: SSRI’S increase gastric acid secretion, irritant to gastric mucosa, increase risk of peptic ulcer. To control for this just lower the dose of the SSRI

Reuptake Inhibitors (RI) are Indirect Agonists (5HT:1A, 1B, 1D, 1E, 1F, 2A, 2B, 2C, 3, 4, 5A, 5B, 6, 7). Increases 5-HT indirectly over entire body increasing probability of stimulating/agonizing ALL 5-HT receptors

Specific Serotonin (5HT) Receptors and Their Action

Specific Serotonin (5HT) Reuptake Inhibitors (RI) - Indirect Agonists - & Their Action

Dopamine (DA)

(Used to be considered related to: 5R’s Randy, Raunchy, Rewarding, Risky, Rowdy now know that is a means to the end)

Dose Dependent

• Low dose increased renal perfusion
• Mid Dose increased ionotropy
• High dose increased vasoconstriction

Fine Motor Movement

Reward

Dopamine is the neurotransmitter that makes work seem effortless. The minute you are sexually attracted then dopamine kicks in. The minute the person says OK then dopamine stops dead in its track. It is responsible for the motivation to get what you want.

• eg: 40-year-old woman has crap marriage, crap job, work used to be fun and enjoyable, I just can’t seem to focus, concentration and pay attention: Oooo you have ADHD bad. Put on amphetamine which is full of dopamine and she says I am concentrating better. It makes all work seem effortless.
• Eg: If a kids are on amphetamine too much they lose pleasure in their life.

Roles of Dopamine (DA)

Dopamine (DA) Outside CNS

• Increases Noradrenaline + excretion in kidneys
  • Decreases Insulin in pancreas
  • Decreases GI motility, protects intestinal mucosa
  • Decreases Urine output
  • Decreases Norepinephrine
  • Decreases Activity of lymphocytes initiating immune response

Dopamine (DA)

• Reward
• Fine Motor Movement
• The Neurotransmitter that makes work seem effortless!
• Reward & Fine Motor Movement
• Anti-Psychotics: D2 Blockade

Dopamine (DA) Pathways

• Mesolimbic Pathway – positive side effects symptoms of schizophrenia
• Mesocortical Pathway – negative side effects symptoms of schizophrenia
• Nigrostriatal Pathway - causes movement disorders
• Tuberoinfundibular Pathway – controls the secretions deficits of prolactin

Dopamine (DA) Receptors & their action

Norepinephrine (NE)

Noradrenalin

The Adrenergic System, “Fight, Fright, Flight”

Responsible For:

• Motivation
• Fatigue
• Executive Function (attention, concentration, planning, problem solving)

Norepinephrine (NE) Receptors

Alpha1 (α1) & Alpha 2 (α2)

Beta Receptors (1-3) (Beta Agonists & Beta Blockers)

Acetylcholine (ACh)

Vagusstoff” [“stuff from the vagus nerve”]

The Parasympathetic System

• Muscarinic/Cholinergic System

“Rest, Digest, Take Out the Trash”

• Memory, Cognition, Movement
• Balance between DA and Ach

Amino Acids

GABA – inhibitory

• Sedative-hypnotics
• Anticonvulsants
• Anti-anxiety

Glutamate – excitatory

• Neural plasticity, neurotoxic
• memory
• NMDA receptors – drugs that block are neuroprotective

Cholinergic/Muscarinic Receptors (M1)

Parasympathetic System

Agonist: “SLUDG” Salivation, Lacrimation, Urination, Defecation, & GI Distress”

Antagonize (Anti-cholinergic): “DUCTS” “Dry Mouth, Urinary Retention, Constipation, Tachycardia, Sedation”

Histamine Receptors

H1: Sedation & – Weight Gain

H2: Gastric Acid Secretion (Gerd)

H3: Thermogenesis

Psychopharmacology Timeline

1921 Acetylcholine discovered by Otto Loewi, first known neurotransmitter

1933 Enteramine (serotonin) (5-HT) discovered in gut by Vittorio Erspamer

1935 Dupont creates insecticide using methylene blue

1937 First double-blind randomized placebo controlled clinical trial

1947-48 5-HT discovered in blood vessels. Name changed to “serotonin” Discovered by Cleveland Clinic.

1948  Cade discovers Lithium as treatment for mania

1953 5-HT (serotonin) discovered in CNS

1954 Humphrey-Durham Amendment, established prescription requirement

1954 Martha Vogt discovered NE (Norepinephrine) in brain

1954 Thorazine discovered

1958 Clozapine discovered

1959 Dopamine discovered in CNS

1962 Thalidomide disaster

1963 Carlsson & Lindquist Theory of Schizophrenia

1964 Locus Coeruleus discovered in brain

1965 Biogenic Amine Hypothesis of Depression