adrenaline, sympathetic system

1. Adrenergic System And Drugs
Dr. Javed Akhtar
JR-II
Department Of Pharmacology
K.G.M.U, Lucknow

2. • Adrenergic nervous system, a part of autonomic nervous
system that uses adrenaline or noradrenaline as its
neurotransmitter
• The sympathetic nervous system stimulate the
body's fight-or-flight response
• Like acceleration of heart, liberation of metabolic energy
sources, dilation of blood vessels for muscles,
constriction of blood vessels in many parts of the body

3. Synthesis of CA
• Catecholamines are synthesized from the amino acid phenylalanine
• Site of synthesis: chromaffin cells of adrenal medulla(adrenaline) and
sympathetic ganglian(noadrenaline)
• Tyrosine hydroxylase is a specific and the rate limiting enzyme
• Carbidopa relatively non specific enzyme
• Dopamine β- hydroxylase also non specific enzyme, located in
vesicles
• Phenylethanolamine N-methyl transferases(PNMT) mainly present in
adrenal medulla

5. Storage of CA
• NA is stored in synaptic vesicles or ‘granules’ within the adrenergic
nerve terminal
• The vesicular membrane actively takes up DA from the cytoplasm
• The final step of synthesis of NA takes place inside the vesicle which
contains dopamine β- hydroxylase
• NA is then stored as a complex with ATP (in a ratio of 4 : 1) which is
adsorbed on a protein chromogranin A

7. Release of CA
• The nerve impulse coupled release of CA takes place by
exocytosis and all the vesicular contents (NA or Adr, ATP,
dopamine β hydroxylase, chromogranin) are poured out
• In case of vesicles which in addition contain peptides
neuropeptide Y (NPY), these cotransmitters are
simultaneously released
• The release is modulated by presynaptic receptors, of which
α2 inhibitory control is dominant

8. • The autoreceptors of other cotransmitters (NPY and ATP)
also inhibit transmitter release
• In addition, numerous heteroreceptors are expressed on the
adrenergic neurone which either
• Inhibit (dopaminergic, serotonergic, muscarinic and PGE2)
• Enhance (β2 adrenergic, angiotensin AT1 and nicotinic) NA
release

9. Uptake of CA
• The action of NA is terminated mainly by reuptake of transmitter in to
nerve terminal
• Axonal uptake An active amine pump (NET) is present at the neuronal
membrane which transports NA by a Na+ coupled mechanism.
• Takes up NA at a higher rate than Adr and had been labelled uptake-1
• This uptake is the most important mechanism for terminating the
postjunctional action of NA
• From 75% to 90% of released NA is retaken back into the neurone
• This pump is inhibited by cocaine, desipramine and few other drugs

10. • Vesicular uptake at membrane of intracellular vesicles has
another amine pump the ‘vesicular monoamine transporter’
(VMAT-2), which transports CA from the cytoplasm to the
interior of the storage vesicle.
• The VMAT-2 transports monoamines by exchanging with H+ ions.
• This carrier also takes up DA formed in the axoplasm for further
synthesis to NA.
• This uptake is inhibited by reserpine, resulting in depletion of
CAs.

11. Extraneuronal uptake of CAs (uptake-2)
• Carried out by extraneuronal amine transporter (ENT), and
organic cation transporters OCT1 and OCT2 into cells of
other tissues like smooth muscle, cardiac muscle
• In contrast to NET this uptake transports Adr at a higher rate
than NA
• Not of physiological or pharmacological importance.

12. Metabolism of CAs
Mono Amine Oxidase (MAO)
• Intracellular bound to mitochondrial membrane
• Present in NA neuron terminals and liver/ intestine
• MAO inhibitors are used as antidepressants
Catechol-o-methyl-transferase (COMT)
• Absent in nonadrenergic neruon
• Present in medulla and other tissue
• VMA levels are diagnostic for tumours

13. DRUGS THAT AFFECT NORADRENERGIC NEURONS

14. DRUGS THAT AFFECT NORADRENERGIC NEURONS
• α-methyltyrosine:-which inhibits tyrosine hydroxylase (used rarely to
treat phaeochromocytoma)
• Carbidopa:-inhibits dopa decarboxylase and is used in the treatment
of parkinsonism .
• Methyldopa:-false transmitter precursor
• Hypotensive action
• It produces side effects typical of centrally acting antiadrenergic
drugs (e.g. sedation), as well as carrying a risk of immune
haemolytic reactions and liver toxicity
• So it is now little used, except for hypertension in pregnancy

