2. Noradrenergic transmission
• Nor-adrenaline is the major neurotransmitter
of the Sympathetic system
• Noradrenergic neurons are postganglionic
sympathetic neurons with cell bodies in the
sympathetic ganglia
• Have long axons which end in varicosities
where NA is synthesized and stored
3. Adrenergic transmission
• Catecholamines:
• Natural: Adrenaline, Noradrenaline, Dopamine
• Synthetic: Isoprenaline, Dobutamine
• Non-Catecholamines:
• Ephedrine, Amphetamines, Phenylepherine,
Methoxamine, Mephentermine
• Also called sympathomimetic amines as most of
them contain an intact or partially substituted
amino (NH2) group
6. Release
• Release of CA takes place by exocytosis
• All the vesicular contents (NA or Adr, ATP,
dopamine β hydroxylase, chromogranin)are
released
• enkephalin or neuropeptide Y (NPY) released
7. Uptake
Axonal uptake
• active amine pump (NET)is present at the neuronal
membrane which transports NA by a Na+ coupled
mechanism
• Called uptake-1
• inhibited by cocaine, desipramine
Extraneuronal uptake
• by extraneuronal amine transporter (ENT or OCT3)
• inhibited by corticosterone
• not of physiological or pharmacological importance.
8. Contd.
• Vesicular uptake
• ‘vesicular monoamine transporter’ (VMAT-2),
which transports CA from the cytoplasm to
the interior of the storage vesicle
• inhibited by reserpine
14. ADRENERGIC DRUGS
(Sympathomimetics)
• Direct sympathomimetics
• Directly as agonists on α and/or β adrenoceptors
• Adr, NA, isoprenaline (Iso), phenylephrine,
methoxamine, xylometazoline, salbutamol
• Indirect sympathomimetics
• act on adrenergic neurone to release NA
• then acts on the adrenoceptors
• tyramine, amphetamine
15. • Mixed action sympathomimetics:
• Act directly as well as indirectly
• ephedrine, dopamine, mephentermine
16.
17. ACTIONS
• Adrealine:α1 + α2 + β1 + β2 and weak β3
action
• NA : α1 + α2 + β1 + β3 but no β2 action
• Iso : β1 + β2 + β3 but no α action
18. α actions β actions
Constriction of arterioles and veins → rise
inBP (α1 + α2)
Dilatation of arterioles and veins → fall in
BP (β2)
Heart—little action, arrhythmia at high
dose (α1)
Cardiac stimulation (β1), ↑ rate, force and
conduction velocity
-------------------------- Bronchodilatation (β2)
Contraction of radial muscles of iris
→mydriasis (α1), decreased aqueous
secretion
Enhanced aqueous secretion
Intestinal relaxation Intestinal relaxation (β2)
Bladder trigone—contraction (α1) Detrusor—relaxation (β2)
Uterus—contraction (α1) Relaxation (β2)
Splenic capsule—contraction (α1) Relaxation (β2) (slight)
Neuromuscular transmission facilitated, ↑
ACh release
Active state—prolonged in fast contracting
muscle, abbreviated in slow contracting
muscle; tremors (β2)
-------------------------- Liver—glycogenolysis (β2)→hyperglycaemia
Fat—lipolysis (β1 + β2 + β3) → increased
blood FFA,
19. alfa beta
----------------------- Renin release from kidney (β1)
Male sex organs—ejaculation (α1) ---------------
------------------------------ ADH secretion from posterior pituitary
(β1)
21. Effects on cardiovascular system:
A. Heart :
- ↑ in heart rate(SA node)
- ↑ed conduction velocity through AV node
bundle of his & purkinje fibers
- ↑ed force of contraction &↑ed BP
- ↑ed stroke volume & CO
Reflex bradycardia due to
compensatory vagal discharge
22. B. Blood vessels:
– Constriction predominates in cutaneous, mucous
membrane and renal vessels.
– Dilatation predominates in skeletal muscles, liver
and coronaries.
– Total PR decreases as vascular β2 are more sensitive
than α.
23. Adr giyen by slow i.v. or s.c.
Rise in SBP but fall in DBP
As PR is decreased
(rise in MBP & PP)
Vascular β2 receptors are
more sensitive than
α receptors.
Adr by rapid i.v. injection
Rise in both SBP & DBP
(rise in MBP)
At high concentration α response
predominates and vasoconstriction
occurs
BP returns to normal and fall
in MBP after few minutes due
to rapid uptake and dissipation
of Adr.(low conc β2 but no α effect)
With α blockers → only fall in BP
VASOMOTOR REVERSAL OF DALE
24. Therapeutic uses
Allergic reactions(Anaphylaxis) :
Manifestations of serious acute hypersensitivity reactions
from food, bee sting, or drug allergy.
S.C/I.M. injection of epinephrine rapidly relieves itching,
and swelling of lips, eyelids, and tongue.
I.M route is preferred in anaphylactic shock as absorption
is poor after S.C.
