NEUROPHARM INTRO

 Neurotransmitters: monoamine often paired with neuropeptide in each neuron (fine tuning)
 Neuropeptides:
 Amino acids: excitatory - glutamate; inhibitory - GABA, glycine
 too much glutamate  neuronal death (Alzheimer’s, Parkinson’s, ALS, ischemic stroke)
 Biogenic amines: ACh, dopamine, etc…
 Purines: caffeine = adenosine receptor antagonist
 Other: CO, NO, zinc
 Fatty acids: anandamide (endogenous cannabinoid, retrograde nt)
 Neurogenesis:
 Cell loss/ atrophy factors: stress, depression, aging
 Cell growth factors: learning, exercise, growth factors, antidepressants, psychotherapy
 repulsive growth factors
 attractive growth factors
 Neuronal Selection:
 neurons formed in excess, good neurons chosen, defective neurons degraded
 abnormal in epilepsy, schizophrenia, bipolar disorder
 neurotrophic factors are critical to development & maintenance
 Synapses
 Long term potentiation (LTP) – long lasting enhancement between two neurons
 encoded by synaptic strength (keeping neurotransmitter localized better in synaptic cleft)
 most synapses present at age 6 (half removed over next 5-10 years)
 Pruning – removal of unnecessary dendrites
 Glial Cells – support cells, give structure, remove debris, buffer [K+], guide neuron migration
 astrocytes may communicate with neurons at NMDA sites via GABA in hippocampus
 control # of functional synapses
 excitable via Ca2+-signaling mechanisms

 Clinical Correlates:
 Alzheimer’s disease:
 abnormal clusters of protein fragments between cells (plaques)
 dead & dying nerve cells contain twisted strands of proteins (tangles)
 ADHD
 from under-pruning
 visible condition at age 7 (pruning is slow)
NEUROTRANSMITTER TARGETS
 Agonist Spectrum:
 Agonist: what the body uses ONLY, produce tolerance & withdrawal
 Partial agonist:
 stabilizers
 have part of the effect of an agonist
 too much potent partial agonist displaces agonist  withdrawal symptoms
 Antagonist: no effect by itself, requires agonist pair (usually)

 DOPAMINE:  SEROTONIN:
 Disease targets:  Disease targets:
 Parkinson’s Disorder  depression
 Attention Deficit Disorder  OCD & other anxiety disorders
 Schizophrenia  pain
 Nigrostriatal pathway:  Synthesis: in Raphe nuclei (midline neurons
in brainstem)
 cell bodies in substantia nigra
 axons to striatal pathway  Receptors:
 Receptors: all metabotropic  5HT1 family: metabotropic
 D1 Family: D1, D5   cAMP • temp regulation, mood, anxiety
 D2 Family: D2, D3, D4   cAMP • migraines, anxiety, depressive
 Function: disorders

