Adrenergic system

1. ADRENERGIC SYSTEM &
DRUGS ACTING ON IT
Jeena M Joy
1

2. Human Nervous System
CNS PNS
Parasympathetic
nervous system
SOMATIC NS
ANS
Sympathetic nervous
system
2

3. Sympathetic Nervous System
• Responsible for ‘fight or flight’ response
• Neurotransmitters: Adr, NA and DA (Closely related CAs)
• CAs are compound that has a catechol (benzene with 2
hydroxyl side chains) & amine containing side chain.
3

4. SYNTHESIS OF CAs
Phenylalanine
Tyrosine
DOPA
Dopamine
Noradrenaline
Adrenaline
Hydroxylase
Tyrosine Hydroxylase
Dopa Decarboxylase
Β Hydroxylase
N-Methyltransferase
Adrenal
medulla
Vesicle
Adrenergic
neuronal
cytoplasm
Liver
Metyrosine
Glucocorticoids
4

5. RELEASE OF CAs
• The nerve impulse coupled release of CA takes place by exocytosis
coupled with Ca2+ influx
HOMORECPTORS AUTORECEPTORS HETERORECEPTORS
INHIBITS ENHANCES INHIBITS INHIBITS ENHANCERS
α2adrenergic β2 adrenergic Y2 receptor of NPY Serotonergic Angiotensin AT1
Dopaminergic Nicotinic receptors
P1 receptor of ATP
Muscarinic
PGE2
5

6. REUPTAKE OF CAs
AXONAL UPTAKE/
UPTAKE 1
VESICULAR
UPTAKE
6
EXTRANEUTONAL UPTAKE
1 2
3

7. REUPTAKE OF CAs
AXONAL UPTAKE/ UPTAKE 1
• For intake of NA>>Adr, Amphetamine/ tryramine into nerves.
• Uses active amine pump NE transporter(NET) in neuronal membrane.
• Transport coupled with Na influx.
• Helps in termination of post junctional action of NA.
• Inhibitor :Cocaine, Desipramine
7

8. VESICULAR UPTAKE
• For intake of NA,Dopamine into neuronal vesicles.
• Uses Vesicular monoamine transporter(VMAT) in vesical membrane.
• Transport coupled with H+ ione efflux .
• Helps in
1. Recapturing leaked NA
2. Uptake of DA for NA synthesis
• Inhibitor :Reserpine
8

9. EXTRANEUTONAL UPTAKE
• Uses Extra neuronal amine transporter(ENT, OCT3) 0CT1, 0CT2
• Adr>>NA
• Helps capturing of circulating Adr by various organs.
• Inhibited by Corticosteroids.
9

10. METABOLISM OF CAs
Adrenaline
Metanephrine Normetanephrine
VMA
DOMA
DOPGAL
MOPEG
Noradrenaline
COMT
COMT
COMT
MAO MAO
MAO MAO
Glucoronide or sulpate conjugation
**
*3 methoxy 4 hydroxy phenyl glycol
**3,4 dihydroxy mandelic acid
*
10

11. Adrenergic receptors
Alpha Beta
α1 α2
α1
β1
α1
β2
α1
β3
Gq Gi/Go
Membrane bound G-protein coupled receptors.
Gs
IP3, DAG cAMP
cAMP
Raymond Perry Ahlquist
11

12. SITE OF RECEPTORS
ALPHA 1
(α1)
ALPHA 2
(α2)
BETA 1
(β1)
BETA 2
(β2)
BETA 3
(β3)
Postsynaptic
1. Eye(α1A)
2.Blood Vessels(α1B)
3.Spincter, Bladder
trigon & prostatic
urethra(α1A/1D)
4.Glands
5.smooth
muscles(uterus)
6.Gut
•Prejunctional on
nerve ending(α2A)
•Postjunctional in
1. Brain
2. Pancreatic β
cells
• Extrajunctional
1. Blood vessels
2. Platelets
•Heart
•Kidney
•Eye
•Bronchi
•Blood vessels
•Liver
•GIT
•Skeletal
muscles
•Uterus
•Urinary tract
•Adipose
tissue
•Detrusor
muscle
12