In some pt. careful I.V. infusion to have prompt
cardiovascular effects.
Dose 0.3-0.5 ml 1:1000 soln.
25. Bronchial asthma:
Epinephrine causes bronchodilation(β2) & decongestion of
bronchial mucosa(α).
Epinephrine has a striking therapeutic effect
↓
physiological antagonist to substances that cause
bronchoconstriction in asthma.
Inhibition of antigen-induced release of inflammatory
mediators from mast cells(β2)
Dose 0.3-0.5 ml 1:1000 soln. S.C
26. Cardiac resuscitation:
Intracardiac injection
0.1mg/ml
C/I – Ventricular fibrillation
To reverse the sudden cardiac arrest like with drowning and
electrocution.
To control bleeding:
To control bleeding as in epistaxis and in ENT surgery
Used as Local Spray
As a topical hemostatic agent on bleeding surfaces such as in the
mouth or in bleeding peptic ulcers during endoscopy of the
stomach and duodenum
27. To prolong the Duration of Local Anaesthetic
action:
Being vasoconstrictor → Antagonises the vasodilating effect
of LA.
Retards their systemic absorption from the local site
Duration of LA action prolonged
Systemic toxicity decreased
S.C. or Intradermal with LA
28. Adverse effects:
Cerebral hemorrhage from the sharp rise in blood pressure
Cardiac arrhythmias
↑in cardiac work & contractility → Coronary
insufficiancy,angina,arrythmia
Restlessness
Throbbing headache
Tremor
29. Contraindication:
Hyperthyroidism - more responsive to Adr.
Angina & hypertension
Interaction:
TCAs-Prevent reuptake of Adr.
Halothane group of GAs-Increases sensitivity of
myocardium towards Adr.
MAO inhibitors-Metabolism is hampered.
31. Effects on cardiovascular system
• SBP, DBP & PP increased.
• CO is unchanged or decreased, and TPR raised.
• Compensatory vagal reflex activity
slows the heart.
• Renal blood flow, mesenteric, splanchnic
and hepatic blood flow reduced.
• Coronary flow increased due to indirect coronary dilation and
poor β2 agonistic effect.
32. Adverse effects:
Similar to those of epinephrine
Greater elevation of blood pressure with NE
Necrosis and sloughing at the site of intravenous injection
due to extravasation of the drug
Reduced blood flow to organs such as kidney and intestines
33. Therapeutic uses
• To treat Cardiogenic shock
• To treat hypotensive state following surgical shock or MI.
• Inj NE (4 mg) dissolved in 1 ltr of 5% glucose soln and given as
0.5-1 mg/ml.
35. Features :
Non selective β receptor agonist
Very low affinity for α receptors(almost no action)
Receptor affinity β1 = β2 ˃ ˃ β3 ˃ ˃ ˃ ˃ α
36. Effects on cardiovascular system
DBP falls, SBP may remain unchanged or rise
MBP typically falls.
Intravenous infusion lowers TPR primarily in skeletal
muscle but also in renal and mesenteric vascular beds.
CO increased because of the positive inotropic and
chronotropic effects .
38. Therapeutic uses
Used in emergencies to stimulate heart rate in patients with
bradycardia or heart block
In anticipation of inserting an artificial cardiac pacemaker or
in patients with the ventricular arrhythmia torsades de
pointes.
41. Effects on Cardiovascular system
I.V. upto 2-5 mcg/kg/min
Acts on D1 receptors & causes
dilation of renal vessels,
increased GFR,renal blood flow
& excretion of sodium.
I.V. upto 5-10 mcg/kg/min
Also stimulate β1 receptors,so
increse in CO,But TPR & MBP
are unchanged due to D1
mediated Vasodilation.
42. Contd…..
I.V. > 10 mcg/kg/min
Vasoconstriction by α1
receptors &
beneficial low dose effect
are nullified.
43. Therapeutic uses
Cardiogenic shock from MI,trauma or surgery.
In treatment of CHF,renal failure, liver failure.
Low CO with Compromised renal function.
(Clinical assessment of myocardial function,BP,HR, perfusion of
vital organs such as the brain, and the production of urine).
The content of ampoule(40mg/ml) diluted in 100ml of 5%
dextrose or 0.9% NS.so conc. Of 400mcg/ml is given at a rate of
5-10mcg/kg/min.
46. • Synthetic catecholamine derivative
• Bulky aromatic residue on the amino terminus
• Racemic mixture :
l - form – Potent α1 agonist
d - form – Potent α1 antagonist & β1 agonist
Prominent selective β1 agonistic effect
So selective inotropic effect w/o change in TPR & BP
47. Therapeutic uses:
Heart failure associated with MI,surgery or trauma
For short term management of CHF
2-5 mcg/kg/min I.V. infusion
48. Dipivefrine
• Prodrug for epinephrine
• Enhanced corneal permeability
• 0.1% soln. used for Glaucoma
S/E –
Conjunctival hyperaemia
Photosensitivity
49. Dopexamine
• Stimulate β2 receptors and peripheral DA receptors
• Inhibit neuronal uptake of NE.
