1. ADRENERGIC SYSTEM PHARMACOLOGY
DR. ISHOLA I.O.
DEPT OF PHARMACOLOGY, THERAPEUTICS AND TOXICOLOGY
CMUL

2. ADRENERGIC TRANSMISSION
Adrenergic transmission is restricted to the sympathetic nervous system
Norepinephrine is the transmitter at post-ganglionic sympathetic nerves – except sweat glands
Epinephrine (Epi)– major hormone of the adrenal medulla
Dopamine- the predominant transmitter of the mammalian extrapyramidal, mesocortical and mesolimbic neuronal pathways

3. ADRENERGIC TRANSMISSION
Naturally occurring catecholamines - Epinephrine, Norepinephrine, Dopamine.
Synthesis of Epi from tyrosine was proposed by Blaschko in 1939
Some of the enzymes for synthesis are not specific except tyrosine hydroxylase (TH)(Rate limiting)
Stimulation of adrenergic nerves activate TH
TH is a substrate for cAMP-dependent, Ca-calmodulin sensitive protein and PKC

4. Cont’d TH is subject to feedback inhibition by catechol compounds
The storage vesicles contain NA (approx. 21%), Aa, ATP, chromogrannins, DBH, NPY, & enkephalins
2 types of storage vesicles:
Large dense core (chromafin granules)
Small dense core (NA, ATP, DBH)

5. SUMMARY OF SYNTHESIS 3-Hydroxylation of Tyrosine to DOPA
Decarboxylation of dopa to DA
AT of DA to vesicle or else deaminated to DOPAC or O-methylated to HVA
β-hydroxylation of DA to NA
NA diffuse into cytoplasm N-methylated to Epi
Epi enters chromaffin cells until release
Glucocorticoid controls the release of Epi

6. Cont’d
Hydroxylation of tyrosine by tyrosine hydroxylase in the presence of THB, O2, ferric ion (rate limiting step in biosynthesis of catecholamines)

9. ADRENERGIC TRANSMISSION
STORAGE :
The granules take up dopamine from the cytoplasm and synthesis of NE occurs within the granules.
NE is stored in the granules within the adrenergic terminal .
Released by exocytosis
Storage decreases intraneuronal metabolism of NT
Vesicular monoamine transporter (VMAT-2) is driven by pH and potential gradients

10. Cont’d
For every molecule of amine taken up, 2 hydrogen ions are extruded
Reserpine inhibits monoamine transport into storage vesicles
There are two neuronal membrane transporters for catecholamines; NET and DAT
NET is sodium ion dependent (blocked by cocaine, TCA (imipramine)
Indirectly acting sympathomimetic (ephedrine, tyramine

11. ADRENERGIC TRANSMISSION
RELEASE :
Nerve impulse effects the release of NE
Entrance of calcium ion into cells results in the extrusion by exocytosis of granular contents (ADR, ATP, NPY, Chromogranins and DBH)
The release of CA takes by exocytosis .
Indirectly acting amines (tyramine and amphetamine) induce the release of NE by displacing it from the nerve endings.
They make carrier available at the inner surface of the membrane for the outward transport of NE (facilitated diffusion)
Reserpine inhibit uptake -1
Uptake-2 not sodium ion dependent

12. CONT’D
Influx of Ca2+ plays an important role in coupling nerve impulses, membrane depolarization, and opening of voltage gated Ca2+ channels with the release of NE
Blockade of N-type Ca2+ channels lead to hypotension

15. ADRENERGIC TRANSMISSION
UPTAKE 2 (extra neuronal uptake) : CA are taken into other tissues.
ADRENERGIC TRANSMISSION
UPTAKE OF CA : It is an efficient mechanism after the release of NE –
Axonal uptake (Uptake 1 ) : Transports NE at a higher rate than E.
It is the most important mechanism for the termination of the NE.
Cocaine, Imipramine inhibits this uptake 1.

16. Termination of the action of CAT
Reuptake into nerve terminals by NET
Dilution by diffusion out of the junctional cleft and uptake at extraneuronal sites by ENT,
Metaboilic transformation (MAO, COMT and sulphotransferases) – little effect
Termination of action of ACh by AChE is absent

17. Metabolism does not play a significant role in the termination of the action of the NE .

18. ADRENERGIC TRANSMISSION
COMT plays a major role in the metabolism of catecholamines particularly in liver.
ADRENERGIC TRANSMISSION
METABOLISM : by two enzyme systems – MAO and COMT.
NE after uptake -1 into the axoplasm is acted upon by MAO.
NE which diffuses into the circulation is acted upon by COMT, mainly in the liver
The major metabolites excreted in urine is VMA (Vanillyl mandelic acid)

20. ADRENERGIC TRANSMISSION
Adrenergic receptors are G protein coupled receptors which acts by increasing or decreasing the production of c AMP
ADRENERGIC RECEPTORS
ALPHA – A , B , D
ALPHA – A , B , C

21. ADRENERGIC TRANSMISSION
ALPHA 1 :
Acts by activating Phospholipase C – production of inositol triphosphate (IP3) and DAG
IP3 promotes the release of calcium from the intracellular stores ---increase cytoplasm calcium

22. Adrenergic System ALPHA 1 receptors
EYE – radial fibers – contraction –mydriasis
Arterioles and veins – contraction – can increase peripheral resistance.
Bladder trigone and sphincter – contraction – urinary retention
Liver – Glycogenolysis.
Vas deferens – ejaculation.

