Adrenergic & Antiadrenergic Drugs

By Prof. Alhaider

Adrenergics & Antiadrenergics

Anatomy of the sympathetic nervous system

Neurotransmission at adrenergic neurons

Adrenoceptors Adrenergic Drugs Centrally-acting sympatholytic drugs

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

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

Adrenoceptors The adrenergic receptors are

classified into α1 α2 β1 β2 β3

There are some subtypes

α1– Adrenoceptors

Mechanism of action Site of α1 – adrenoreceptor & the

effects of their stimulation Drugs effects at these receptors

Molecular Mechanism of Action of Sympathomimetics

α1– adrenoceptors (continue)

Site of α1– adrenoceptors & the effects of their stimulation

In vascular smooth muscle. α1 stimulation cause VC :

Vasoconstriction in the skin & viscera cause increase TVR causing increase BP α1 – 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 α1

Vasoconstriction in the nasal blood vessels cause relief congestion

In the radial muscle of iris. α1 stimulation causes contraction of the radial

muscle causing mydriasis (dilation of the pupil)

Cont…. In the smooth muscle of the sphincters of GIT.

α1 stimulation cause contraction of all sphincters. opposite to ACH

In the smooth muscle of internal sphincter of urinary bladder (Very important). α1a subtypes stimulation cause contraction and closure of the sphincters (ppt urinary retention) opposite to ACH

In the seminal vesicles. (with α2) α stimulation cause ejaculation. Thus, all α blockers

inhibit ejaculation In the liver.

α1 stimulation causes increase glycogenolysis & gluconeogenesis

In the fat cells. α1 stimulation causes increased lipolysis

Adrenoceptorsα 1 – adrenoceptorsDrugs effects :

α1 selective agonist E.g.

Phenyl ephrine

α1 selective antagonists E.g.

Prazosin Terazosin Doxazosin Tamsolusin ( α1a) (has a different clinical

use)

α2 – adrenoceptors

Mechanism of action Site of α2– adrenoreceptors & the

effects of their stimulation Drugs effects at these receptors

Molecular Mechanism of Action of Sympathomimetics

α2– adrenoceptors

Mechanism of action

α2 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 α1 and α2 adrenoceptors?

α2–adrenoceptorsSite of α2– adrenoceptors & the effects of their stimulation

In adrenergic nerve terminals (presynaptic). α2 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 α1– adrenoceptors)

Fat cells (same as α1– adrenoceptors).

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 β2)

α2 stimulation cause relaxation of the wall causing decreased peristalsis (This is attributed to decrease in ACH release)

α2– adrenoceptors (Continue)

Drugs effects :

α2 selective agonists E.g.

Clonidine; Methyldopa (Antihypertensive)

α2 selective antagonists E.g.

Yohimbine; Mertazapine (Antidepressant) Apraclonidine (Topical for Eye)

β1 – adrenoceptors

Mechanism of action Site of β1– adrenoreceptors & the

effects of their stimulation Drugs effects at these receptors

Molecular Mechanism of Action of Sympathomimetics

Adrenoceptorsβ 1 – adrenoceptorsSite of β 1 – adrenoceptors & the effects of their stimulation

In the heart. β 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. β 1 stimulation cause increased renin release.

Then causes increase in BP In fat cells (with α1, α2 & β 3)

β 1 stimulation causes increased Lipolysis In fat cells (with α1, α2 & β 3)

Adrenoceptorsβ 1 – adrenoceptorDrugs affecting them

β 1 selective agonists E.g.

Dobutamine

β 1 selective antagonists E.g.

Atenolol Esmolol Metoprolol

β2 – adrenoceptors

Mechanism of action Site of β2– adrenoreceptors & the

effects of their stimulation Drugs affecting these receptors

Molecular Mechanism of Action of Sympathomimetics

β 2 – adrenoceptorSite of β 2–adrenoceptor & the effects of their stimulation

In the bronchial smooth muscle (very important clinically). β2 stimulation causes relaxation of

smooth muscle (bronchodilatation) In the smooth muscle of blood vessels

supplying the skeletal muscle. β2 stimulation causes relaxation of

smooth muscle (Vasodilatation) This VD effects is usually masked by the

potent VC effect of α1 – receptors

Cont…. In the smooth muscle of GIT wall.

