1. Sympatholytic pharmacology
Selective vs. Non-selective
Antagonist vs. Partial Agonist
Reversible vs. Irreversible

2. Receptor agonists activate signal transduction pathways2 N
Norepinephrine NH 3
COOH G q
Phospho -
lipase C
(+)
PIP 2 IP
Diacylglycerol
Increase Ca 2+
Activate Protein
Kinase C
Response
a1 adrenergic
receptor

3. Receptor antagonists block agonist binding to the receptor2 N
Norepinephrine
Antagonist NH 3
Phospho - G
lipase C q
What effect would an antagonist alone have on receptor activation?
COOH

4. Clinical pharmacology of a-adrenergic receptor antagonists
Route of
Drug
Receptor
admin.
Clinical uses
Phenoxybenzamine a
, a
Oral
Pheochromocytoma, hypertensive crisis 1 2
Phentolamine a
, a
Parenteral
Pheochromocytoma, hypertensive crisis, 1 2
male impotence
Prazosin a
Oral
Hypertension, benign prostatic 1
hypertrophy
Terazosin a
Oral
Hypertension, benign prostatic 1
hypertrophy
Doxazosin a
Oral
Hypertension, benign prostatic 1
hypertrophy
Side effects of a1 receptor antagonists:
Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia

5. Non-selective adrenergic receptor antagonists
b-Haloalkylamines
R= aromatic, alkyl
X= Cl-, Br-, etc.

6. Non-selective adrenergic receptor antagonists
b-Haloalkylamines
Non-selective a receptor antagonist
Also blocks acetylcholine, histamine, and serotonin receptors
Irreversible antagonist resulting from covalent modification of receptor
Phenoxybenzamine (Dibenzyline)

7. Non-selective adrenergic receptor antagonists
b-Haloalkylamines: Mechanism of receptor inactivation
receptor
alkylated
receptor

8. Non-selective adrenergic receptor antagonists
Imidazolines
Non-selective a receptor antagonist
Competitive (reversible) blocker
Potent vasodilator, but induces pronouced reflex tachycardia
Block of presynaptic a2 receptors may promote release of NE
Also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist
Phentolamine (Regitine)

9. Reversible vs. Irreversible receptor blockade
1 M Phent
1 M Phenox
10 M Phenox
10 M Phent
+ Phentolamine
+ Phenoxybenzamine

10. a1-adrenergic receptor antagonists
“Quinazolines”
Vary in half-life:
Prazosin 3 hrs
Terazosin 12 hrs
Doxazosin 20 hrs
Undergo extensive metabolism, excreted mainly in the bile
Vasodilators
Relaxation of smooth muscle in enlarged prostate and in bladder base
“First-dose” effect

11. Other a adrenergic receptor antagonists
Ergot alkaloids
Derivatives of Lysergic Acid
Product of the grain fungus Claviceps purpura
5 Major alkaloids based on R and R’; Ergotamine the most common
Used in the treatment of migraine
Ergots possess strong oxytocic action

12. a2-adrenergic receptor antagonists
Indole alkaloid
Found in Rubaceae and related trees. Also in Rauwolfia Serpentina.
Blockade of a2 receptors increases sympathetic discharge
Folklore suggests use in the treatment of male impotence
Yohimbine (Yocon)

13. b-adrenergic receptor antagonists
Aryloxypropanolamines
Note: non-carbon atom
in side chain

14. b-adrenergic receptor antagonists
Non-selective
Lipophilic
Local anesthetic properties
Blockade is activity-dependent P r o p r a n o l o l ( I n d e r a l )

15. b-adrenergic receptor antagonists
Pharmacological effects
Decreased cardiac output and heart rate
Reduced renin release
Increase VLDL, Decrease HDL
Inhibit lipolysis
Inhibit compensatory glycogenolysis and glucose release in response to hypoglycemia
Increase bronchial airway resistance P r o p r a n o l o l ( I n d e r a l )
Therapeutic uses for b-adrenergic receptor antagonists:
Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III)

16. Non-selective b-adrenergic receptor antagonists
Less lipophilic than propranolol
Long half-life: ~20 hours
Mostly excreted unchanged in urine
Administered: Oral
Uses: Hypertension, angina, migraine
Nadolol (Corgard)
Thiadiazole nucleus with morpholine ring
Administered: Oral, Ophthalmic
Uses: Hypertension, angina, migraine, glaucoma
Timolol (Timoptic, Blocadren)
How will -blockers affect
pupil size?

17. Non-selective b-adrenergic receptor antagonists
Possesses “Intrinsic sympathomimetic activity (ISA)
Partial agonist
Less likely to cause bradycardia and lipid abnormalities
Administered: Oral
Uses: Hypertension, angina, migraine
Pindolol (Visken)
What would a pindolol dose-response curve look like?