13. ADRENERGIC DRUGS CLASSIFICATION
(Sympathomimetic)
• Drugs that mimics the actions of epinephrine or norepinephrine.
13
Direct sympathomimetics Indirect
sympathomimetics
Mixed
sympathomimetics
Catecholamies Noncatecholamines
Endogenous Exogenous
Adrenaline
Noradrenaline
Dopamine
Isoprenaline
Dobutamine
Dopexamine
Fenoldopam
Phenylephrine
Methoxamine
Clonidine
Salbutamol
Tyramine
Amphetamine
Ephedrine
Pseudoephedrine
Mephentermine

14. COMPARISON BTW Adr, NA, Isoprenaline
14

15. ADRENALINE (EPINEPHRINE)
• Secreted by Adrenal medulla (80-90%) and stored in chromaffin cells .
• Adrenaline has nonselective action on both α and β receptors.
• For systemic action .2-.5mg sc/im given, action last for half to 2 hrs.
John Jacob Abel
15

16. Pharmacological Actions
Cardiovascular system
1.Heart (due to β1 actions)
 HR-acting on SA node
 FOC & rate of development of of tension &relaxation- Short systole
 Conduction velocity of AV node , BOH, Atria & ventricle
 CO &O2demand
 in excitability
 At high dose- BP-Reflex depression of SAN-Adr activates latent pacemakers
in AVN & PF- Arrythmia can occur.
16

17. 2.Blood Vessels
 Vasoconstriction (α1 receptors)
- skin, mucosal, renal and splanchnic blood vessels.
 Dilatation (β2 receptors)
- skeletal muscles, liver and coronary blood vessels.
3.Blood Pressure
on slow infusion on fast IV Infusion
SBP
DBP
MBP
17

18. Respiratory System
 Potent Bronchodilator causing relaxation of bronchial muscle ( β2)
 Nasal decongestant
 Stimulate Respiratory center –seldom manifest clinically
 Higher dose-reflex inhibition of RC- transient apnoea
 Toxic dose-Shift blood from systemic to pulmonary circulation.-
Pulmonary odema
 Eye
Mydriasis due to contraction of radial muscles (α1)
Effect on aqueous humor
• α1- vasoconstriction of ciliary vessels reduced aqueous humor
• α2 - secretory activity of ciliary epithelium
• α - uveo scleral outflow
• β2 - secretory activity of ciliary epithelium & trabecular outflow
18

19. GI Tract
Relaxation of the gut
Constriction Of Sphincters
Genitourinary Tract
Relaxation of detrusor (β2, β3)
Contraction of trigone (α1)
Ejaculation occurs in males (α1)
Relaxation of uterus at term (β2)
19

20. SKELETAL MUSCLE
• α 1receptor activation on motor nerve endings augments Ach release.
• Direct action of β2
CNS
• Adrenaline poorly penetrates brain
• Restlessness, apprehension & tremors
Slow contracting red fibres Rapidly contracting white fibres
Active state Abbreviated prolonged
Tension Less increase
Incomplete fusion of individual responses & enhanced
firing cause tremors
20

21. Metabolic
Lipolysis – β3 receptors
Increased Gluconeogenesis and Glycogenolysis
(β2 action)
Hyperkalemia followed by hypokalemia (β2 action)
Decrease Insulin release from pancreas (α2 action)
Increase Glucagon secretion (β2 action )
Kidney
 Increases renin release from JG cells
(β1 receptors)
21

22. A/E
• Restlessness, headache ,anxiety, palpitations, tremours & pallor.
• Rapid iv-Marked rise in BP leading to cerebral haemorrhage,
ventricular tachycardia , angina & MI.
CONTRAINDICATIONS
Thyrotoxicosis
Hypertension
Arteriosclerosis
Angina
During anesthesia with Halothane
Patients receiving β- blockers
22

23. USES
Anaphylactic shock-.3-.5ml of 1:1000 im (reverse hypotension,
laryngeal odema and laryngeal spasm)
Cardiac Arrest due to drowning & electrocution-ic 1mg
Control of hemorrhage-1:10000 to 1:20000 as topical hemostatic.-
tooth bleed and epitaxis.
Along with local Anesthetics-1:80000 to 1:200000
23

24. NORADRENALINE
• Noradrenaline has selectively act as α and β1 agonist.
• Causes vasoconstriction of blood vessels .
• SBP,DBP &MBP-Reflex Bradycardia occurs
• Action declines in 5mins
USES
• In Shock to BP (2-4 mcg/min )slow iv
24

25. DROXIDOPA
• Synthetic compound is a prodrug converted to NA by dopa
decarboxylase
• peripheral vascular resistance
• Used in orthostatic hypotention.
25

