2. Adrenergic Agonists
Differences
Catecholamine
• Cannot use orally
• Cannot cross BBB
Short-half live
Examples:
Norepinephrine
Epinephrine
Isoproteronol
Dopamine
Dobutamine
Noncatecholamines
• Can use orally
• Can cross BBB
Longer half life
Examples:
Ephedrine
Phenylephrine
Terbutaline
Amphetamines
Methoxamine
Mephentermine
3. 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
4. • Catecholamines:
Compounds containing a
catechol nucleus (Benzene
ring with 2 adjacent OH
groups) and an amine
containing side chain ( that
why its not penterat BBB)
• Non-
catecholamines lack
hydroxyl (OH) group (good
lipophilic )
5. 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
15. Epinephrine as prototype
• Potent stimulant of alpha and beta receptors.
• Complex actions on target organs.
• At low concentration vasodilatation.
• At high concentration vasoconstriction.
17. 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
18. 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
19. 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
20. Blood Pressure
• Depends on the Catecholamine involved
• NA causes rise in Systolic, diastolic and mean BP rise
(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
21. 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
22. 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
23. 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
24. 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
26. • Adverse effects:
– Extensions of their effects in the CVS and the CNS
– Anxiety, tenseness, headache and paranoia
– tachycardia, dysrhythmias
– Large dose IV – cerebral hemorrhage, pulmonary
edema
• Route of administration:
– Inhalation
– Injection (IM, SC, IV), not PO
– Topical application
– Rapidly degraded
27. ADRs
• Restlessness, Throbbing headache, Tremor,
Palpitations
• Cerebral hemorrhage, cardiac arrhythmias
• Contraindicated in hypertensives,
hyperthyroid and angina poctoris
• Halothane and beta-blockers – not indicated
28. 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
29. 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 .
30. 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
31. 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
33. 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)
34. 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)
35. 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
36. 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
37. 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)
40. 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
41. 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
42. 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
43. 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
45. 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
46. 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
48. Mix action
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
49. 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
50. 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.