Adrenergic%20

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Adrenergic Antiadrenergic Drugs

• By Prof. Alhaider

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Anatomy of the sympathetic nervous system

• The origin is from thoracolumbar segments all
  thoracic lumbers L1, L2, L3 and L4
• They have short preganglionic fibers, and it
  relays in sympathetic chain ganglia release Ach
  in these ganglia
• They have long postganglionic fibers that
  innervate their body organs release
  Norepinephrine as a neurotransmitter there

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Neurotransmission at adrenergic neurons

• Synthesis of norepinephrine (NE)
• Storage of dopamine (DA) and NE in vesicles
• Release of NE
• Metabolism (COMT 20 MAO 80)
• Binding to receptors
• Uptake mechanism

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We ask the doctor about the drugs are they
included in the exam he said its up to you
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Adrenoceptors

• The adrenergic receptors are classified into
• a1
• a2
• ß1
• ß2
• ß3
• There are some subtypes

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a1 Adrenoceptors
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a1 adrenoceptors (continue) Site of a1
adrenoceptors the effects of their stimulation

• In vascular smooth muscle.
• a1 stimulation cause vasoconstriction (VC)
• Vasoconstriction in the skin viscera cause
  increase total vascular resistance (TVR) causing
  increase blood pressure (BP)
• a1 adrenoceptors the most determine of
  arteriolar tone. When their stimulated no others
  receptors have an affects on BP. So, hypertension
  may be treated by blocking a1
• Vasoconstriction in the nasal blood vessels cause
  relief of congestion
• In the radial muscle of iris.
• a1 stimulation causes contraction of the radial
  muscle causing mydriasis (dilation of the pupil)

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Cont.

• In the smooth muscle of the sphincters of GIT.
• a1 stimulation cause contraction of all
  sphincters
• In the smooth muscle of internal sphincter of
  urinary bladder (Very important).
• a1a subtypes stimulation cause contraction and
  closure of the sphincters (precipitate urinary
  retention)
• In the seminal vesicles. (with a2)
• a stimulation cause ejaculation. Thus, all a
  blockers inhibit ejaculation
• In the liver.
• a1 stimulation causes increase glycogenolysis
  gluconeogenesis
• In the fat cells.
• a1 stimulation causes increased lipolysis

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Adrenoceptorsa 1 adrenoceptorsDrugs effects

• a1 selective agonist
• E.g.
• Phenyl ephrine
• a1 selective antagonists
• E.g.
• Prazosin
• Terazosin
• Doxazosin
• Tamsolusin ( a1a) (has a different clinical use)

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a2 adrenoceptorsMechanism of action

• a2 stimulation leads to either
• Decreased adenylyl cyclase activity(mediated by
  the inhibitory regulatory Gi protein)
• Lead to decrease cAMP causing decrease NE release
  causing
• relaxation of smooth muscle
• decreased glandular secretion
• Increase K channel activity ? hyperpolarization

So a1 receptors are stimulatory while a2
receptors are inhibitory
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a2adrenoceptorsSite of a2 adrenoceptors the
effects of their stimulation

• In adrenergic nerve terminals (presynaptic).
• a2 stimulation cause decreased Norepinephrine
  release (autoregulatory mechanism). It opposes
  the action of sympathetic stimulation.
• In pancreas.
• causes decreased insulin release
• In platelets.
• Increase platelets aggregation via c-AMP
• In liver (same as a1 adrenoceptors)
• Fat cells (same as a1 adrenoceptors).

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Cont

• In ciliary epithelium.
• Increase the out flow of aqueous humor.(good for
  glaucoma)
• In the smooth muscle of GIT wall. (with ß2)
• a2 stimulation cause relaxation of the wall
  causing decreased peristalsis (indirectly by
  reducing the release of ACH)

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a2 adrenoceptors (Continue)Drugs effects

• a2 selective agonists
• E.g.
• Clonidine
• Methyldopa (Antihypertensive)
• Apraclonidine (topical for eye)
• a2 selective antagonists
• E.g.
• Yohimbine Mertazapine (Antidepressant)