26. DOPAMINE
• Central neurotransmitter & Naturally occurring precursor of NA
• Acts on dopaminergic (D1, D2) and Adrenergic (α1+α2+β1)
receptors.
• At clinically employed dose it cause CO & raise SBP
• Regular BP monitoring and rate of urine flow to be monitored.
USES
• Acute heart failure with Oliguria (0.2-1mg/min iv infusion)
• Cardiogenic and Septic Shock
26

27. • At 2-5mcg/kg/min dosage - stimulates D1 receptors in renal, coronary
and mesenteric blood vessels– improves perfusion GFR and Na
excretion(PCT)
• At doses of 5-10mcg/kg/min, it acts as D1+ β1 agonist+ NA release-
positive inotropic with little chronotropic effect
• At doses 11-20mcg/kg/min, predominantly it activates α
adrenoreceptors– vasoconstriction, decreases Renal blood flow, urine
output and aggravation of heart failure
27

28. ISOPRENALINE
• Synthetic CA with predominant β action
• Cardiac stimulant and smooth muscle relaxant
• BP remain unchanged / slightly raised , DBP , MAP
• Heart rate increases, CO
USES
Maintaining idioventricular rate till pacemaker is implanted
Dose: 5-10mcg/miniv infusion, 1-2mg im, 20mg sublingual
28

29. DOBUTAMINE
• Derivative of dopamine, but not a D1 or D2 agonist.
• It’s a relatively selective β1 receptors.
• Force of contraction & CO( 2-8mcg/kg/min iv)
• No significant changes in HR, BP and peripheral resistance occurs.
29

30. • Unlike dopamine, it doesn’t cause Renal vasodilation and increase in
myocardial demand is less marked.
USES
-As Inotropic agent in pump failure accompanying MI, Cardiac surgery
and short term management of CHF.
30

31. FENOLDOPAM
• Selective D1 agonist
• Dilates coronary, renal & mesenteric arteries
• Use-IV infusion in short term management of severe HTN to rapidly
reduce BP.
31

32. Dipivefrine
• Prodrug gets converted to adrenaline in eye by action of corneal esterases.
• Highly lipid soluble so has good penetrability
• Longer duration of action that Adr
A/E
• Ocular burning
USES
• Add on therapy in poorly controlled Glaucoma patients.
Dose: PROPINE 0.1% eye drops; 1 drop BD
32

33. NON CAs-DIRECT ACTING
SYMPATHOMIMETICS
α1 SELECTIVE
PHENYLEPHRINE-
• Selective α1 stimulant. (negligible β action)
• Vasoconstiction- BP
• Little cardiac action, so reflex bradycardia prominent.
• USES- a) Topical /oral nasal decongestant
b) Mydriatic without cycloplegia
• Reduce IOP
33

34. Methoxamine
• Similar to phenylephrine.
• Direct acting α1 agonist( No β action)
• Increases BP due to vasoconstriction
• Occasionally used as pressor agent
34

35. α2 SELECTIVE
CLONIDINE
• Imidazoline derivative
• α2 agonist with high affinity and high intrinsic activity at α2A receptor.
• Imidazoline receptors present in brain and periphery triggers
medullary α2A receptors sympathetic outflowBP& Bradycardia
(due to enhanced vagal tone)
35

36. Oral doses reduces BP due to action on α2A
Pharmacokinetics:
• Well observed orally
• Plasma t1/2 – 8-12hours
• Excreted Unchanged in urine
INTERACTIONS:
TCAs and Chlorpromazine inhibits alpha action.
36

37. ARD
o Sedation, mental depression, disturbed sleep;
odryness of mouth, nose and eyes – secretion reduced by central action
o constipation-antisecretory effect in intestine
oImpotence
osalt and water retention- decrease renin levels
o bradycardia
oAlarming rise in BP in excess of pre-treatment level when dose is
missed for 1-2 days.
37

38. USES
A) Treatment of HTN- Occasionally used.
B) Opioid withdrawal : Supress the symptoms by acting on the same
effector organs and reduce craving
C) Alcohol withdrawal and smoking cessation
D) Analgesic- substitute morphine for intrathecal/epidural surgical and
postoperative analgesia.
E) Attenuates vasomotor symptoms of menopausal symtoms
F) Control loose motion due to diabetic nephropathy.-alpha 2 mediated
enhancement of salt absorption in gut mucosa
38