 motor planning & execution  5HT2 family: metabotropic

 reward processing • mood, anxiety
 cognition, attention, working memory, • antidepressants, antipsychotic drugs
motivation
 mood, emotions  5HT3 family: ligand-gated inotropic
 sleep • emesis
 prolactin production
 Transporter:
 L-variant gene: longer, more protein,
more serotonin reuptake (OCD, etc…)
 S-variant gene: shorter, less protein,
slower transporter transmission
 Function:
 fear and flight reaction
 sensory processing
 pain control
 sleep-wake cycle
 appetite control
 emotions, psychosis
 excitatory or inhibitory
 NOREPINEPHRINE:
 Disease Targets:
 opiate withdrawal
 anxiety, stress-related disorders
 depression
 pain, inflammation
 Receptors:
 α1:
 α2: presynaptic
 β:
 Functions:
 arousal
 sleep wake cycle
 pain, inflammation
 emotions
 learning and memory
 ACETYLCHOLINE:
 Disease targets:
 Alzheimer’s disease
 Receptors: in basal ganglia, basal nucleus of Meynert, septal area of hippocampus  memory
 M1, M2, M3, M4, M5: metabotropic
 Functions:
 CNS: cortical activation, cognitive functioning, REM sleep, motor coordination
 PNS: heart, lung, upper GI, sweat & salivary glands, pupil size, blood vessels
 GABA:
 Disease targets:
 acute anxiety
 sleep onset & duration
 epilepsy
 Receptors: Cl- channels open directly or indirectly
 GABA A: ionotropic
•  Cl- conductance
 GABA B: metabotropic
•  K+ conductance
• inhibitory interneurons at all levels
 Functions: major inhibitory neurotransmitter
 motor coordination
 sleep-wake cycle
 modulate excitatory neurons
 GLUTAMATE:
 Disease targets:
 epilepsy (block NMDA, AMPA, kainate)
 cognition (partial agonists, agonists)
 hallucinations
 neuronal excitotoxicity
 neurodevelopmental & degenerative diseases
 Synthesis:
 released as glutamate, taken up by astrocytes, converted to glutamine
 astrocytes release glutamine, taken up by glutamatergic neuron, converted to glutamate
 Receptors: pyramidal cells in cerebral cortex mainly
 NMDA: ionotropic
• blocked by Mg ion (removed by depolarization)
• opened by glutamate & glycine binding (depolarization still required to remove Mg ion)
 AMPA: ionotropic
 Kainate: ionotropic
 Glutamate receptors (8 subtypes): metabotropic
• 1  NMDA receptor activity
• 2  NMDA activity
 Functions: excitatory neurotransmitter
 long-term potentiation (memory, learning)
 neuronal regulation (plasticity)
 Clinical Correlates:
 Schizophrenia:
 dopamine too high and too low in different areas
 Drug Targets: antipsychotics
• dopamine neurons
• serotonin neurons
• glutamate
 Bipolar Disorder (Mood Disorder II):
 Mania state drug targets: similar to schizophrenia (high dopamine areas)
 Depression state drugs: atypical antipsychotics mixed with antidepressants
 Depression:
 low serotonin or other monoamines
 weak or damaged neurons in hippocampus
 treat with exercise, learning, growth factors, antidepressants (reuptake inhibitors), therapy
 Attention deficit disorder (ADD):
 low dopamine and NE in cortex
 treat with drugs to enhance nt’s in cortical brain areas
 50% of children grow out of disorder
 Anxiety Disorders:
 treat by enhancing GABA A channels, antidepressants
 Sleep Disorders:
 altered GABA A function
 treat with drugs
 Epilepsy:
 excessive neuronal firing
 treat with drugs that enhance GABA (block ion channels)
 Degenerative disorders:
 Alzheimer’s disease – cholinergic system loss
 Parkinson’s disease – dopaminergic system loss
 Drug Abuse:
 euphoria by enhancing dopamine in nucleus accumbens
 treat by minimizing euphoria & withdrawal symptoms
• slow reduction of drug
• change to longer acting drug with longer half life
• give an alternative drug with similar mechanism (often same class)
PAIN & TREATMENT
 Pain Descriptions:
 Fast/Stinging vs. Slow/Burning
 Epicritic – easily discriminable, well-localized
 Protopathic – not definitely localized, described generally only
 Pain Classifications:
 Acute Pain – occurs in response to tissue trauma, accompanies pathology, resolves with healing
 Headache
 Chronic – extends beyond healing, not explained by pathology, disrupts sleep/normal activities
 Neuropathic
• peripheral neuropathy complicated by CNS changes (sensitization, reorganization of dorsal horn)
♦ sensitize w/ frequent stimulation, don’t adapt like usual (C fibers)
 mediated by repeat activation of NMDA receptors (Wind-up Theory)
 inflamed tissue very sensitive after wind-up
 more Na+ channels = more firing at lower stimulus