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ß1 adrenoceptors

• In the heart.
• ß 1 stimulation causes
• In S.A node increase heart rate (HR) (ve
  chronotropic)
• In Myocardium tissue increase contractility
  (ve inotropic)
• In Conducting system increase conduction
  velocity (ve dromotropic)
• Increase ectopic beats
• In the Juxtaglomerular Apparatus of the kidney.
• ß 1 stimulation cause increased renin release.
  Then causes increase in BP
• In fat cells (with a1, a2 ß 3)
• ß 1 stimulation causes increased Lipolysis

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Adrenoceptorsß 1 adrenoceptorDrugs affecting
them

• ß 1 selective agonists
• E.g.
• Dobutamine
• ß 1 selective antagonists
• E.g.
• Atenolol
• Esmolol
• Metoprolol

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ß2 adrenoceptors

• In the bronchial smooth muscle
• ß2 stimulation causes relaxation of smooth muscle
  (bronchodilatation)
• In the smooth muscle of blood vessels supplying
  the skeletal muscle.
• ß2 stimulation causes relaxation of smooth muscle
  ? Vasodilatation(VD)
• This VD effects is usually masked by the potent
  VC effect of a1 receptors

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Cont.

• In the smooth muscle of GIT wall.
• ß2 stimulation cause relaxation of the wall
  leading to decreased peristalsis
• In the smooth muscle of the wall of urinary
  bladder.
• ß 2 stimulation causes relaxation of the wall
• Note Adrenergic stimulation is opposite to the
  cholinergic in the wall and sphincters in GIT and
  genitourinary tract .

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Cont.

• In the smooth muscle of the uterus
• ß2 stimulation causes relaxation of the uterus
  (Ritodrine delay the labor)
• In the liver.
• ß2 stimulation causes increased Glycogenolysis
  Gluconeogenesis
• In the pancreas.
• ß2 stimulation causes slight increase in insulin
  secretion (hypoglycemia), but the effect on the
  liver is predominant.
• Effect on potassium .
• ß2 stimulation increase potassium influx.

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Cont.

• In ciliary muscle.
• ß2 stimulation causes relaxation of the ciliary
  muscle leading to
• Accommodation for far vision
• Decrease outflow of aqueous humor via the canal
  of Schlemm
• In the ciliary epithelium
• ß2 stimulation causes increased production of
  aqueous humor

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Adrenoceptorsß 2 adrenoceptorsDrugs affecting
them

• ß 2 selective agonists
• E.g.
• Salbutamol (asthma ref heperkalemia)
• Salmetrol
• Terbutaline
• Ritodrine
• Formetrol
• ß 2 selective antagonists
• E.g.
• ICI118551 (still under investigation)

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b1 and b2 adrenoceptor agonistsMechanism of
action

• ß stimulation causes increase adneylyl cyclase
  activity leading to increase cAMP leading to
  cellular effect. E.g.
• ß 1 in the heart cause increase intracellular
  Ca release leading to increased contractility
• ß 2 in smooth muscle cause inhibition of myosin
  kinase enzyme causing relaxation
• ß 2 in the liver cause increase Glycogen
  phosphorylase enzyme activity causing increased
  glycogenolysis

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ß 3 adrenoceptors

• In brown adipose tissue
• ß 3 stimulation causes increased Lipolysis

• ß 3 selective agonist
• E.g.
• BRL 37344
• ß 3 selective antagonist
• E.g.
• CGP 20712A

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Adrenergic Drugs

• Adrenoreceptor Agonists
• Non selective
• Selective
• Adrenoreceptor Antagonists
• a blockers
• ß blockers

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Adrenoceptor AgonistsI. Non selective drugs
noncatecolamines catecholamines
Low potency High potency
Long t1/2 Short t1/2
Can be Given orally Given parenterally
Non polar polar
Not inactivated by COMT Inactivated by COMT

• These drugs include
• 1) Catecholamine Drugs
• A. endogenous
• Norepinephrine
• Epinephrine
• Dopamine
• b) Synthetic (exogenous)
• Isoprenaline
• 2) Non-catecholamine Drugs
• Amphetamine
• Ephedrine
• Pseudo ephedrine
• Phenylpropranolamine

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Norepinephrine (NE)(Noradrenaline)

• NE is a neurotransmitter released from the
  postganglionic sympathetic fiber in most organs
• It also released from the adrenal medulla (20 of
  medulla secretion)
• It is a direct nonselective adrenergic agonist
  which acts on all adrenoceptors, Except ß2

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Cont.