39. METHYLDOPA
• Centrally acting Antihypertensive agent
Methyldopa
Aromatic amino acid decarboxylase
α Methyldopamine
α Methyl norepinephrine
• Stored in secretory vesicles of adrenergic neurons substituting for
NE
• When Adrenergic neuron discharges its neurotransmitter, α Methyl
norepinephrine is released instead of NE Inhibits NE release
39

40. • Methyl-NE is central α2 receptors agonist
sympathetic tone
Circulating levels of NA and renin
TPR
BP
• In large doses, methyldopa inhibits DOPA decarboxylase enzyme in brain &
periphery NA synthesis
40

41. A/E:
• M/C- Sedation, lethargy and reduced mental capacity
• Dryness of mouth, nosal stuffiness, headache , fluid retention,
weight gain and impotence
• Postural hypotension-mild
• Positive coomb’s test in few patients
• Hemolytic anaemia
• Thrombocytopenia
INTERACTIONS
TCAs
USES:
Hypertension in Pregnancy 41

42. Apraclonidine
• Selective α2 receptor agonist with slight α1 action.
• Aqueous production by α2 action on ciliary epithelium
A/E:
-Itching, lid dermatitis
-Follicular conjunctivitis
-Eyelid retraction
-Dryness of mouth and nose
USES
• Adjunctive therapy in Glaucoma
• Used to control IOP after laser trabeculoplasty / iridotomy
42

43. Nasal decongestants
XYLOMETAZOLINE OXYMETAZOLINE, NAPHAZOLINE
• α agonists which on topical application as dilute solution (0.05--0.1
%) produce vasoconstriction in the nasal mucosa.
• They are Imidazoline compounds , if taken in large doses causes
HYPOTENSION(clonidine like effect)
A/E
• initial stinging sensation (specially naphazoline).
• Atrophic rhinitis & anosmia
• Can produce systemic effects, mainly CNS depression and rise in BP
43

44. β2 SELECTIVE
• These include:
-Short acting: salbutamol, terbutaline
-Long acting: salmeterol, formoterol Isoxsuprine and
ritodrine.
• Causes bronchodilatation,vasodilatation and uterine relaxation
44

45. USES
• Ritodrine is the preferred drug -As uterine relaxant to delay
premature labour.
• In hyperkalaemic familial periodic paralysis β2 agonists benefit by
enhancing K+ uptake into muscles, thereby lowering plasma K+
levels.
A/E
• muscle tremor;
• tachycardia and arrhythmias are less likely.
45

46. Isoxsuprine
• It is an orally effective long-acting
• Direct smooth muscle relaxant property
Used
Uterine relaxant for threatened abortion and dysmenorrhoea
A/E
Nausea, tachycardia, flushing, hypotension, tremors
46

47. MIXED SYMPATHOMIMETICS
Ephedrine
• An alkaloid obtained from Ephedra vulgaris
• Agonist at both α and β receptors and enhances release of NE from
sympathetic neurons
• Resistant to MAO, so orally effective and longer acting.
• Cross BBB and produce CNS effects-inosmia. Restlessness, anxiety,
tremors
• Raises BP(beta1 and alpha), bronchodilator
• Repeated injections produce tachyphylaxis
47

48. USES
• Narcolepsy
• Nocturnal enuresis
• Mild chronic bronchial asthma
• Hypotension that occur after spinal anesthesia
PSEUDOEPHEDRINE
• Enantiomer of Ephedrine used orally for decongestion
• Vasoconstriction in mucosa and skin
• Fewer CNS , branchial and cardiac effects.
• Used in symptomatic relief in common cold, allergic rhinitis, blocked
Eustachian tube & URTI
48

49. Mephentermine
• Cardiac stimulation and vasoconstriction actions
• CO, SBP, DBP, MBP are increased.- Reflex bradycardia
• The direct positive chronotropic effect on heart is generally counter
balanced by vagal stimulation due to rise in mean BP.
• Not a substrate for either MAO or COMT. Therefore it is active orally
with longer duration or action (2- 6 hr). It
• crosses blood-brain barrier -excitatory effects at higher doses.
• used to prevent and treat hypotension due to spinal anesthesia and
surgical procedures, shock in myocardial infarction and other
hypotensive state
49

