Adrenergic & Antiadrenergic Drugs By Prof. Alhaider

Adrenoceptors  The adrenergic receptors are classified into α1 α2 β1 β2 β3  There are some subtypes

α 1 – Adrenoceptors

α 1 – adrenoceptors (continue) Site of α 1 – adrenoceptors & the effects of their stimulation  In vascular smooth muscle. α 1 stimulation cause vasoconstriction (VC) :  Vasoconstriction in the skin & viscera cause increase total vascular resistance (TVR) causing increase blood pressure (BP) hypertension may be treated by blocking α1  Vasoconstriction in the nasal blood vessels cause relief of congestion α1 muscle causes mydriasis (dilation of the pupil)

Cont …. α1 stimulation cause contraction of all sphincters α 1a subtypes stimulation cause contraction and closure of the sphincters (precipitate urinary retention)  In the seminal vesicles. (with α 2 ) 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

Adrenoceptors α 1 – adrenoceptors Drugs effects :  α 1 selective agonist E.g.  Phenyl ephrine  α1 selective antagonists E.g.  Prazosin  Terazosin  Doxazosin  Tamsolusin ( α1 a ) (has a different clinical use)

α 2 – adrenoceptors Mechanism of action  α 2 stimulation leads to either Decreased adenylyl cyclase activity( mediated by the inhibitory regulatory G i protein)  Lead to decrease cAMP causing decrease NE release causing relaxation of smooth muscle & decreased glandular secretion Increase K+ - channel activity. ???? So α 1 receptors are stimulatory while α 2 receptors are inhibitory

α 2 – adrenoceptors Site of α 2 – adrenoceptors & the effects of their stimulation α 2 stimulation cause decreased Norepinephrine release (autoregulatory mechanism causes decreased insulin release Increase platelets aggregation via c-AMP  In liver (same as α 1 – adrenoceptors)  Fat cells (same as α 1 – adrenoceptors).

Cont …  In ciliary epithelium. Increase the out flow of aqueous humor.(good for glaucoma) In the smooth muscle of GIT wall. (with β 2 ) α 2 stimulation cause relaxation of the wall causing decreased peristalsis (indirectly by reducing the release of ACH)

α 2 – adrenoceptors (Continue) Drugs effects :  α 2 selective agonists E.g.  Clonidine  Methyldopa (Antihypertensive)  Apraclonidine (topical for eye)  α 2 selective antagonists E.g.  Yohimbine; Mertazapine (Antidepressant)

β 1 – adrenoceptors  In the heart. β 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. 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

Adrenoceptors β 1 – adrenoceptor Drugs affecting them  β 1 selective agonists E.g.  Dobutamine  β 1 selective antagonists E.g.  Atenolol  Esmolol  Metoprolol

β 2 – adrenoceptors  In the bronchial smooth muscle (bronchodilatation)  In the smooth muscle of blood vessels supplying the skeletal muscle. Vasodilatation(VD)

Cont ….  In the smooth muscle of GIT wall. 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 Note: Adrenergic stimulation is opposite to the cholinergic in the wall and sphincters in GIT and genitourinary tract.

Cont ….  In the smooth muscle of the uterus relaxation of the uterus  In the liver. β 2 stimulation causes increased Glycogenolysis & Gluconeogenesis  In the pancreas. β 2 stimulation causes slight increase in insulin secretion (hypoglycemia)  Effect on potassium. β 2 stimulation increase potassium influx.

