Full Lecture of Adrenal agonist Pharmacologicaly

1. Adrenergic Agonist Agents
By Dr.SaraSami
Yuzuncu yil university
2015

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

6. Metabolism of CAs
(Homovanillic acid) (Vanillylmandelic acid)

7. ENDOGENOUS CATECHOLAMINES
Naturally occurring in body:
Norepinephrine -Sites: postganglionic sympathetic
sites (except sweat glands , erector pillorie, hair
follicles, )
• Epinephrine- Secreted by adrenal medulla
• Dopamine- Major transmitter in basal ganglia, CTZ,
limbic system, anterior pitutory.

8. ADRENERGIC DRUGS
Symphathomimetics
• DIRECT SYMPHATHOMIMETICS
• Adrenaline
• Noradrenaline
• Isoproterenol/ Isoprenaline
• Phenylephrine
• Methoxamine
• salmeterol
• Xylometazoline
• Salbutamol / Albutrol
• INDIRECT SYMPHATHOMIMETICS
• Tyramine
• Amphetamine
• Cocaine
• MIXED SYMPHATHOMIMETICS
• Ephedrine
• Pesudoephedrine
• Dopamine
• Mephenteramine

9. Pressor agents
Noradrenaline Phenylephrine
Ephedrine Methoxamine
Dopamine Mephentermine
Cardiac stimulants
Adrenaline Dobutamine
Isoprenaline
Bronchodilators
Adrenali Terbutaline
Isoprenaline Salmeterol
Salbutamol Formoterol
(Albuterol) Bambuterol
THERAPEUTIC CLASSIFICATION OF
ADRENERGIC DRUGS

10. Nasal decongestants
Phenylephrine Naphazoline
Xylometazoline Pseudoephedrine
Oxymetazoline Phenyl propanolamine
CNS stimulants
Amphetamine, Dexamphetamine, Methamphetamine
Anorectics
Fenfluramine Dexfenfluramine Sibutramine
Uterine relaxant and vasodilators
Ritodrine Salbutamol
Isoxsuprine Terbutaline

11. DIRECT SYMPHATHOMIMETICS
• Adrenaline
• Noradrenaline
• Isoproterenol/
Isoprenaline
• Phenylephrine
• Methoxamine
• salmeterol
• Xylometazoline
• Salbutamol /
Albutrol

12. Biosynthesis of Catecholamines

13. STORAGE, RELEASE, UPTAKE
L-Phenylalanine
Hepatic
hydroxylase

14. Stimulation of neuron

15. Epinephrine as prototype
• Potent stimulant of alpha and beta receptors.
• Complex actions on target organs.
• At low concentration vasodilatation.
• At high concentration vasoconstriction.

16. Epinephrine:
• Dose-dependent effects:
α
β
Dose of epinephrine →

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

25. CPR - Image

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

32. Adrenaline, NA and Isoprenaline -
Summary

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)

38. Phenylephrine:
• Acts on α receptors
• Vasoconstriction (↑ BP)
• Longer lasting than epinephrine
• Clinical use:
– Hypotension and shock
– Nasal decongestant
Salbutamol:
• Selective β2 agonist
• Dilates bronchial smooth muscle
• Clinical use:
– Antiasthmatic

39. phenylephrine(neosynephrine)
and methoxamine
• 1.selective α1-R agonists: shock,
hypotension
• 2.paroxysmal atrial tachycardia
• 3.renal vasoconstriction significant
• 4.phenylephrine→mydriasis

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

44. INDIRECT SYMPHATHOMIMETICS
•Tyramine
•Amphetamine
•Cocaine

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

47. MIXED SYMPHATHOMIMETICS
• Ephedrine
• Pesudoephedrine
• Dopamine
• Mephenteramine

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.