3. 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
They have long axons
which end in varicosities
where NA is synthesized
and stored
4. 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
5. • Catecholamines:
Compounds containing
a catechol nucleus
(Benzene ring with 2
adjacent OH groups)
and an amine
containing side chain
• Non-catecholamines
lack hydroxyl (OH)
group
11. Reuptake
Sympathetic nerves take up amines and release
them as neurotransmitters
Uptake I is a high efficiency system more specific
for NA
Located in neuronal membrane
Inhibited by Cocaine, TCAD, Amphetamines
Uptake 2 is less specific for NA
Located in smooth muscle/ cardiac muscle
Inhibited by steroids/ phenoxybenzamine
No Physiological or Pharmacological importance
12. Metabolism of CAs
Mono Amine Oxidase (MAO)
Intracellular bound to mitochondrial membrane
Present in NA terminals and liver/ intestine
MAO inhibitors are used as antidepressants
Catechol-o-methyl-transferase (COMT)
Neuronal and non-neuronal tissue
Acts on catecholamines and byproducts
VMA levels are diagnostic for tumours
16. Adrenergic Receptors
Adrenergic receptors (or adrenoceptors) are a class of G-protein
coupled receptors that are the target of catecholamines
Adrenergic receptors specifically bind their endogenous ligands –
catecholamines (adrenaline and noradrenline)
Increase or decrease of 2nd messengers cAMP or IP3/DAG
Many cells possess these receptors, and the binding of an
agonist will generally cause the cell to respond in a flight-fight
manner.
For instance, the heart will start beating quicker and the pupils
will dilate
17. How Many of them ????
Adenoreceptors
Alpha (α) Beta (β)
α 1 α 2 β1 β 2 β3
α 2A α 2B α 2C
α 1A α 1B α 1D
18. Differences - Adrenergic
Receptors (α and β) !
Alpha (α) and Beta (β)
Agonist affinity of alpha (α):
adrenaline > noradrenaline > isoprenaline
Antagonist: Phenoxybenzamine
IP3/DAG, cAMP and K+ channel opening
Agonist affinity of beta (β):
isoprenaline > adrenaline > noradrenaline
Propranolol
cAMP and Ca+ channel opening
19. Potency of catecholamines on
Adrenergic Receptors
Aortic strip contraction Bronchial relaxation
Adr NA
α β
Iso
Iso Adr
NA
Log Concentration
21. Recall: Adenylyl cyclase: cAMP
pathway
PKA alters the functions of many
Enzymes, ion channels,
transporters
and structural proteins.
PKA Phospholamban
Increased
Interaction with
Ca++
Faster relaxation
Troponin
Cardiac
contractility
Other
Functional
proteins
Faster sequestration of
Ca++ in SR
23. Beta receptors
All β receptors activate adenylate cyclase, raising the intracellular cAMP
concentration
Type β1:
These are present in heart tissue, and cause an increased heart rate by
acting on the cardiac pacemaker cells
Type β2:
These are in the vessels of skeletal muscle, and cause vasodilatation, which
allows more blood to flow to the muscles, and reduce total peripheral
resistance
Beta-2 receptors are also present in bronchial smooth muscle, and cause
bronchodilatation when activated
Stimulated by adrenaline, but not noradrenaline
Bronchodilator salbutamol work by binding to and stimulating the β2
receptors
Type β3:
Beta-3 receptors are present in adipose tissue and are thought to have a
role in the regulation of lipid metabolism
24. Differences between β1, β2 and β3
Beta-1 Beta-2 Beta-3
Location Heart and JG cells Bronchi, uterus,
Blood vessels,
liver, urinary tract,
eye
Adipose
tissue
Agonist Dobutamine Salbutamol -
Antagonist Metoprolol, Atenolol Alpha-methyl
propranolol
-
Action on
NA
Moderate Weak Strong
25. Clinical Effects of β-receptor
stimulation
β1: Adrenaline, NA and Isoprenaline:
Tachycardia
Increased myocardial contractility
Increased Lipolysis
Increased Renin Release
β2: Adrenaline and Isoprenaline (not NA)
Bronchi – Relaxation
SM of Arterioles (skeletal Muscle) – Dilatation
Uterus – Relaxation
Skeletal Muscle – Tremor
Hypokalaemia
Hepatic Glycogenolysis and hyperlactiacidemia
β3: Increased Plasma free fatty acid – increased O2 consumption -
increased heat production
26. Adrenergic receptors - alpha
Type α1
Blood vessels with alpha-1 receptors are present in the
skin and the genitourinary system, and during the fight-or-flight
response there is decreased blood flow to these
organs
Acts by phospholipase C activation, which forms IP3 and
DAG
In blood vessels these cause vasoconstriction
Type α2
These are found on pre-synaptic nerve terminals
Acts by inactivation of adenylate cyclase, cyclic AMP levels
within the cell decrease (cAMP)
27. Differences between α1 and α2
Alpha-1 Alpha-2
Location Post junctional – blood vessels
of skin and mucous
membrane, Pilomotor muscle
& sweat gland, radial muscles
of Iris
Prejunctional
Function Stimulatory – GU,
Vasoconstriction, gland
secretion, Gut relaxation,
Glycogenolysis
Inhibition of transmitter
release, vasoconstriction,
decreased central symp.
