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Adrenergic Drugs

Synthesis And Release Of Atecholamines





  1. all enzymes of CA synthesis are rather nonspecific and can act on closely related substrates e.g. dopa decarboxylase can from 5-HT from S-hydroxytryptophan and a methyl DA from methyl dopa.
  2. It requires high concentration of glucocorticoids reaching through portal circulation for induction of the N metlyl transferase enzyme.
  3. Genetic defaults in, or complete absence of Phenylalanine Hydroxylase leads to a disease called phenylketoneuria PKU
  4. Tyrosine hydroxylase is the rate-limiting enzyme in this pathway. Because this is the rate-limiting step, inhibition of this enzyme is the most likely way to reduce NE, DA, or EP levels significantly.
  5. The drug alpha-Methyltyrosine is useful in the management of malignant hypertension and in pheochromocytoma.
  6. The cofactor for DOPA decarboxylase is Pyridoxal (the aldehyde form of pyridoxine, vitamin B6).
  1. Storage of CAs:
    1. NA is stored in synaptic vesicles or granules within the adrenergic nerve terminal.
    2. The vesicular membrane actively takes up DA from the cytoplasm and the final step of synthesis of NA takes place inside the vesicle, which contains dopamine Beta-hydroxylase.
    3. NA is then stored as a complex with ATP (in a ratio of 4:1), which is adsorbed on a protein chromogranin.
    4. NA is methylated and Adr so formed is again taken up by a separate set of granules. The cytoplasmic pool of CAs is kept low by the enzyme monoamine oxidase MAO) present on the outer surface of mitochondria.
  2. Release of CAs:
    1. The nerve impulse coupled release of CA takes place by exocytosis and all the vesicular contents (NA or Adr, ATP, dopamine beta hydroxylase, chromogranin) are poured out.
    2. In case of vesicles which in addition contain peptides like enkephalin or neuropeptide Y (NPY), these cotransmitters are simultaneously released. The release is modulated by presynaptic receptors, of which  inhibitory control is dominant.
  3. Uptake of CA’s:
  • Axonal uptake: An active amine pump (NET) is present at the neuronal membrane which transports NA by a Na* coupled mechanism.This pump is inhibited by Cocaine, Desipramine and few other drugs.
  1. Metabolism:
    1. A Part of the NA leaking out from granules into cytoplasm as well as that taken up by axonal transport is first attacked by MAO, while that which diffuses into circulation is first acted upon by catechol-o- methyl transferase (COMT) in liver and other tissues.
    2. In both cases, the alternative enzyme can subsequently act to produce vanillylmandelic acid (VMA). The major metabolites excreted in urine are VMA and 3-methoxy-4-hydroxy phenylethylene glycol (a reduced product) along with some metanephrine, normetanephrine and 3,4dihydroxvymandelic acid.
    3. These metabolites are mostly conjugated with glucuronic acid or sulfate before excretion in urine. However, metabolisms DOES NOT play an important role in terminating the action of neuronally released CAs.

Sympathomimetic Receptors (Ahlquist – 1948)




Beta (


 IP3/DAG, cAMP, + Channels

 cAMP,  Ca2+ channels


Adr > NA > Isoprenaline

Isoprenaline > Adr > NA







Postjunctional on effector organs

Prejunctional on nerve ending (), (Autoreceptors)
Postjunctional in brain, pancreatic Beta cells
Extrajunctional in
certain blood vessels, platelets.

Function Subserved

GU Smooth muscle--contraction
Liver - Glycogenolysis
Heart -arrhythmia

Inhibition of transmitter release
Liver-glycogenolysrs Heart -arrhythmia
Decreased central sympathetic flow Decreased insulin reieasePlatelet aggregatio

Selective agonist

Phenylephrine, Methoxamine


Selective antagonist







 J-G cells in kidney

Bronchi, blood vessels, uterus, liver, git, urinary tract, eye

Adipose tissue
Coronary Arteries



Salbutamol, terbutaline



Metoprolol, Atenolol

ICI 118551
methyl propranolol


Action of NA













1. Ejaculatory duct

a. Ejaculation

2. Prostate

a.  SMC                           b. Capsule

3. Post-ganglionic neurons

4. Iris

a.   Mydriasis

5. Blood vessels - Increase BP


Preganglionic neurons (Auto-receptors)

