Adrenergic

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Adrenergic Antiadrenergic Drugs

• By Prof. Alhaider

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Adrenergics Antiadrenergics

• Anatomy of the sympathetic nervous system
• Neurotransmission at adrenergic neurons
• Adrenoceptors
• Adrenergic Drugs
• Centrally-acting sympatholytic drugs

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

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Figure 1
p.67 lippin 3rd ed
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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

• Mechanism of action
• Site of a1 adrenoreceptor the effects of
  their stimulation
• Drugs effects at these receptors

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Molecular Mechanism of Action of Sympathomimetics
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a1 adrenoceptors (continue) Site of a1
adrenoceptors the effects of their stimulation

• In vascular smooth muscle.
• a1 stimulation cause VC
• Vasoconstriction in the skin viscera cause
  increase TVR causing increase BP
• a1 adrenoreceptorare 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 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. opposite to ACH
• In the smooth muscle of internal sphincter of
  urinary bladder (Very important).
• a1a subtypes stimulation cause contraction and
  closure of the sphincters (ppt urinary retention)
  opposite to ACH
• 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 adrenoceptors

• Mechanism of action
• Site of a2 adrenoreceptors the effects of
  their stimulation
• Drugs effects at these receptors

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Molecular Mechanism of Action of Sympathomimetics
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a2 adrenoceptorsMechanism of action

• a2 stimulation leads to either
• Decreased adenylyl cyclase activity.
• Lead to decrease cAMP causing decrease NE release
  causing
• relaxation of smooth muscle
• decreased glandular secretion
• Increase K - channel activity.
• This is mediated by the inhibitory regulatory Gi
  protein
• What is the main difference between a1 and a2
  adrenoceptors?

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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). Very
  important effect Why?
• 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.
• Is it good for glaucoma or not?.
• In the smooth muscle of GIT wall. (with ß2)
• a2 stimulation cause relaxation of the wall
  causing decreased peristalsis (This is attributed
  to decrease in ACH release)

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a2 adrenoceptors (Continue)Drugs effects

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

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ß1 adrenoceptors

• Mechanism of action
• Site of ß1 adrenoreceptors the effects of
  their stimulation
• Drugs effects at these receptors

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Molecular Mechanism of Action of Sympathomimetics
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Adrenoceptorsß 1 adrenoceptorsSite of ß 1
adrenoceptors the effects of their stimulation

• In the heart.
• ß 1 stimulation causes
• In S.A node increase 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
• In fat cells (with a1, a2 ß 3)

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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

• Mechanism of action
• Site of ß2 adrenoreceptors the effects of
  their stimulation
• Drugs affecting these receptors

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Molecular Mechanism of Action of Sympathomimetics
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ß 2 adrenoceptorSite of ß 2adrenoceptor
the effects of their stimulation

• In the bronchial smooth muscle (very important
  clinically).
• 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)
• 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
  (opposite to ACH)
• Note Adrenergic stimulation is opposite to the
  cholinergic in the wall and sphincters in GIT and
  GUS.

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Cont.

• In the smooth muscle of the uterus
• ß2 stimulation causes relaxation of the uterus
• So, ß2 agonists
• In the liver.
• ß2 stimulation causes increased Glycogenolysis
  Gluconeogenesis
• In the pancreas.
• ß2 stimulation causes slight increase in insulin
  secretion
• Then, what is the effect of ß2 stimulation on
  blood sugar?
• Effect on potassium .
• ß2 stimulation increase potassium influx. Useful
  Clinically

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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
• Can we use b-adrenergic agonists for glaucoma?

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Adrenoceptorsß 2 adrenoceptorsDrugs affecting
them

• ß 2 selective agonists
• E.g.
• Salbutamol
• 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 c-AMP leading to
  increased intracellular Ca release leading to
  increased contractility
• ß 2 in smooth muscle cause increase cAMP leading
  to inhibition of myosin kinase enzyme causing
  relaxation
• ß 2 in the liver cause increase in cAMP leading
  to increased Glycogen phosphorylase enzyme
  activity causing increased glycogenolysis

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ß 3 adrenoceptors

• Site of ß 3 adrenoceptors the effects of
  their stimulation
• Drugs affecting them
• Mechanism of action

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Adrenoceptorsß 3 adrenoceptorsSite of ß 3
adrenoceptors the effects of their stimulation

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

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Adrenoceptorsß 3 adrenoceptorsDrugs affecting
them

• 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

• These drugs include
• 1) Catecholamine Drugs
• A. endogenous
• Norepinephrine
• Epinephrine
• Dopamine
• b) Synthetic (exogenous)
• Isoprenaline
• 2) Non-catecholamine Drugs
• Amphetamine
• Ephedrine
• Pseudo ephedrine
• Phenylpropranolamine
• What are the differences between catechoamines
  and non-catecholamines?

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Norepinephrine (Noradrenaline)

• Introduction
• Synthesis
• Metabolism of NE
• Pharmacokinetics

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NorepinephrineIntroduction

• 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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Figure 1
p.67 lippin 3rd ed
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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 SBP DBP
• So, in shock, it will increase BP
• Why NE cannot be given orally?

