adrenergic transmission . sympathomimetics

1. Adrenergic Transmission and
Adrenergic Drugs

2. INTRODUCTION
• ADRENERGIC TRANSMISSION
• ADRENERGIC RECEPTORS
• ADRENERGIC DRUGS
( SYMPATHOMIMETICS )

3. Adrenergic Transmission
Endogenous Catecholamines:
- Noradrenaline
- Adrenaline
- Dopamine

4. SYNTHESIS ,STORAGE ,RELEASE & METABOLISM
OF CAs

5. Steps in the enzymatic synthesis of dopamine, norepinephrine
and epinephrine.

6. Enzyme Cofactor
requirement
Tyrosine hydroxylase Tetrahydro biopterin, O2,
Fe2++
Aromatic L –a.a
decarboxylase (non-
selective)
Pyridoxal phosphate
Dopamine β hydroxylase Ascorbic acid, O2
Cu ++
Phenyl ethanolamine N-
methyl transferase
S -Adenosyl
Methionine (CH3 donor)

8. Drugs modulating Release
Release –
α2 Agonists
β2 blockers
Adre. Neurone
blockers
Bretylium
Guanethidine
Guanadrel
Release –
β2 agonists
α2 blockers
Tyramine
AmphetamineNE
NE

9. Termination of action
1) Reuptake into nerve terminals by NET
(Na+ dependent )
2) Dilution by diffusion out of Jn: cleft followed by Extra-neuronal
uptake (not Na+ dependent )
3) Metabolic transformation by MAO & COMT

11. METABOLISM OF CATECHOLAMINES

12. Adrenergic Receptors
- α Receptors
- β Receptors
- Dopamine receptors

13. α Receptors
-α 1 Receptors:
α1A, α1B, α1D : Gq CR
- α2 Receptors:
α2A, α2B , α2C : Gi/Go CR

17. Adrenoceptor types and subtypes

18. Receptor specificity
• Adr : 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

19. Organ system effects of sympathomimetic drugs

20. Adrenergic drugs: overall actions
Heart
(β1)
• IncreasesHR
• Activateslatent pacemakers–arrhythmia at higherdoses
• Forceof contraction, cardiacoutput andoxygen consumption-
increased
• Increasedconduction velocity –mayovercome partial heart
block

21. Blood Pressure
• NA: risein systolic, diastolic andmeanBP(α)
• Iso:risein systolicBP,marked fall in diastolic BP(β1&β2)
• Adr: (slowi.v.)risein systolic,fall in diastolic, meanBP rises

22. ADERNALINE NA ISOPRENALINE
HR ↑ ↓ ↑↑
CARDIAC OUTPUT ↑↑ - ↑↑
BP- SYSTOLIC
DIASTOLIC
MEAN
↑↑
↓↑
↑
↑↑
↑↑
↑↑
↑
↓↓
↓

23. Blood vessels
• Vasoconstriction (α1and α2): cutaneous,mucous
membrane, renalbeds
• Vasodilation(β2): skeletalmuscles,liver, coronaries
• Action more marked in arterioles andprecapillary
sphincters

24. VASOMOTOR REVERSAL OF DALE
• ALPHA blocker only fall in B.P

25. BLOOD FLOW
BLOOD FLOW ADRENALINE NA ISO
SKIN AND MM
SK.MUSCLE
KIDNEY
LIVER
CORONARY
↓
↑↑
↓
↑↑
↑
↓
-, ↓
↓
-
↑
-
↑
-
↑
↑

26. Adrenergic drugs: overall actions
Respiration
• Adr&Iso:potentbronchodilator(β2)
• Adr: Bronchial mucosadecongestant
• ToxicdoseofAdr:pulmonaryedema
Eye
• Mydriasis(α1:radialmusclecontraction;
poor withAdr)
• Reducedaqueousformationandoutflow
facilitated

28. Adrenergic drugs: overall actions
Metabolic
• Causesglycogenolysis: hyperglycaemia,
hyperlactacidemia
• Lipolysis: rise in plasmafree fatty acids,
calorigenesis
• Transient hyperkalemia followedby
hypokalemia

30. ADRENERGIC DRUGS
 Direct
-adrenaline , NA , Isoprenaline
 Indirect
- act on adrenergic neurons to release NA
- tyramine ,amphetamine
 Mixed
-ephedrine, mephentermine

