Pharm Exam 2 - Α-Adrenergic Receptor Agonists/antagonists

Front 1

adrenergic neurons synthesize, store, and release mainly...

Back 1

Norepinephrine (NE)

Front 2

_____ is synthesized and released from adrenal medulla into blood stream and acts as a ______

Back 2

Epinephrine (EPI); hormone

Front 3

Receptors that respond to NE/EPI

Back 3

α-1, α-2, β-1

Front 4

sympathomimetic drugs mimic and sympatholyic drugs block the effect of...

Back 4

EPI/NE

Front 5

α-1 receptor

(G-protein, 2nd msgr, ligands, tissue/organ/gland, effect of agonist)

Back 5

1. G-protein- Gq
2. 2nd messenger - ↑IP3, ↑DAG, ↑Ca2+
3. ligands - EPI/NE
4. tissue/organ/gland - artery/vein, EYE, smooth muscles (constriction)
5. effect of agonist - vasoconstrict (↑BP), mydriasis

Front 6

α-2 receptor

(G-protein, 2nd msgr, ligands, tissue/organ/gland, effect of agonist)

Back 6

1. G-protein- Gi
2. 2nd messenger - ↓cAMP
3. ligands - EPI/NE
4. tissue/organ/gland - none
5. effect of agonist - ↓SANS activity

Front 7

special action of ACh in SANS

Back 7

innervation of M3 by ACh releases NO to relax smooth muscle arterioles that supply skeletal muscle

Front 8

α-1 receptor mechanism

Back 8

α-1 couples to Gq to ↑Ca2+

Front 9

α-1 activation tissue responses

Back 9

contraction of vascular smooth muscle = ↑PVR and ↑BP

contraction of iris radial muscles = dilates pupil

contraction of urinary and GI sphincters

contraction of prostate

Front 10

clinical use of α-1 AGONIST drugs

Back 10

1. treatment of shock to ↑BP
2. ↑BP in hypotension
3. topically as mydriatic
4. topically as nasal decongestant
5. topically for allergeic ocular hyperemia

Front 11

Clinical use of α-1 ANTAGONIST drugs

Back 11

1. ↓BP
2. relief of benign prostatic hyperplasia
3. pheochromocytoma

Front 12

Presynaptic α-2 receptors mechanism

Back 12

α-2 binds to Gi, ↓cAMP, hyperpolarizes terminal and block nerve transmission

NE activates α-2 to inhibit its own release (negative feedback control)

α-2 receptors contract vascular smooth muscle; peripheral effect

Front 13

Clinical use of α-2 AGONIST drugs

Back 13

1. α-2 receptors in brain are used as anti-hypertensive agents
2. reduce SANS symptoms during opioid withdrawal
3. skeletal muscle relaxants
4. topically ↓IOP to treat glaucoma

Front 14

Clinical use of α-2 ANTAGONIST drugs

Back 14

1. orthostatic hypotension
2. reverses hypotension caused by α-2 agonists
3. erectile dysfunction

Front 15

ß-1 Receptor

(G-Protein, 2nd msgr, ligand, tissue/organ/gland, effect of agonist)

Back 15

1. G-Protein - Gs
2. 2nd Messenger - ↑cAMP
3. Endogenous Ligand - NE, EPI
4. Tissue/Organ/Gland - Heart, Kidney
5. Effect of Agonist - ↑HR, ↑force of atrial contraction, ↑renin release

Front 16

ß-2 Receptor

(G-Protein, 2nd msgr, ligand, tissue/organ/gland, effect of agonist)

Back 16

1. G-Protein - Gs
2. 2nd Messenger - ↑cAMP
3. Endogenous Ligand - EPI
4. Tissue/Organ/Gland - Lungs, Artery/Vein, Liver
5. Effect of Agonist - dilate bronchioles, vasodilate (↓BP), ↑blood glucose

Front 17

ß-3 Receptor

(G-Protein, 2nd msgr, ligand, tissue/organ/gland, effect of agonist)

Back 17

1. G-Protein - Gs
2. 2nd Messenger - ↑cAMP
3. Endogenous Ligand - EPI
4. Tissue/Organ/Gland - Adipose tissue
5. Effect of Agonist - ↑Lipolysis (free fatty acids)

Front 18

Norepinephrine binds to...

Back 18

α-1, α-2, ß-1

Front 19

Epinephrine binds to....

Back 19

α-1, α-2, ß-1, ß-2, ß-3

Front 20

ß-1 receptor mechanism

Back 20

ß-1 couples Gs, ↑cAMP, activates kinases

Front 21

Clinical use of ß-1 receptor AGONIST drugs

Back 21

short term relief as cardiostimulant in acute heart failure

Front 22

ß-2 receptor mechanism

Back 22

ß-2 couples Gs, ↑cAMP, protein kinase A (PKA) inactivates myosin light chain kinase (MLCK) to RELAX smooth muscles

Front 23

Clinical use of ß-2 receptor AGONIST drugs

Back 23

1. relaxes bronchial smooth muscle -> asthma; physiological antagonist to histamine
2. relaxes uterine smooth muscle to prevent premature labor (physiological antagonist to oxytocin)

Front 24

NE/EPI Metabolism

Back 24

Phase I - Oxidation - MAO
Phase II - Conjugation - Catechol O-Methyl Transferase (COMT)

