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Adrenergic Pharm
Introduction to Autonomic Pharmacology 1: Adrenergics
| Question | Answer |
|---|---|
| Where are the cell bodies of the sympathetic nervous system? | In the lateral horns of the spinal segments, T1-L2 (thoracolumbar outflow) |
| How do the postganglionic sympathetic fibers travel? | After synapsing in one of the sympathetic chain ganglia, return to chain via grey communicating rami-->conveyed to effector organ |
| All pre-ganglionic sympathetic neurons release ___. It acts on a ___ receptor at the preganglionic synapse. | Acetylcholine (ACh); nicotinic |
| The ___ ___ is embryologically and anatomically similar to the sympathetic ganglia; it is innervated by preganglionic fibers that travel via the ___ ___ and directly synapse with chromaffin cells. | Adrenal medulla; greater splanchnic nerve |
| What are release by the adrenal gland? | Catecholamines are released from the adrenal gland by release of Ach and stimulation of nicotinic (cholinergic) receptors |
| In general, ALL sympathetic postganglionic neurons release ____. What is the only exception? | Norepinephrine; sweat glands (acetylcholine [cholinergic]) |
| Describe the synthesis pathway for the conversion of tyrosine to epinephrine | Tyrosine --> DOPA --> Dopamine --> Norepinephrine --> epinephrine |
| What is the first step in norepinephrine synthesis? | Uptake of amino acid L-tyrosine by adrenergic neurons, where it is synthesized into DOPA by tyrosine hydroxylase (RATE LIMITING STEP) |
| Where is dopamine converted norepinephrine? | In the storage vesicles; converted by dopamine-beta-hydroxylase |
| In adrenergic neurons, the end product of tyrosine is ___; in adrenal gland, the syntehsis is carried one step further to give ___. | Norepinephrine (neurotransmitter); epinephrine (neurohormone) |
| What substance(s) does the adrenal gland release when stimulated? | 80% epinephrine; 20% norepinephrine |
| Why does the neuron store NE in vesicles (as opposed to letting them stay in the cytosol)? | Storage in vesicles DECREASES its intraneuronal metabolism and its leakage outside of the cell |
| What is VMAT2? | Vesicular monoamine transporter (nonspecific); transports catcholamines (DA, NE, and Epi) and serotonin |
| What does reserpine do? | Antihypertensive; Inhibits VMAT2 and ultimately displaces NE from nerve terminals to extracellular fluid |
| What does guanetidine do? | Antihypertensive; inhibits release of stored NE |
| What does amphetamine do? | Stimulates NE release |
| NE is released from nerve endings by action potentials via ____. | Exocytosis |
| What 5 things can happen to released NE? | Neurotransmission, autoregulation of neurotransmission, NE spillover, Uptake-1, Uptake-2 |
| What is neurotransmission? | When NT interacts with postsynaptic receptor |
| What is autoregulation of neurotransmission? | When NT interacts with PREsynaptic receptor |
| What is NE spillover? | When the NT diffuses out of synaptic cleft into circulation |
| What is uptake-1 of NE? | When NE is taken up by active transport through presynaptic membrane and back into sympathetic nerve ending |
| What is NET? What inhibits it? | NET is the norepinephrine transport (involved in Uptake 1); inhibited by cocaine and TCA |
| What is Uptake-2? | NE is taken up through postynaptic membranes by other tissues |
| What is ENT? What inhibits it? | ENT is the extraneuronal transporter involved in Uptake-2; inhibited by corticosteroids |
| What transporter system is responsible for most of the recapture of transmitter in the nerve terminal? | High affinity transporter system (Uptake-1), aka NET |
| Wha main mechanism that terminates the action of NE? | Uptake-1 |
| What is the ultimate fate of the spilled-over NE? | metabolized by monoamine oxidase (MAO) or catechol-o-methyl transferase (COMT), which are widely distributed |
| Why would inhibition of MAO and COMT not be an effective way of potentiating the effect of NE in the system? | Only a small fraction of NE spills over (8%), and reptake removes most of it (in synaptic cleft) |
| What is the ultimate metabolite product that appears in the urine from catecholamines (including NE) that spill over into system? What enzymes synthesize it? | Vanillylmandelic acid (VMA); MAO and COMT (in any order, but has to be both) |
| What would happen if you inhibited tyrosine hydroxylase? | Can't convert tyrosine to DOPA-->rate limiting step in production of NE-->DEPLETION OF NE! |
| What would happen if you inhibited the transporter system at the nerve terminal (e.g. via cocaine or TCA)? | Buildup of NE at the receptor (increased activity!) |
| What would happen if you inhiited the trasnporter system at the storage vesicles? (e.g. via reserpine)? | Depletion of NE from adrenergic terminals and subsequent destruction of NE by MAO |
| What would happen if you promoted NE exocytosis or NE displacement from vesicles (e.g. via amphetamines)? | sympathomimetic |
