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Adrenergic Agonist &
Antagonist
-Guide: Dr R K Solanki Sir
Dr Neelam Mam
Dr Kailash Mittal
Synthesis,Storage , Release and Degradation
The metabolites are excreted in urine as:
 Vinyl mandelic acid , 3,4 dihydroxy mandelic acid
 Metanephrine
 Nor-metanep...
Subtypes/Locations & Characteristics of Adrenoceptors
Rece
ptor
Location Pharmacologic effects Result of Agonist
binding
α...
subtypes/locations & characteristics of Adrenoceptors
Rece
ptor
Location Pharmacologic
effects
Result of
Agonist
binding
α...
subtypes/locations & characteristics of Adrenoceptors
Rec
epto
r
Location Pharmacologic effect Result of Agonist
binding
β...
subtypes/locations & characteristics of Adrenoceptors
Receptor Location Pharmacologic effects Result of
Agonist binding
β2...
subtypes/locations & characteristics of peripheral Dopamine
receptors
Receptor Location Pharmacologic
effects
Result of Ag...
Receptor regulation
 Up regulation of β receptors: Increase in number of receptors
Seen on prolonged use of β antagonists...
Chemical Classification
I. Catecholamines
Natural: Epinephrine (Adrenaline)
Nor epinephrine (Noradrenaline)
Dopamine
Synth...
II. Non- Catecholamines
 Ephedrine
 Pseudoephedrine
 Amphetamine
 Dexamphetamine
 Orciprenaline
 Metaraminol
 Terbu...
Adrenergic agonist
Relative Receptor Affinities
Alpha Agonists
Phenylephrine , Methoxamine
Clonidine, dexmedetomidine
α1 > α2 >>>>> β
α2 > α1...
Beta Agonists
Dobutamine
Isoproterenol
Terbutaline, Metaproterenol,
Albuterol, Ritodrine
β1> β2 >>>> α
β1= β2 >>>> α
β2>> ...
Epinephrine(Adrenaline)
 Source: Natural Catecholamine produced by
cells of adrenal medulla & certain areas of brain.
Rel...
 Cardiovascular
 Heart rate, myochondrial contractality & c o - increase
(β1)
Cutaneous, renal, splachnic vascular beds...
 Effects on eye:
Mydriasis--- dilation of pupil ; stimulation of α1 in radial
muscle of iris
 Effect on Lungs:
 Smooth ...
 Metabolic Effects:
Blood glucose: Hyperglycemia due to
 ↑glycogenolysis in liver, ↑ glucose release into the circulatio...
 Effects on G.I.T:
 Smooth muscles relaxed ( β)
 sphincters - contraction (α1 )
 Effects on G.U.T:
 Uterine and urina...
 THERAPEUTIC USES
Anaphylactic shock
Status Asthmatics
To prolong action of infiltration L.A & to ↓systemic
toxicity.
...
Anaphylactic shock:
 Epinephrine is the drug of first choice.
 IV Dose 100-500mcg repeated if necessary followed by
infu...
To prolong action of infiltration L.A & to
↓systemic toxicity.
1 in 200,000 solution of Epinephrine is added to LA.
This p...
Adverse Effects:
 Cardiac arrhythmias: due to increased automaticity of latent
pacemakers
 Anginal pain
 Cerebral hemor...
Interactions:
 Hyperthyroidism: Enhanced CVS effects
 With Cocaine: Enhanced CVS effects
 Diabetes: Risk of Hyperglycem...
NOREPINPHRINE
 released from postganglionic sympathetic nerve endings
 Also released from adrenal medulla (10-20 %) with...
USE :
 refractory hypotention in severe sepsis
 Septic shock bolus (0.1mcg/kg) or infusion at a rate of 3–12 μ
g/min.
Ad...
DOPAMINE
 Dopamine is an endogenous catecholamine
 D1-vasodialation in renal, mesentric, coronary & cerebral vascular
be...
Uses
 Shock to improve cardiac output, support blood pressure, and
maintain renal function.
 Refractory CHF.
 Combinati...
DOBUTAMINE
 Synthetic Catecholamine - 50:50 racemic mixture of two
stereoisomers.
o Levorotary (- ) potent α1 adrenergic ...
Uses
 Favorable effects on myocardial oxygen balance make
dobutamine a good choice for patients with the
combination of c...
Isoproterenol (Isoprenaline)
 Synthetic Catecholamine
 Relative βselective agonist
 Activates both β1 & β2 receptors eq...
PHENYLEPHRINE
 Noncatecholamine with predominantly α1-agonist activity
(high doses may stimulate α2- and β-receptors) & s...
 Dosage
 Small intravenous boluses of 40–100 μg of phenylephrine
rapidly reverse reductions in blood pressure caused by
...