50. INDIRECT SYMPATHOMIMETICS
Amphetamines
• Synthetic compound.
• Potent CNS stimulant and weaker peripheral cardiovascular actions.
• Maximal selectivity is exhibited by dextroamphetamine and
methamphetamine.
• Stimulant effect on mood and alertness and a depressant effect on
Appetite
50

51. • Central effects includes- alertness, increased concentration, attention
span, euphoria, talkativeness
• Peripheral effects on heart and BP are not significant.
• Weak anticonvulsant, analgesic and antiemetic actions
• Drug of abuse
• Repeated use leads to behavioral abnormalities
51

52. Toxicity :
• High doses produce euphoria, marked excitement, leading to mental
confusion, delirium, hallucinations.
• Peripheral component includes vasomotor effects, palpitation,
arrythmias, vomiting, abdominal cramps and vascular collapse.
• Death is usually preceded by convulsions and coma
• Rx- chlorpromazine
52

53. USES
• ADHD
• Narcolepsy
• Obesity
• Epilepsy
MODAFINIL
CNS stimulant acts by stimulation alpha 1 receptors( Also GABA &
serotonin receptors)
- Ideal use for sleep disorders
- Recent use among call center workers and shift workers to enhance
performance in working hours.
53

54. TYRAMINE
• Contains in protein rich foods
• Metabolized by MAO in liver
• Inactive when taken orally
• Parenteral administration Release of stored CAs
• Treating with MAO inhibitors(MAO-A)- the effect of Tyramine
intensifies- BP
• Cheese Reaction
54

55. Sibutramine(ANORECTIC)
• Serotonin and NE reuptake inhibitor
• Activates thermogenesis
• Appetite suppressant for obesity
• Associated with strokes in patients with
cardiovascular diseases
Other Anorectics- Phentermine (noradrenergic)
-Fenfluramine(serotonergic)
55

56. ALPHAADRENERGIC
BLOCKING AGENTS
Hans-Jürgen Hess 56

57. α Receptor Blockers
• α receptor antagonist block adrenergic response mediated through α
receptor
• They are of two types
Non equilibrium type/ Non competitive blocker
Equilibrium type/ Competitive blockers
1. Non Selective α blocker
2. Selective α blocker
oα 1 selective blocker
oα2 receptor blocker-Not of any clinical use.
57

58. CLASSIFICATION
58

59. COMMON FEATURES OF SELECTIVE AND NON SELECTIVE BLOCKERS
• Both of them block α 1 Vasodilation BP Reflex Tachycardia
• So useful in treatment of HTN
• Nonselective blockes α 2 also NA release *β1 HR(Significant tachy)
*β2 Vasodilation BP
Selective α 1 blocker α2 is active NA release inhibited
So non selective blocker is used in sever HTN
A/E -Postural hypotension and severe palpitation
DIFFERENCE BETWEEN SELECTIVE AND NON SELECTIVE BLOCKERS :
59

60. DIFFERENCE BETWEEN REVERSIBLE &
IRREVERSIBLE NON SELECTIVE BLOCKERS
• Being irreversible(Phenoxybenzamine) long DOA (3-4days)
Used when acute action is not needed.
• Being reversible (Phentolamine) Shorter DOA
Used in acute conditions.
Eg: Cheese reaction & Clonidine withdrawal
onset of action is gradual
Rapid onset of action
60

61. GENERAL EFFECTS
• Vasodilatation (α 1 blockage)
• Increase heart rate and cardiac output(α 2 blockage)
• Nasal stuffiness & miosis
• Increased intestinal motility
• BP- renal blood supply- GFR- Na & water retention
• tone of smooth muscles in bladder trigon, spincter & prostrate.
• Inhibits ejaculation-impotence
61

62. Phenoxybenzamine
• Halogenated alkylamine
• Cyclizes to form ethyleniminium intermedated
• This reacts and forms strong covalent bonds with α receptors and other
biomolecules.
• Partial blockage of 5-HT, histaminic , muscarinic receptors at higher dose.
• Slow onset of action & longer duration
• More prominent venodilation than arteriolar dilation
62

63. • Shift blood from pulmonary to systemic circuit & also shifts fluid from
extravascular to vascular compartment
• On rapid i.v. injection -penetrates brain, produceing CNS stimulation,
nausea and vomiting.
• On oral dose- CNS depression, tiredness and lethargy
PK
• Given iv as oral absorption is erratic and incomplete; i.m. and s.c.
injections are very painful-
• Mostly excreted in urine in 24 hours.
• Chronic administration leads to accumulation in adipose tissue.
63