Outflow, platelet
aggregation
Agonist Phenylephrine, Methoxamine Clonidine
Antagonist Prazosin Yohimbine
29. Molecular Basis of Adrenergic
Receptors
Also glycogenolysis
in liver
Inhibition of
Insulin
release and
Platelet
aggregation
Gluconeogen
esis
30. Dopamine receptors
D1-receptors are post synaptic receptors
located in blood vessels and CNS
D2-receptors are presynaptic present in CNS,
ganglia, renal cortex
31. Summary of agents modifying
adrenergic transmission
Step Actions Drug
Synthesis of NA Inhibition α - methyl-p-tyrosine
Axonal uptake Block Cocaine, guanethidine,
ephedrine
Vesicular uptake Block Reserpine
Vesicular NA Displacement Guanethidine
Membrane NA pool Exchange diffusion Tyramine, Ephedrine
Metabolism MAO-A inhibition
MAO-B inhibition
COMT inhibition
Moclobemide
Selegiline
Tolcapone
Receptors α 1
α 2
β1 + β2
β1
Prazosin
Yohimbine
Propranolol
Metoprolol
32.
33. Adrenaline as prototype
Potent stimulant of alpha and beta receptors
Complex actions on target organs
34. Heart
Beta-1 mediated action - Powerful Cardiac stimulant - +ve
chronotropic, +ve inotropic
Acts on beta-1 receptors in myocardium, pacemaker cells and
conducting tissue
Heart rate increases by increasing slow diastolic depolarization of cells
in SAN
High doses cause marked rise in heart rate and BP causing reflex
depression of SAN – unmasking of latent pacemaker cells in AVN and
PF – arrhythmia (sensitization of arrhythmogenic effects by Halothane)
Cardiac systole is shorter and more powerful
Cardiac output is enhanced and Oxygen consumption is increased
Cardiac efficiency is markedly decreased
Conduction velocity in AVN, atrial muscle fibre, ventricular fibre and
Bundle of His increased – benefit in partial AV block
Reduced refractory period in all cardiac cells
35. Blood Vessels
Seen mainly in the smaller vessels –
arterioles – Vasoconstriction (alpha) and
vasodilatation (beta) – depends on the drug
Decreased blood flow to skin and mucus
membranes and renal beds – alpha effect (1
and 2) -
Increased blood flow to skeletal muscles,
coronary and liver vessels - (Beta-2 effect)
counterbalanced by a vasoconstrictor effect
of alpha receptors
36. Blood Pressure
Depends on the Catecholamine involved
NA causes rise in Systolic, diastolic and mean
BP (no beta-2 action) – unopposed alpha action
Isoprenaline causes rise in systolic but fall in
diastolic BP – mean BP falls (beta-1 and beta-2)
Adr causes rise in systolic BP, but fall in diastolic
BP – mean BP generally rises (slow injection)