• Sites of metabolism
• In adrenergic nerves
• 80 by MAO in presynaptic nerve terminals after
  reuptake (This is very important clinically)
• If MAO is inhibited, NE will be reuptake but not
  metabolized, leads to release of NE again
• 15 by COMT in postsynaptic membrane (This is not
  important clinically)
• 5 reach the blood and metabolized In the Liver

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Norepinephrine Pharmacokinetics

• T1/2 of NE 2 3 min
• Very short because it has rapid metabolism
• NE causes increased systolic blood pressure (SBP)
  diastolic blood pressure (DBP)
• So, in shock, it will increase BP
• Not given orally because it will be inactivated
  by intestinal enzymes

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• Clinical Uses
• Note NE is not commonly used in clinical
  practice like Epinephrine, However it can be used
  in
• Cardiac Arrest
• Shock

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Epinephrine (EP)(Adrenaline)

• EP is released from adrenal medulla (80) and in
  certain areas of the brain
• EP is a direct acting non-selective adrenergic
  agonist in all receptors including ß2 receptor.
• T1/2 2 5 min
• Like NE, It is given parenterally (SC, I.V and
  I.M) not orally
• Has the same pharmacokinetics as NE

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EpinephrineTherapeutic use
b

• Epinephrine is commonly used in practice as
  compared to NE.
• In bronchial asthma
• It is given SC to act on ß2 receptors to cause
  bronchodilation
• Now it is not commonly used because of its side
  effects (tachycardia and arrhythmia)
• In cardiogenic shock
• It is given I.V to increase SBP, BP, HR and
  cardiac output (CO)
• In anaphylactic shock
• It is given SC to act on
• a1 cause VC, lead to increase BP relief of
  congestion
• ß 1 cause increase HR leading to increase CO, so,
  increase BP
• ß 2 cause bronchodilation so, relieve bronchospasm

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Cont

• In cardiac arrest (for Bradycardia)
• It is given I.V. if there is no response, EP
  given directly into the lung, and if there is no
  response, it given intracardially, and if there
  is no response, direct current is applied for 3
  times at most
• During surgery
• EP is added to the local anesthetic to cause VC
  in the surgery area in order to
• Decrease bleeding
• Decrease the amount of local anesthetic which
  will reach the systemic circulation. Therefore,
  it will decrease the cardiodepressant effect of
  the local anesthetic

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Isoprenaline (isoproterenol)

• It is directly acting synthetic adrenoreceptor
  agonist acting only on ßreceptors, with no
  effects on a adrenoceptos.
• T1/2 5 7 min
• Like all catecholamines, It is given parenterally
  (not orally)
• The I.V must be given carefully because the
  overdoses cause cardiac arrest

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Iso pre nalineAction

• Isoprenaline will stimulate
• ß1 in the heart to cause
• Increased HR cause arrhythmia may lead to
  cardiac arrest
• ß2 in the blood vessels to cause
• VD leads to decreased BP (mainly DBP)

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IsoprenalineTherapeutic uses

• It is no longer used to treat the bronchial
  asthma because of its side effects on the heart
• Its only used now to reverse the heart block
  which is produced by overdoses of ß blockers
• N.B. cardiac arrest means complete cessation
  of hearts activity. While heart block means
  partial or complete inhibition of the spread of
  conduction of the electrical impulse from the
  atria to the ventricles

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Effects of I.V. infusion of Epinephrine,
Norepinephrine Isoprenaline in Humans
Epinepherine and isoprenaline decrease DBP
because they act on ß2
Reflex bradycardia
Isoprenaline decrease resistance because it acts
on ß only without a
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Dopamine

• DA is a nonselective adrenergic agonist, which
  acts either directly on DA receptors in
  addition to b1- adrenergic receptors or
  indirectly by releasing NE
• Like all catecholamines, It is given parenterally
  only (not orally)
• It doesnt cause tolerance
• T1/2 3 5 min
• Metabolized by either
• Converted to NE in adrenergic neurons or
• By MAO in the Liver

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Dopamine (Cont)

• Clinical Uses
• In small dose of DA (lt 5ug / Kg / min by I.V
  infusion) Renal dose
• It will stimulate DAreceptors only
• It will cause vasodilatation (VD) in
• Renal vascular bed
• Cerebral vascular bed
• Coronary vascular bed
• Mesenteric vascular bed
• Therefore, it is useful in treatment of shock to
  save these vital organs from hypoxia (also see
  Dobutamine)
• N.B At higher doses, VD effect of DA
  receptors is masked by the VC effect of
  a1receptors(see next slide)

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Cont.