1. Fat

o Inhibit lipolysis

2. Platelets

o Aggregation

3. Pancreas

o Reduce insulin

4. Juxta-glomerular apparatus

o Reduce rennin

5. Blood vessels

o Increase BP






1. JG apparatus

a. Increase rennin release

2. Heart

b.  Inotropic (Increase force)                

 i.  Chronotropic (Increase rate)
ii. Lusitropic (Atrial relaxation)             
c. Dromotropic (Increase conduction)
d. Bathmotropic (Ectopic tissue stimulation)

1. Bronchi


2. Coronaries

Coronary dilators

3. Cilliary body

Increase aqueous humor formation

4. Pancreas

Increase insulin

5. Liver


6. Skeletal muscles

 a. Tremors                    
b. Vasodilator
 Increase potassium uptake


Adrenergic Drugs 

  1. Drugs like adrenaline
  • Two types
  1. ENDOGENOUS Catecholamines (Monoamines)
    1. Adrenaline            
    2. Noradrenaline              
    3. Dopamine            
    4. Serotonin
  2. Non-catecholamines
    1. Dobutamine          
    2. Amphetamine            
    3. ​Ephedrine
  1. Four types depending upon action
    1. Direct       -   Adrenaline
    2. Indirect    -   Tyramine
    3. Mixed        -   Ephedrine
    4. Pure -   Pure alpha (Methoxamine) & Pure beta (isoproteranol)
  2. Cardio stimulants
    1. Adrenaline                      
    2. Noradrenaline              
    3. Dopamine        
    4. Dobutamine            
    5. Isoproterenol
  3. Vasopressors
    1. Adrenaline                            
    2. Noradrenaline            
    3. Ephedrine            
    4. Phenylephrine 
    5. Methoxamine (Alpha agonist)          
    6. Mephenteramine (Alpha agonist)
    7. Metaraminol (Alpha agonist)
  4. Nasal decongestants
    1. Nephazoline
    2. Xylometazoline    
    3. Ephedrine      
    4. Psedoephedrine   
    5. Phenylpropanolamine
  5. Anorectics
    1. Methamphetamine          
    2. Sibutramine        
    3. Fenfluramine                      
    4. Orlistat        
    5. Rimonabent            
    6. Mazindol                
    7. Diethylpropion                    
    8. Narcolepsy drug
    9. Modafinil (AIPG Jan 09)
  6. Drugs for postural hypotension
    1. Ephedrine        
    2. Midodrine
  7. Uterine relaxants
    1. Isoxsuprine      
    2. Ritodrine    
    3. MgSO4  
    4. Progesterone                
    5. Ethanol        
    6. CCBs
  8. CNS stimulant
    1. Methylphenidate (DOC-ADHD)        
    2. Atomoxetine
  1. Individual drugs
    1. Adrenaline
      1. Discovered by Dale (1914)                        
      2. Acts upon alpha & beta receptors
      3. Beta-2>> Beta-1                            
      4. Short acting drug                 
      5. DOC
        1. Anaphylaxis
        2. Angioedema
        3. Cardiac arrest
      6. Also used in glaucoma (Dipivefrine, a prodrug is used POAG)
      7. Increases outflow and reduces production (alpha 1)
    2. Noradrenaline
      1. Powerful vasopressor
      2. Acts on alpha 1, alpha 2, beta 1 but not on beta-2
      3. Increases SBP, DBP, MAP         
        1. PP may remain same or reduced          
        2. Decreases HR
  • Transplated heart patients may have tachycardia
  • Prior atropinization reduces this response
  1. Isoprenaline
    1. Pure sympathomimetic                  
    2. Beta-1, beta-2 agonist        
    3. Beta-1>>beta-2   
    4. Short acting                            
    5. Decreases DBP                  
    6. Increases SBP
    7. C/I in HOCM & Tetrology of Fallot’s
      It is occasionally used to maintain ventricular rate till pacemaker is implanted.
  2. Dopamine
    1. D1 agonist                               
    2. Renal vasodilator     
    3. Short acting (2-5 mins half life)           
    4. Dose dependent property
      1. 1-2 microgram/kg/min---increases RBF (IN ARF)  
      2. 2-10 microgram/kg/min-HR  (IN CHF)
      3. >10 microgram/kg/min-Increases BP (IN HYPOTENSION/ SHOCK)


