Exam 4 - Lecture 37-38, Pharmacology of Sympathomimetics

NE, E, DA

a and b adrenergic receptors Dopamine receptors Monoamine transporters biosynthetic pathways

Releases E and NE Increases Heart and Lung action Constricts bodily blood vessels, but increase blood flow to muscle Increase BP, HR, BS, and fats Releases Glucagon (increase glucose) Inhibit digestion, relax bladder and inhibit erection Promote clotting

NET, DAT, SERT transport monoamines, rely on Na gradient to passively transport monoamines

responsible for pacing monoamines into vesicles preventing MAO degradation. relies on trans-vesicular proton gradient for driving force Vesicles contain ATP and chromogranin A

Passive transport, no ATP Bind 1 molecule or ion, changes conformation and releases cargo opposite side of membrane Transports HA, 5HT, NE, DA, MPP+ Found on SM, Cardiac Muscle, Endothelium inhibited by drugs of abuse; cocaine, MDMA, amphetamines

Describes the property of a ligand having greater affinity for one receptor over another Can be “overcome” with high concentrations of ligand, when other receptors experience binding and activation

Depends on drug structure, dose, receptor number, receptor status, physiology, disease state, polymorphisms, species Also mood, atmosphere, place, diet, will, spirituality

Vmat2 over Vmat 1

EMT as quick transport and has higher saturation than Neuronal MT

Bronchi GI tract GI sphincters Uterus Bladder sphincter Seminal tract Iris (radial muscle) Liver (hepatocytes) Salivary gland

GI tract Directly on Pancreatic islet (beta cells) + Platelets Brain stem Nerve terminals Predominantly presynaptic nerve terminals on brainstem causing presyanptic inhibitory effect

HEART and salivary gland

BRONCHI and uterus, heart, mast cells, liver

Bladder detrusor Skeletal muscle Fat

Calcium binds troponin allowing for troponin to interact with actin/myosin allowing for muscle contraction Fast and direct mechanism, little pharamcological activity

Still fast but has a plateau period (~100ms) after initial rapid depolarization. Cardiac specific RyR Ca channels release Ca2+ from sarcoplasmic reticulum. contractile machinery of Troponin/Ca troponin resembles SKM Ca2+ release from RyR Ca channels may cause arrhythmia. Of interest in adrenergic blockers

Large organ variance in contraction. ** Not entirely dependent on depolarization as GPCR ligands by IP3 trigger Ca2+ release from the ER. cAMP regulates myosin Lc kinase and myosin phosphatase to balance contraction/relaxation several ways to have smooth muscle contraction

Epinephrine> Norepinephrine affinity (but effect same) a1 stimulates Gq coupled to PLC; PLC gets phosphorylated (activated) PLC then hydrolyzes phosphoinositides, produces IP3 and DAG DAG activates PKC and leads to cellular response IP3 releases stored intracellular Ca and activates Ca channels increased cytoplasmic Ca activates Ca dependent kinases leading to cellular response Predominantly found in SM, all types of SM (except GI tract) contract in response to stimulation of a1-adrenoceptors

Contraction (narrowing)

relaxation(decrease motility) + contraction (decrease motility)

contraction (child birth/miscarriage)

contraction (narrowing)

contraction (ejaculation)