• In medium dose (5-15ug/Kg/min by I.V infusion)
  Cardiac dose
• It will stimulate ß1 receptors to cause
  increase HR, CO and BP
• In high dose of DA (gt 15ug / Kg / min by I.V
  infusion)
• It will stimulate a1 receptors (direct Via
  release of NE) to cause VC leading to increase
  BP and decrease organ perfusion
• So, the high dose of DA is not recommended in
  shock.

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• What is the effect of Dopamine on Bronchioles?
• It has no effect on the bronchioles because
  it doesnt stimulate ß2 receptors (even
  indirectly , because NE does not stimulate ß2
  receptors ).

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Centrally Acting Sympathomimetic Agents e.g 1.
Amphetamine

• It is non-selective adrenergic agonist,
  noncatecholamine
• Acts mainly indirectly via, enhancing NE release
  and DA.
• Since it is non-catecholamine, it can be given
  orally
• It is lipidsoluble enough to be absorbed from
  intestines and goes to all parts including CNS
  (This leads to CNS stimulation like
  Restlessness??? and Insomnia ?????).
• t1/2 45 60 min (long duration of action)
• It is metabolized in the Liver.

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Clinical use of Amphetamine-like drugs

• To suppress appetite
• In very obese persons Amphetamine can act
  centrally on the hunger center in the
  hypothalamus to suppress appetite
• In narcolepsy
• Narcolepsy is irresistible attacks of sleep
  during the day in spite of enough sleep at night
• Amphetamine stimulates the CNS makes the
  patient awake
• In ADHD Attention Deficit Hyperactivity Disease

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Clinical use of Amphetamine-like drugs
(controlled Drugs)

• Note Amphetamine is a drug of abuse, that should
  not be prescribed. However, amphetamine-like
  drugs can be prescribed for the following
  conditions
• In ADHD
• (Methylphenidate, Dexamfetamine)
• In narcolepsy
• (Dexamfetamine and Modafinil)
• To suppress appetite

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AmphetaminesSide effects

• The side effects are due to chronic use
• These include
• Tolerance
• Dependence
• Addiction
• Paranoia (thought process heavily influenced by
  anxiety or fear)
• Psychosis (loss of contact with reality)

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2. Ephedrine

• It is non selective adrenergic agonist
• It
• Directly acts on the receptors (a,b1,and b2) It
  is Like an oral form of Epinephrine.
• Indirectly by releasing NE
• PK almost similar to amphetamine
• It causes tolerance but no addiction
• Like amphetamine, it is CNS and respiratory
  stimulant.
• It does not suppress the appetite

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EphedrineClinical uses

• Pressor agent (used to increase BP)
• Decongestant
• It is no longer used to treated bronchial asthma.
  (because its less potent slow onset of action)

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3. Pseudoephedrine

• Has similar pharmacological activities to
  ephedrine
• It is not controlled OTC (over the counter)
  ???? ???? ???? ????
• It is commonly used as a decongestant.

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4. Phenylpropranolamine

• Again it is similar to pseudoephedrine, and was
  used as decongestant, but it was stopped because
  it may cause cerebral hemorrhage
• Oxymetazoline
• Has a1 and a2 agonistic activity. Used as a
  decongestant.