18. Dose-Response Curves and Partial AgonistsNE
NE +
Pindolol
Pindolol %
NE +
Propranolol

19. Non-selective b-adrenergic receptor antagonists
Possesses “Intrinsic sympathomimetic activity (ISA)
Partial agonist
Less likely to cause bradycardia and lipid abnormalities
Administered: Oral, Opththalmic
Uses: Hypertension, glaucoma

20. Selective b1-adrenergic receptor antagonists
“Cardioselective”
Less bronchconstriction
Moderate lipophilicity
Half-life: 3-4 hours
Significant first-pass metabolism
Administered: Oral, parenteral
Uses: Hypertension, angina, antiarrhythmic, congestive heart failure

21. Selective b1-adrenergic receptor antagonists
“Cardioselective”
Less bronchconstriction
Low lipophilicity
Half-life: 6-9 hours
Administered: Oral, parenteral
Uses: Hypertension, angina
Atenolol (Tenormin)

22. Selective b1-adrenergic receptor antagonists
Very short acting
Half-life: 9 minutes
Rapid hydrolysis by esterases found in red blood cells
Administered: Parenteral Note: incompatible with sodium bicarbonate
Uses: Supraventricular tachycardia, atrial fibrillation/flutter, perioperative hypertension
Esmolol (Brevibloc)

23. Side effects of b-blockers:
Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome

24. Effect of chronic b-receptor blockade
Na+
Presynaptic neuron
Tyrosine
Na+
Dopamine
Tyrosine
Action Potential H+
MAO DA NE NE
Ca2+
Uptake 1
Na+, Cl- NE NE NE NE
Effector organ

25. Effect of chronic b-receptor blockade:
Receptor up-regulation
Na+
Tyrosine
Na+
Dopamine
Tyrosine
Action Potential H+
MAO DA NE NE
Ca2+
Uptake 1
Na+, Cl- NE NE NE NE
Effector organ

26. Side effects of b-blockers:
Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome
Contraindications:
Asthma, COPD, congestive heart failure (Type IV)

27. Mixed adrenergic receptor antagonists
Non-selective b receptor antagonist
a1 receptor antagonist
Two asymmetric carbons (1 and 1’)
(1R, 1’R)-isomer possesses b-blocking activity
(1S, 1’R)-isomer possesses greatest a1 receptor blocking activity
b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists
Administered: Oral, parenteral
Uses: Hypertension, hypertensive crisis
Labetalol (Normodyne, Trandate)

28. Mixed adrenergic receptor antagonists
Carvedilol (Coreg)
Non-selective b receptor antagonist
a1 receptor antagonist
Both enantiomers antagonize a1 receptors
Only (S)-enantiomer possesses b-blocking activity
b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists
Administered: Oral
Uses: Hypertension, congestive heart failure (Types II and III)

29. 1 2 3 Pharmacologic manipulation of the adrenergic system
Na+
Presynaptic neuron
Tyrosine
Na+ 1
Dopamine
Tyrosine 2
Action Potential H+
MAO DA NE NE
Ca2+
Uptake 1 3
Na+, Cl- NE NE NE NE b
Effector organ

30. Inhibition of norepinephrine synthesisC H 2 C H N H T Y R O S I N E 2 C O O H
Metyrosine X t y r o s i n e h y d r o x y l a s e
Inhibition of norepinephrine synthesis H O H O C H C H N H 2 2 D O P A C O O H a r o m a t i c L - a m i n o a c i d d e c a r b o x y l a s e H O H O C H C H N H D O P A M I N E 2 2 2 d o p a m i n e b - h y d r o x y l a s e H O H O C H C H N H N O R E P I N E P H R I N E 2 2 O H p h e n y l e t h a n o l a m i n e - H O N - m e t h y l t r a n s f e r a s e H O C H C H 2 N H E P I N E P H R I N E O H C H 3

31. Drugs that reduce storage or release of NE
Na+
Tyrosine
Na+
Dopamine
Tyrosine
Reserpine
Guanethidine
Action Potential H+
MAO NE NE
Ca2+ NE
Guanethidine,
Bretylium
Guanethidine b
Effector organ

32. Catecholamine depleters
Reserpine (Serpasil)
Indole alkaloid obtained from the root of Rauwolfia serpentina
Block vesicular monoamine transporters
Deplete vesicular pool of NE
Slow onset of action
Sustained effect (weeks)
Used in the treatment of hypertension
May precipitate depression

33. Drugs that reduce storage or release of NE
Possess guanidino moiety (pKa > 12)
Resonance stabilization of cation “spreads” positive charge over the entire four atom system
Almost completely protonated at physiological pH
“Pharmacologic sympathectomy”
Effects can be blocked by transport blockers
Uses: Hypertension
Guanethidine (Ismelin)

34. Drugs that reduce storage or release of NE
Na+
Tyrosine
Na+
Dopamine
Guanethidine
Tyrosine
Action Potential H+
MAO NE NE
Ca2+ NE
Guanethidine,
Guanethidine b
Effector organ

35. Drugs that reduce storage or release of NE
Bretylium tosylate (Bretylol)
Aromatic quaternary ammonium
Precise mechanism unknown
Displace and release NE and prevent further release (depletion)
Local anesthetic
Administered: Parenteral
Uses: Antiarrhythmic (ventricular fibrillation)