Pharmacology Unit 4 Study Guide PDF

**Glutamatergic Pharmacology** major excitatory neurotransmitter - Synthesis of Glutamate: alpha-ketoglutarate glutamate by GABA-T - Storage: in vesicles through VGLUT - Antiporter= H+ out, glutamate in - Release: in response to action potential ↑ Ca+2 Exocytosis into synaptic cl...

**Glutamatergic Pharmacology** major excitatory neurotransmitter - Synthesis of Glutamate: alpha-ketoglutarate glutamate by GABA-T - Storage: in vesicles through VGLUT - Antiporter= H+ out, glutamate in - Release: in response to action potential ↑ Ca+2 Exocytosis into synaptic cleft - Deactivation: 1. Reuptake into presynaptic nerve terminals by Gt(n) transporters 2. Uptake into glial cells by glial Gt(g) transporters - GluGln through glutamine synthetase, Gln migrate to presynaptic nerve terminals, then GlnGlu by mitochondria-associated glutaminase - Ionotropic Glutamate Receptors: \*all ion channels\* - Subtypes: AMPA, Kainate, NMDA - AMPA: ↑Na+ influx, ↑K+ efflux - Kainate: ↑Na+ influx, ↑K+ efflux - ANMDA: ↑Ca+2 influx, ↑K+ efflux spinal cord - Glutamate-gated ion channels (Na+, K+, Ca+2) (DIRECT) - Fast response, excitatory - Metabotropic Glutamate Receptors (mGluRs) \*all GPCRs\* - Subtypes: Group I (2), Group II (2), Group III (4) - Group I (only POST-Synaptic neurons) ↑ neuronal activity - Activate AC or PLC and inhibit K+ to ↑ neuronal activity - Group II ↓ neuronal activity - Post-synaptic: inhibit AC and activate K+ = ↓ neuronal activity - Pre-synaptic: inhibit AC and Ca+2 = ↓ neuronal activity - Group III (only PRE-Synaptic neurons) ↓ neuronal activity - Inhibit AC = ↓ neuronal activity - Negative feedback: inhibit Ca+2 ↓glutamate release = ↓ neuronal activity - Affect ion channels through secondary messengers (INDIRECT) - Slow response - Gαs: activates adenylyl cyclase (AC) = ↑cAMP↑PKC= ↑phosphorylation = ↑ neuronal activity - Gαi: inhibits adenylyl cyclase = ↓cAMP ↓PKC = ↓neuronal activity - Gαq: activates phospholipase C (PLC) ↑IP3 and ↑DAG ↑Ca+2 and ↑PKC= ↑neuronal activity - Affect both pre- and post- synaptic neurons 1. Post-synaptic modulation a. α subunit AC/PLC b. βγ subunits K+ efflux/Ca+2 influx 2. Pre-synaptic modulation = negative feedback modulation c. ↓Ca+2 ↓ glutamate release - Pathophysiology (can induce seizures) Excitotoxicity - Caused by disruption of glutamate neurotransmission - ↑ glutamate release or ↓ glutamate uptake ↑ synaptic glutamate ↑Ca+2 = degradation of enzymes cell death - Neurodegenerative disease: Alzheimer's, Parkinson's, Huntington\'s, ALS - Clinical Applications (drugs) decrease excitotoxicity 1. Riluzole (treat ALS): ↓Na+ ↓action potential ↓glutamate release 2. Memantine (treat AD) and Felbamate (refractory seizures): ↓Ca+2 influx = NMDA receptor antagonist 3. Amantadine (treat PD): ↓Ca+2 influx; used with levodopa to ↓ dyskinesia 4. Lamotrigine (refractory seizures): stabilize Na+ channel ↓ action potential ↓ glutamate release 5. Lecanemab (treat AD): monoclonal antibody that removes plaque from the brain, slowed progression by 27% 6. Donanemab (treat AD): monoclonal antibody to remove plaque for mild AD, slowed progression by 32% **GABAergic Pharmacology** major inhibitory neurotransmitter - Synthesis: glutamate GABA by GAD - Storage: synaptic vesicle by VGAT (antiporter H+ out, GABA in) - Release: response to action potential ↑ Ca+2 influx ↑ exocytosis - Deactivation: 1. Reuptake into presynaptic nerve terminals 2. Uptake into glial cells by GAT (GABA transporters) - GABA succinic semialdehyde by GABA-T Succinic acid