β2 stimulation cause relaxation of the wall leading to decreased peristalsis

In the smooth muscle of the wall of urinary bladder. β 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.

Cont…. In the smooth muscle of the uterus

β2 stimulation causes relaxation of the uterus

So, β2 agonists In the liver.

β2 stimulation causes increased Glycogenolysis & Gluconeogenesis

In the pancreas. β2 stimulation causes slight increase in insulin

secretionThen, what is the effect of β2 stimulation on blood sugar?

Effect on potassium . β2 stimulation increase potassium influx. Useful

Clinically

Cont…. In ciliary muscle.

β2 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 β2 stimulation causes

increased production of aqueous humor

Can we use b-adrenergic agonists for glaucoma?

Adrenoceptorsβ 2 – adrenoceptorsDrugs affecting them

β 2 selective agonists E.g.

Salbutamol Salmetrol Terbutaline Ritodrine Formetrol

β 2 selective antagonists E.g.

ICI118551 (still under investigation)

1 and 2 – adrenoceptor agonistsMechanism of action

β stimulation causes increase adneylyl cyclase activity leading to increase cAMP leading to cellular effect. E.g. β 1 in the heart cause increase c-AMP leading

to increased intracellular Ca++ release leading to increased contractility

β 2 in smooth muscle cause increase cAMP leading to inhibition of myosin kinase enzyme causing relaxation

β 2 in the liver cause increase in cAMP leading to increased Glycogen phosphorylase enzyme activity causing increased glycogenolysis

β 3 – adrenoceptors

Site of β 3 – adrenoceptors & the effects of their stimulation

Drugs affecting them Mechanism of action

Adrenoceptorsβ 3– adrenoceptorsSite of β 3 – adrenoceptors & the effects of their stimulation

In brown adipose tissue β 3 stimulation causes increased

Lipolysis

Adrenoceptorsβ 3– adrenoceptorsDrugs affecting them

β 3 selective agonist E.g.

BRL 37344

β 3 selective antagonist E.g.

CGP 20712A

Adrenergic Drugs

Adrenoreceptor Agonists Non selective Selective

Adrenoreceptor Antagonists α– blockers β– blockers

Adrenoceptor AgonistsI. Non selective drugs

These drugs include 1) Catecholamine Drugs

A. endogenous: Norepinephrine Epinephrine Dopamineb) Synthetic (exogenous) Isoprenaline

2) Non-catecholamine Drugs Amphetamine Ephedrine Pseudo ephedrine Phenylpropranolamine What are the differences between

catechoamines and non-catecholamines?

Norepinephrine (Noradrenaline)

Introduction Synthesis Metabolism of NE Pharmacokinetics

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 non–selective adrenergic agonist which acts on all adrenoceptors, Except β2

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Figure 1

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

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?

Clinical Uses: Note: NE is not commonly used in

clinical practice like Epinephrine, However it can be used in: Cardiac Arrest Shock

Epinephrine (Adrenaline)

Introduction Synthesis (Methylated form of NE) Therapeutic uses

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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 β2 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?

EpinephrineTherapeutic use

Epinephrine is commonly used in practice as compared to NE.

In bronchial asthma It is given SC to act on β2 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 α1 cause VC, lead to increase BP & relief of congestion β 1 cause increase HR leading to increase CO, so, increase

BP β 2 cause bronchodilation so, relieve bronchospasm

What are the main differences between Epinephrine and NE?

b

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

Iso pre naline

Introduction Actions Therapeutic uses

Iso pre nalineIntroduction

It is directly acting synthetic adrenoreceptor agonist acting only on β–receptors, with no effects on 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

Iso pre nalineAction

Isoprenaline will stimulate β1 in the heart to cause

Increased HR & cause arrhythmia & may lead to cardiac arrest

β2 in the blood vessels to cause VD leads to decreased BP (mainly DBP)