Decreased peripheral resistance at low conc. Beta
receptors are more sensitive to Adr than alpha
receptors
37. Blood Pressure – contd.
Rapid IV injection of Adrenaline marked rise in
Systolic and diastolic BP
Large concentration alpha action predominates –
vasoconstriction even in skeletal muscle
But BP returns to normal in few minutes
A secondary fall in mean BP occurs
Mechanism – rapid uptake and dissipation of
Adr – at low conc. Alpha action lost but beta
action predominates – Dale`s Vasomotor
reversal phenomenon
39. Actions of Adrenaline
Respiratory:
Powerful bronchodilator
Relaxes bronchial smooth muscle (not NA)
Beta-2 mediated effect
Physiological antagonist to mediators of
bronchoconstriction e.g. Histamine
GIT : Relaxation of gut muscles (alpha and beta) and constricted
sphincters – reduced peristalsis – not clinical importance
Bladder: relaxed detrusor muscle (beta) muscle but constriction of
Trigone – both are anti-voiding effect
Uterus: Adr contracts and relaxes Uterus (alpha and beta action)
but net effect depends on status of uterus and species – pregnant
relaxes but non-pregnant - contracts
40. Actions of Adrenaline – contd.
Skeletal Muscle:
Facilitation of Ach release in NM junction (alpha -1)
Beta-2 acts directly on Muscle fibres
Abbreviated active state and less tension in slow
conducting fibres and enhanced muscle spindle firing
– tremor
CNS: No visible clinical effect in normal doses – as low
penetration except restlessness, apprehension and
tremor
Activation of alpha-2 in CNS decreases sympathetic outflow and
reduction in BP and bradycardia - clonidine
41. Metabolic effects
Increases concentration of glucose and lactic
acid
Calorigenesis (β-2 and β-3)
Inhibits insulin secretion (α-2)
Decreases uptake of glucose by peripheral
tissue
Simulates glycogenolysis - Beta effect
Increases free fatty acid concentration in blood
Hypokalaemia – initial hyperkalaemia
42. ADME
All Catecholamines are ineffective orally
Absorbed slowly from subcutaneous tissue
Faster from IM site
Inhalation is locally effective
Not usually given IV
Rapidly inactivated in Liver by MAO and
COMT
43. Clinical Question!
Question: A Nurse was injecting a dose of penicillin
to a patient in Medicine ward without prior skin test
and patient suddenly developed immediate
hypersensitivity reactions. What would you do?
Answer: As the patient has developed Anaphylactic
reaction, the only way to resuscitate the patient is
injection of Adrenaline
0.5 mg (0.5 ml of 1:10000) IM and repeat after 5-10
minutes
Antihistaminics: Chlorpheniramine 10 – 20 mg IM or IV
Hydrocortisone 100 – 200 mg
44. Adrenaline – Clinical uses
Injectable preparations are available in dilutions
1:1000, 1:10000 and 1:100000
Usual dose is 0.3-0.5 mg sc of 1: 10000 solution
Used in:
Anaphylactic shock…
Prolong action of local anaesthetics
Cardiac arrest
Topically, to stop bleeding
Hyperkinetic children – ADHD, minimal brain dysfunction
Anorectic
48. Noradrenaline
Neurotransmitter released from
postganglionic adrenergic nerve endings
(80%)
Orally ineffective and poor SC absorption
IV administered
Metabolized by MAO, COMT
Short duration of action
49. Actions and uses
Agonist at α1(predominant), α2 and β1 Adrenergic receptors
Equipotent with Adr on β1, but No effect on β2
Increases systolic, diastolic B.P, mean pressure, pulse pressure
and stroke volume
Total peripheral resistance (TPR) increases due to vasoconstriction -
Pressor agent
Increases coronary blood flow
Decreases blood flow to kidney, liver and skeletal muscles
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
Problems: Down regulation of receptors, Renal Vasoconstriction
Septic and neurogenic shock (?)