Cont ….  In ciliary muscle. β 2 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 β 2 stimulation causes increased production of aqueous humor

Adrenoceptors β 2 – adrenoceptors Drugs affecting them  β 2 selective agonists E.g.  Salbutamol (asthma + ref heperkalemia)  Salmetrol  Terbutaline  Ritodrine  Formetrol  β 2 selective antagonists E.g.  ICI (still under investigation)

Adrenergic Drugs  Adrenoreceptor Agonists Non selective Selective  Adrenoreceptor Antagonists α – blockers β – blockers

Adrenoceptor Agonists I. 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 noncatecolamine s catecholamines Low potencyHigh potency Long t 1/2 Short t 1/2 Given orallyGiven parenterally Non polarpolar Not inactivated by COMT Inactivated by COMT

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

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  T 1/2 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

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

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 β 2 receptor.  T 1/2 = 2 – 5 min  Like NE, It is given parenterally (SC, I.V and I.M) not orally  Has the same pharmacokinetics as NE

Epinephrine Therapeutic 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 cardiac output (CO)  In anaphylactic shock b

Cont …  In cardiac arrest (for Bradycardia)  During surgery EP is added to the local anesthetic to cause VC in the surgery

Iso pre naline  It is directly acting synthetic adrenoreceptor agonist acting only on β – receptors, with no effects on  adrenoceptos.  T 1/2 = 5 – 7 min  Like all catecholamines, It is given parenterally (not orally)

Iso pre naline Action  Isoprenaline will stimulate β 1 in the heart to cause  Increased HR & cause arrhythmia & may lead to cardiac arrest β 2 in the blood vessels to cause  VD leads to decreased BP (mainly DBP)

Isoprenaline Therapeutic 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

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  T 1/2 = 3 – 5 min  Metabolized by either Converted to NE in adrenergic neurons or By MAO in the Liver

 What is the effect of Dopamine on Bronchioles? no effect

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 lipid – soluble enough to be absorbed from intestines and goes to all parts including CNS (This leads to CNS stimulation like Restlessness قلق and Insomnia الارق ). t 1/2 = 45 – 60 min (long duration of action) It is metabolized in the Liver.

Clinical use of Amphetamine-like drugs  To suppress appetite  In narcolepsy  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 (Methylphenidate, Dexamfetamine)  In narcolepsy (Dexamfetamine and Modafinil)  To suppress appetite

Amphetamines Side 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)

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 stimulant. It does not suppress the appetite

Ephedrine Clinical uses:  Pressor agent (used to increase BP)  Decongestant  It is no longer used to treated bronchial asthma. (because it’s less potent + slow onset of action)

3. Pseudoephedrine:  Has similar pharmacological activities to ephedrine  It is not controlled : OTC (over the counter) يباع بدون وصفة طبية  It is commonly used as a decongestant.

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 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

Adrenoreceptor Agonists Selective drugs  These drugs include : Phenyl Ephrine (relatively α1) Clonidine (α2) Dobutamine (β1) Salbutamol (β2) Ritodrine (β2)

Adrenoreceptor Agonists 1. Phenyl Ephrine (others: methoxamine, metaraminol, mephentermine )  It is relatively selective α 1 – agonist  It is directly acting  PK: not-catecholamine and thus not metabolized by COMT  It has longer duration of action than other catecholamines

Phenylephrine Clinical uses:  As a mydriatic agent to examine the fundus of the eye  As a decongestant  As a vasopressor agent in case of hypotension

Clonidine:  It is a selective α2 – agonist  Mechanism of action : (Acts centrally as a central sympatholytic drug.) Cloni dine is Lipid – soluble, so, it freely passes BBB & reaches CNS to stimulate α2 – 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  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

Cont ….  Adverse affects Depression Dizziness, insomnia, & nightmares Impotence Alopecia تساقط الشعر Urticaria Weight gain Fluid retention Sudden withdrawal leads to rebound hypertension

3. Apraclonidine  Like clonidine it is selective α2 adrenoceptor agonist, however, main uses as adjuvant therapy for glaucoma via decrease of aqueous humour formation.

Adrenoreceptor Agonists (Cont..) 4. Dobutamine:  It is direct acting β 1 – selective agonist  T 1/2 = 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.

Adrenoreceptor Agonists 5. Salbutamol:  It is β 2 – selective agonist  Can be used orally, IV and by inhalation  Clinical Uses bronchial asthma by β 2 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 bronchial Asthma

7. Ritodrine:  It is another β2 – selective agonist but  It is used to delay premature labour

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)