EPHEDRINE
 Non catecholamine sympathmimetic act partly due to direct
stimulation of adrenergic receptors ( α & β ) & part...
α 2 adrenergic receptor agonists
 An α2-agonist by negative feedback - decrease norepinephrine
release
 Inhibit insulin ...
clonidine
 Uses- in regional anesthesia, including peripheral nerve
block, clonidine prolongs the duration of the block.....
dexmedetomidine
 Higher affinity for α2-receptors than clonidine. (1600:1)
 Uses as sedative, analgesic, due to central ...
Selective Β 2 Adrenergic Agonists
•Relax bronchiole and uterine smooth muscles
•Used in bronchospasm in asthma
•Metabolic ...
 DOSES-
 Albuterol-
 MDI-100 mcg/puff. 2 puffs repeated over 4-6 hrs.max 16-20
puffs daily
 Nebulization- 0.5-1 ml .5%...
.
Blockade of α1 Receptors
 Inhibition of α1 mediated contraction of arterial & venous smooth
muscles.
 Inhibition of cont...
Phentolamine
 Reversible/ competetive antagonist
 Transient (10-15min) nonselective alpha blockade
 Peripheral vasodila...
Clinical Uses-
 Acute HTN emergencies- 30 to 70 mcg/kg IV
 Intraop manipulation of pheocrhomocytoma-
infusion 0.1-2 mg/m...
Phenoxybenzamine
 Non-selective / irreversable blocker.
 Alpha-1 block > Alpha-2 block
 Slow onset (up to 60 min to rea...
 Cardiac Effects
 Orthostatic hypotension (if HTN or hypovolemia)
 Impairement of compensatory vasoconstriction 
exagg...
 Non-Cardiac effects
 increases insulin secretion
 Catecholamine-induced Glycogenolysis in skeletal
muscle or lipolysis...
 Clinical Uses
 Preoperative treatment of HTN of pt with
pheochromocytoma (0.5-1 mg/kg po)
 Given to Pt with excessive ...
Alpha-1 Selective Blockers
 Generally reflex tachycardia is less prevalent as negative
feed back by NE ,mediated by α2 is...
Therapeutic Uses
 mild hypertension alone or in combination with other
antihypertensives
 benign prostatic hypertrophy: ...
Prototype Alpha-1 Blocker : Prazosin
 Highly selective for α1 receptors , 1000 fold > α2
 Relaxes vascular smooth muscle...
Other α-Blockers
 Yohimbine
 Selective α2 blocker
 improves erectile function
 May cause anxiety(crosses BBB)
 Tolazo...
.
-Adrenergic Receptor Blockers
Mode of action:
 Bind to Beta adrenergic receptors and block effects of
catecholamines & s...
Significance of Cardioselectivity/
Non-selectivity:
 Some drugs like Atenolol block β1 preferentially than β2but the
sele...
Intrinsic Sympathomimetic Activity (ISA)
 Partial agonistic activity at β- receptors.
 ISA can prevent A/E like precipi...
 Membrane stabilizing Activity (MSA)
 Local anesthetic action due to Na+ channel blockade.
 Not important for systemic ...
Propranolol
 Non-selective β blocker with MSA.
 First Beta antagonist introduced clinically
 Highly lipid soluble ---- ...
Propanolol & Local Anesthetics
 Decreases clearance of amide L.A. by decrease hepatic blood flow &
inhibition of liver m...
Pharmacological Actions
(A)Effects on CVS:
Heart: Mainly blocks β1 receptors
 HR ----- ↓
 Contractility ----- ↓↓↓
 Exc...
Blood Vessels & Blood Pressure
 Initially there is ↑ PVR due to inhibition of β2 receptor
mediated vasodilatation.
 On l...
(B)Effects on Respiratory System:
 Bronchoconstriction (blockade of β2) by non-selective β
blockers Increased airway resi...
(D) Metabolism:
1.Effect on lipid metabolism:
 ↓ lipolysis (β3 blockade)
2. Effect on carbohydrate metabolism:
 ↓ glycog...
Atenolol
 Most selective Beta1 Blocker
 50% of PO dose (50-100mg/day) absorbed by GI
 Little/no hepatic metabolism
 Re...
Metoprolol
 Beta 1 selective
 High hepatic first-pass metabolism (only 40% reaches systemic
circulation)
 Low protein b...
Esmolol
 Rapid onset, short acting Beta1 blocker given ONLY IV (0.5mg/kg)
 T1/210min (rapid hydrolysis in blood by plas...
 Uses
 HTN/Tachy in response to intraop noxious stimulation &
intubation (eg 150mg IV 2min before Laryngoscopy)
 prior ...
