ppt on adrenergic agonit and antagonist

1. Adrenergic Agonist &
Antagonist
-Guide: Dr R K Solanki Sir
Dr Neelam Mam
Dr Kailash Mittal

3. Synthesis,Storage , Release and Degradation

4. The metabolites are excreted in urine as:
 Vinyl mandelic acid , 3,4 dihydroxy mandelic acid
 Metanephrine
 Nor-metanephrine.
Presynaptic regulation of NE release:
 By Autoreceptors: autoregulation of the release of
norepinephrine.
β1---- positive feed back
α2 ----- Negative feed back

5. Subtypes/Locations & Characteristics of Adrenoceptors
Rece
ptor
Location Pharmacologic effects Result of Agonist
binding
α1
subtypes
α1A
α1B
α1D
Postsynaptic
smooth muscles of BV
specially of skin & mucosa.
Radial muscle of eye
GIT sphincters
SM of prostate& bladder base
(α1A )
hair follicles
Splenic capsule
Contraction
Vasoconstriction
Mydriasis
Contraction
Contraction
Through Gq
Stimulation of
phospholipase C ↑IP3,
DAG , ↑ intracellular
Ca++
Adrenergic Receptors : Different types. All are GPCR.

6. subtypes/locations & characteristics of Adrenoceptors
Rece
ptor
Location Pharmacologic
effects
Result of
Agonist
binding
α2
subtyp
e
α2A
α2B
α2C
Presynaptic nerve terminals
Postsynaptic effector cells of
platelets
lipocytes
Some vascular SM
CNS
Inhibition of
N E release
Aggregation
Inhibition of lipolysis
Contraction
Reduce sympathetic
outflow & sedation
Through Gi
Inhibition of
Adenylyl cyclase
↓cAMP

7. subtypes/locations & characteristics of Adrenoceptors
Rec
epto
r
Location Pharmacologic effect Result of Agonist
binding
β1
Postsynaptic effector cells
heart
JGA of renal tubules
ciliary body epithelium
Presynaptic adrenergic &
cholinergic
nerve terminals,
↑ HR & force of contraction
↑ renin release
↑ secretion of aqueous humor
↑ transmitter release
Through Gs
Stimulation of
Adenylyl cyclase
↑ cAMP

8. subtypes/locations & characteristics of Adrenoceptors
Receptor Location Pharmacologic effects Result of
Agonist binding
β2
Postsynaptic effector cells
Smooth Msl of some BV ,
specially of skeletal M
Brochi
u. bladder
Vasodilation
Bronchodilation
Relaxation
Promotes potassium uptake
Activates glycogenolysis
Through Gs
Stimulation of
Adenylyl cyclase
↑ cAMP
β3
Postsynaptic effector cells
lipocytes,(fat cells) Activates lipolysis
Same

9. subtypes/locations & characteristics of peripheral Dopamine
receptors
Receptor Location Pharmacologic
effects
Result of Agonist
binding
D1
Postsynaptic
SM of renal & other
splanchnic BV.
Dilation of BV
Through Gs
Stimulation of Adenylyl
cyclase ↑cAMP
D2
Presynaptic Nerve terminals Modulates
transmitter release
Through Gi
Inhibition of
Adenylyl cyclase
↓cAMP

10. Receptor regulation
 Up regulation of β receptors: Increase in number of receptors
Seen on prolonged use of β antagonists.
 Desensitization / Down regulation:
Prolonged exposure to catecholamines (agonists)reduces the
responsiveness.
Example: The therapeutic effect of β2 agonists (
bronchodilation )-decreases on prolonged in Asthma.

11. Chemical Classification
I. Catecholamines
Natural: Epinephrine (Adrenaline)
Nor epinephrine (Noradrenaline)
Dopamine
Synthetic: Isoprenaline
Dobutamine
Rimiterol
Isoetharine
Hexoprenaline

12. II. Non- Catecholamines
 Ephedrine
 Pseudoephedrine
 Amphetamine
 Dexamphetamine
 Orciprenaline
 Metaraminol
 Terbutaline
 Albuterol
 Phenylephrine
 Methoxamine
& many more

13. Adrenergic agonist

14. Relative Receptor Affinities
Alpha Agonists
Phenylephrine , Methoxamine
Clonidine, dexmedetomidine
α1 > α2 >>>>> β
α2 > α1 >>>>> β
Mixed Alpha & Beta Agonists
Norepinephrine
Epinephrine
α1 = α2 ; β1>> β2
α1 = α2 ; β1= β2