31. Therapeutic Classification: Adrenergic Drugs
TherapeuticClass Examples
Pressoragents Noradrenaline, Phenylephrine,Ephedrine,Methoxamine, Dopamine,Mephentermine
Cardiacstimulants Adrenaline, Dobutamine,Isoprenaline
Bronchodilators Isoprenaline,Salmeterol,Salbutamol,Formeterol, Bambuterol,Terbutaline
Nasaldecongestants Phenylephrine, Naphazoline, Xylometazoline, Pseudoephedrine,Oxymetazoline,
Phenylpropanolamine
CNSstimulants Amphetamine, Methamphetamine,Dexamphetamine, Methyl phenidate
Anorectics Fenfluramine, Sibutramine,Dexfenfluramine
Uterine relaxant Ritodrine,salbutamol,Isosuxprine,Terubtaline

32. Specific sympathomimetic drugs

33. Endogenous catecholamines
• Epinephrine
• Norepinephrine
• Dopamine

34. EPINEPHRINE
• agonist at both α and β receptors
• Potent Vasoconstrictor & Cardiac stimulant
• ↑ systolic BP and ↓ DBP

35. PK/PREP/DOSE/ROUTE
• Not effective orally
• Solution unstable in alkaline PH- turns pink on exposure
to air
• Inj. Adrenaline- 1/1000 (1mg/ml)
1/10000 (0.1mg/ml)
1/20000 (0.5mg/ml)

36. CONT……
• Usually 0.2-0.5 ml of a 1/1000,given S/C
• In shock (IM) & cardiac arrest (I/T, IV)
• Other routes- Endotracheal, I/Osseous

37. CONTRA-INDICATIONS
• Hypertension
• Ischemic heart diseases
• Cardiac arrhythmias
• Hyperthyroidism
• Patients receiving Halothane, MAOI nonselective β
blockers

38. ADVERSE REACTIONS
• Cold clammy skin, Tachycardia, palpitation, Anxiety, tremor etc.
• I/V – HTN- Cerebral Hemorrhage , Angina, Arrhythmia , Pulmonary
edema
DRUG INTERACTIONS
• GA- Halothane, Cyclopropane – Arrythmia

39. USES
1) Acute Bronchial Asthma
0.3-0.5 ml of a 1/1000,given S/C, 1/100 (N)
2) Cardiac arrest, resuscitation
0.2-0.5 ml of a 1/1000,given I/T
3) Anaphylactic shock – DOC
0.2-0.5 ml of a 1/1000,given IM

40. 4) Local Haemostatic- after tonsillectomy,
Tooth extraction etc.
Epinephrine pack dipped in 1/10000,1/20000 solution
5) Along with LA- 1/20000,1/100000 solution
(prolongs action, decreases toxicity)
6) Glaucoma- Prodrug –Dipivefrine
after absorption converted into Epinephrine
AH formation

41. NOREPINEPHRINE
LEVARTERENOL
L-norEpinephrine
(α1, α2, β1, β3)
• Constitute 10-20% of CA content of adrenal medulla
• up to 97% in some pheochromocytoma as they do not express
PNMT

42. COMPARATIVE EFFECTS OF INFUSIONS OF EPINEPHRINE
AND NOREPINEPHRINE IN HUMAN BEINGS

43. COMPARATIVE EFFECTS OF INFUSIONS OF EPINEPHRINE
AND NOREPINEPHRINE IN HUMAN BEINGS

44. ADR
Headache
Anxiety
Tremor
Angina
Ischemic necrosis if extravasated
High doses- hyperglycemia

45. USE
• Treatment of refractory Hypotension (neurogenic)
• Effect disappear 1-2’ after stopping infusion
So taper it off gradually.

46. DOPAMINE
(3,4 di OH phenyl ethylamine) MIXED ACTING
D1, β1, α1, Indirect Action
ACTIONS
Central - neurotransmitter involved in the
regulation of movement
Periphery - synthesized in the PCT ( local diuretic & natriuretic
effect)
On BP - ↑ SBP & PP, no effect on DBP.

47. ACTIONS
Low doses (0.5 -2 µg/kg/mt)
D1- ↑ renal, mesenteric & coronary blood flow
• ↑ RBF, ↑ GFR, & ↑ excretion of Na & H2O – Diuretic
action.