50. Noradrenaline - ADRs
Anxiety, palpitation, respiratory difficulty
Acute Rise of BP, headache
Extravasations causes necrosis, gangrene
Contracts gravid uterus
Severe hypertension, violent headache,
photophobia, anginal pain, pallor and
sweating in hyperthyroid and hypertensive
patients
51. Isoprenaline
Catecholamine acting on beta-1 and beta-2 receptors – negligible
action on alpha receptor
Therefore main action on Heart and muscle
vasculature
Main Actions: Fall in Diastolic pressure, Bronchodilatation and
relaxation of Gut
ADME: Not effective orally, sublingual and inhalation (10mg tab. SL)
Overall effect is Cardiac stimulant (beta-1)
Increase in SBP but decrease in DBP (beta-2)
Decrease in mean BP
Used as Bronchodilator and for treatment of AV block, Stokes-Adam
Syndrome etc. – but not preferred anymore
53. Dopamine
Immediate metabolic precursor of
Noradrenalin
High concentration in CNS - basal ganglia,
limbic system and hypothalamus and also in
Adrenal medulla
Central neurotransmitter, regulates body
movements ineffective orally, IV use only,
Short T 1/2 (3-5minutes)
54. Dopamine
MECHANISM:
Agonists at dopaminergic D1, D2 receptors
Agonist at adrenergic α1 and β1
55. Dopamine
In small doses 2-5 μg/kg/minute, it stimulates D1-
receptors in renal, mesenteric and coronary vessels
leading to vasodilatation (Increase in cAMP)
Recall: Renal vasoconstriction occurs in CVS shock due to
sympathetic over activity
Increases renal blood flow, GFR an causes natriuresis
Interaction with D2 receptors (present in presynaptic adrenergic
neurones) – suppression of NA release (no alpha effect)
56. Dopamine – cond.
Moderate dose (5-10 μg/kg/minute), stimulates β1-
receptors in heart producing positive inotropic and
chronotropic actions actions
Releases Noradrenaline from nerves by β1-
stimulation
Does not change TPR and HR
Great Clinical benefit in CVS shock and CCF
High dose (10-30 μg/kg/minute), stimulates vascular
adrenergic α1-receptors (NA release) –
vasoconstriction and decreased renal blood flow
57. Why renal and mesenteric
vasodilatation is useful in Shock?
Increases renal blood flow, GFR an
causes natriuresis
In CVS shock – excessive sympathetic
activity leading to ischemia of gut,
sloughening and entry of Bacteria to
systemic circulation - septicemia
58. Dobutamine - Derivative of
Dopamine
MOA:
Acts on both alpha and beta receptors but more prominently in beta-1
receptor – increase in contractility and CO
Does not act on D1 or D2 receptors – No release of NA and thereby
hypertension
Predominantly a beta-1 agonist with weak beta-2 and selective alpha-1
activity
Racemic mixture consisting of both (+) and (−) isomers - the (+) isomer
is a potent β1 agonist and α1 antagonist, while the (−) isomer is an α1
agonist
Overall beta-1 activity and weak beta-2 activity
Increase in force of contraction and cardiac output but no change in
heart rate
Uses: Clinically give in dose of 2-8 mcg/kg/min IV infusion in Heart
failure in cardiac surgery, Septic and cardiogenic shock, Congestive Heart
failure
ADRs: Tachycardia, hyperension, angina and fatal arrhythmia
61. 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)
Used as bronchodilator, mydriatic, in heart block, mucosal
vasoconstriction & in myasthenia gravis
Not used commonly due to non-specific action
Uses: Mild Bronchial asthma, hypotension due to spinal anaesthesia
Available as tablets, nasal drop and injection
62. 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
Use:
hypovolaemic shock as pressor agent
Sinusitis & Rhinitis as nasal decongestant (common in oral preparations)
Mydriatic in the form of eye drops and lowers intraocular pressure
ADRs: Photosensitivity, conjunctival hyperemia and hypersensitivity
Administered parenteraly & topically (eye, nose)
63. What are Mucosal Decongestants?
Nasal and bronchial decongestants are the drugs 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
However, 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
Use only a few days since longer application reduces ciliary action
64. Nasal Decongestants
Pseudoephedrine to Ephedrine but less CNS and Cardiac
effects
Poor Bronchodilator
Given in combination with antihistaminics, antitussives and NSAIDs
in common cold and, allergic rhinitis, blocked Eustachian tube etc.