DOC: cardiogenic shock and hypovolemic shock


Increases both HR & BP

  1. Dobutamine
    1. Beta-1 agonist (2-8 mcg/kg)            
    2. Less arrythmogenic than Adr
    3. Inotropic drug                  
    4. Used in Dobutamine stress Echo         


  1. Cardiogenic shock         
  2. Myocardial pump failure
  3. Also used in refractory CHF 

Tolerance develops; not suitable for long term

  1. Ephedrine: Mainly acts indirectly but has some direct action receptors also. Use is now restricted to that in mild chronic bronchial asthma and for hypotension during spinal anaesthesia; occasionally for postural hypotension
  2. Pseudophedrine: A stereoisomer of ephedrine; causes vasoconstriction, especially in mucosae and skin, but has fewer CNS and cardiac effect and is a poor bronchodilator (little p, agonistic activity). Used orally as a Decongestant of upper respiratory tract, nose and eustachian tubes.
  3. Phenylephrine: It is a selective alpha-1 agonist, has negligible Beta action. It raises BP by causing vasoconstriction. Because it has little cardiac action, reflex bradycardia is prominent. Topically it is used as a Nasal Decongestant and for producing Mydriasis when cycloplegia is not required. Phenylephrine tends to reduce intraocular tension by constricting ciliary body blood vessels. Similar congener is Methoxamine.
  4. Amphetamine like drugs: Amphetamine, Tyramine, Methylphenidate, Modafinil, Pemoline
    Acts Indirectly by displacement of Nor-adrenaline from vesicle and increases its concentration in synaptic space.
    1. Amphetamine: approved for obesity, ADHD and has abusive potential
    2. Methylphenidate:  DOC for ADHD and also approved for NARCOLEPSY
    3. Modafinil: DOC for narcolepsy and used as adjunctive drug for OBSTRUCTIVE SLEEP APNOEA
    4. Pemoline: approved for ADHD but NOT USED clinically because of hepatotoxicity as side effect
    5. Tyramine: present in food products like cheese and red wine. When taken in high concentration can lead to CHEESE REACTION. DOC for cheese reaction is PHENTOLAMINE.

Anorectic Agents

  1. Because of adverse central effects, the amphetamines to suppress appetite cant be justified.
  2. A number of related drugs have been developed which inhibit feeding centre like amphetamine) but have little/no CNS stimulating action or abuse liabiliiy.
  3. All of them act by inhibiting the reuptake of NA/DA or 5-HT, enhancing monoaminergic transmission in the brain.

Adrenergic agents

Serotonergic agents

Noradrenergic/serotonergic agents



Phentermine, PhenylpropanolamineDiethylpropion,
(Increase incidence of Hemmorhagic stroke and behavioural abnormality. BANNED)

Fenfluramine, Dexfenfluramine
(Ecocardiographic abnormalities, valvular defects, pulmonary hypertension and sudden death were related to the use of a combined preparation fenfluramine + phentermine. These are BANNED in India and most other countries.

(Sibutramine was marketed for several years but was BANNED because of increasing evidence of cardiovascular toxicity.)

GI lipase inhibitor
Reduces absorption of fats since triglycerides not split
S/E: Flatulence, steatorrhea, fecal incontinence

Selective 5-HT2C receptor agonist
S/E Headache; tumorigenesis in rats
Approval Denied by FDA because of lack of safety and effectiveness.


  1. Orlistat is the only non-amphetamine drug currently approved in the United States for the treatment of obesity.
  2. Rimonabant: A selective cannabinoid (CB-1) receptor antagonist that blocks hunger promoting action of cannabis has been found in clinical trials to decrease appetite and help weight reduction by the obese. Nausea is a side effect. Rimonabant has also been tried to help smoking cessation and alcohol dependence.
  3. Olestra is a sucrose polyester which can be used as a cooking medium in place of fat but is neither digested nor absorbed. Its acceptability is inconsistent.
  4. Leptin (the endogenous slimming peptide) analogues, neuropeptide Y antagonists and beta2 adrenergic agonlst are under investigation as anti-obesity drugs.

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