48. Moderate doses (2-10µg/kg/mt)
D1 + β1 & release NE (contribute -effect on the heart)
• ↑β1 : +ve inotropic action
• ↑ in BP due to + inotropic action. Also ↑ blood flow to vital organs
• little chronotropic & ↓ arrhythmogenic.
High doses (10-20 µg/kg/mt)
α1
• ↑ BP by VC &
• ↓ blood flow to vital organs

49. PREPARATION & DOSE –
• Dopamine hydrochloride - 200 mg in 200ml of 5% dextrose : 8-16
drops/min
ADVERSE EFFECTS
N,V, tachycardia, angina, arrhythmia, HTN, peripheral VC (high doses)
• Extravasation – ischemic necrosis & sloughing

50. USES
Severe CCF in patients with oliguria & low or normal PR
Improves physiological parameters in the Rx of
cardiogenic & septic shock
Improve cardiac & renal function in severely ill patients
with chronic heart d/s or renal failure

51. DIRECT ACTING
SYMAPTHOMIMETICS

52. Phenylephrine
Action - α1 stimulation
↑BP, reflex bradycardia
Uses
• Nasal decongestant- Topically, orally
Eye
• Mydriatic when cycloplegia is not required-fundoscopy
• Wide angle glaucoma-↓IOP

53. MIDODRINE
• Prodrug Desglymidodrine
• Alpha 1 agonist action
• Use – orthostatic hypertension

54. Methoxamine
• Direct-acting α 1 -receptor agonist
• Blood pressure vasoconstriction
• Also causes a vagally mediated bradycardia.
• Clinical application – hypotensive states

55. α2 AGONISTS
Sympatholytic action
• CLONIDINE
• α METHYL DOPA
• GUANABENZ
• GUANFACINE

56. Clonidine
• Imidazoline derivative
• Rapid I/V infusion - acute rise in BP
( activation of post synaptic α2 in vascular smooth muscles )
Mechanism of action
-(1) activation of α2 receptors in the VMC.
(2) Imidazoline receptors (GPCR) I 1,2,3
(3) activates presynaptic α2 to ↓ NE release

57. Clonidine
• Pharmacokinetics
- well absorbed orally
- t ½- 8-12 hour
- max. hypotensive effect after 2-4 hrs.
Preparations
- oral
- i/v
- Epidural
- TD patch

58. ADR
• Dry mouth & sedation
• Bradycardia
• Impotence
• Clonidine withdrawal syndrome
• Constipation
Interaction
TCA ,CHLORPROMAZINE

59. USES
1) Antihypertensive (moderate HTN) – 100 µg BD
2) opioid & nicotine withdrawal symptoms
(↓ craving )
(3) Prophylaxis of Migraine
(4) Along with anesthetics
(5) ↓ Pain in severe painful conditions like cancer, post –op,
labor etc

60. CLONIDINE- T/D- Menopausal syndrome for ↓ hot
flashes
Miscellaneous uses of clonidine
Atrial Fibrillation
Attention Deficit Hyperactivity Disorder
Hyperhidrosis
Mania
Post Herpetic Neuralgia
Ulcerative Colitis, etc

61. α Methyl DOPA
• central action - similar to clonidine in action
• Peripheral - “false transmitter” (α methyl NE)
• Not as potent as NE
• Used in PIH

62. ISOPRENALINE
(Isoproterenol, Isopropyl arterenol)
• Nonselective β agonist
• β1 similar to Epinephrine- ↑ HR & AV conduction,
↑ contractility
• β2 – relax vascular & non-vascular smooth muscle
↓ Mediator release.
• Metabolic Effect- ↑ glycogenolysis (β2)

63. Kinetics – inefficient orally – COMT
ADR
Tachycardia, palpitation, angina, arrhythmia - β1
Headache, flushing, dizziness, tremor - β2
Combined administration with E- Fatal

64. Uses
1. A/c Bronchial asthma
2. Complete AV block- to stimulate HR
3. Syncope attack a/w AV block.
4. Bacteremic shock

65. Xylometazoline and oxymetazoline
• Direct-acting α agonists
• Use : topical decongestants
• S/E: hypotension

66. Dobutamine
■ Derivative ofDopamine
■ Selective β1agonist
■ Uses-
■ Asaninotropic agent in pump failure accompanying:
– MyocardialInfarction
– Cardiacsurgery
■ Short term managementof severecongestive heart failure

67. Prenalterol
• Moderate inotropic action (sympathetic – low)
• Marked inotropic action ( symp activity high) – during exercise
• Use –
for short term control of mild to moderate heart failure
( i/v infusion)

