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Flashcards in Adrenergic Agonists Deck (31):
1

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

2

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

3

Describe the somatic system.

- pre-ganglionic cell releases ACh on nicotinic receptors of skeletal muscles

4

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

5

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

6

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

7

List the following in order of their affinity for the adrenergic receptors:
- epi
- norepi
- isoproterenol

ALPHA receptors: epi > NE >> Iso
BETA-1 receptors: iso > epi = NE
BETA-2 receptors: iso > epi >> NE

8

Categorize the adrenergic receptor agonists according to their affinity for the different receptors.

1. dopamine binds to D1 > B1 > alpha as concentration increases
2. epinephrine binds to all; prefers B2 at low conc.
3. norepinephrine binds to all but B2;

9

List 4 commonly used indirect acting sympathomimetics.

- amphetamine
- methylphenidate
- ephedrine
- pseudo-ephedrine

(others: methamphetamine, tyramine)

10

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

11

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)

12

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

13

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)

14

What currents contribute to SA node pacemaker activity? Which of these currents is affected by sympathetic innervation?

1. inward calcium current
2. funny current (hyperpolarization-induced)
3. 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)

15

Describe the mechanisms and steps of adrenergic neurotransmission (5).

1. NT SYNTHESIS
- tyrosine is converted to L-DOPA via tyrosine hydroxylase
- L-DOPA is metabolized to dopamine via dopa decarboxylase

2. 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)

3. RELEASE
- voltage-gated calcium channels open to allow influx of calcium
- vesicular and synaptic membrane SNAREs interact and exocytose NT inside

4. BINDING
- depends on receptor type, second messenger system, and machinery of cell type

5. TERMINATION
- reuptake
- diffusion out of synaptic cleft
- metabolic transformation via MAO (intracellular, after reuptake) and COMT (circulation)

16

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

17

List the tissue and actions associated with alpha-2 adrenergic receptors.

TISSUES => ACTIONS
- platelets => aggregation
- nerve terminals => inhibits NT release

18

List the tissue and actions associated with beta-1 adrenergic receptors.

TISSUES => ACTIONS
- heart => stimulates rate and force
- juxtaglomerular cells => stimulates renin release

19

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

20

List the tissue and actions associated with beta-3 adrenergic receptors.

TISSUES => ACTIONS
- fat cells => lipolysis

21

List the tissue and actions associated with dopamine-1 adrenergic receptors.

TISSUES => ACTIONS
- renal/splanchnic blood vessels => relaxation => reduces vascular resistance

22

Describe the mechanism by which alpha-1 receptors mediate vascular smooth muscle contraction.

1. Gaq => PLC => IP3 and DAG
2. IP3 activates IP3 receptor that acts as a calcium channel of the sarcoplasmic reticulum (SR)
3. IP3R releases stored calcium => increases free calcium in cytoplasm
4. increased calcium stimulates smooth muscle contraction

23

Describe the mechanism by which beta-1 receptors stimulate force and rate of heart muscle contractions.

1. Gas => AC => cAMP => PKA
2. PKA => phosphorylation of N-type calcium channels => increased inward Ca current
3. faster SA node depolarization

24

Describe the mechanism by which beta-1 receptors stimulate increased contractility of heart muscle.

1. Gas => AC => cAMP => PKA
2. PKA => phosphorylation of L-type calcium channels
3. larger trigger signal for calcium release from SR
4. trigger calcium also enters the SR => increased calcium storage for the next contraction

25

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?

1. Gas => AC => cAMP => PKA
2. phosphorylation and INactivation of myosin light chain kinase (MLCK)
3. reduced affinity of MLCK for Ca-calmodulin
4. reduced MLCK enzymatic activity => no phosphorylation of myosin light chain => no myosin-actin cross-bridging => no contraction
5. reduced smooth muscle contraction

ALPHA-2
1. Gi => no AC => no cAMP => no PKA => MLCK => phosphorylation of MLC => vascular constriction

26

What are the endogenous ligands for adrenergic receptors?

- NE
- Epi
- DA

27

Define direct-acting sympathomimetics.

interact directly with adrenergic receptors

28

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

29

Define isoproterenol structure.

- has large amino group substitution
- selective for beta-adrenergic receptors

30

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

31

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