15. Beta Agonists
Dobutamine
Isoproterenol
Terbutaline, Metaproterenol,
Albuterol, Ritodrine
β1> β2 >>>> α
β1= β2 >>>> α
β2>> β1 >>>> α
Dopamine Agonists
Dopamine
Fenoldopam
D1 = D2 >> β >> α
D1 >> D2

16. Epinephrine(Adrenaline)
 Source: Natural Catecholamine produced by
cells of adrenal medulla & certain areas of brain.
Released into the circulation 80-90% along with
Nor-epinephrine 10-20 %
 MOA of Epinephrine
Acts as agonist on adrenergic receptors

17.  Cardiovascular
 Heart rate, myochondrial contractality & c o - increase
(β1)
Cutaneous, renal, splachnic vascular beds & pulmonary
artery - constricted (α1 )
 Skeletal muscle –vasodilated (β2)
Coronary blood flow- increase (β2)
Cerebral ---- no significant change related to systemic
blood pressure
• Blood Pressure
Systolic ↑↑ (α1 effect)
Diastolic Generally ↓( β2 effect)
Mean blood pressure↑
Pulse pressure --- ↑↑

18.  Effects on eye:
Mydriasis--- dilation of pupil ; stimulation of α1 in radial
muscle of iris
 Effect on Lungs:
 Smooth muscles– Bronchodilation β2
 BV constricted -- decongestion (α1 ) .
 ↓ release of vasoactive mediators from mast cells--- β2.
 Inhibit microvascular leakage & ↑ ciliary activity.
 Anti Allergic effects:
Physiological antagonist to histamine

19.  Metabolic Effects:
Blood glucose: Hyperglycemia due to
 ↑glycogenolysis in liver, ↑ glucose release into the circulation (
β2 )
 ↓ Insulin secretion --- ( α2 effect).
 Increased release of Glucagon.
 Lipocytes contain β3 & α2: β3 ↑ lipolysis--- ↑ fatty acids
& glycerol (predominant effect) , α2 ↓ lipolysis.
 K+ Level ↓ - activate Na+ K+ pump ( β2 )

20.  Effects on G.I.T:
 Smooth muscles relaxed ( β)
 sphincters - contraction (α1 )
 Effects on G.U.T:
 Uterine and urinary bladder smooth muscles - relaxed β2 .
 Ejaculation depends on α activation in ductus deference, seminal
vesicles, & prostate.
 U. bladder trigone, sphincter & prostate contracted via α1A .
 Effect on Endocrine function.
 Release of Renin: ↑ through β1 & inhibited by α2.
 Coagulation accelerated by increase platlet aggregation & factor v
activity

21.  THERAPEUTIC USES
Anaphylactic shock
Status Asthmatics
To prolong action of infiltration L.A & to ↓systemic
toxicity.
Topical Hemostatic
Cardiac Resuscitation

22. Anaphylactic shock:
 Epinephrine is the drug of first choice.
 IV Dose 100-500mcg repeated if necessary followed by
infusion 2-20mcg/min
 IM - 1:1000 sol 0.3-0.5 ml. May be repeated after 10-20
minutes
Status Asthmatics / Acute severe Asthma:
 S/C injection of epinephrine 0.3 ml of 1 in 1,000 solution, .
Repeated in 20. min (max. 3 dose).

23. To prolong action of infiltration L.A & to
↓systemic toxicity.
1 in 200,000 solution of Epinephrine is added to LA.
This prolongs the DOA due to vasoconstriction & ↓systemic
toxicity.
Topical Hemostatic:
1 : 200,000 or 1:400,000 Nasal packs for epistaxis or
gingival string for gingivectomy.
Cardiac Resuscitation: in complete heart block &
cardiac arrest. dosage - .5 – 1 mg repeated over 3-5 min.

24. Adverse Effects:
 Cardiac arrhythmias: due to increased automaticity of latent
pacemakers
 Anginal pain
 Cerebral hemorrhage
 Pulmonary edema may be produced.
 CNS : Only at high doses
fear, Anxiety, Restlessness, Headache ,Tremors.

