Principles of Psychopharmacology

Principles of Psychopharmacology

• A drug is an exogenous chemical, not an essential nutrient, that significantly alters the function of cells when taken in low doses.
• Drugs can change physiological processes and behavior, like analgesia and sedation.
• A psychoactive drug alters mood, thought, or behavior, managing psychopathology or recreational purposes.
• Drug action sites include molecules on or within cells.

Pharmacokinetics

• Pharmacokinetics studies how drugs are absorbed, distributed, metabolized, and excreted in the body (ADME).

Pharmacodynamics

• Pharmacodynamics studies the effectiveness of drugs and what they do to the body, including the drug's effectiveness, onset, duration of action, and therapeutic range.
• Pharmacokinetics is what the body does to a drug.

Routes of Drug Administration

• Drugs can be ingested/absorbed orally, sublingually, as a suppository, or topically (including skin patches).
• Drugs can be injected peripherally via subcutaneous, intra-muscular, intraperitoneal, or intravenous routes.
• Inhalation is also a route of administration.
• Drugs can be injected spinally/intracranially using intrathecal, intracerebroventricular, or intraparenchymal methods.
• Drugs injected directly into the brain act quickly in low doses due to the absence of barriers.
• Oral administration is the safest and most convenient method.
• Weak acids pass from the stomach into the bloodstream, while weak bases pass from the intestines.
• Drugs encounter varying levels of barriers based on the route of administration

Distribution of Psychoactive Drugs

• Lipid solubility is a key factor in determining how drugs enter through the blood-brain barrier (BBB).
• Brain capillaries have tight junctions and are covered with astrocyte feet, forming the BBB which prevents easy movement of materials.
• Small, uncharged molecules can pass through the endothelial membrane and reach the brain.
• Active transport carries certain molecules across the membrane.
• Large and electrically charged molecules cannot pass.
• Capillaries in the body are more leaky with fewer tight junctions, allowing easier movement of materials.

Metabolism of Psychoactive Drugs

• The rate of enzymatic breakdown and excretion determines a drug's half-life.
• Some drugs break down into biologically active molecules, extending their effective lifespan.
• Metabolism rates differ between individuals due to physiology, genetics, lifestyle, and environment.

Effectiveness of Psychoactive Drugs

• The study of biochemical and physiological actions and the relationship between drug dose and effect.
• Dose-response function plots drug effectiveness across doses.
• After a certain point, increasing the dose doesn't produce a stronger effect.
• Potency can be compared between drugs using dose-response functions.

Therapeutic Index

• Drugs usually have more than one effect. The therapeutic index compares doses that exert beneficial effects versus toxic effects, indicating the margin of safety (LD50/ED50)

Sensitization and Tolerance

• Sensitization increases drug effectiveness with repeated/chronic exposure.
• Tolerance decreases drug effectiveness with repeated/chronic exposure.
• Cross-sensitization/cross-tolerance involves effectiveness changes to a novel drug after exposure to a different drug.
• Sensitization and tolerance are action-specific and may be dissociable

Psychoactive Drug Classes

• Agonists mimic or increase neurotransmitter actions.
• Antagonists block or decrease neurotransmitter actions.
• Competitive (direct) agonist/antagonists attach to the same binding site as the endogenous neurotransmitter.
• Non-competitive (indirect) agonists/antagonists engage in actions through binding to a noncompetitive site.
• A drug's affinity is its attraction to its target, and efficacy is its ability to exert its physiological action.

Additional Psychoactive Drug Info

• Irreversible antagonists modify receptors, rendering them permanently inactive.
• Partial agonists exert agonist actions that are not as effective as a full agonist.
• Inverse agonists bind to the same receptor as an agonist but produce the opposite action.

