Catecholamine Catch & Release Indirect Sympathomimetics

2.2 – “Catec “Catecholamine holamine Catch & Release”: Indirec Indirectt sy sympathomimetics mpathomimetics (coca (cocaine, ine, ephedrine, amp amphetamine, hetamine, met methylphenidate, hylphenidate, modafinil, ato atomoxetine) moxetine) • Indirect sympathomimetics enhance catecholamines by displacing them from nn ending or by inhibiting reuptake or metabolism (same scene, indirect perspective. Mime for mimetics. Catecholamine catfish). All act to ↑catecholamine concentration at adrenergic nerve terminals (dock = nerve terminals) • Adrenergic transmission at the synapse: o Tyrosine precursor to catecholamines is transported to nn terminals (tire being drawn to dock). o Once at terminal, tyrosine → L-dopa→ dopamine (tyrosine tire, L-shaped winch handle, dopamine dope rope). • In dopaminergic neurons, here ends the process. • In most sympathetic presynaptic nn, dopamine in vesicles is converted to E & norepinephrine (vessel) o Dopamine is converted to norepinephrine by dopamine β-hydroxylase (navigator with North oriented compass) o Dopamine is then release from the vesicle in response to intracellular ↑Ca o Synaptic transmission is discontinued by diffusion of dopamine or reuptake into the cell o NE Transporter (NET) transports catecholamines back into the presynaptic neuron; DAT is specific to dopamine (hauling in a net of catfish on presynaptic dock; “NET DAT Catfish!”) o Can be recycled into vesicles by vesicular monoamine transporter (VMAT) (catfish being hauled in on mat with Vs) Dopamine Rece Receptor ptor activat activation ion • D1 is a GsPCR, D2 is Gi (Dope Rope Swing – for D1 & D2 respectively) o D1 ▪ GsPCR→↑cAMP → PKA activation → smooth muscle relaxation • Renal vasculature stimulation → ↑ RBF, GFR, Na excretion. This is in contrast to norepinephrine & E α1-mediated constriction of renal afferents (Dope Rope 1 has a kidney on the end) ▪ DBA • Dopamine activates dopamine Receptors at low doses, β-adrenergic receptors ad higher doses, & α-adrenergic receptors at high doses. (bugler higher than kidney & scout with single candle highest up) o D2 (swing with 2 ropes) ▪ Important in CNS • Metyrosine (counselor claiming, “my tire!”) o a tyrosine analog o inhibits conversion of tyrosine to L-dopa • Cocaine o Inhibits NET & DAT → accumulation of NTs in synapse (scouts with hot cocoa not taking up net). Results in a variety of effects: ▪ Peripherally: HTN, tachycardia, mydriasis (flushed scout); coronary vasospasm, angina, a/o MI (crown on mug; angina anvil; clutching chest) ▪ Central DAT inhibition →↑dopamine in CNS → arousal, addiction, seizures o May see nasal mucosal atrophy or septal perforation d/t vasoconstriction (scout with bloody nose) o Management is supportive. NEVER give β-blockers; will → unopposed α1 action & HTN crisis (β1 bugle causing excessive head pressures) • Atomoxetine inhibits NET o Treats ADHD (kid distracted by AD channel in HD next to net) • Reserpine (serpent blocking catfish storage) o Inhibits VMAT o Not used clinically • Amphetamines (Friend of Mine shirt on ichthyophile) o CNS stimulated via norepinephrine > dopamine release. Mood elevating effect. Improved attention to repetitive tasks, & stimulating effects o Appetite suppression effects (untouched plate of dinner) o Methylphenidate for ADHD (distracted kid watching “Friend Date” on HDTV) o Modafinil used for narcolepsy (clock in sleep mode) ▪ Fewer adverse effects than straight amphetamines