25. Interactions:
 Hyperthyroidism: Enhanced CVS effects
 With Cocaine: Enhanced CVS effects
 Diabetes: Risk of Hyperglycemia
 Beta blockers: Marked effect on alpha receptors--- Rise in blood
pressure.
 With Inhalational General anesthetics:
Inhalational General anesthetics sensitize the heart to action of
epinephrine---- risk of Cardiac arrhythmias

26. NOREPINPHRINE
 released from postganglionic sympathetic nerve endings
 Also released from adrenal medulla (10-20 %) with Epinephrine.
In pheochromocytoma ,it may be 97%
MOA:
 Effects similar to epinephrine on α & β1 receptors.
 Relative little effects on β2 receptors
Clinical Considerations
 Direct α1-stimulation in the absence of β2-activity induces intense
vasoconstriction of arterial and venous vessels.
 β1 stimulation – increased contractility of myocardium
 Incease systemic vascular resistance, diastolic &systolic blood pressure ,
mean arterial pressure& minimal change in heart rate( baroreceptor
reflex)

27. USE :
 refractory hypotention in severe sepsis
 Septic shock bolus (0.1mcg/kg) or infusion at a rate of 3–12 μ
g/min.
Adverse effects :
 Use cautiously in pt with right ventricular failure
 Extravasation of norepinephrine at the site of intravenous
administration can cause tissue necrosis.

28. DOPAMINE
 Dopamine is an endogenous catecholamine
 D1-vasodialation in renal, mesentric, coronary & cerebral vascular
beds
 D2- inhibit release of norepinephrine ,leading vasodialation.
Activate emetic center in medulla- nausea & vomiting ,
suppress secretion &function of ant. Pitutatary harmone
 Act on β1 & α receptor (high dose)
 The clinical effects of dopamine (DA), a nonselective direct and
indirect adrenergic agonist, vary markedly with the dose.
 Small doses ( .5-2 μg/kg/min) renal dose– d1 and d2 receptors.
 moderate doses (2–10 μ g/kg/min)- β1-stimulation .
 higher doses(>10μg/kg/min)-α1-effects become prominent

29. Uses
 Shock to improve cardiac output, support blood pressure, and
maintain renal function.
 Refractory CHF.
 Combination therapy dopamine with dobutamine to increase
cardiac output & coronary perfusion
Dosage
 as a continuous infusion at a rate of 1–20 μg/kg/min.

30. DOBUTAMINE
 Synthetic Catecholamine - 50:50 racemic mixture of two
stereoisomers.
o Levorotary (- ) potent α1 adrenergic agonist & weak β1 ,β2
adrenergic agonist
o Dextrorotary (+) α1 adrenergic antagonist & potent β1 ,β2
adrenergic agonist
Pharmacodynamics
 Its primary cardiovascular effect is a rise in cardiac output as a
result of increased myocardial contractility.
 Minimal effect on mean arterial pressure as increased cardiac
output offset decreased in peripheral vascular resistance.
 Heart rate increases are less marked than dopamine &
isoproterenol but may be greater than norepinephrine

31. Uses
 Favorable effects on myocardial oxygen balance make
dobutamine a good choice for patients with the
combination of congestive heart failure and coronary artery
disease, particularly if peripheral vascular resistance
already elevated.
Dosage
 infusion at a rate of 2.5–10 μg/kg/min.

32. Isoproterenol (Isoprenaline)
 Synthetic Catecholamine
 Relative βselective agonist
 Activates both β1 & β2 receptors equally . β 1-Effects increase heart
rate, contractility, and cardiac output.
 β2-decreases PVR and diastolic BP .Myocardial oxygen demand
increases while oxygen supply falls, making isoproterenol or any
pure β -agonist a poor inotropic choice in most situations.
Therapeutic Uses:
 In emergencies (bradycardia , heart blocks) to stimulate HR
specially before insertion of artificial pace maker.
 Pulmonary hypertention & right ventricular dysfunction
 Bronchial asthma (β2 selective drugs preferred).
 To overcome the cardiac effects of beta blockers overdose---
cardiodepression ,heart blocks.