23. Adrenergic System ALPHA 2 : acts by inhibiting adenylyl cyclase – cAMP
Platelets - aggregation
Prejunctional receptors – decrease release of transmitter (NE)
Pancreas -- decrease insulin release (predominant)

24. Adrenergic System
BETA : beta receptors stimulate adenylyl cyclase – increasing the cAMP
Beta 1
Heart
JG cells in kidney (increase renin release).

25. Adrenergic System Blood vessels to skeletal muscle – Vasodilation
Beta 2 receptors : cAMP
Blood vessels to skeletal muscle – Vasodilation
Uterus – Relaxation
Bronchioles – Dilatation
Skeletal muscles – tremors
Liver - Glycogenolysis

26. Adrenergic System Dopamine 1 receptors :
Acts by stimulation of adenylyl cyclase and increased cAMP
Renal and mesenteric vasculature – vasodilation and increase blood flow and Na excretion.
Dopamine 2 receptors :
Acts by inhibition of adenylyl cyclase, decrease cAMP, open potassium channels,
Brain

27. Adrenergic System
Adrenergic Drugs:
Directly acting : Epinephrine, Norepinephrine, Phenylephrine, Albuterol
Indirectly acting : acts by release of NE : Tyramine, Amphetamine
Mixed : Ephedrine

28. Adrenergic System Epinephrine acts on alpha 1, 2 beta 1, 2
Norepinephrine acts on alpha 1, 2
beta 1
Isoprenaline acts on beta 1 , 2
Dopamine 1 receptors agonist :
Dobutamine, Fenoldopam

29. Adrenergic System AGENTS ACTING AT DIFFERENT SITES
INTERFERE WITH THE SYNTHESIS : Metyrosine
BLOCKADE OF UPTAKE 1 AT NERVE TERMINAL : Cocaine, Imipramine
BLOCKADE OF STORAGE IN GRANULE OR GRANULAR UPTAKE : Reserpine
PROMOTION OF RELEASE : Amphetamine
PREVENTION OF RELEASE : Bretylium, Guanethidine

30. Metabolism does not play a significant role in the termination of the action of the NE .

31. Adrenergic System
MAO
MAO –A present in the nerves /intestine/ liver or Anywhere
Metabolizes NE, 5-HT and tyramine
Inhibitors are Phenelzine, Tranylcypromine
MAO – B
Present mainly in the Brain
Metabolizes preferentially dopamine
Inhibitors are Selegiline

32. Adrenergic System
COMT INHIBITORS : Tolcapone Long acting Entacapone -- Short acting

33. Adrenergic System
Agonist acting on Alpha 1 receptors
Phenylephrine, Methoxamine
Given systemically they increase the mean blood pressure via vasoconstriction with minimal effect on pulse pressure (PP).
The increase in BP can elicits reflex bradycardia.

34. Adrenergic System Alpha 2 receptors : Clonidine, Alpha Methyldopa
Agonist acting specifically on
Alpha 2 receptors : Clonidine, Alpha Methyldopa
Beta 1 and beta 2 : Isoproterenol
Beta 1 : Dobutamine
Beta 2 : Terbutaline, Albuterol, Ritodrine, Metaproterenol

35. Adrenergic System Beta agonists : Beta 1 and Beta 2 Isoproterenol
Beta 1 agonists increase the HR, stroke volume and cardiac output.
Beta 2 agonists decrease the total peripheral resistance.
Adrenergic System
Beta agonists : Beta 1 and Beta 2
Isoproterenol
It cause a decrease in peripheral resistance, a decrease in mean BP due to beta 2 receptor action and a reflex increase in heart rate. Systolic blood pressure does not fall significantly as diastolic, due to beta 1 receptor action, so the pulse pressure increases .

36. Adrenergic System Norepinephrine :
It has little effect on beta 2 receptors.
It increases TPR and both diastolic and systolic blood pressure.
Positive inotropic action results in increase of pulse pressure.
Compensatory vagal reflexes tend to overcome the direct chronotropic action of NE -- reflex bradycardia may occur.

37. Adrenergic System Epinephrine : Acts on alpha 1, 2 and beta 1 and 2.
Epinephrine increase the HR, systolic BP and PP.
Its effects on diastolic blood pressure depends on dose.

38. Adrenergic System
Epinephrine :
At low dose, beta 2 activation predominates resulting in decrease of diastolic pressure and TPR, although mean BP may not decrease significantly.
At medium dose, increase in heart rate, increase in mean blood pressure and increase in pulse pressure due to both beta 1 and 2 receptor action.

39. Adrenergic System Non-selective Phenoxybenzamine, Phentolamine
Tamsulosin ( Flomax)
Adrenergic System
ALPHA BLOCKERS:
Non-selective
Phenoxybenzamine, Phentolamine
Alpha -1 selective
Prazosin, Terazosin, Tamsulosin
Alpha-2 selective
Yohimbine

40. Adrenergic System Non selective : Propranolol, Nadolol, Timolol
BETA BLOCKERS:
Non selective : Propranolol, Nadolol, Timolol
With Partial agonist : Pindolol
Beta 1 selective : Atenolol, Metoprolol
Beta and alpha 1 blocker : Labetolol, Carvedilol

41. 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

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

43. 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)

44. 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)

45. 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

46. 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

47. 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)

48. 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 )

49. 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)

50. 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?

51. 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?

52. 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

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

54. 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)

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

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

57. 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)

58. 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

59. 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)