♦ Nerve lesion (denervation of Aβ  inhibitory interneuron inputs)
 glutamate excitotoxicity
• disproportionate to stimulation of receptor (hyperalgesia & allodynia), not protective
• Pathologic pain – burning, electric, tingling, shooting, in normal areas, aggravated by touch
• chronic & severe cases unresponsive to OTC analgesics
 Mixed
 Nociceptive
• proportionate to stimulation (degree of injury)
• protective (injury, malignancy, infection, inflammation, tissue damage)
• Types: post-operative pain, acute burns, bone fractures
♦ Visceral – diffuse, gnawing or cramping (liver)
♦ Somatic – well localized, sharp, aching, throbbing (bone)
• Nociceptor Types:
♦ Mechanical (crushing pressure, large receptive fields)
♦ Thermal (45◦C, < 15◦C)
♦ Polymodal (high threshold mechanical, chemical, thermal)
• Nociceptor fibers:
♦ Aδ – fast, thin, myelinated, localized intense pain (the 1st pain felt) - glutamate
♦ C – slow, small, unmyelinated, slow throbbing long-lasting pain - glutamate
• Excitation:
♦ damaged tissue releases bradykinin, 5-HT, prostaglandin  excite nociceptors
♦ Nociceptor nerve endings release substance P & CGRP
 Substance P - causes histamine release from Mast cells  excites nociceptors
 CGRP – dilates blood vessels  edema & additional bradykinin release
 Pain Suppression:
 Periaqueductal grey (PAG) – Nucleus Raphe Magnus (NRM) System – Spinomesencephalic tract
 PAG neurons (enkephalin-rich) inhibit (via GABA) NRM neurons under normal conditions
 Lamina V neurons activate PAG via Spinomesencephalic tract (via collateral if pain intense)
 activated PAG stop inhibiting NRM (via enkephalin)  NRM neurons activated (disinhibited)
 NRM excites enkephalinergic interneurons more enkephalin release =  nociceptor fibers activity
 Gate-Control Theory:
 Both nociceptive & some non-nociceptive neurons use spinothalamic tract
 Stimulated large Aβ fibers activate inhibitory interneuron  small C fibers (pain) suppressed
 Aβ fibers activated through deep rubbing (massage)
 Clinical Correlates:;
 Congenital pain insensitivity:
 autosomal-recessive
 cannot feel acute pain
 Children have skin lesions, bone fractures, bite tongue, etc…
 Phantom Limb Pain:
 sensation of pain after amputee of body part
 Thalamic Pain Syndrome:
 lesions to posterior thalamus  chronic pain
 Referred Pain:
 Lamina V receives non-nociceptive & nociceptive fibers
 Visceral nociceptive fiber impulse carried to shared interneuron
 Body thinks pain is from non-nociceptive innervated region (i.e. skin)
INTRO ENDOCRINE PHARMACOLOGY
 Prototype drug – member of a group of drugs, against which other members of the group are compared
 not necessarily drug of choice
 Hormone Chemical Nature:
 Route of Administration:
 peptide/protein/glycoprotein hormones  IV, IM, SC, intranasally, intraocularly
 Steroid hormones  absorbed from all epithelial surfaces
 thyroid hormones  oral
 Biological half-life:
 Increasing order:
• small peptides
• proteins
• glycoproteins
• steroids (minutes – hours)
• modified AA’s/thyroid hormones (days)
 MOA:
 peptide/protein/glycoprotein hormones  membrane-bound receptors (rapid)
 steroid hormones  intracellular receptors (slow, prolonged), membrane receptors (rapid, short)
• substrates of p450 reactions (activation & deactivation)
 thyroid hormones  intracellular receptors (slow, prolonged)
 Ability to formulate drugs & analogs:
 small peptides  chemically synthesized, easy analog production
 larger proteins  rDNA, analog production possible
 glycoproteins  isolation from biological products
 Molecular/Cellular MOA:
 Agonist vs. Antagonist:
 agonist  activates receptor (causes receptor’s action)
 antagonist  prevents agonist binding the receptor (stops receptor’s action)
 Signaling mechanism & drug actions:
 membrane receptors (peptides & proteins)
• g-protein coupled
• enzyme-linked
• ion channel-linked
 intracellular receptors (thyroid hormones & steroids)
• transcription factors – bind as heterodimers or homodimers
 Ligand/receptor promiscuity:
 multiple receptors for single signal = many subsets of effects
  Desensitization:
 from continuous, high dose exposure of ligand
 loss of responsiveness via internalization of receptor or metabolism of receptor
 pulsatile delivery vs. continuous
 Therapeutic applications:
 Hormone replacement therapy
 Control inappropriate hormone secretion
 Evoke or block hormone action for desired metabolic effect
 Determine where malfunction is in the feedback system