15. • Reserpine:- deplete NA stores by inhibiting VMAT,
Used in hypertension(obsolete now)
• Guanethidine
 Inhibit NA release
 Causes NA depletion
 Damage NA neurons irreversibly
 Used in hypertension(obsolete now)
• Imipramine:- block NET, use in depression
• Cocaine:- also block NET, rarely used as local anastheics

16. • Nialamide, tranylcypromine(MAO-inhibition):-Potentiation of NA
(slight) —of tyramine (marked)
• Moclobemide (MAO-A inhibition):-Potentiation of NA and
tyramine (slight)
• Selegiline (MAO-B inhibition):- Potentiation of DA in brain
• Tolcapone, entacapone (COMT inhibition):-Potentiation of NA
and DA (slight)

17. Adrenergic Receptors
• Adrenergic receptors are membrane bound G-protein
coupled receptors
• Function primarily by increasing or decreasing the
intracellular production of second messengers cAMP or
IP3/DAG
• Ahlquist (1948), on the basis of two distinct rank order of
potencies of adrenergic agonists classified adrenergic
receptors into two types α and β

19. Alpha(α) receptors
α1receptor
• Loaction: postsynaptic
• Coupling protein: Gq
• Effector pathway: IP3/DAG ↑, Phospholipase A2 ↑—PG
release
• Selective agonist: Phenylephrine, Methoxamine
• Selective antagonist: Prazosin

20. Subtype of α1 adrenergic receptors
• α1A –high density in prostate gland, eye, also found in arteries
and veins, smooth muscle
• α1B – most abundant type in heart, blood vessels
• α1D – coronary blood vessel and aorta
• Function subserved: Smooth muscle–contraction
Vasoconstriction
Gland—secretion
Gut—relaxation
Eye—mydriasis

21. α2 receptor
• Loaction: presynaptic/postsynaptically
• Coupling protein: Gi/Go
• Effector pathway: K+ channel ↑, Ca2+ channel ↓ or ↑,
↓ adenyl cyclase, ↓ cAMP
• Selective agonist: Clonidine
• Selective antagonist: Yohimbine

22. • Subtype Of α2 Adrenergic Receptors
• α2A –inhibitory autoreceptor found on presynaptic nerve endings
of sympatheic and also parasympathetic nerves
• α2B –on peripheral blood vessels
• α2C –predominately inhibitory present in adrenal medulla and on
nerve endings
• Function subserved: Inhibition of transmitter release
Vasoconstriction
Decreased central sympathetic flow
Decreased insulin release
Platelet aggregation

23. Beta(β) receptor
• Loaction: Postsynaptic
• Coupling protein: Gs
• Effector pathway: cAMP↑, Ca2+ channel ↑
On the basis of relative organ specificity of selective
agonists and antagonists the β receptors were further
subdivided into β1, β2 and β3

24. Differences between β1, β2 and β3
receptors
β1 β2 β3
1. Location Heart, JG cells in
kidney
Bronchi, blood
vessels, uterus, liver,
g.i.t., urinary tract,
eye
Adipose tissue
Urinary bladder
2. Selective agonist Dobutamine Salbutamol,
terbutaline
miragebron
3 Relative potency
of NA and Adr
NA < Adr NA << Adr NA > Adr

25. Action of sympathetic system
1. Heart:-due to β1 receptor in myocardium, pacemaker cells
• Positive chronotropic
• Positive ionotropic
• Positive dromotropic
2. Blood vessel
• Vasoconstriction (α1)
• Vasodilatation (β2)
• Constriction predominates in cutaneous, mucous membrane and renal beds
• Dilatation predominates in skeletal muscles, liver and coronaries

26. 3. BP
Systolic blood pressure is determine by cardiac output(β1)
Diastolic blood pressure is determine by state of blood vessel
• α1 stimulation increase DBP
• β2 stimulation decreases DBP
4. Respiration
• Bronchial smooth muscle contain β2(bronchodilation)
• Mucosal vasoconstriction by α1 that also increase luminal diameter
of bronchus

27. 5. Eye
• α1 receptor stimulation present on dilator pupillary muscle cause
mydriasis
• β2 receptor stimulation by ciliary vasodilation increase formation
aqueous humor
• α1 and α2 receptor stimulation decrease aqueous humor secretion
6. Urinary system
• urinary retention occur
• α1 contraction of trigone sphincter
• β2 and β3 relaxation of detrusor muscle

