Exam 4: Adrenergic Agents Flashcards
Where would adrenergic drug act on?
- Effector cells through adrenoceptors (activated by NE/E)
- Neurons that release norepinephrine
What does adrenergic mean?
Admin of adrenaline (E) producing similar effects of stimulation the Sympathetic NS (adrenergic system)
Describe the adrenergic transmission/NE biosynthesis in a neuron?
- Tyrosine and Na+ enter the neuron through an aromatic L-amino acid transporter
- Tyrosine is converted into L-DOPA by Tyrosine hydroxylase
- L-DOPA -> Dopamine by DOPA-decarboxylase
- Dopamine is transported into a synaptic vesicle by VMAT while H+ leaves
- Dopamine is synthesized into NE by Dopamine B-hydroxylate
- Ca2+ mediates depolarization of neuron and vesicle exits to synaptic cleft and binds to a and b receptors
What are the post synaptic adrenergic the receptors?
a1, b1, b2
What is the adrenergic auto receptor?
a2
What is an autoreceptor?
Inhibitory receptor that prevents presynaptic neurons from releasing NE
What are the fates of NE after presynaptic neuron release?
Brownian motion push NE to different places
1. Bind to postsynaptic adrenergic receptors
2. Binds to autoreceptor
3. Goes back to presynaptic neuron through NE transporter and convert to DOPGAL by MAO
Draw the structure of NE
Draw the structure of VMA
Describe the major metabolism processes of NE for excretion
- NE under goes non-specific NON-CYP oxidative deamination by MAO to DOPGAL
- DOPGAL is metabolized by non-cyp aldehyde dehydrogenase into DOMA
- DOMA is synthesized to VMA (Vanillylmandelic acid) by non-cyp phase 2 COMT
- VMA is excreted into urine
What is the optimal structure for NE b2-receptor binding according to Easson- Stedman
Hypothesis?
- Catechol
- Beta OH
- Protonated amine
What bonds are associated with NE receptor binding?
- Optimal H-bond with 2 OH on catechol and 2 serines
- Pi-pistacking with catechol ring and Phe
- Ionic binding with protonated amine and Asp
Draw the structure of Epinephrine
Describe the difference between +E and -E configurations
+E does not fully occupy the Receptor site from the secondary OH (less active)
-E fully binds to receptor by secondary OH (more active)
What are the a1 signaling molecules?
Gq, Gi, Go
What are the tissue effects of a1 receptors?
- Vascular smooth muscle contraction
- Genitourinary smooth contraction
- Intestinal smooth muscle relaxation
- Increased isotropy and excitability in heart
- Glycogenolysis and gluconeogensis in liver
What are the signaling molecules of a2?
Gi and Go
What are the tissue effects of a2?
- Decreased insulin secretion by pancreatic b-cells
- Platelet aggregation
- Decreased nerve NE release
- Vascular smooth muscle contraction
What are the tissue effects of B1?
- Increased chronotropy and inotropy in heart
- Increased AV node conduction velocity in heart
- Increased renin secretion in Renal juxtaglomerular cells
What are the signaling mediators of B2?
Gs
What are the tissue effects for B2?
- Smooth muscle relaxation
- Glycogenolysis and gluconeogensis in liver
- Glycogenolysis and K+ uptake in skeletal muscle
What are the signaling mediators for B1?
Gs
What are the B3 signaling mediators?
Gs
What are the tissue effects of B3?
Lipolysis in adipose tissue
What receptor types are associated with arteriole constriction?
a1, a2
What receptor types are associated with skeletal muscle dialtion?
B2
What receptor types are associated with radial eye muscle contraction (miosis)?
a1
What receptor types are associated with lung relaxation (bronchodilation)?
B2
What receptor types are associated with gluconeogenesis and glycogenolysis?
a1, b2
What receptor types are associated with lipolysis in fat cells?
a1, b3
What receptor types are associated with uterine contraction (pregnant)?
a1
What receptor types are associated with decrease in intestine motility?
a1, b2
What is the therapeutic use for a1 agonists?
- Shock, hypotension (raise BP)
- Nasal decongestants
What is the therapeutic use for a1 antagonists?
Antihypertensives
What is the therapeutic use for a2 agonists?
- Antihypertensives
- Glaucoma
- Analgesia
- Sedatives
What is the therapeutic use for b1 antagonists?
- Antihypertensives
- Antiarrhythmics
What is the therapeutic use for b2 agonists?
Bronchodilators (asthma and COPD)
What is the therapeutic use for b3 agonists?
Weight loss
What is myriad effect of a1?
- Vasoconstriction
- Increased peripheral resistance
- Increased BP
- Mydriasis
- Increased closure of sphincter of bladder
What is myriad effect of a2?
- Inhibition of NE release
- Inhibition of ACh release
- Inhibition of insulin release
What is myriad effect of b1?
- Tachycardia
- Increased lipolysis
- Increased myocardial contractility
- Increased renin release