• Actions:
Increased CO
Peripheral vasodilation
Increase in renal & mesenteric blood flow
• Use:
To provide hemodynamic support in CHF & shock.
• S/E:
Tachycardia,hypotension,dyspnoea
50. Fenoldopam
• Selective D1 receptor agonist
• No α or β activity
• Vasodilatation in coronary,ranal & mesenteric arteries.
• Use:
Short term management of severe HT with impaired renal
function
• S/E:
Reflex tachycardia
Increased IOP, headache
Hypokalaemia
51. Ephedrine
• Plant alkaloid obtained from Ephedra vulgaris
– Mixed acting drug (also metaraminol)
– effective orally
• Crosses BBB and Centrally – Increased
alertness, anxiety, insomnia, tremor and
nausea in adults& Sleepiness in children
• Effects appear slowly but lasts longer (t1/2-4h)
– 100 times less potent
• Tachyphylaxis on repeated dosing (low
neuronal pool)
52. • Not used commonly due to non-specific action
• Uses: Mild Bronchial asthma, hypotension
due to spinal anaesthesia
• Available as tablets, nasal drop and injection
53. Phenylepherine - Selective,
synthetic and direct α1 agonist
• Actions qualitatively similar to noradrenaline
• Long duration of action
• Resistant to MAO and COMT
• Does not cross BBB, so no CNS effects
• Peripheral vasoconstriction leads to rise in BP
but Reflex bradycardia
• Produces mydriasis and nasal decongestion
54. • Use:
• hypovolaemic shock as pressor agent
• Sinusitis & Rhinitis as nasal decongestant
• Mydriatic in the form of eye drops and lowers
intraocular pressure
• ADRs: Photosensitivity, conjunctival
hyperemia and hypersensitivity
55. Nasal Decongestants
• Used in allergic rhinitis, colds, coughs and sinusitis as nasal
drops
• Sympathomimetic vasoconstrictors with α- effects are used
• Drugs: Phenylepherine, xylometazoline, Oxymetazoline,
PPA, Pseudoephidrine etc
• Drawbacks:
• Rebound congestion due to overuse
• mucosal ischaemic damage occurs if used excessively (more
often than 3 hrly) or for prolonged periods (>3weeks)
• CNS Toxicity
• Failure of antihypertensive therapy
• Fatal hypertensive crisis in patients on MAOIs
56. Contd.
• Use only a few days since longer application
reduces ciliary action
• Pseudophedrine
• fewer CNS and cardiac effect
• poor bronchodilator
• used orally as a decongestant of upper
respiratory tract, nose and eustachian tubes
• rise in BP can occur, especially in hypertensives
57. Amphetamine
• Synthetic compound similar to Ephedrine
Pharmacologically
• CNS stimulant action – psychoactive drug and also
performance enhancing drug
• Actions:
– alertness, euphoria, talkativeness and increased work
capacity
– Fatigue is allayed: acts on DA and NA
neurotransmitters etc. –reward pathway
– increased physical performance without fatigue –
short lasting
– (Banned drug and included in the list of drugs of
“Dope Test)
– RAS Stimulation – wakefulness, sleep deprivation
58. Contd.
– Other actions: Stimulation of respiratory centre, Hunger
suppression, also anticonvulsant, analgesic and antiemetic
actions
• Generally, Teenage abusers - thrill or kick
• High Dose – Euphoria, excitement and may progress to
delirium, hallucination and acute psychotic state
• Repeated Dose – Long term behavioural abnormalities
• Starvation – acidic urine
• Treatment of toxicity :
• administration of chlorpromazine which controls both
central as well as peripheral α adrenergic effects
• Uses: Hyperkinetic Children (ADHD), Narcolepsy,
• Epilepsy and Parkinsonism
59. Anorectics
• Drugs used for suppression of appetite
• MOA: Inhibition of NA/DA or 5-HT uptake –
enhancement of monoaminergic transmission
• NA agents affect the appetite centre
• Serotonergics act on satiety centre
• Fenfluramine, dexfenfluramine and sibutramine –
ALL ARE BANNED NOW
• Reasons: Heart valve defects, fibrosis and
pulmonary hypertension etc.
60. Clonidine
• Acts on alfa2 receptor in brainstem &↓
central sympathetic outflow
• Decrease in BP and cardiac output
• Uses:hypertension
61. β2 Adrenergic Agonists
• Short acting : Salbutamol, Terbutaline,
• Selective for β2 receptor subtype
• Used for acute inhalational treatment of
bronchospasm
62. Uterine Relaxants
• tocolytic agents
• β2 agonists relax uterus
• Used by i.v. infusion to inhibit premature
labour
• Isoxsuprine, Terbutaline, Ritodrine,
Salbutamol
• Tachycardia & hypotension occur