28. 7. Genital system
• Pregnant uterus relaxed by β2 stimulation
• Non pregnant uterus contracted by α1 stimulation
• α1 receptor in vas deferens, seminal vesicle and prostate facilitate
ejaculation
8. GIT
• Smooth muscle of git are relaxed by
• direct action of β2
• indirect action of α2 (present post synaptically on cholinergic
neuron and decrease Ach)
• Sphincter are contracted by α receptor activation

29. 9. CNS
• Does not produce any marked CNS effects
• Restlessness, apprehension and tremor may occur
• Activation of α2 receptors in the brainstem (by selective α2 agonists)
results in decreased sympathetic outflow → fall in BP and
bradycardia.
10. Skeletal muscle
• The direct effect on muscle fibres is exerted through β2
• Tremors
• Increases muscle mass
• Increase speed of contraction
• Glycogenolysis

30. 11. Kidney
• β1 stimulation JG cells (renin secretion)
12. Metabolic effects
• Glycogenolysis → hyperglycaemia, hyperlactacidaemia (β2)
• Lipolysis → rise in plasma free fatty acid (FFA) and calorigenesis
(β2 + β3)
• Reduction of insulin (α2 adrenoreceptor)
• Augmentation of glucagon (β2 adrenoreceptor)
• Transient hyperkalaemia followed by hypokalaemia

32. ADRENERGIC DRUGS
These drugs increase the activity of adrenergic system and
divided into
1.Directly acting: stimulates α & β receptors
2.Indirectly acting: increase the amount of NA in synapse
3.Mixed: possess both activity

33. Directly acting sympathomimetic
I. Cathecholamine
1. Endogenous
• Adrenaline
• Nor-adrenaline
• Dopamine
2. Exogenous
• Dobutamine
• Isoprenaline
II.Non-catecholamine
• Xylomethazoline
• Clonidine
• Phenylephrine
• Salbutamol
• Methoxamine

34. Indirect sympathomimetics
1. Action by displacement
• Amphetamine
• Methylphenidate
• Tyramine
2. Reuptake inhibitor
• Cocaine
• TCA
Mixed action
sympathomimetics
• Ephedrine
• Pseudophedrine

35. Adrenaline: α1 + α2 +β1+β2 and weak β3 action
1. Adr 0.5 mg injected promptly i.m. is the drug of choice
in anaphylactic shock
2. Cardiac arrest
3. Along with local anaesthetics
4. Control of local bleeding
5. Insulin hypoglycemia
6. Bronchial asthma if selective β2 agonist not available

36. ADME
• All Catecholamines are ineffective orally due to
rapid inactivation in Liver and intestine by MAO
and COMT
• Absorbed slowly from subcutaneous tissue
• Faster from IM site
• Inhalation is locally effective
• Not usually given IV(arrhythmias can occur)

37. Adverse Effects And Contraindications
• Restlessness , headache, palpitation, anxiety, tremor
• Cerebral haemorrhage, ventricular tachycardia/fibrillation,
angina, myocardial infarction
• C/I in hypertensive, hyperthyroid and angina patients
• Adr should not be given with halothane (risk of arrhythmias)and
with β blockers (marked rise in BP can occur due to unopposed α
action).

38. Noradrenaline: α1 + α2 + β1 + β3 but no β2action
• Uses: Injection Noradrenal bitartrate slow IV infusion at the rate
of 2-4mg/ minute used as a vasopressor agent in treatment of
hypovolemic shock and other hypotensive states in order to raise
B.P during intense care
Isopraline: β1+β2 +β3 but no α action
• Used as Bronchodilator and for treatment of AV block, Stokes-
Adam Syndrome (but not preferred anymore)

39. Dopamine
• Agonists at dopaminergic D1, D2 receptors
• Agonist at adrenergic α1 and β1
• No β2 action
• Acts
• On D1 (1-2 mcg/kg/min)
• On β1 (2-10 mcg/kg/min)
• On α1 (> 10 mcg/kg/min)
• It’s a DOC for cardiogenic shock with oliguric renal failure

40. Dobutamine
• A derivative of DA
• Do not act on D1 or D2 receptor
• Acts on both α and β adrenergic receptors, the only prominent
action is increased force of cardiac contraction and output,
without significant change in heart rate, peripheral resistance
and BP
• As such, it is considered to be a relatively selective β1 agonist