| What does sympathomimetic mean? | A response that mimics the sympathetic system |
| What would happen if you prevented NE from being released from storage vesicles (e.g. via bretilium, or guanetidine)? | Sympatholytic (inhibits postganglionic sympathetic pathway), antihypertensive |
| What would happen if you inhibited catcholamine metabolism (e.g. via non-selective MAO inhibitors)? | Little effect on NE or sympathetic response? potentiation of tyramine |
| What would happen if you inhibited catecholamine metabolism (e.g. via COMT inhibitors) | Antiparkinson effects |
| What would happen if you mimicked NE at the postsynaptic sites (e.g. via alpha-1, alpha 2, beta 1, and beta 2 agonists)? | Sympathomimetic response (DERP) |
| What is the rank of potency of the agonists for the beta adrenergic receptor? | Isoproterenol>Epi>>NE |
| What is the rank of potency of the agonists for the alpha adrenergic receptor? | Epi>=NE>>Isoproterenol |
| What are the different types of adrenergic receptors? | Alpha: 1 (A,B,D), 2(A,B,C) and Beta: 1,2,3 |
| What are the different types of dopamine receptors? | Dopamine1-like (D1 and D5) and Dopamine2-like (D2, D3, D4) |
| What is the binding affinity of norepinephrine for different receptors (high to low)? | alpha1, alpha2, beta1 |
| What is the binding affinity of epinephrine for different receptors (high to low)? | beta2, beta1, alpha1, alpha2 |
| What is the binding affinity of dopamine for different receptors (high to low)? | D > alpha 1 ; (where D can be D1 or D2) |
| What does stimulation of the alpha2 receptor on sympathetic nerve by NE do? | Inhibits further release of NE |
| What does the alpha2 receptor in the brain do? | In vasomotor center: inhibits central sympathetic outflow. Giving alpha2 agonist will induce central sympathetic outflow and stimulation |
| What does stimulation of the alpha1 receptors on vascular smooth muscle cells do? What about alpha2? | Induces vasoconstriction; also vasoconstricts |
| * * What is the most predominant alpha1 receptor in prostate? In blood vessels? Why is this important? | Alpha1a; alpha1b; because of different localization (tissue receptor differences), can give selective inhibitors (e.g. alpha1B for hypertension and alpha1A for prostate hypertrophy) |
| What signal transduction process is used by the alpha1 adrenergic receptors? What happens to cells that are overstimulated? | Gq protein --> PLC --> PLA2 --> Ca++ --> Na+/K+ --> MAPK signaling; overstimulation leads to death of cells (Ca++ concentrations...?) |
| What signaling pathway do alpha2 adrenergic receptors use? | Gi --> inhibition of Ac --> decrease of acetylcholine --> decrease in PKA |
| What is the predominant receptor that regulates vasoconstriction? | alpha2 (especifically, alpha2B); it is the predominant subtype 2 postsynaptic receptor mediating vasoconstriction |
| What does Beta2 stimulation in vascular smooth muscle cells do? In smooth muscles? What stimulates it? | Reduces contraction (activates Gs, increasing cAMP, which INHIBITS myosin light chain action--> relaxes--> vasodilation); same in smooth muscle; CIRCULATING EPINEPHRINE |
| Stimulation of B2 receptors does what in lung? | Bronchodilation |
| What is the predominant adrenergic receptor in the heart? What does it do when stimulated? | Beta1; has + ionotropic effect on heart increased cardiac output |
| Where is the B1 receptor primarily located (of great importance)? | HEART, KIDNEY, adipocytes, skeletal muscle, cortex, brainstem |
| Where is the B2 receptor primarily located (of great importance)? | HEART, BRONCHIAL BLOOD VESSELS, Lung, GI SMCs, cortex |
| Where is the B3 receptor primarily located (of great importance)? | ADIPOSE TISSUE, GI tract, heart |
| What are the effects of the sympathetic nervous system on cardiac function? What receptor is responsible for an increase in these effects? | Inotropic, chronotropic, dromotropic, bathmotropic, lusitropic; beta stimulation |
| Why would you want a lusitropic effect on your heart? | Lusitropic (regards myocardial relaxation); increasing the rate at which muscle cells pump out Ca++ allows the heart muscles to relax, allowing the heart to refill w/ blood before next contraction |
| What is a bathmotropic effect? | Modification of the heart muscle membrane excitability-->ease of generating a action potential changed |
| What is a dromotropic effect? | Modification of the conduction speed in the AV node (rate of electrical impulses in the heart); from Greek word DROMOS, meaning running, race |
| What is a chronotropic effect? | Change in heart rate |
| What is an inotropic effect? | Alters the force or energy of muscular contractions-->postively inotropic agents increase the strength of muscular contraction |
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karkis77
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