64. • S/E- postural hypotension, palpitation, nasal blockage, miosis,
inhibition of ejaculation.
• Dose: 20-60 mg/day oral; 1 mg/kg by slow i.v. infusion over 1 hour.
• Uses
oPheochromocytoma- definitive therapy for inoperable and malignant
pheochromocytoma. Also given 1- 2 weeks preoperatively and
infused i.v. during surgery.
64

65. Phentolamine
• This is a rapidly acting α blocker with short duration of action
• Venodilatation predominates over arteriolar dilatation.
USES
• Diagnosis and intraoperative management of pheochromocytoma,
• Control of hypertension due to clonidine withdrawal, cheese reaction,
• Counteract vasoconstriction due to extravasated NA/DA during their
i.v. infusion.
Dose
• 5 mg i.v. repeated as required
65

66. PRAZOSIN
• Highly selective a 1 blockers having α 1 : α 2 selectivity ratio 1000: 1.
• Fall in BP with only mild tachycardia
• Prazosin dilates arterioles more than veins.
• Postural hypotension may occur as 'first dose effect’, minimized by starting
with low dose at bedtime.
• Inhibits PDE which degrades cAMP. cAMP in smooth muscle.
PK
• effective orally (bioavailability ~60%),
• highly bound to plasma proteins
66

67. • metabolized in liver and excreted primarily in bile.
• Plasma t½ is 2-3 hours: effect lasts for 6-8 hours.
USES
• Prazosin is primarily used as an antihypertensive
• Raynaud's disease
• benign hypertrophy of prostate (BHP).
67

68. PRAZOSIN CONGENERS
TERAZOSIN Doxazosin ALFUZOSIN
Oral BA 90%
Plasma t1/2 12hrs 18hrs 3- 5 hours
Apoptosis of prostate The metabolism of
alfuzosin is inhibited by
CYP34A inhibitors
Used on HTN &BPH
Dose: 1mg OD(increased if
required-mantanence
dose 2-10mg OD
1mg OD, increased upto
8mg BD
2.5 mg BD-QID or 10 mg
OD as extended release
(ER) tablet
68

69. TAMSULOSINE
• Uroselective α1A/ α1D blocker
• α1A-bladder base & prostatic / α1B- Blood vessals.
• Does not cause significant changes in BP or HR
• Plasma t½=6-9hrs, MR cap(.2-.4mg) can be given OD
USE: in treatment BHP
A/E: Dizziness , retrograde ejaculation & floppy iris during cataract
surgery.
• Silodosine is a longer acting α1A blocker t½=13hrs but can cause
failure of ejaculation.
69

70. BETA BLOCKERS
Sir James Whyte Black developed propranolol in 1958.
He was awarded the Nobel Prize for Medicine in 1988.
70

71. CLASSIFICATION OF BETA BLOCKERS
First gen/Non selective 2nd gen/Selective beta 1 blocker 3rd gen
Propranolol-(MSA)
Timolol
Pindolol-(ISA,MSA)
Sotalol
Bisoprolol
Atenolol
Esmolol
Acebutalol(ISA,MSA)
Metaprolol(MSA)
Alpha blocking Vasodilatory
Labetolol(MSA)
Carvedolol
Nebivolol
Betaxolol
Celiprolol(ISA)
ISA
Celiprolol
Acebutalol
Pindolo
MSA
Pindolol
Metaprolol
Labetolol
Acebutalol
Propranolol
LLS
Atenolol
Bisoprolol
Celiprolol
Sotalol
71

72. PHARMACOLOGICALACTIONS OF PROPRANOLOL
CVS
1. Heart
• HR
• FOC
• Contractility
• CO
• Cardiac work done &O2 consumption
72

73. 2.BLOOD VESSALS
• Initially SBP due to CO
DBP due to TPR
– Little acute change in BP
• With continued treatment, resistance vessels gradually adapt to
chronically reduced CO, so that TPR & both SBP&DBP
73

74. Other mechanisms that may contribute to
antihypertensive action.
• Reduced NA release from sympathetic terminals
• Decreased renin release from kidney
• Central action reducing sympathetic outflow.
74

75.  Respiratory tract
• Bronchial resistance
• worsened and precipitated a severe attack of asthma.
CNS
With long-term use of relatively high doses
• Forgetfulness
• dreaming
• nightmares
75