41. • Uses: as an inotropic agent
• In pump failure accompanying myocardial infarction
• Cardiac surgery
• For short term management of severe congestive heart
failure.
• ADRs: Tachycardia, hypertension, angina and fatal
arrhythmia

42. Selective α1 agonist
• Phenylepherine:-
• mydriatics(does not cause cycloplegia)
• It raises BP by causing vasoconstriction
• Reduce intraocular tension by constricting ciliary
body blood vessels.
• orally administered nasal decongestant preparations
• Methoxamine: occasionally used as vasopressor agent
• Midodrine: orally effective prodrug
used for orthostatic hypotension

43. Selective α2 agonist
Clonidine centrally acting α2 adrenergic agonist
and imidazoline receptor agonist
Used
• Hypertension
• Prophylaxis of migraine
• Opioids withdrawal
• Epidurally, in opoid conjugation for pain relief
• Diarrhea in diabetic neuropathy
Adverse Effects
• Dry mouth and sedation, bradycardia
• Sexual dysfunction also may occur

44. Apraclonidine, brimonidine:
• Decreases aquesous humor formation
• used topically for glaucoma
Methyldopa: used in the clinical treatment of
• High blood pressure
• Gestational hypertension(or pregnancy-induced
hypertension)
• Pre-eclampsia

45. Dexmeditomidine:
• central α2 agonist used for pre anasthetic agents
• Also for sedation in intubated patient in ICU
Tizanidine:
• central α2 agonist
• used as muscle relaxant

46. Selective β agonist
Prenaterol (Selective β1 agonist):
• Non catecholamine
• Promoted recently for reversal of β blockade
Miragebron(Selective β3 agonist)
• Indicated for overactive bladder

47. Selective β2 agonist: causes bronchodilatation,
vasodilatation and uterine relaxation and hyperkalemia
without causing cardiac stimulation
• Salbutamol, terbutaline, salmeterol, formoterol:
Bronchial asthma
Salmeterol, formoterol are longer acting
• Isoxsuprine(oral) and ritodrine(i.v.): for delay of
Preterm labor

48. • β2 agonists benefit by enhancing K+ uptake into
muscles, thereby lowering plasma K+ levels
Side effect is muscle tremor, tachycardia, hypokalemia
and arrhythmias
• Clenbuterol: anabolic action to increase muscle
strength

49. NASAL DECONGESTANTS
• α agonists which on topical application as dilute
solution (0.05–0.1%) produce local vasoconstriction.
• Naphazoline , Xylometazoline and Oxymetazoline are
relatively selective α2 agonist
• They have a longer duration of action (12 hours) than
ephedrine
• Long term use atrophic rhinitis and anosmia

50. Indirect sympathomimetics
Tyramine
• Taken up by NET (the norepinephrine reuptake transporter) and
causes the release of catecholamines
• No clinical uses, present in various food
• Cheese reaction can occur if given with MAO inhibitor
Methylphenidate
• Acts by blocking the dopamine transporter and norepinephrine
transporter
• Leading to increased concentrations of dopamine and
norepinephrine within the synaptic cleft
• Preferred drug for attention deficit hyperkinetic disorder(AHDH)

51. Amphetamines
• Increases noradrenaline mainly by exchange diffusion and reverse
transport involving transporters like NET, DAT and VMAT2
• Uses
• Hyperkinetic Children (ADHD)
• Narcolepsy
• Anorectic agent
• Nocturnal enuresis
• Side effects
• Hypertension
• Insomnia
• Dependence
• Acute psychosis with overdose

52. Mixed Sympathomimetics
Ephedrine
• Mainly acts indirectly(by increasing NA)
• Also has some direct action as well on α and β receptors
• The use of ephedrine as a bronchodilator in asthmatic
patients is less common with the availability of β2-selective
agonists.
• Treat the hypotension that may occur with spinal anesthesia
• Vasopressor of choice in pregnancy does not interfere with
placental circulation

53. Pseudoephedrine A stereoisomer of ephedrine
• Causes vasoconstriction, especially in mucosae and skin
• Fewer CNS and cardiac effect and is a poor bronchodilator
(little β2 agonistic activity).
• It has been used orally as a decongestant of upper
respiratory tract, nose and eustachian tubes
• Pseudoephedrine is also used as a first-line prophylactic for
recurrent priapism