Krebs cycle alpha-ketoglutarate glutamate by GABA-T glutamine presynaptic nerve terminals \*GABAnergic neurons only release GABA and Glutamatergic neurons only release glutamate\* - Ionotropic GABA receptors - GABAa and GABAc - GABAa most abundant GABA receptor in CNS (regulated by modulators) - Pentamer (2 α, 2 β. 1 γ subunit) - 2 GABA binding sites between α and γ subunits - 2 GABA bind to binding sites ↑Cl ↑hyperpolarization = ↓action potential - Modulatory sites: do NOT directly regulate the receptor channel (benzodiazepenes) - Inhibition of GABAa receptors = seizures - Mutations in GABAa = epilepsies - Enhanced GABAa receptor = ↓ neuronal excitabilityimpairment of CNS - GABAc receptor (retina) - Pentameric Cl- channels - GABA gated Cl- channels Cl- influx=↑polarization and ↑threshold, need more + to overcome the -- threshold to activate the neuron (direct) - Fast response, inhibitory - Metabotropic GABA receptors (GPCR) - GABAb activation inhibits ion channel = ↓ GABA release (SPINAL CORD) - Presynaptic negative feedback modulation: ↓Ca+2 influx ↓GABA release↑postsynaptic neuronal excitability - Postsynaptic inhibitory modulation (Gαi): - α inhibits AC/PLC ↓ neuronal activity - βγ ↑K+ efflux/↓Ca+2 influx ↓ neuronal excitability - Affect ion currents through secondary messengers (indirect) - Slow response **GABAergic Drugs (no GABAc drugs)** - Clinical applications: sedation, hypnosis, seizure control, neuroprotection - Inhibitors of GABA Metabolism 1. Tiagabine (epilepsy): inhibit GAT-1 = block reuptake of GABA ↑GABA in cleft = ↑ GABAergic transmission 2. Vigabatrin (epilepsy): inhibit GABA-T = block degradation of GABA = ↑concentration of GABA in vesicle ↑GABA release - GABAa receptor agonists and antagonists (not drugs, natural compounds) 1. Muscimol 2. Bicuculline 3. Picrotoxin - GABAa modulators (efficacy: barbiturates\>benzodiazepines; potency: benzodiazepines\>barbiturates) - Benzodiazepines (treat anxiety) metabolized by hepatic P450 in liver (drug-drug interactions) - Bind modulatory site between α and γ - Only bind to GABAa receptors (α1, α2, α3, α5 require histidine residue) - Enhance GABAa receptor = ↓postsynaptic neuronal excitability - Potentiate the inhibitory affects of GABA - Use benzodiazepines in addition to P4S to enhance maximal activation - Use for short-term (long-term = tolerance, dependence, addiction) 1. Chlordiazepoxide (alcohol withdrawal syndrome) 2. Midazolam (sedation) 3. Alprazolam (panic disorder) 4. Lorazepam (insomnia, seizures) 5. Clonazepam (panic disorder and seizures) 6. Diazepam (sedation, seizure disorders, muscle spasm, alcohol withdrawal syndrome) 7. Clobazam (Lennox-gestalt syndrome) 8. Triazolam, Estazolam, Temazepam, Flurazepam, Quazepam (insomnia) 9. Z-drugs (zolpidem, zaleplon) treat insomnia only bind α1 subunit - Barbiturates replaced by benzodiazepines (enhance the inhibitory efficacy of GABA) - Wide-spread affects (non-specific GABA subunit)affect all subunits - Suppress RASsedation, amnesia, loss of consciousness - In the spinal cord, relax muscles and suppress reflexes - OD causes death OD treated with sodium bicarbonate (IV) ↑ clearance of barbituates - Pharmacologic effects: inhibit glutamatergic neurotransmission ↓ AMPA ↓ neuronal excitability 1. Pentobarbital (anesthetic): agonist at GABAa receptors (enhance GABAa responses) - ↓Na+ channels ↓ neuronal excitability 2. Phenobarbital (anticonvulsant): less direct agonism on GABA (treat seizures) - Etomidate/Propofol: induction of anesthesia bind to receptors that contain β2 