76. LOCALANAESTHETIC
• Propranolol has membrane stabilizing (Na- channel blocking) property and is
a potent local anaesthetic.
• Not a clinically useable local anaesthetic due to irritant action.
METABOLIC
• Abnormal lipid profile- Plasma FFA, TG, LDL/HDL ratio
• Recovery from insulin hypoglycaemia is delayed.-Masks its manifestations
• prolonged propranolol therapy may impair carbohydrate tolerance by insulin
release.
76

77. Skeletal muscle
• Inhibits adrenergically provoked tremor. (Beta2 block)
• Exercise capacity- Blood supply & glucose production. (beta2 block)
Eye
• AH secrection- IOP
77

78. PHARMACOKINETICS
• Good oral absorption
• BA due to high first pass metabolism in liver.
• Metabolism of propranolol is dependent on hepatic blood flow
• Chronic use of propranolol itself decreases hepatic blood flow: its own
oral bioavailability is increased and its t½ is prolonged (by about 30%)
on repeated administration
• The metabolites are excreted in urine, mostly as glucuronides
78

79. USES of Propranolol
Cardiac uses
• Angina pectoris
• Arrythmia
• HTN
• MI
• HOCM
Non Cardiac uses
• Pheochromocytoma
• Thyrotoxicosis
• Migraine prophylaxis
• Anxiety
• Essential tremors
79

80. Adverse effects
• Bronchoconstriction
• HF
• Heart block
• Bradycardia
• Hypotension
• Hypoglysemia
• Claudication
• Fatigue, nightmares, depression, parethesis & skin rashes.
80

81. INTERACTIONS
• Digitalis & verapamil - cardiac arrest can occur.
• Delays recovery from hypoglycaemia due to insulin and oral antidiabetics.
Warning signs of hypoglycaemia suppressed.
• Alpha agonists present in cold remedies can cause marked rise in BP due to
blockade of sympathetic vasodilatation.
• NSAlDs attenuate the antihypertensive action of P blockers.
• Retards lidocaine metabolism by reducing hepatic blood flow.
81

82. CONTRAINDICATIONS
• Acute decompensated heart failure
• Severe bradycardia
• 2 & 3rd degree heart block
• Variant (vasospastic) angina
• COPD & bronchial asthma.
• DM
• PVD
• Severe depression
82

83. CARDIOSELECTIVE BETA BLOCKERS
• These drugs are more potent in blocking cardiac β1 than bronchial
(β2) receptors. However, selectivity is only relative and is lost at high
doses.
1. Bisoprolol
2. Atenolol
3. Esmolol
4. Acebutalol(ISA,MSA)
5. Metaprolol(MSA)
6. Nebivolol
83

84. Properties of beta 1 selective blockers
• Less bronchoconstriction-Safer in COPD & Asthamatic
• Less vasoconstriction-No cold hands & feet, Safer in PVD.
• Less interference with carb. Metabolism-Safer in DM
• Less deleterious effect on blood lipid profile.-Safer in CAD
• Less impairment of exercise capacity.
• Ineffective in supressing essential tremors.
84

85. Intrinsic sympathiomimetic activity
• These drugs themselves activate β1 , and/or β2 receptors submaximal
1. Celiprolol
2. Acebutolol
3. Pindolol
85

86. Properties of intrinsic sympathomimetic
drugs. (Partial agonist)
• Lesser bradycardia & cardiac depressant action.
• Less rebound effect on withdrawal .
• Less deleterious effect on blood lipid profile.-Safer in CAD
• Not effective in migraine prophylaxis- they dilate cerebral vessels.
• Not suitable for secondary prophylaxis of MI
86

87. Properties of BB with Low lipid solubility
• Incomplete oral absorption.
• Do not undergo first pass metabolism
• Do not cross BBB-less likely to produce sleep disturbances, nightmares,
or to increase the incidence of mental depression.
• Primarily excreted unchanged in urine
• Longer acting (t½ 6-20 hours)
• Effective in a narrow dose range.
Eg:Atenolol, Bisoprolol, Celiprolol, Sotalol
87

88. Timolol
• Non selective , short acting BB.
• First ocular BB to be used topically- Absent LA action & Good lipid solubility
• Orally indicated in
oHypertension,
oAngina
oProphylaxis of myocardial infarction
Dose:10-40mgdaily, 5% eye drops
88