33. PHENYLEPHRINE
 Noncatecholamine with predominantly α1-agonist activity
(high doses may stimulate α2- and β-receptors) & small part
due to release of norepinephrine.
 Increase systemic bp with decrease co (baroreceptor
mediated reflex bradycardia)
 Oral clonidine premedication augment pressor response of
phenylephrine (potentiat α1 mediated vasoconstriction).
 Continuous infusion during acute potassium loading
interfere with transfer of k in to cells
 Use
 Systemic blood pressure decreases in presence of
sympathetic blockade produce by regional anesthesia or
hypotention due to inhaled or injected anesthetic.
 Maternal hypotention in cesarean section because not
altered uterine blood flow & higher umblical artery ph
compare to ephedrine

34.  Dosage
 Small intravenous boluses of 40–100 μg of phenylephrine
rapidly reverse reductions in blood pressure caused by
peripheral vasodilation (eg, spinal anesthesia).
 continuous infusion (10-20 μg/min) in adult to
maintane normal blood pressure during surgery.
 Nasal spray 1% for nasal decongestant

35. EPHEDRINE
 Non catecholamine sympathmimetic act partly due to direct
stimulation of adrenergic receptors ( α & β ) & partly due to
stimulation of release of endogenous norepinephrine (indirect)
 Increase systolic & diastolic blood pressure, heart rate, cardiac output
 Renal ,splanchnic blood flow decrease & coronary ,skeleton muscle
increase.
 Use
 Increase systemic bp in presence of sympathetic blockade produce by
regional anaesthesia or hypotension due to inhaled or injected
anaesthetic
 Decongestant oraly
 Dosage – adults: bolus of 2.5–25 mg IV 25-50 mg IM
children :bolus of 0.1 mg/kg. Subsequent doses produce
less effect ( tachyphylaxis) due to depletion N E store

36. α 2 adrenergic receptor agonists
 An α2-agonist by negative feedback - decrease norepinephrine
release
 Inhibit insulin , increase glucagon release
 have sedative properties.
 on withdrawal present with rebound effect – increase in heart
rate and hypertension

37. clonidine
 Uses- in regional anesthesia, including peripheral nerve
block, clonidine prolongs the duration of the block..
 Other benefits include decreased postoperative shivering,
inhibition of opioid-induced muscle rigidity, attenuation of
opioid withdrawal symptoms, and the treatment of some
chronic pain syndromes.
 Side effects :: bradycardia, hypotension, sedation,
respiratory depression, and dry mouth
 Dosage ::
 oral (3–5μg/kg)
 intramuscular (2 μg/kg)
 intravenous (1–3μ g/kg), transdermal (0.1–0.3 mg
released per day)
 intrathecal (10-50μg)
 epidural (1–2μg/kg)

38. dexmedetomidine
 Higher affinity for α2-receptors than clonidine. (1600:1)
 Uses as sedative, analgesic, due to central sympatholytic effects
 iv infusion .1 – 1.5 μg/kg/min
 large intravenous bolus( .25-1 μg/kg) over 3 to 5 min.Result
paradoxical hypertension with decrease heart rate
 Extensive biotransformation is in liver and excreted in urine.
 Physiological dependance- as potent binding and short half life.
 Withdrawal phenomenon present as clonodine.

39. Selective Β 2 Adrenergic Agonists
•Relax bronchiole and uterine smooth muscles
•Used in bronchospasm in asthma
•Metabolic response- hyperglycemia, hypokalemia,
hypomagnesemia.
•Side effects- tremors due to direct stimulation of B2
receptors in skeletal muscles.
•Route of administration- oral, sc, MDI

40.  DOSES-
 Albuterol-
 MDI-100 mcg/puff. 2 puffs repeated over 4-6 hrs.max 16-20
puffs daily
 Nebulization- 0.5-1 ml .5% solution in 5 ml NS. Rpted every 15
min for 4 doses then hourly in initial hrs.
 Metaproterenol-
 650 mcg/puff. Max 16 puffs.
 Terbutaline-
 SC- .25 mg
 MDI- 200mcg/puff. Max 16 puffs.
 Oral

42. .

43. Blockade of α1 Receptors
 Inhibition of α1 mediated contraction of arterial & venous smooth
muscles.
 Inhibition of contraction of other smooth muscles i.e. eye, GIT , UB &
prostate.
 Inhibition of ejaculation in males.
Blockade of α2 Receptors
 increase of sympathetic outflow from CNS (VMC ) to periphery
 Inhibit Negative feed back control of NE release----- increase NE
release

44. Phentolamine
 Reversible/ competetive antagonist
 Transient (10-15min) nonselective alpha blockade
 Peripheral vasodilation (alpha-1 block) & decreased
BP within 2 min (lasts 10-15 min) elicit
baroreceptor- mediated cardiac stimulation reflex
 Enhanced neural release of N.E. (alpha-2 block) 
increase HR/CO, angina, dysrhythmias
 Parasympathetic “override”: hyperperistalsis,
abdominal pain, diarrhea.