and β3 subunits - High concentrations = GABAa agonist - Low concentration = potentiate GABAa receptor activation by GABA - GABAb receptor agonists 1. Baclofen GABAb receptor activation ↑ postsynaptic K+ efflux = inhibition of neurotransmitters - Treatment of spasticity associated with motor neuron disease or spinal cord injury - Withdrawal syndromes are treated with benzodiazepines or propofol **Dopaminergic Pharmacology** - Monoamine: dopamine, norepinephrine, epinephrine, serotonin, and tyramine (dietary) - Use VMAT to get into vesicle - Tyramine: metabolized by MAO-A, NET takes up and transports by VMAT - Push norepinephrine out of vesicle into terminal hypertensive crisis - Catecholamine: dopamine, norepinephrine, epinephrine - Dopamine synthesis: tyrosine L-DOPA by TH (rate limiting) dopamine by AADC - Storage: synaptic vesicle through VMAT (antiporter) - Release: in response to action potential ↑ Ca+2 influx exocytosis - Deactivation: reuptake into presynaptic terminal by dopamine transporter (DAT) 1. Recycled back into vesicles for further use 2. Degraded by monoamine oxidase (MAO) - MAO-A (periphery), non-selective and metabolizes all monoamines, inhibition=toxicity - MAO-B (brain), oxidizes dopamine, inhibition=↑ dopamine in brain - COMT (brain and periphery) - Dopamine Receptors: D1 and D2 both located in the striatum and limbic system - D1: increase neuronal activity - D2: decrease neuronal activity - Short presynaptic - Long postsynaptic - Central Dopamine Pathways: 1. Nigrostriatal (SNPc): substantia nigra striatum a. Longest and associated with Parkinson's Disease 2. Mesocorticolimbic (VTA): midbrain frontal cortex and limbic system b. Schizophrenia 3. Tuberoinfundibular (hypothal): hypothalamus c. Inhibits prolactin secretion d. Source of side effects 4. Area postrema (emesis center) control connection between blood and brain e. Stimulation of D2 receptors nausea and vomiting f. Source of side effects - Human disease due to Dopamine: - Parkinson's Disease - Schizophrenia - Drug addiction - Parkinson's Disease - Male predominance - Motor features: resting tremor, rigidity, bradykinesia, impaired postural balance - Non-motor features: cognitive impairment and dementia - CAUSED BY: loss dopaminergic neurons in SUBSTANTIA NIGRA - Environmental cause: MPTP - Genetic cause: alpha-synuclein mutations - Nigrostriatal Pathways in Control Movement 1. Substantia Nigra a. In midbrain b. Headquarter of Dopaminergic neurons c. Consists of 2 parts: Pars Compacta (SNc input) and Pars Retiulata (SNr output) 2. Striatum d. GABAergic neuron that expresses D1 or D2 receptors i. D1 = direct pathway ii. D2 = indirect pathway e. Cholinergic interneurons = communication between the direct and indirect pathways 3. Thalamus f. Relays sensory and motor signals to the cerebral cortex (spinal cord) iii. Spinothalamic tract (sensory) iv. Thalamocortical radiation (basal ganglia and the cortex) - Cortico striato pallido thalamo cortical loop - The direct pathway (D1 receptors): GABA release inhibition of GABA release in thalamus cortex - Activation = stimulates movement - The indirect pathway (D2 receptors): GABA release in STNglutamate release in GPi GABA release in thalamus NOT go to cortex - CAUSE of Parkinsons disease - Activation = inhibits the movement - Under Normal Conditions: ↑ Dopamine release in striatum = ↑ direct pathway = promote movement - Under Parkinson's Disease Conditions: ↓ Dopamine release in striatum = ↑ indirect pathway = inhibit movement - Anti-Parkinson Drugs: Treatment Strategies - Restore dopaminergic activity in striatum (Dopamine precursors, Dopamine receptor agonists, and inhibit Dopamine degradation) - Dopamine Precursors: - Advantages: symptomatic improvement - Disadvantage: gradual loss of therapeutic efficacy of prolonged usage, fluctuation in motor functions ("on/off") - Side effect: dyskinesias = involuntary movement associate with too much dopamine 1. L-DOPA and Carbidopa - L-DOPA dopamine by AADC in GI tract - Carbidopa inhibits AADC = ↑ L-DOPA entry into the brain 2. Istradefulline: promotes D2 receptor activity ↓ indirect pathway activity - Selective adenosine A2A receptor antagonists - Dopamine Receptor Agonists only affect D2 receptors - ↓ activity of indirect pathway = ↑ movement - Advantages: longer half-lives (dosing more convenient), delayed onset of "off" periods and dyskinesias - Disadvantages: adverse cognitive effects (excessive sedation, hallucinations) and dopamine dysregulation syndrome 1. Pramipexole 2. Ropinirole - Inhibitors of Dopamine Degradation 1. Selegiline: - at low concentration selective for MAO-B - at high concentration inhibits MAO-A 2. Rasagline - MAO-B inhibitor 3. Tolcapone/Entacapone - COMT inhibitor - Entacapone: inhibits the peripheral metabolism of L-DOPA - Most widely used COMT inhibitor - Tolcapone: inhibits the metabolism of both dopamine and L-DOPA - Associated with fatal hepatic toxicity - Non-dopaminergic Drugs treat symptoms 1. Amantadine: NMDAR (glutamate receptor) antagonist - Used to treat L-DOPA induced dyskinesias 2. Trihexyphenidyl/Benztropine: mAChR (muscarinic ACh receptor) antagonists - Inhibit striatal cholinergic activity - More effective for tremors than bradykinesia - Parkinson's Treatment theory: 1. Start conservatively (non-dopaminergic drug) 2. When symptoms advance (use dopaminergic drug) 3. Young patients use D2 receptor agonists, NOT used in elderly patients 4. Then use L-DOPA as last treatment of Parkinson's disease for most efficacy - Schizophrenia: characterized by one or more episodes of psychosis - Positive symptoms (development of abnormal functions): - Delusions - Hallucinations (auditory and visual) - Disorganized speech - Catatonic behavior - Negative symptoms (loss of normal functions) - Affective flattening, alogia, avolition - Schizophrenia Pathophysiology: opposite to Parkinson's Disease - Excessive dopamine neurotransmission in striatum - Caused by dysregulation in 2 locations: 1. Mesolimbic system hyperactivity = positive symptoms of schizophrenia 2. Mesocortical system hyperactivity = negative symptoms of schizophrenia - Drugs used to treat Schizophrenia antipsychotics - Typical antipsychotics: D2 receptor antagonism - Antagonists in mesolimbic pathway - More effective to treat + symptoms - Adverse effects: - On-Target effects (D2 antagonism outside of the mesolimbic system) 1\. Extrapyramidal effects 2\. Neuroleptic malignant syndrome (hypothalamus) 3\. Tardive dyskinesia (D2 in striatum) 4\. Increased prolactin secretion - Off-Target effects: 1. Anti-cholinergic (muscarinic) effects = dry mouth, constipation, difficulty urination 2. Anti-adrenergic effects: hypotension, sedation 1. Chlorpromazine: D2 antagonism a. Therapeutic efficacy and extrapyramidal adverse effects b. Higher affinity for D2 receptors = lower doses to control psychotic symptoms - Atypical antipsychotics: act on D4, 5-HT2A, D3, and D2 (but less prominent antagonism) - More effective for negative symptoms - Significantly less D2-mediated adverse effects \- reduces both POSITIVE and NEGATIVE symptoms