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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 (Adrenaline)

• Introduction
• Synthesis (Methylated form of NE)
• Therapeutic uses

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P.70 lippin 3rd edi
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EpinephrineIntroduction

• 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
• Does PK of Epinephrine different from NE?

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EpinephrineTherapeutic use

• 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 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
• What are the main differences between Epinephrine
  and NE?

b
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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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Iso pre naline

• Introduction
• Actions
• Therapeutic uses

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Iso pre nalineIntroduction

• 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)
• It has no effects on a receptors

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P.75 lippin 3rd.ed.
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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
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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

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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?

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Centrally Acting Sympathomimetic Agents e.g 1.
Amphetamine

• Introduction
• Clinical uses
• Side effects

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AmphetamineIntroduction

• It is non-selective adrenergic agonist,
  non-catecholamine
• 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 make 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 Attention Deficit Hyperactivity Disease
• (Methylphenidate, Dexamfetamine)
• In narcolepsy
• Narcolepsy is irresistible attacks of sleep
  during the day in spite of enough sleep at night
• Amphetamine-like drugs stimulats the CNS make
  the patient awake (Dexamfetamine and Modafinil)
• To suppress appetite
• In very obese persons Amphetamine can act
  centrally on the hunger center in the
  hypothalamus to suppress appetite (Considers as
  obsolete use)

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AmphetaminesSide effects

• The side effects are due to chronic use
• These include
• Tolerance
• Dependence
• Addiction
• Paranoia ???? ??????
• Psychosis ?????? ???????
• Hypertension

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2. Ephedrine

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

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EphedrineClinical uses

• Pressor agent
• Decongestant
• It is no longer used to treated bronchial asthma.
  Why?

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3. Pseudoephedrine

• Has similar pharmacological activities to
  ephedrine
• It is not controlled OTC (over the counter)
  ???? ???? ???? ????

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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

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Side effects of centrally acting
sympathomimetics

• Sympathomimetic means
• These drugs can produce sympathatic actions
  similar to EP and Nor EP
• They include
• Amphetamine
• Ephedrine
• Pseudo ephedrine
• Phenyl Pro Pranolamine
• They are lipid soluble and can pass BBB to
  cause
• Insomnia
• Restlessness
• Confusion
• Irritability
• Anxiety
• Loss of appetite
• Hypertension
• Amphetamine has additional side effect see slide
  57

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Adrenoreceptor AgonistSelective drugs

• These drugs include
• Phenyl Ephrine relatively a1 agonist
• Clonidine a2 agonist
• Dobutamine ß 1 agonist
• Salbutamol ß 2 agonist
• Ritodrine ß 2 agonist

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

• Introduction
• Metabolism
• Clinical uses

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Adrenoreceptor Agonists 1. Phenyl Ephrine

• 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
• Uses see next

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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 used any more)

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Adrenoreceptor Agonists (Cont)2. Clonidine

• It is a2 selective agonist
• However, this is sympatholytic agent,
• used in treatment of hypertension
• It acts centrally at presynaptic a2-adrenoceptor.
  This leads to decrease in NE release and to
  decrease in TVR.
• Note Although it is adrenergic agonist,
  clonidine acts as a central sympatholytic drug.

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• 3. Apraclonidine (Like clonidine it is selective
  alpha 2 adrenoceptor agonist, however, main uses
  as adjuvant therapy for glaucoma via decrease of
  aqueous humor
• formatiom
• What is methyldopa and does it differ from
  clonidine?

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Adrenoreceptor Agonists (Cont..)4. Dobutamine

• It is direct acting ß 1 selective agonist
  (only)
• 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. Why?
• It has less arrhythmogenic effects than dopamine
• Uses Inotropic agent for Heart Failure in
  septic and cardiogenic shock.
• Can you make comparison between Dopamine and
  Dobutamine?

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Adrenoreceptor Agonists5. Salbutamol

• It is ß2 selective agonist
• Can be used orally, IV and by inhalation
• Clinical Uses
• Formulations (Tablets Syrup Injection
  solution and Inhalation)
• 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 B. Asthma

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Adrenoreceptor Agonist 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
  foetus

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Adrenoreceptor AgonistsSide effects of
sympathomimetic drugs

• On the CVS
• Hypertension
• Cardiac arrhythmia
• Myocardial infarction
• Increased severity of angina pectoris and of
  myocardial infarction
• On the eye
• Increased I.O.P leading to Glaucoma
• On the CNS
• See slide 64

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Glaucoma

• a disease of the eye characterized by increased
  intraocular pressure and excavation and atrophy
  of the optic nerve produces defects in the
  visual field and may result in blindness.

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Clinical applications of Sympathomimetic drugs

• In hypotension
• we use Phenyl Ephrine
• 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

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Cont.

• To reduce BF in certain organs
• We use Adrenaline with local anesthetic for minor
  surgery in order to
• Decrease bleeding
• Prevent spread of local anesthetic into systemic
  circulation
• In paroxysmal tachycardia
• In bronchial asthma
• In cardiac arrest
• For mydriasis
• For delaying of labor
• For hyper kinetic children syndrome
• For narcolepsy

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Adrenoreceptor Antagonists

• a blockers
• Non selective
• Relatively selective
• Selective
• ß blockers
• Non selective
• Relatively selective
• Selective