Adrenergic Agonists Flashcards
Describe the following characteristics of the sympathetic system:
- anatomy and chemistry
- origin
- pathway
- NTs released from pre-ganglionic cells
- NTs released from post-ganglionic cells
ANATOMY
- aka thoracolumbar division
- fight or flight
- IML => short pre-ganglionic cells => sympathetic chain => long post-ganglionic cells => effector organs
NTs
- pre-ganglionic cells release ACh onto nicotinic receptors
- post-ganglionic cells release NE onto alpha- and beta-adrenergic receptors
- NOTE: sympathetics innervating the sweat glands will release ACh onto muscarinic receptors
Describe the following characteristics of the parasympathetic system:
- anatomy and chemistry
- origin
- pathway
- NTs released from pre-ganglionic cells
- NTs released from post-ganglionic cells
ANATOMY
- aka craniosacral division
- rest and digest
- originate from cranial nerves or pelvic nerves (S1-3)
- long pre-ganglionic cells and short post-ganglionic cells
NTs
- pre-ganglionic cells release ACh onto nicotinic receptors
- post-ganglionic cells releases ACh onto muscarinic receptors
Describe the somatic system.
- pre-ganglionic cell releases ACh on nicotinic receptors of skeletal muscles
List the major organs innervated by the parasympathetic systems and their functional responses.
EYE
- miosis: pupillary sphincter constriction
- accommodation: ciliary body muscle constriction
HEART
- SA node; reduces heart rate
- AV node; slows conduction
BRONCHIOLES
- constriction of smooth muscle
GI TRACT
- promotes secretions and motility
BLADDER
- contraction of detrusor muscle; bladder emptying
Describe the basic distribution of the adrenergic receptor subtypes in the following organs and their functional response:
- eye
- heart
- bronchiole smooth muscle
- kidney
- vascular smooth muscle
- splanchnic vaculature
- eye: alpha-1, dilation of pupil via contraction of dilator
- heart: beta-1, stimulates rate and force of heartbeats
- bronchiole smooth muscle: beta-2, relaxation
- kidney: beta-1; stimulates RAAT
- vascular smooth muscle: alpha-1; constriction causes increased vascular resistance
- splanchnic vasculature: dopamine-1; relaxation causes decreased vascular resistance
List the 4 main subtypes of adrenergic receptors, their associated second messenger system, and functional response.
ALPHA-1
- Gaq => PhosphoLipase C => increases IP3 and DAG
- increased Ca (Ca-calmodulin-dependent kinase activation) and PKC activation respectively
ALPHA-2
- Gi => inhibits adenylyl cyclase => inhibits cAMP formation => reduction of PKA activity => reduced activation of N-type calcium channels => prevents NT release
BETA-1
- Gas => activates adenylyl cyclase => increases cAMP formation
- increased PKA activation => phosphorylation and activation of downstream signals
BETA-2
- Gas => activates adenylyl cyclase => increases cAMP formation
List the following in order of their affinity for the adrenergic receptors:
- epi
- norepi
- isoproterenol
ALPHA receptors: epi > NE»_space; Iso
BETA-1 receptors: iso > epi = NE
BETA-2 receptors: iso > epi»_space; NE
Categorize the adrenergic receptor agonists according to their affinity for the different receptors.
- dopamine binds to D1 > B1 > alpha as concentration increases
- epinephrine binds to all; prefers B2 at low conc.
- norepinephrine binds to all but B2;
List 4 commonly used indirect acting sympathomimetics.
- amphetamine
- methylphenidate
- ephedrine
- pseudo-ephedrine
(others: methamphetamine, tyramine)
Describe the most important toxic side effects and therapeutic uses of indirect acting sympathomimetic drugs. (only bold)
toxicity = tachycardia, anxiety therapeutics = ADD, narcolepsy, nasal decongestants
Describe the enteric system. What does innervation by sympathetic and parasympathetic provide?
- ENS innervates GI, pancreas, and gallbladder
- functions autonomously, but is moderated by symp/para
- moderation by sympathetic/parasympathetic provides
=> second level of control over digestion
=> override in times of stress or emergency (fight or flight)
Describe adrenal sympathetic innervation.
- adrenal medulla acts as a modified sympathetic ganglion
- short pre-ganglionic cells arise from IML
- pre-ganglionic cells release ACh onto nicotinic receptors directly on chromaffin cells
- chromaffin cells then secrete NE and Epi directly into bloodstream (no post-ganglionic cells)
- NE is converted to Epi via phenylethanolamine-N-methyltransferase
List the major organs innervated by the sympathetic nervous system and their functional responses.
EYE
- mydriasis; activation of dilator muscle; pupil dilates
- ciliary epithelium regulates production of aqueous humor
HEART
- increases SA node depolarization; increased HR
BRONCHIOLES
- relaxation of smooth muscle
BLOOD VESSELS
- contraction and relaxation
- depends on adrenergic receptor subtype and ligand
GI TRACT
- decreased motility
- overrides ENS during fight or flight
BLADDER
- contraction of urethral sphincters
- relaxation of detrusor muscle
- inhibits emptying
METABOLISM
- increased BG (glycogenolysis, glycolysis, lipolysis)
What currents contribute to SA node pacemaker activity? Which of these currents is affected by sympathetic innervation?