45. Clinical Uses-
 Acute HTN emergencies- 30 to 70 mcg/kg IV
 Intraop manipulation of pheocrhomocytoma-
infusion 0.1-2 mg/min
 Accidental extravascular injection of
sympathomimetic drug
 local infiltration of phentolamine-containing solution (5
to 15mg in 10ml NS)
 erectile dysfunction: phentolamine with papaverine,

46. Phenoxybenzamine
 Non-selective / irreversable blocker.
 Alpha-1 block > Alpha-2 block
 Slow onset (up to 60 min to reach peak) IV or PO.
Long time required for structural change of the
molecule needed to render drug active
 Elimination half-time: 24 hr (cumulative effect with
repeated doses)

47.  Cardiac Effects
 Orthostatic hypotension (if HTN or hypovolemia)
 Impairement of compensatory vasoconstriction 
exaggerated drop in BP in response to blood loss or
vasodilating drugs(e.g. volatile anesthetics)
 CO, renal blood flow unchanged (unless
preexisting renal vasoconstriction)
 Cerebral/coronary vascular resistances don’t
change

48.  Non-Cardiac effects
 increases insulin secretion
 Catecholamine-induced Glycogenolysis in skeletal
muscle or lipolysis not altered
 miosis
 Sedation
 Nasal stuffiness (d/t unopposed alpha blockade
vasodilation in mucous membranes)

49.  Clinical Uses
 Preoperative treatment of HTN of pt with
pheochromocytoma (0.5-1 mg/kg po)
 Given to Pt with excessive vasoconstriction with associated
tissue ischemia (eg. hemorrhagic shock) but only after IV
fluid volume is replenished
 Raynaud’s disease

50. Alpha-1 Selective Blockers
 Generally reflex tachycardia is less prevalent as negative
feed back by NE ,mediated by α2 is not blocked.
 Syncope is noted when first administered in a large group
of patients. Caution should be taken to avoid sudden
postural changes.
 Postural hypotension is much less pronounced than the
non-selective α-blockers possibly because of lower effect
on veins.

51. Therapeutic Uses
 mild hypertension alone or in combination with other
antihypertensives
 benign prostatic hypertrophy: Blockade of α1-
adrenoceptors at the base of the bladder and the prostate
possibly reduces the symptoms of obstruction and the
urinary urgency
o Tamsulosin has antagonistic affinity to α1A receptors (in
vas deferens) more than to α1B in vascular smooth
muscles

52. Prototype Alpha-1 Blocker : Prazosin
 Highly selective for α1 receptors , 1000 fold > α2
 Relaxes vascular smooth muscle  ↓ PVR & ↓ blood pressure --
-- useful anti-hypertensive.
 preoperative treatment of HTN in pheochromocytoma (0.5-1
mg/kg po)
 Relaxes vascular smooth muscle in the prostate & bladder base
 useful in urinary obstruction , improves urinary flow.
 A/E: First dose phenomenon– marked hypotension with first
dose specially in patients who are volume & salt depleted.. So
first dose should be small & given at bed time.

53. Other α-Blockers
 Yohimbine
 Selective α2 blocker
 improves erectile function
 May cause anxiety(crosses BBB)
 Tolazoline
 Reversible non selective α antagonist
 uses: persistent pulmonary hypertension in new born
 A/E: hypotension, reflex tachycardia, pulmonary and git
haemorrhage.

54. .

55. -Adrenergic Receptor Blockers
Mode of action:
 Bind to Beta adrenergic receptors and block effects of
catecholamines & sympathomimetics on the heart & smooth
muscles of the airways & blood vessels.
Chemistry:
 Resemble Isoproterenol.
 Beta blockers should be continued during periop period to avoid
reflex CNS hyperactivity.
 Beta blockade can be reversed by Beta agonist by displacement
from occupied receptors if large amount of agonist is given

56. Significance of Cardioselectivity/
Non-selectivity:
 Some drugs like Atenolol block β1 preferentially than β2but the
selectivity may be lost at higher conc.as they are not receptor specific
,only selective
 Use of selective β1 blockers is safer in patients with :
- Asthma /COPD as β2 receptors in bronchial smooth muscles are not
blocked which may produce bronchoconstriction--- worsening of
Asthma
-Insulin dependent Diabetics--- less chances of hypoglycemia &
recovery is not delayed.
- Severe peripheral vascular disease or spastic disorders.