No COMT in synaptic cleft

Front 25

selective α-1 agonists

Back 25

phenylephrine, midodrine

Front 26

selective α-2 agonists

Back 26

clonidine, methyldopa, guanabenz, aproclonidine, bromonidine, guanfacine

Front 27

mixed α, ß agonists

Back 27

NE, EPI, ephedrine

NE: α-1, α-2, ß-1
EPI: α-1, α-2, ß-1, ß-2
Ephedrine: same as EPI

Front 28

selective α-1 antagonists

Back 28

"SINS" - prazosin, terazosin, doxazosin

Front 29

selective α-2 antagonists

Back 29

yohimbine

Front 30

non-selective α antagonists (α-1 = α-2)

Back 30

phentolamine, phenoxybenzamine

Front 31

mixed α antagonists

Back 31

labetalol, carvedilol

Front 32

Direct Mixed-Acting: NE

(Effects and Adverse Effects)

Back 32

released from SANS, administered as IV

Effects:
1. Heart - ↑HR, force of atrial contraction (↑CO)
2. Blood Vessels - ↑PVR and venous return

Adverse Effects: hypertension, arrhythmias, hyperthyroidism

Front 33

Direct Mixed-Acting: EPI

(Effects and Adverse Effects)

Back 33

released from adrenal medulla (hormone), administered as IV, local injection, oral inhalant, topical

Effects:
1. Heart - ↑HR, force of atrial contraction (↑CO)
2. Bronchioles - relaxes smooth muscle, bronchodilation
3. Blood Vessels - ß-2, low dose vasodilates, high dose vasoconstricts
4. Liver - glycogenolysis, ↑free glucose
5. Adipose - ↑free fatty acids (lipolysis)
6. Skeletal muscle - increase blood flow to contracting SKM

Adverse Effects: hypertension, arrhythmias, hyperglycemia

Front 34

Direct Mixed-Acting: Ephedrine

(Properties and Adverse Effects)

Back 34

Properties:
1. Same effects as EPI but weaker
2. Non-catechol resists metabolism by MAO and COMT
3. long duration and passes blood brain barrier
4. potent stimulant, good bronchodilator

Adverse Effects: inomnia, hypertension, palpitations, ventricular tachyharrythias (FATAL)

Front 35

Selective Acting: Phenylephrine

(Effects, Uses, Adverse Effects)

Back 35

α-1 AGONIST

Effects: constricts arteries and veins, ↑BP (systolic/diastolic)

Uses: produce mydriasis, ↑BP in hypotension, runny nose, eye drops (allergies)

Adverse Effects: hypertension, rebound congestion, reflex bradycardia

Front 36

Selective Acting: Midodrine

(Effects, Uses, Adverse Effects)

Back 36

α-1 AGONIST

Effects: ↑BP

Uses: orthostatic hypotension

Adverse Effects: supine hypertension, urinary retention, goosebumps

Front 37

Selective Acting: Clonidine, Guanabenz, α-Methyldopa

(Effects, Uses, Adverse Effects)

Back 37

α-2 AGONIST

Act at Vasomotor Center (VMC) in brain, inhibit SANS

Effects: ↓BP by overriding peripheral effects of α-2 activation

Uses - Hypertension

Adverse Effects: CNS depression/drowsiness, must taper or rebound hypertension and tachycardia

Front 38

Selective Acting: α-Methyldopa

(Effects, Uses, Adverse Effects)

Back 38

prodrug, metabolized to α-methyl NE

Effects:
1. activates α-2 in periphery and brain
2. False neurotransmitter when released from SANS

Uses: ↓BP in pregnant women

Front 39

Indirect Acting: Amphetamine

(Actions, Effects, Uses)

Back 39

Agonist

Actions:
1. displace NE from vesicles
2. blocks reuptake (Uptake-1)
3. Inhibits MAO

Effects:
1. ↑NE in synapse

Uses: ADHD, obesity, narcolepsy

Front 40

Indirect Acting: Tyramine

Back 40

Comes from cheese and wine
Metabolized by MAO

Outcomes:
1. Acute: consumption of large amount of Tyramine causes NE displacement and hypertensive crisis
2. Chronic - consumption while on MAOIs causes Tyramine -> Octopamine = orthostatic hypotension

Front 41

Indirect Acting: Guanethidine

Back 41

Agonist

Displaces NE

Clinically antihypertensive agent

Front 42

Non-Selective Antagonist - Phenoxybenzamine

Back 42

α antagonist

long-acting, irreversible inhibition

RARELY used clinically

Front 43

Non-Selective Antagonist - Phentolamine

Back 43

α antagonist

short-active, reversible

used clincally for pre-operative pheochromocyoma

Front 44

Non-Selective α Antagonists - Reflex Tachycardia

Back 44

Drugs that nonselectively block α-1 and α-2 are very likely to cause reflex tachycardia because α-1 causes ↓BP and α-2 causes ↑NE

Front 45

Selective Antagonists: SINS

Back 45

α-1 Antagonists

Prazosin, Terazosin, Doxazosin

Effects - reduce PVR and BP

Adverse effects: hypotensions, rebound congestion, reflex tachycardia, urinary incontinence, miosis

Front 46

Selective Antagonist: Yohimbine

Back 46

α-2 antagonist

↑NE release

Effects: ↑HR and ↑PVR

Uses: orthostatic hypotension, erectile dysfunction

Adverse Effects: ↑release of insulin