- inward calcium current
- funny current (hyperpolarization-induced)
- outward K+ current
SYMPATHETICS
- increases inward calcium and funny currents
- promotes faster depolarization during phase 4
- lowers threshold for activation
- greater contractile force (calcium influx in myocytes)
Describe the mechanisms and steps of adrenergic neurotransmission (5).
- NT SYNTHESIS
- tyrosine is converted to L-DOPA via tyrosine hydroxylase
- L-DOPA is metabolized to dopamine via dopa decarboxylase - VESICULAR STORAGE
- dopamine is transported into vesicles via Vesicle MonoAmine Transporter (VMAT)
- storage vesicles contain ATP
- DA is converted to NE by dopamine beta-hydroxylase (found in vesicles) - RELEASE
- voltage-gated calcium channels open to allow influx of calcium
- vesicular and synaptic membrane SNAREs interact and exocytose NT inside - BINDING
- depends on receptor type, second messenger system, and machinery of cell type - TERMINATION
- reuptake
- diffusion out of synaptic cleft
- metabolic transformation via MAO (intracellular, after reuptake) and COMT (circulation)
List the tissue and actions associated with alpha-1 adrenergic receptors.
TISSUES => ACTIONS
- vascular smooth muscle => contracts to increase vascular resistance
- pupillary dilator muscle => contracts => dilates the pupil
List the tissue and actions associated with alpha-2 adrenergic receptors.
TISSUES => ACTIONS
- platelets => aggregation
- nerve terminals => inhibits NT release
List the tissue and actions associated with beta-1 adrenergic receptors.
TISSUES => ACTIONS
- heart => stimulates rate and force
- juxtaglomerular cells => stimulates renin release
List the tissue and actions associated with beta-2 adrenergic receptors.
TISSUES => ACTIONS
- bronchiole smooth muscle => relaxation
- uterine smooth muscle => relaxation
- vascular smooth muscle => relaxation
- somatic nerve terminals => tremor of voluntary muscles
List the tissue and actions associated with beta-3 adrenergic receptors.
TISSUES => ACTIONS
- fat cells => lipolysis
List the tissue and actions associated with dopamine-1 adrenergic receptors.
TISSUES => ACTIONS
- renal/splanchnic blood vessels => relaxation => reduces vascular resistance
Describe the mechanism by which alpha-1 receptors mediate vascular smooth muscle contraction.
- Gaq => PLC => IP3 and DAG
- IP3 activates IP3 receptor that acts as a calcium channel of the sarcoplasmic reticulum (SR)
- IP3R releases stored calcium => increases free calcium in cytoplasm
- increased calcium stimulates smooth muscle contraction
Describe the mechanism by which beta-1 receptors stimulate force and rate of heart muscle contractions.
- Gas => AC => cAMP => PKA
- PKA => phosphorylation of N-type calcium channels => increased inward Ca current
- faster SA node depolarization
Describe the mechanism by which beta-1 receptors stimulate increased contractility of heart muscle.
- Gas => AC => cAMP => PKA
- PKA => phosphorylation of L-type calcium channels
- larger trigger signal for calcium release from SR
- trigger calcium also enters the SR => increased calcium storage for the next contraction
Describe the mechanism by which beta-2 receptors stimulate bronchiole vascular smooth muscle relaxation. How does this relate to the function of alpha-2 receptors?
- Gas => AC => cAMP => PKA
- phosphorylation and INactivation of myosin light chain kinase (MLCK)
- reduced affinity of MLCK for Ca-calmodulin
- reduced MLCK enzymatic activity => no phosphorylation of myosin light chain => no myosin-actin cross-bridging => no contraction
- reduced smooth muscle contraction
ALPHA-2
1. Gi => no AC => no cAMP => no PKA => MLCK => phosphorylation of MLC => vascular constriction
What are the endogenous ligands for adrenergic receptors?
- NE
- Epi
- DA
Define direct-acting sympathomimetics.
interact directly with adrenergic receptors
Describe the structure of catecholamines and how it relates to degradation and specificity.
Structure = phenyl ring with 2 OH + ethylamine with side chain
- prone to degradation
- can be made more or less specific by altering amino side chain
- can be made more or less lipophilic by altering OH groups on phenyl
- can be made more or less susceptible to degradation
Define isoproterenol structure.
- has large amino group substitution
- selective for beta-adrenergic receptors
Describe which factors of mean arterial pressure are most affected by adrenergic receptors:
MAP = CO x TPR
- adrenergic receptors in the vasculature have more of an effect on TPR and diastolic pressure, since it is mediated by vascular arterial vasoconstriction
=> alpha-1, beta-2 - adrenergic receptors in the cardiac tissue have more of an effect on CO and systolic pressure, since that is determined by contractility
=> beta-1
Define indirect-acting sympathomimetics.
- increase concentration of endogenous catecholamines in synapse and circulation leading to INdirect activation of adrenergic receptors
- mechanism
1. release of cytoplasmic catecholamines
2. blockade of reuptake transporters