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Side effects of centrally acting
sympathomimetics

• Sympathomimetic means
• These drugs can produce sympathatic actions
  similar to EP and NE
• They include
• Amphetamine
• Ephedrine
• Pseudo ephedrine
• Phenyl Pro Pranolamine
• They are lipid soluble and can pass BBB to
  cause
• Insomnia
• Restlessness
• Confusion
• Irritability
• Anxiety
• Hypertension

Remember that amphetamine has additional side
effects
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Adrenoreceptor AgonistsSelective drugs

• These drugs include
• Phenyl Ephrine (relatively a1)
• Clonidine (a2)
• Dobutamine (ß1)
• Salbutamol (ß2)
• Ritodrine (ß2)

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Adrenoreceptor Agonists 1. Phenyl Ephrine
(others methoxamine, metaraminol,
mephentermine)

• It is relatively selective a1agonist
• It is directly acting
• PK not-catecholamine and thus not metabolized
  by COMT
• It has longer duration of action than other
  catecholamines

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PhenylephrineClinical uses

• As a mydriatic agent to examine the fundus of the
  eye
• It acts on a1 receptors in the radial dilator
  pupillary muscle
• As a decongestant
• Used as nasal drops to cause VC in the nasal
  blood vessels relief congestion
• As a vasopressor agent in case of hypotension
• a1 stimulation causes VC leading to increase BP
• In case of paroxysmal tachycardia
• It cause VC elevate BP. This stimulate the
  baroreceptors resulting in increased reflex vagal
  discharge which brings the heart into the normal
  sinus rhythm (not in use nowadays)

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Clonidine

• It is a selective a2 agonist
• Mechanism of action (Acts centrally as a
  central sympatholytic drug.)
• Clonidine is Lipid soluble, so, it freely
  passes BBB reaches CNS to stimulate a2
  receptors in medulla and pons causing decreased
  sympathetic tone and finally decrease BP
• It act by it self not like Methyldopa
• Clinical use include
• Treatment of mild to moderate hypertension
• Treatment of morphine withdrawal symptoms
• As analgesic during labour
• The dose 1.25 ug/day
• It can be given I.M
• It can be used in patients with renal failure
  because it dose not affect renal blood flow or
  GFR CO

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Cont.

• Adverse affects of Clonidine
• Depression
• Dizziness, insomnia, nightmares
• Impotence
• Alopecia ????? ?????
• Urticaria
• Weight gain
• Fluid retention
• Sudden withdrawal leads to rebound hypertension

Methyldopa and the comparison between it and
clonidine are in the lecture (adrenergic
antagonists)
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3. Apraclonidine

• Like clonidine it is selective a2 adrenoceptor
  agonist, however, main uses as adjuvant therapy
  for glaucoma via decrease of aqueous humour
  formation.

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Adrenoreceptor Agonists (Cont..)4. Dobutamine

• It is direct acting ß 1 selective agonist
• T1/2 10 15 min
• It is metabolized in the liver by oxidative
  deamination
• There is tolerance to its action
• Given only parenterally (not orally)
• It causes increases in CO with minimal effect on
  HR.(because of the baroreceptor reflex)
• It has less arrhythmogenic effects than dopamine
• Uses Inotropic agent for Heart Failure in
  septic and cardiogenic shock.

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Adrenoreceptor Agonists5. Salbutamol

• It is ß2 selective agonist
• Can be used orally, IV and by inhalation
• Formulations (Tablets Syrup Injection
  solution and Inhalation)
• Clinical Uses
• bronchial asthma by ß2 stimulation, which leads
  to relaxation of bronchial smooth muscle and
  bronchodilation.
• Treatment of refractory hyperkalemia (I.V)
  

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6. Salmetrol and Formoterol

• These selective beta agonists, have longer
  duration of action as compared to Salbutamole.
• Uses As inhalors for bronchial Asthma

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7. Ritodrine

• It is another ß2 selective agonist but
• It is used to delay premature labour
• ß 2 stimulation leads to relaxation of uterine
  smooth muscle leading to delay of labour
• This is done to ensure adequate maturation of
  fetus

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Clinical applications of Sympathomimetic drugs

• In shock
• Type of shock include
• Hypovolamic shock
• Septic shock
• Anaphylactic shock
• Symptoms include
• Congestion in the Lung, Heart Kidney due to VD
  V.Per??
• Bronchoconstriction
• Hypotension
• We use EP with steroid and antihistamine to cause
  
• Bronchodilation
• Increase BP
• Decongestant
• Neurogenic shock
• Cardiogenic shock
• We use DA Dobutamine together
• All type lead to increases in BP??? (I think
  shock is associated with increased BP)