57. Intrinsic Sympathomimetic Activity (ISA)
 Partial agonistic activity at β- receptors.
 ISA can prevent A/E like precipitation of
bronchoconstriction in patients of COPD
 Less likely to cause Bradycardia & plasma lipid
abnormalities
 Beneficial in patients with brady arrhythmias or
peripheral vascular disease.
 Not as effective as pure antagonist in secondary
prevention of Myocardial Infarction.
 Examples: Acebutolol, Pindolol, Carteolol, Oxpranolol ,
Celiprolol, Penbutolol.
Effects not related to β- blockade

58.  Membrane stabilizing Activity (MSA)
 Local anesthetic action due to Na+ channel blockade.
 Not important for systemic effects but for topical use in
Glaucoma.
 Local anesthetic action produces loss of sensation of cornea---
absent corneal reflex ,which is protective.
So β blockers without MSA are used as eye drops in
Glaucoma e.g. Timolol, Betaxolol .
eg: Propranolol, Pindolol, Labetalol, Acebutolol, Metoprolol,
 Inverse Agonistic Activity :
 Some drugs like Betaxolol ,Metoprolol have inverse agonist
activity– they reduce the constitutive activity of Beta receptors
in some tissues .

59. Propranolol
 Non-selective β blocker with MSA.
 First Beta antagonist introduced clinically
 Highly lipid soluble ---- crosses BBB(produce some drowsiness)
 Low oral bioavailability (30%) due to extensive 1st pass hepatic
metabolism .
Dose- PO dose 40-800mg/day is much higher than IV dose
(0.05mg/kg in increments of 0.5-1mg q5min)
 Elimination half life --- 2– 3 hrs
 Elimination is decreased when hepatic blood flow decreases.
May decrease its own clearance rate by decreasing C.O. and
hepatic blood flow
 Renal failure does not alter elimination half-life BUT
accumulation of metabolites takes place

60. Propanolol & Local Anesthetics
 Decreases clearance of amide L.A. by decrease hepatic blood flow &
inhibition of liver metabolism
 Bupivacaine clearance is decreased 35%
 Higher chance of systemic toxicity of bupivacaine and other amide
L.A.
Propanolol & Opioids
 Pulmonary first-pass uptake of Fentanyl is highly decreased in pts
taking propanolol
 2-4 times as much injected Fentanyl enters systemic circulation right
after injection (more chance of overdosing with Fentanyl in pt who
takes Propanolol)
 This response reflects ability of one basic lipophilic amine
(propanolol) to inhibit pulmonary uptake of another basic lipophilic
amine (fentanyl)

61. Pharmacological Actions
(A)Effects on CVS:
Heart: Mainly blocks β1 receptors
 HR ----- ↓
 Contractility ----- ↓↓↓
 Excitability --- ↓
 Automaticity --- ↓
 Conduction velocity.---- ↓
 Stroke volume ---- ↓
 Cardiac output ---- ↓
 Work load ---- ↓  ↓ oxygen demand
ECG:
 ↑ PR interval in ECG due to slowed AV conduction

62. Blood Vessels & Blood Pressure
 Initially there is ↑ PVR due to inhibition of β2 receptor
mediated vasodilatation.
 On long term ---- ↓ peripheral resistance & ↓ blood pressure
due to β1-blockade :
a) ↓ CO
b) Anti Renin effects

63. (B)Effects on Respiratory System:
 Bronchoconstriction (blockade of β2) by non-selective β
blockers Increased airway resistance--- worsening of
asthma.
 No β1-Selective antagonist is sufficiently specific for β1 ,
so generally they should be avoided in patients with
concomitant asthma.
 β1-Selective antagonists are relatively safe in patients with
concomitant COPD.
(C)Effects on Eye:
 ↓ IOP---- ↓ synthesis of aqueous humour due to blockade
of β1 in ciliary epithelium.
 β blockers without MSA are used in glaucoma.
e.g. Timolol, Betaxolol – topically as eye drops

64. (D) Metabolism:
1.Effect on lipid metabolism:
 ↓ lipolysis (β3 blockade)
2. Effect on carbohydrate metabolism:
 ↓ glycogenolysis in liver (β2 blockade)
 Delay in recovery from hypoglycemia in Insulin dependent
Diabetics; specially in patients with low Glucagon reserve
3.Effect on lipoprotiens:
 ↑ VLDL & ↓ HDL cholesterol ----- ↑ risk of coronary
artery disease (CAD).
 Less likely to occur with β blockers possessing ISA.