68. Selective β2 STIMULANTS
Uses
• Bronchodilators
• Vasodilators
• Uterine relaxants.

69. β2 AGONISTS USED IN ASTHMA
 SALBUTAMOL
 TERBUTALINE
 SALMETEROL
 FORMOTEROL
 BAMBUTEROL longestacting

70. ISOXSUPRINE Ut.relaxant&V.D
 RITODRINE Uterine relaxant
• IV infusion – treatment of preterm labour.

72. INDIRECTLY ACTING
• AMPHETAMINE
• Catecholamine Reuptake Inhibitors

73. AMPHETAMINE
• D-isomer- dexamphetamine- CNS action
(Most potent sympathomimetic amine in stimulating CNS)
• L-isomer – methamphetamine- CVS action

74. AMPHETAMINEAMPHETAMINE

75. Mech. of CNS action
Release of
• NE (alerting & anorectic actions)
• Dopamine ( locomotor activity & stereotype behavior)
• 5HT (disturbance of perception & overt psychotic
behavior)

76. ACTIONS
• CNS - Produces alertness, initiative,
• ↑ concentration & self confidence.
• delays onset of fatigue
• Improves physical performance, ( due to cortical action)
• Produce wakefulness by ↑ RAS
• CVS - Cardiac stimulation, ↑ BP - β1
• Smooth muscle- contract sphincters – α1
• Others- Respiratory stimulant, suppress appetite

77. ADR
Anxiety, restlessness, tremor, irritability, delirium,
psychosis, tachycardia, palpitation, angina, arrhythmia
Dry mouth , metallic taste, N,V, D, Urine retension
Fatal doses- convulsions, coma & cerebral H’ages
Use – seldom used due to addiction liability & risk of
psychosis
Narcolepsy, obesity, ADHD,

78. Tyramine
• By product of tyrosine metabolism
• Metabolized by MAO ( liver )
• High first-pass effect
• Spectrum of action is similar to that of norepinephrine
• Patients taking MAO inhibitors must be very careful to avoid tyramine-
containing foods

79. Catecholamine Reuptake Inhibitors
• Atomoxetine ( norepinephrine reuptake transporter)
• Reboxetine
• Sibutramine - NE & 5 HT reuptake (-)
- appetite suppressant for long-term treatment of obesity

80. Catecholamine Reuptake Inhibitors
• Duloxetine
serotonin and norepinephrine transporter
• Milnacipran
• Cocaine
- produces an amphetamine-like psychological effect
- inhibit dopamine reuptake into neurons in the “pleasure
centers

81. MIXED ACTING
• EPHEDRINE
• Pseudoephedrine

82. EPHEDRINE
• Alkaloid - Ephedra Vulgaris
• Actions- MIXED ACTING –mainly indirectly + direct
action on α & β
• CNS- Anxiety, restlessness, tremor, insomnia
• α1 – VC-↑ BP, Mydriatic
• β1- +ve inotropic
• β2 - VD, Uterine relaxation

83. • PK - Effective orally-Resistant to MAO
• cross BBB & potent CNS stimulant.
• Tolerance develops rapidly.
Uses
mild chronic Bronchial asthma
Hypotension due to spinal injuries, spinal
anesthesia

84. Pseudoephedrine
• Enantiomer of ephedrine
• Vasoconstriction
• Fewer CNS and CVS effects

85. TACHYPHYLAXIS
acute tolerance
With drugs like Ephedrine, Tyramine, Amphetamine, 5HT,
Isoprenaline when administered repeatedly, at very short intervals,
the pharmacological response elicited decreases progressively.

86. Therapeutic uses

87. VASCULAR
• Hypotensive states -
• ( adrenaline in anaphylactic shock)
• Along with local anaesthetics
• Control of local bleeding
• Nasal decongestant
• Peripheral vascular disease

88. CARDIAC
• Cardiac arrest
• Partial A-V block
• CCF
• Bronchial asthma
• Allergic disorders
• Mydriatic / open angle glaucoma

89. CENTRAL USES
• Hyperkinetic children
• Obesity
• Nocturnal enuresis in children
• Uterine relaxant

90. SUMMARY
• Adrenergic transmission
• Receptors
• Endogenous CAs
• Organ specific effects of NE
• Sympathomimetic drugs and use

91. THANK YOU