89. Pindolol-(ISA,MSA)
• Non selective BB
• Partial agonist at β1 & β2.
• It has been used primarily as antihypertensive with marked
bradycardia with propranolol.
• Chances of rebound hypertension on withdrawal are also less.
• Plasma lipid profile may not worsen.
• Better tolerated by asthmatic.
• Dose: 10-30mg daily
89

90. Sotalol
• Non selective BB with low lipid solubility.
• It has additional class III antiarrhythmic property
PK: Well absorbed orally.
• No first pass effect
• Excreted unchanged in urine.
Uses: Anti arrhythmic agent in VT/SVT
Dose : 160-480mg/ day given BD
90

91. Metoprolol
• Prototype of cardioselective blockers
• Safer in asthma, diabetics receiving insulin or oral hypoglycaemics &
in patients c/o cold hands & feet while on propranolol.
PK
• Well absorbed orally.
• First pass metabolism present but is less marked.
• 90% or more is ultimately hydroxylated by CYP2D6 before excretion
in urine.
91

92. USES
• Given orally for hypertension, angina and controlled CHF,
• i.v. injection (5-15 mg) has been used in myocardial infarction
provided bradycardia is absent.
Dose:
• 100-400mg daily given BD
92

93. ATENOLOL
• Cardioselective BB with low lipid solubility. (Less CNS S/E)
• It is incompletely absorbed orally, but first pass metabolism is not
significant.
• Because of longer duration of action, once daily dose is often
sufficient.
• No deleterious effects on lipid profile have been noted.
USE
hypertension and angina.
Dose: 25-100mg OD/BD
93

94. Acebutolol
• Another cardioselective agent with significant partial agonistic and
membrane stabilizing properties.
• Less likely to cause bradycardia .
• Acebutolol is rapidly metabolized to an active metabolite diacetolol
• Excreted by kidney.
USES
• HTN
• Arrythmia
DOSE:400-1200mg/day orally , 20-40mg iv
94

95. Esmolol
• Ultra-short acting β1 agonist
• Inactivated by esterases in blood.
• Plasma t½ is < 10min;
• Rapid onset, short lasting( action disappears 15 20 min)
• Used iv in case of emergency .
95

96.  Uses:
o Terminate SVT, episodic atrial fibrillation/flutter, arrhythmia during
anaesthesia.
oReducing HR & BP during and after cardiac surgery, in aortic
dissection and in early treatment of MI.
Dose: a loading dose of 0.5 mg/kg is given followed by 0.05-0.2
mg/kg/min infusion.
96

97. Nebivolol
• This highly selective β1 blocker with vasodilator action
• Activates endothelial nitric oxide (NO) synthase and enhances NO
production.
• Improve endothelial function, which delays atherosclerosis.
• Absence of deleterious effect on plasma lipids and on carbohydrate
metabolism is another advantage.
• It tends to increase insulin sensitivity
USES:HTN, CHF.
 Dose.· 5 mg (elderly 2.5 mg) OD
97

98. CELIPROLOL
• 3rd generation selective β1 blocker having additional weak β 2
agonistic activity .
• Activates endothelial nitric oxide (NO) synthase and enhances NO
production.
• Dose: 200-600 mg OD
• USE: HTN
98

99. Labetalol
• It has β 1 + β 2 + α 1 blocking as well as weak β 2 agonistic activity
• Inhibit NA uptake by adrenergic nerve endings.
• Fall in BP (both systolic and diastolic) is due to β 1 and α 1 blockade
as well as β 2 agonism (vasodilatation).
• Relatively high doses reduce both c.o. and t.p.r.
USES:
• Rapid BP reduction in cheese reaction, clonidine withdrawal,
Preclampsia, Hypertensive emergencies.
• Oral labetalol therapy is restricted to moderately severe hypertension
not responding to a pure β blocker.
99

100. CARVEDILOL
• Combined α1 & β blocker
• Vasodilation due to α1 & CCB activity
• Has additional antioxidant/free radical scavenging properties.
• Antioxidant property present
• Oral bioavailability of carvedilol is 30%.
• It is primarily metabolized CYP2D6.
100

101. Uses: long-term treatment of CHF, and is approved as an
antihypertensive
Doses
• CHF: Start with 3.125 mg BD for 2 weeks, if well tolerated gradually
increase to max. of 25 mg BD.
• HTN: 6.25 mg BD initially, titrate to max. of 25 mg BD.
101

102. THANK YOU
102