65. Atenolol
 Most selective Beta1 Blocker
 50% of PO dose (50-100mg/day) absorbed by GI
 Little/no hepatic metabolism
 Renal excretion
 Elimination half-life: 6-8hrs (more than 24 hrs in renal failure)
 IV dose for acute MI (5mg over 5min followed by another 5mg 10min
later)
 Periop Tx will decrease incidence of post op MI in CAD pts
 Enters CNS in very small amounts but fatigue/depression still occurs
 Can be used with caution in IDDM pts whose HTN is not controlled
with other antiHTN (does not potentiate Insulin-Induced
Hypoglycemia seen with nonselective Beta blockers)

66. Metoprolol
 Beta 1 selective
 High hepatic first-pass metabolism (only 40% reaches systemic
circulation)
 Low protein binding (10% bound)
 Elimination half-life 3-4hrs
 Can be used in COPD/PVD pts since no Beta2 blocking properties at
normal dose (2-15mg IV).

67. Esmolol
 Rapid onset, short acting Beta1 blocker given ONLY IV (0.5mg/kg)
 T1/210min (rapid hydrolysis in blood by plasma esterases,
independent of renal & hepatic function)
 Plasma esterases that hydrolyze Esmolol are different than
Plasma Cholinesterase
 Dose: 0.5-1mg/kg (peaks 5min). Return of HR to predrug level
within 10-30min
 Poor lipid solubility limits crossing into CNS/placenta
 Esmolol (1mg/kg) iv followed by 250 mcg/kg/min decreases
plasma conc of propofol required to prevent patient movement in
response to surgical incision.

68.  Uses
 HTN/Tachy in response to intraop noxious stimulation &
intubation (eg 150mg IV 2min before Laryngoscopy)
 prior to ECT : attenuation of increased HR & decrease
length of seizure (dose 500 mcg/kg/min)
 In Pheochromocytoma, thyrotoxicosis, PIH, epinephrine- or
cocaine-induced cardiovascular toxicity

69. Therapeutic Uses of β-blockers
(1) Treatment of hypertension:
• Selective β1-blockers are preferable in asthmatic & diabetic
patients and in patients with Raynaud’s disease
• Postural hypotension is not prominent.
• very useful as mono therapy in mild to moderate hypertension
 In hypertensive emergencies (Labetalol , Esmolol)
 Intraoperative & Postoperative hypertension (Esmolol)
 Hypertension with chronic heart failure (Carvedilol , Metoprolol,
Bisoprolol)
 Hypertension with pheochromocytoma use β- blocker after α blocker.

70. (2)Myocardial Infarction (MI):
• given immediately (few hours) after MI reduces the infarct
size and enhance cardiac reperfusion and recovery;
esmolol,atenolol, propranolol, and metoprolol are used
• β-blockers administered 1-4weeks after MI reduce much the
probability of myocardial re-infarction possibly by reducing
cardiac work.
(3)Angina:
 Useful for prophylaxis of Classical angina.
 They reduce the frequency of anginal attacks.
 Improve exercise tolerance.
 Not useful in acute attack.
 The beneficial effects are related to hemodynamic
effects— ↓ HR ,force of contraction–↓ Work load ---- 
↓ oxygen demand

71. (4)Cardiac supraventricular arrhythmias
β1-receptor blockade results in the following:
• decreased firing rate of SA node
• decreased AV conduction & prolongation of AV-nodal
refractory period
• decreased ventricular response to atrial flutter
Esmolol is a cardio-selective β1-blocker that is used only by IV
route for emergency treatment of supraventricular arrhythmias
arising during surgery

72. (5)Dissecting aortic aneurysm:
 β- blockers decrease the rate of rise in the systolic blood
pressure.
 β- blockers are also useful in selected high risk patients in
the prevention of adverse cardiovascular outcomes
resulting from non-cardiac surgery.
(6) Pheochromocytoma :
 β- blockers may be given after Alpha blockers to reverse the
cardiac effects of catecholamines.
 If given before Alpha blockers,there will be enhanced
effects of catecholamines on alpha receptors--- further rise
in blood pressure.