Mechanisms of Psychoactive Drugs Interacting with Neurotransmitters

• The drug could be a precursor.
• It could inactivate the biosynthetic enzyme.
• The drug might prevent storage.
• It might stimulate NT release.
• The drug may activate postsynaptic receptors.
• Conversely it could block postsynaptic receptors

Classical Neurotransmitter Criteria

• Synthesized by presynaptic neuron.
• Released by presynaptic neuron when stimulated.
• Can be chemically or pharmacologically identified.
• Binds to specific receptors on the postsynaptic membrane and effect the stimulation of a presynaptic neuron.
• Active mechanisms terminate chemical actions.
• Substances that don't match classical criteria exist.

Definitions of Neurotransmitter and Neuromodulator

• Glutamate, GABA, and glycine are considered principle effectors.
• Neuromodulators influence functional circuits broadly.
• Acetylcholine arouses the cortex and helps learning.
• Norepinephrine increases arousal and vigilance.
• Dopamine involves behavioral reinforcement.

Neuromodulatory Actions

• Synaptic actions modulate glutamate, GABA, and glycine through metabotropic receptors.
• Extrasynaptic actions modulate via receptors outside the synapse.

More Actions

• Axoaxonic synapses modulate neurotransmitter release.
• There is a presynaptic facilitation/presynaptic inhibition.
• Cytosolic and nuclear receptors involve lipid-soluble hormones.
• Retrograde signaling involves lipid-soluble substances signaling back to regulate NT release.

Classical Neurotransmitters

• Quaternary amine (acetylcholine).
• Monoamines (catecholamines and indoleamines).
• Amino acids.
• Mostly synthesized in nerve terminals.
• Active reuptake.
• Presence of specific enzymes determines the type of biogenic amine synthesized.

Classical Neurotransmitters - Acetylcholine (ACh)

• Synthesized by choline acetyltransferase (ChAT)
• Packaged into vesicles by VACHT.
• Hydrolyzed by acetylcholinesterase (AChE) and butyrylcholinesterase.
• Choline is reuptaken and converted back to ACh.

Acetycholine (ACh) - Neuroanatomy

• Found in preganglionic fibers of sympathetic and parasympathetic nervous systems.
• Released at all neuromuscular junctions
• Also in the brainstem and basal forebrain.

Acetycholine (ACh) - Receptors

• Binds to ionotropic nicotinic receptors (Na+ channel)
• Binds to metabotropic muscarinic receptors.

Acetycholine (ACh) - Functional Implications

• Implicated in motor function.
• Also in REM sleep, learning and memory.
• Deficits occur in Alzheimer's disease and Myasthenia Gravis.

Acetycholine (ACh) - Drugs

• Drugs can act as agonists or antagonists
• Can stimulate or active
• Can block or release from stimulation

Catecholamines

• Derived from Tyrosine with enzymatic modifications.
• Inactivated by reuptake (DAT or NET)
• Can prevent storage.
• Reuptake is sometimes spontaneous or drug-induced.

Dopamine

• Mostly in nigrostriatal, mesocorticolimbic, and tubero-infundibular neurons

Dopamine - Receptors

• Binds to metabotropic receptors (D1-D5) that mediate various affects.
• These effects will mediate EPSPs and IPSPs.
• D2 acts as an autoreceptor for dendrites and somas.

Dopamine - Implcations

• Involved in movement, attention, learning and motivation
• Also is linked to lactation.
• Deficits can indicate Parkinson's, Schizophrenia or a variety of addictions.

Dopamine - Drugs

• Can be a precurssor or prevent storage.
• Can reverse reuptake or inactivate metabolizing enzyme.
• Terminal buttons also have high affiinity for apomorphine.

Norepinephrine

• Synthesized in postganglionic fibers and released at sympathetic innervation targets
• Synthesized in cells that project varicosities

Norepinephrine - Receptors

• binds to metabotropic receptors
• α₁, α2, β₁, β2 adrenoceptors found in CNS and PNS
• adrenoceptors in PNS especially

Norepinephrine - Implications

• Involved in mood, arousal, autonomic responses or fight or flight
• Deficiency or dysregulation may point to ADHD or Schizophrenia
• Deficiency could result from Alzheimer's.

Norepinephrine - Drugs

• act as precursers or prevent storage of drug
• activate autonomic receptors to inhibit the signal.
• blocks reuptake as well.