Rise in BP inhypertensives
Phenylpropanolamine (PPA) is similar to ephedrine and used
as decongestants in many cold and cough preparations
Also as weight loosing agent
Xylometazoline, Oxymetazoline etc.
65. Amphetamine
Synthetic compound similar to Ephedrine Pharmacologically
Known because of its 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)” – deterioration
occurs
RAS Stimulation – wakefulness, sleep deprivation (then physical
disability)
However, anxiety, restlessness, tremor and dysphoria occurs
Other actions: Stimulation of respiratory centre, Hunger
suppression, also anticonvulsant, analgesic and antiemetic
actions
66. Amphetamine – contd.
Drug of abuse – marked psychological effect but little
physical dependence
Generally, Teenage abusers - thrill or kick
High Dose – Euphoria, excitement and may progress to
delirium, hallucination and acute psychotic state
Also peripheral effects like arrhythmia, palpitation, vascular
collapse etc.
Repeated Dose – Long term behavioural abnormalities
Starvation – acidic urine
Uses: Hyperkinetic Children (ADHD), Narcolepsy,
Epilepsy and Parkinsonism
67. 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 and
Serotonergics act on satiety centre
Fenfluramine, dexfenfluramine and
sibutramine – ALL ARE BANNED NOW
Reasons: Heart valve defects, fibrosis and
pulmonary hypertension etc.
68. Clonidine
Centrally acting: Agonist to postsynaptic α2A
adrenoceptors in brain – vasomotor centre in
brainstem (presynaptic Ca++ level – increased NA
release)
Decrease in BP and cardiac output
Peripherally action: High dose activates peripheral
presynaptic autoreceptors on adrenergic nerve
ending mediating negative feedback suppression of
noradrenaline release
Overdose stimulates peripheral postsynaptic α1
adrenoceptors & cause hypertension by
vasoconstriction
69. Clonidine – contd.
Uses: ADHD in children, opioid withdrawal (restless legs, jitters and
hypertension), alcohol withdrawal (0.3 to 0.6 mg)
Abrupt or gradual withdrawal causes rebound hypertension
Onset may be rapid (a few hours) or delayed for as long as 2 days and
subsides over 2-3 days
Never use beta-blockers to treat
Available as tablets, injections and patches
Sedation, dry mouth, dizziness and constipation etc.
TCAs antagonize antihypertensive action & increase rebound
hypertension of abrupt withdrawal
Low dose Clonidine (50-100μg/dl) is used in migraine prophylaxis,
menopausal flushing and chorea
Moxonidine, Rilmenidine – Newer Imidazolines
70. β2 Adrenergic Agonists –
discussed elsewhere!
Short acting : Salbutamol, Metaproterenol, Terbutaline,
pirbuterol
Selective for β2 receptor subtype
Used for acute inhalational treatment of bronchospasm.
Onset of action within 1 to 5 minutes
Bronchodilatation lasts for 2 to 6 hours
Duration of action longer on oral administration
Directly relax airway smooth muscle
Relieve dyspnoea of asthmatic bronchoconstriction
Long acting: Salmeterol, Bitolterol, colterol
71. Uterine Relaxants - discussed
elsewhere!
Antioxytocics or tocolytic agents
β2 agonists relax uterus
Used by i.v. infusion to inhibit premature labour
Isoxsuprine, Terbutaline, Ritodrine, Salbutamol
Tachycardia & hypotension occur
Use minimum fluid volume using 5% dextrose as
diluents
Ritodrine: 50 μg/min, increase by 50 μg/min every
10 minutes until contractions stop or maternal heart
rate is 140 beats/minute. Continue for 12-48 hours
after contractions stop
72. Remember ?
Steps of Biosynthesis of Catecholamine
Distribution of adrenergic receptors
Individual Functions of Adrenergic receptors
All aspects of adrenaline – Dale`s
Phenomenon
Dopamine/Dobutamine actions
Nasal decongestants - Phenylephrine
Amphetamine and Clonidine - Desirable