Therapeutic Uses of β-blockers
(1) Treatment of hypertension:
• Selective β1-blockers are preferable in asthmatic & diabet...
(2)Myocardial Infarction (MI):
• given immediately (few hours) after MI reduces the infarct
size and enhance cardiac reper...
(4)Cardiac supraventricular arrhythmias
β1-receptor blockade results in the following:
• decreased firing rate of SA node
...
(5)Dissecting aortic aneurysm:
 β- blockers decrease the rate of rise in the systolic blood
pressure.
 β- blockers are a...
(7)Hyperthyroidism:
β antagonists are beneficial as they :
 Block the excessive catecholamine action. (there is upregulat...
(9)Migraine prophylaxis
Propranolol reduces the frequency & intensity of migraine
headache
(10)Skeletal muscle tremor :
β ...
ADVERSE EFFECTS of β-blockers
1.On CVS: Generally the extensions of pharmacologic effects.
 Bradycardia
 AV block
Hypot...
Drug withdrawal in patients of IHD: on abrupt
discontinuation of β-antagonists therapy in IHD after
chronic use--
Angina o...
2.Metabolic :
 Hypoglycemic episodes in insulin dependent diabetics
(type I) with non selective β-Blockers
 Masking of p...
3.Respiratory :
 Worsening of pre-existing disease ---- asthma or COPDs
(with non selective β-Blockers).
4. CNS:
 Sedati...
CONTRAINDICATIONS of β-blockers
 DO NOT use in pts with AV Block or h/o heart failure not caused by
tachycardia
 Be caut...
Combined α & β blocker
 Ex:- Labetalol , Carvedilol , Medroxalol
 Non selective β & α1 selective blocker.
 Used as anti...
Labetalol
 Selective Alpha1 and Nonselective Beta Blocker
 Presynaptic Alpha2 receptors are spared
 Beta to Alpha poten...
Uses
 HTN emergencies (eg epi overdose from local)
 20-80mg IV q10min
 Pheochromocytoma pts with rebound HTN after with...
THANK YOU
Adrenergic agonist antagonist
Adrenergic agonist antagonist
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Adrenergic agonist antagonist

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Adrenergic agonist antagonist

  1. 1. Adrenergic Agonist & Antagonist -Guide: Dr R K Solanki Sir Dr Neelam Mam Dr Kailash Mittal
  2. 2. Synthesis,Storage , Release and Degradation
  3. 3. 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
  4. 4. 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.
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. 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.
  10. 10. Chemical Classification I. Catecholamines Natural: Epinephrine (Adrenaline) Nor epinephrine (Noradrenaline) Dopamine Synthetic: Isoprenaline Dobutamine Rimiterol Isoetharine Hexoprenaline
  11. 11. II. Non- Catecholamines  Ephedrine  Pseudoephedrine  Amphetamine  Dexamphetamine  Orciprenaline  Metaraminol  Terbutaline  Albuterol  Phenylephrine  Methoxamine & many more
  12. 12. Adrenergic agonist
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16.  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 --- ↑↑
  17. 17.  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
  18. 18.  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 )
  19. 19.  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
  20. 20.  THERAPEUTIC USES Anaphylactic shock Status Asthmatics To prolong action of infiltration L.A & to ↓systemic toxicity. Topical Hemostatic Cardiac Resuscitation
  21. 21. 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).
  22. 22. 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.
  23. 23. 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.
  24. 24. 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
  25. 25. 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)
  26. 26. 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.
  27. 27. 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
  28. 28. 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.
  29. 29. 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
  30. 30. 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.
  31. 31. 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.
  32. 32. 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
  33. 33.  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
  34. 34. 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
  35. 35. 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
  36. 36. 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)
  37. 37. 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.
  38. 38. 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
  39. 39.  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
  40. 40. .
  41. 41. 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
  42. 42. 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.
  43. 43. 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,
  44. 44. 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)
  45. 45.  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
  46. 46.  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)
  47. 47.  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
  48. 48. 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.
  49. 49. 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
  50. 50. 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.
  51. 51. 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.
  52. 52. .
  53. 53. -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
  54. 54. 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.
  55. 55. 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
  56. 56.  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 .
  57. 57. 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
  58. 58. 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)
  59. 59. 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
  60. 60. 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
  61. 61. (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
  62. 62. (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.
  63. 63. 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)
  64. 64. 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).
  65. 65. 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.
  66. 66.  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
  67. 67. 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.
  68. 68. (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
  69. 69. (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
  70. 70. (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.
  71. 71. (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.
  72. 72. (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.
  73. 73. 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
  74. 74. 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
  75. 75. 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.
  76. 76. 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. . .
  77. 77. 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)
  78. 78. 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%
  79. 79. 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
  80. 80. 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
  81. 81. THANK YOU

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