Epinephrine

• Synthesized by chromaffin cells released in medulla sympathetic innervation.
• Implicated in energy and fight to flight responses.

Indoleamines

• Are a category of monoamines
• Serotonin and melatonin

Serotonin - Biochemistry

• Uses tryptophan as a building block
• Has at least 3 release mechanisms relating to different processes Inactivation primarily uses reuptake, deamination etc.

Serotonin - Neuroanatomy

• Released in varicosities in raphe nuclei.
• Can either perform a diffused non-synapse transmission or uses more conventional methods.

Serotonin - Receptors

• there are at least a dozen different kinds depending on what the brain has
• Each can cause differnet effects depending on the body.

Serotonin - Implications

• implicated in the regulation of: mood, feeding, sleep, arousal, pain, sensory processing

Serotonin- Drugs

• Has drugs that act as agonists and antagonists
• Prevents NT store and blocks reuptake

Classical Neurotransmitters - Melatonin

• released from pineal gland, elevated in the evening, induces sleepiness
• production is impacted by the suprachiasmatic Nucleus

Glutamate

• most abundant excitatory transmitter in the nervous system
• Synthesized through glucose metabolism and some animo-acids
• Glial uptake recycles metabolism to recycle process

Glutamate - Receptors

• multiple types of reuptake that function to pass information
• Multiple binding sites to regulate activity.
• Polyamine promotes growth.

Glutamate -Implcations

• Requires contiguous neuron activity to be effective
• Detects presynaptic neurotransmitter release and postsynaptic depolarization.
• implicated in every neurological function

Glutamate - Drug Interactions

• Drugs can have an effect by
  • acting as a precursor -Stimulating release -Activating postsynaptic receptor

GABA - Biochemistry

• gamma aminobutyric acid: most abundant inhibitory neurotransmitter
• Synthesized from glucose thru Glutamic acid Recycled thry Glial uptake

GABA - Neuroanatomy

• Is ubiquitous and predominant in inhibitory neurotransmitters

GABA - Receptors

• 2 sub types that both use gaba
• • Can effect many sites of binding

GABA Inplications

• Implied in every brain function

GABA - Drug Inerationcations

Prevents storage, stimulates NT release, activates post synaptic interaction

Classical Neurotransmitters - Amine Acids - Glycine, Biochemistry and Neuroanatomy

• derived from glucose metabolism: serine intermediate
• -recicled through glial uiptake and metabolism glutamine
• -binds to receptor in the brain and spinal cord.

The Receptor and Implications

• uses GLycine and other organic compunds/ protiens
• implicated in many bodily functions
• **

The Peptide Neurotransmitters - Peptides

• can classify into opiod and non opiod sections

P- Biochem

• short chains amino acids that are cleaved from macroprotiens by peptdiases produced in the soma and slowly transpoted stored in vesicles and quickly cannot be replaced

POPIOD and Non

• FAIRLY UBIQUITOUS

Opioid peptides

• Receptors that bind metabotropics for binding

IMPLICATIONS IN POPOID and non

• analgesia and socializing and feeding

classical-Opioid-Peptides

Drugs for opioid that have a high/low relationship for many things like

• receptors
• endorphins
• dynorphins

Non-opiod peptides

bind to cells and are responsible for gastric function and rhyhtem

The gas transmissions

• soluable
• synthesized by rapid vessel dialectation
• cannont be stored NO-oxide reaction

• cO is high

###The unusual guys

Lipids

• 2 forms

Ca influc

• diffuse to signal CB1 receptor
• glutamante and GABA for Ca for influx and release Endogenous and what happens there from activity

Released and what does and has long lasting effects on neurological stuff Glutamate and kainate for neuro

Why Multiple Types of Neurotransmitters?

segregation of multiple inputs that carry different information to dendrites, soma differing distances to travel for synaptic and extrasynaptic communication, where

simultaneous stimulation of ionotropic (fast) and metabotropic (enduring and metabolically active) receptors