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 Neuroscience of Psychopharmacology

Psychopharmacology 101

For Non-prescribing

Mental Health Professionals -

A Training Resource

By Jim Messina, Ph.D., CCMHC, NCC, DCMHS-T
Resource for Mental Health Professionals:

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

• Diffuse

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 Indexhow 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

5HT-2A

Spinal Cord - Sexual Difficulties - 80% will get sexual side effects kick in the first dose

Brain Stem – Myoclonus – muscle spasm or shaking

Raphe Nucleus - Mental Agitation

Basal Ganglia - Motor Movement

Cortex – Apathy

5HT-1A

Auto-receptor

Found in:

Hippocampus

Septum

Amygdala

Dorsal Raphe

All involved in fear & anxiety response

 

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

5HT-2B

THINK HEART!

Think “Death Receptor” (Serotonin Induced Angina)

Responsible for:

Heart development – proliferation & specialization

Stomach Contractions

Relaxation of Jugular Vein

5HT-2C

Sleep-wake cycle

Eating

Pain

Anxiogenesis

If blocked - activates monoaminergic neurons (increases NE and DA (dopamine) in prefrontal cortex)

5HT-3

Hypothalamus - Nausea

Gut - Nausea & Vomiting

Most of this receptor’s action is unknown

May modulate GABA, Gutmate, Cholecystokinin, Ach, DA, E, 5-HT, and Substance P

5HT-4

Increase appetite

Potentiation of detrusor muscle contraction

Gastric emptying

Diarrhea

Stress-induced anorexia

Synaptic plasticity

5HT-5A

Unknown if related to:

Novelty Seeking

Circadian Rhythm

5HT-5B

Non-fictional

5HT-6

Modulates ACh () and DA (dopamine)

Implicated in spatial learning & memory

5HT-7

Modulates REM sleep

Inhibits release of luteinizing hormone (regulates menstrual cycle & egg production)

Regulates vagal nerve signal to heart

Modulates ACh (Acetylcholine) and DA (dopamine)

Implicated in spatial learning & memory

 

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

D1

Modulates renin release (aka “angiotensinogenase,” protein/enzyme increase Blood Pressure (BP) and restores perfusion pressure in kidneys)

Reinforces biological drives like eating and hygiene

Excitatory

D2

Control renal blood flow

Modulates DA in striatum

Reward

Modulation of Movement

D3

Modulates anxiety

stimulates yawning

Modulates erection and ejaculation

Reward & reinforcement

Modulates DA synthesis

Regulates kidney function & blood pressure

D4

Implicates in novelty seeking

Modulates Exploration

Regulates water, and electrolyte transport in kidneys

Modulates gastric acid secretion

D5

Implicated in Hypertension

Regulates Acetylcholine (Ach) in hippocampus

Enhances GABA-A in striatal Ach neurons

Enhances glutamate (NMDA) receptor) activity in general tegmental area

 

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)

 

NE Receptor

Agonize

Antagonize

Alpha 1 (α1)

Constrict

Relax

Orthostatic

Hypotension

Alpha 2 (α2)

“Put on Brakes” of SNS

“Cut the Brakes” of SNS (clonidine)

 

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