It has no effects on α receptors

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IsoprenalineTherapeutic uses: It is no longer used to treat the bronchial asthma

because of it’s side effects on the heart It’s only used now to reverse the heart block which is

produced by overdoses of β – blockers

N.B. cardiac arrest means : complete cessation of heart’s activity. While heart block means : partial or complete inhibition of the spread of conduction of the electrical impulse from the atria to the ventricles

Effects of I.V. infusion of Epinephrine, Norepinephrine & Isoprenaline in

Humans

Dopamine

DA is a non–selective adrenergic agonist, which acts either directly on DA – receptors in addition to 1- adrenergic receptors or indirectly by releasing NE

Like all catecholamines, It is given parenterally only (not orally)

It doesn’t cause tolerance T1/2 = 3 – 5 min Metabolized by either

Converted to NE in adrenergic neurons or By MAO in the Liver

Dopamine (Cont…) Clinical Uses :

In small dose of DA (=< 5ug / Kg / min by I.V infusion) Renal dose: It will stimulate DA–receptors 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 α1–receptors

Cont…. In medium dose : (5-15ug/Kg/min by I.V infusion)

Cardiac dose It will stimulate β1 – receptors to cause increase

HR, CO and BP In high dose of DA (> 15ug / Kg / min by I.V

infusion) It will stimulate α1 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.

What is the effect of Dopamine on Bronchioles?

Centrally Acting Sympathomimetic Agents: e.g: 1. Amphetamine

Introduction Clinical uses Side – effects

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 lipid–soluble 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

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”

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)

AmphetaminesSide effects

The side effects are due to chronic use These include :

Tolerance Dependence Addiction Paranoia العظمة جنون Psychosis الشخصية انفصام Hypertension

2. Ephedrine

It is non selective adrenergic agonist It

Directly acts on the receptors (and 2)

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?

EphedrineClinical uses:

Pressor agent Decongestant It is no longer used to treated

bronchial asthma. Why?

3. Pseudoephedrine:

Has similar pharmacological activities to ephedrine

It is not controlled : OTC (over the counter) طبية وصفة بدون يباع

4. Phenylpropranolamine:

Again it is similar to pseudoephedrine, and was used as decongestant, but it was stopped because it may cause cerebral hemorrhage

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

Adrenoreceptor AgonistSelective drugs

These drugs include : Phenyl Ephrine relatively α1 – agonist Clonidine α2 – agonist Dobutamine β 1 –

agonist Salbutamol β 2 –

agonist Ritodrine β 2 –

agonist

Adrenoreceptor Agonists

1. Phenyl Ephrine (others: methoxamine, metaraminol, mephentermine

Introduction Metabolism Clinical uses

Adrenoreceptor Agonists

1. Phenyl Ephrine

It is relatively selective α1–agonist 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

PhenylephrineClinical uses: As a mydriatic agent to examine the fundus of the eye

It acts on α1 – 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

α1 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)

Adrenoreceptor Agonists (Cont…)

2. Clonidine:

It is α2 – selective agonist However, this is sympatholytic

agent, used in treatment of hypertension It acts centrally at presynaptic α2-

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.

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?

Adrenoreceptor Agonists (Cont..)4. Dobutamine:

It is direct acting β 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?

Adrenoreceptor Agonists5. Salbutamol:

It is β2 – selective agonist Can be used orally, IV and by inhalation Clinical Uses Formulations: (Tablets; Syrup;

Injection; solution and Inhalation) bronchial asthma by β2 stimulation, which

leads to relaxation of bronchial smooth muscle and bronchodilation.

Treatment of refractory hyperkalemia (I.V)

6 Salmetrol and Formoterol:

These selective beta agonists, have longer duration of action as compared to Salbutamole.

Uses: As inhalors for B. Asthma

Adrenoreceptor Agonist

7. Ritodrine:

It is another β2 – selective agonist but It is used to delay premature labour

β 2 stimulation leads to relaxation of uterine smooth muscle leading to delay of labour This is done to ensure adequate maturation

of foetus

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

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.

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

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

Adrenoreceptor Antagonists α– blockers

Non selective Relatively selective Selective

β– blockers Non selective Relatively selective Selective