Neuroscience of Psychopharmacology
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Psychopharmacology 101
For Non-prescribing
Mental Health Professionals -
A Training Resource
By Jim Messina, Ph.D., CCMHC, NCC, DCMHS-T
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Resource for Mental Health Professionals:
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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
- No two neurons are separated by more than six steps!
- And each neuron is serviced by 10 glial cells
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Neuron Organization
- Dendrite→Nucleus (Cell Body)→Axon
- Memory Trick: D-N-A
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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 of the transmitters
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What happens after Neurotransmitter (NT) is released?
• Bind
• Re-uptake via Transporter
• Degrade
• Diffuse
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Terminal Button Components & Roles – Listed# on figure above:
1 Drugs serves as neurotransmitter precursor l-DOPA (treats Parkinson)
2 Drug inhibits neurotransmitter synthesis
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
5 Drugs inhibits release of neurotransmitter
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
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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
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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
Therapeutic Index – how safe is the drug
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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
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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!
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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
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Specific Serotonin (5HT) Receptors and Their Action
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5HT-2A
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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
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5HT-1A
Auto-receptor
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Found in:
Hippocampus
Septum
Amygdala
Dorsal Raphe
All involved in fear & anxiety response
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Specific Serotonin (5HT) Reuptake Inhibitors (RI) - Indirect Agonists - & Their Action
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5HT-2B
THINK HEART!
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Think “Death Receptor” (Serotonin Induced Angina)
Responsible for:
Heart development – proliferation & specialization
Stomach Contractions
Relaxation of Jugular Vein
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5HT-2C
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Sleep-wake cycle
Eating
Pain
Anxiogenesis
If blocked - activates monoaminergic neurons (increases NE and DA (dopamine) in prefrontal cortex)
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5HT-3
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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
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5HT-4
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Increase appetite
Potentiation of detrusor muscle contraction
Gastric emptying
Diarrhea
Stress-induced anorexia
Synaptic plasticity
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5HT-5A
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Unknown if related to:
Novelty Seeking
Circadian Rhythm
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5HT-5B
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Non-fictional
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5HT-6
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Modulates ACh () and DA (dopamine)
Implicated in spatial learning & memory
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5HT-7
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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
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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
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D1
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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
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D2
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Control renal blood flow
Modulates DA in striatum
Reward
Modulation of Movement
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D3
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Modulates anxiety
stimulates yawning
Modulates erection and ejaculation
Reward & reinforcement
Modulates DA synthesis
Regulates kidney function & blood pressure
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D4
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Implicates in novelty seeking
Modulates Exploration
Regulates water, and electrolyte transport in kidneys
Modulates gastric acid secretion
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D5
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Implicated in Hypertension
Regulates Acetylcholine (Ach) in hippocampus
Enhances GABA-A in striatal Ach neurons
Enhances glutamate (NMDA) receptor) activity in general tegmental area
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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)
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NE Receptor
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Agonize
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Antagonize
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Alpha 1 (α1)
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Constrict
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Relax
Orthostatic
Hypotension
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Alpha 2 (α2)
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“Put on Brakes” of SNS
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“Cut the Brakes” of SNS (clonidine)
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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
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