73. (7)Hyperthyroidism:
β antagonists are beneficial as they :
 Block the excessive catecholamine action. (there is upregulation
of β receptors in hyperthyroidism).
 Inhibit peripheral conversion of Thyroxine (T4)to
Tri-idothyronine (T3); which is more potent.
 Are useful in thyroid storm to control supraventricular
tachycardia that often precipitates cardiac failure.
(8)Glaucoma:
 β blockers without MSA are used in glaucoma.
e.g. Timolol, Betaxolol as topical eye drops.

74. (9)Migraine prophylaxis
Propranolol reduces the frequency & intensity of migraine
headache
(10)Skeletal muscle tremor :
β antagonists reduce certain tremors as sympathetic activity may
enhance skeletal muscle tremor through β receptors.
(11)Alcohol withdrawal syndrome:
β antagonists reduce symptoms .
(12)Anxiety:
• β antagonists reduce symptoms of anxiety
• Low dose Propranolol ,specially when taken prophylactically ;
is effective to control stage fright--- performance anxiety.

75. ADVERSE EFFECTS of β-blockers
1.On CVS: Generally the extensions of pharmacologic effects.
 Bradycardia
 AV block
Hypotension
 Heart failure---- in patients where CO is dependent upon
sympathetic drive.
Antidote: Isoproterenol & glucagon.
 Coldness of extremities, fatigue with non -selective β-Blockers ,
specially in patients of peripheral vascular disease or vasospastic
disorders

76. Drug withdrawal in patients of IHD: on abrupt
discontinuation of β-antagonists therapy in IHD after
chronic use--
Angina or acute myocardial infarction may occur:-this
may be due to adrenergic receptor super-sensitivity
mediated by receptor up-regulation or re-enhancement
of sympathetic cardiac drive
So the dose should be tapered over 2-3 weeks in
Hypertension & IHD

77. 2.Metabolic :
 Hypoglycemic episodes in insulin dependent diabetics
(type I) with non selective β-Blockers
 Masking of premonitory symptoms of
hypoglycemia(such as tachycardia)
 Delay in recovery from hypoglycemia
 Effect on lipoprotiens:
 ↑ VLDL & ↓ HDL cholesterol ----- ↑ risk of Coronary
Artery Disease..
 Less common with β blockers possessing ISA.

78. 3.Respiratory :
 Worsening of pre-existing disease ---- asthma or COPDs
(with non selective β-Blockers).
4. CNS:
 Sedation, sleep disturbances, & depression.
5. Drug interactions:
 With Verapamil severe hypotension, bradycardia, heart
failure & conduction defects.
.
.

79. CONTRAINDICATIONS of β-blockers
 DO NOT use in pts with AV Block or h/o heart failure not caused by
tachycardia
 Be cautious in hypovolemic pt since Beta Blockade may cause
profound hypotension
 Nonselective Beta Blockers or high dose of Selective Beta Blockers
are not recommended for pts with COPD (can cause
broncoconstriction), PVD (can cause peripheral vasoconstriction),
Diabetes (hypoglycemia may be masked  no increase in HR)

80. Combined α & β blocker
 Ex:- Labetalol , Carvedilol , Medroxalol
 Non selective β & α1 selective blocker.
 Used as antihypertensive ----less tachycardia than α blockers .
Carvedilol
 Highly lipid soluble
 Also has antioxidant properties and protect against vascular
thickening (remodeling)
 Very dramatic results in CHF clinical trials.
 Decreased mortality by 65%

81. Labetalol
 Selective Alpha1 and Nonselective Beta Blocker
 Presynaptic Alpha2 receptors are spared
 Beta to Alpha potency ratio 7:1 (IV) and 3:1 (PO)
 T1/2 = 5-8hrs, prolonged in liver dz, unchanged in renal dz
 Blood pressure is ↓ed by ↓ PVR without significant change in HR
& CO
 BP should be lowered within 5-10min of 0.1-0.5mg/kg IV dose

82. Uses
 HTN emergencies (eg epi overdose from local)
 20-80mg IV q10min
 Pheochromocytoma pts with rebound HTN after withdrawal of
Clonidine
 Used in surgeries where “Controlled Hypotension” needed (10mg
intermittently)
Side effects
 Orthostatic hypotension (most common)
 Bronchospasm (susceptible pts)
 Other Beta Blockade S.E.
 CHF
 Bradycardia
 Heart Block

83. THANK YOU