PHARMACOLOGY Lecture: Adrenergic drugs

OBJECTIVES: •Identify the classification of adrenergic agonists •Describe pharmacokinetics and dynamics of adrenergic agonists • Differentiate between the actions of a and b-adrenoceptors agonists • List the clinical uses of adrenergic agonists. • know adverse effects & contraindications of adrenergic agonists • Identify one specific adrenergic agonist for each of the following special uses: Hypotensive states, shock, heart failure, heart decompensation, asthma, premature labour…ect..

Terminology: Chronotropic = increase cardiac output Inotropic = increase cardiac force of contraction Dromotropic = increase conduction velocity Tocolytics (anti-contraction) are medications used to suppress premature labor. Extravasation: leakage of drug from the vessel into tissues surrounding the injection site Adrenaline = epinephrine (E) Noradrenaline (NA) = norepinephrine (NE) . Important. . Extra notes.

Neurotransmission at adrenergic neurons

Adrenergic transmission: Note: Adrenergic neurons 1) Synthesis of norepinephrine release norepinephrine as the 2) Storage of norepinephrine in vesicles primary neurotransmitter. 3) Release of norepinephrine 4) Binding to post synaptic receptors 5) Ending the action of NE by: • Neuronal reuptake into neuron • Monoamine oxidase (MAO) in neuronal mitochondria • Catechol -O-methyl transferase (COMT) in synaptic space

Adrenergic receptors

Adrenergic receptors

Dopaminergic a- b- adrenoceptors adrenoceptors receptors

a1 a2 b1 b2 b3 e.g. D1

α1 β2 β1 β3 Post-synaptic excitatory in function (cause inhibitory in function excitatory in In adipose contraction) except in GIT. (cause relaxation) function, present tissue mainly in heart Present mainly in smooth muscles. Contraction of pregnant Relaxation of the uterus (Delay ↑ heart rate: ↑ lipolysis uterus. premature labor) + chronotropic ↑ free effect, Tachycardia fatty acids. Vasoconstriction of skin & Relaxation of skeletal & peripheral blood vessels coronary blood vessels ↑ force of →increased peripheral (vasodilatation) contraction : resistance → hypertension. + inotropic effect Relaxation of GIT muscles & urinary bladder’s muscles. Contraction of GIT sphincter (constipation) & urinary bladder’s ↑ conduction sphincter (urinary retention). velocity: + dromotropic Contraction of radial muscle • Relaxation of bronchial effect of eye causes active mydriasis smooth muscles

• Tremor of skeletal muscles ↑ blood pressure • ↑ lipolysis

Increase blood glucose level (hyperglycemia) , by: ↑ renin release Renin is an enzyme • insulin •↑ glucagon release from involved in the production • ↑ glycogenolysis pancreas of angiotensin II, a potent •↑ liver & muscle glycogenolysis vasoconstrictor.

α2 β2

Pre-synaptic Inhibition of norepinephrine release Increase release of NE (negative feed back mechanism). (Positive feed back mechanism).

Adrenergic agonist:

Adrenergic agonist “sympathomimetics” : Drugs that produce an effect similar to that obtained by stimulation of the sympathetic nervous system.

Sympathetic actions:  Mydriasis (dilatation of eye pupil)  Increase heart rate.  Bronchodilation  Inhibit peristalsis of GIT and secretion.  Relaxation of GIT muscles (constipation).  Relaxation of urinary bladder.  Relaxation of the uterus (Delay premature labor)  Increase conversion of glycogen to glucose (hyperglycemia)

Major effects mediated by α- and β-adrenoceptors:

Classification of Adrenergic agonist:

They are classified according to: 1. Chemistry: Catecholamines Non-Catecholamines Rapidly acting Delayed action Have short half-life, due to rapid degradation by Have Long half-life, because they resist MAO & COMT degradation by MOA &COMT in GIT Have catechol ring Lack catechol ring water soluble (polar) ,thus not effective orally Lipid soluble , thus Effective orally and Cross BBB and have Poor penetration to CNS well , have Prominent CNS effects Parenterally administered Orally administered e.g. Natural: NE, E, Dopamine e.g. Ephedrine, amphetamine, phenylephrine, Synthetic: Isoprenaline, dobutamine methoxamine, salbutamol, ritoderine 2. Mode of action:

Direct Indirect Dual

• Stimulate adrenergic • Stimulate adrenergic • Direct and indirect receptors directly receptors by: stimulation of adrenergic e.g. adrenaline, •  NE release from receptors (mixed) noradrenaline, dopamine, presynaptic adrenergic • e.g. ephedrine, isoprenaline, nerve endings. pseudoephedrine phenylephrine, clonidine, e.g. amphetamine dobutamine, salbutamol, • Inhibit uptake of NE  its methoxamine, naphazoline availability in synapse. e.g. Cocaine & antidepressants

3. Spectrum of action:

Non-Selective Selective

•Norepinephrine (a1; a2; B1 ) a1; Phenylephrine

• Epinephrine (a1; a2;b1 ; b2; b3) a2; Clonidine, Brimonidine

• Dopamine (D1; a1; B1 ) b1; Dobutamine • Isoprenaline (B1 ; b2; b3) b2; Salbutamol, Terbutaline, • Ephedrine (a ; b) Ritoderine

Direct acting adrenergic agonists

ADRENALINE

Receptor Non-selective a1; a2; (predominate at high doses ) B1 ; b2; b3 (At low doses) Overview Natural catecholamine. It has fast onset & Short duration of action. Given I.V, S.C, inhalation, topically. Admin. Not effective orally (inactivated by intestinal enzymes), since it’s a catecholamine

Heart inotropic, chronotropic, dromotropic (excitability) (b1) Blood pressure  systolic (b ) • 1  diastolic • high dose stimulates a1  Hypertension • low dose stimulates b2  Hypotension

Vascular SMC constrict skin + peripheral (a1) dilate coronary + skeletal (b2)

Non vascular • Lung  bronchiodilatation (b2) •   (b ) (a Action SMC; GIT motility 2 / contract sphincter 1) • Bladder   detrusor “smooth muscle found in the wall of the

bladder” (b2) / contract trigone & sphincter (a1) • Pregnant uterus  tocolytic action (anti-contraction) (b2) • Eye  active mydriasis (a1), no effect on accommodation

Metabolism insulin (a1) , glucagon (b2)  liver glycogenolysis + sk. m. glycolysis (b2)  adipose lipolysis (b3 /b2)

CNS little, headache, tremors & restlessness (CNS effects ‘re not very prominent)

- as haemostatic (control bleeding) (a1): Nasal pack in epistaxis and in dental practice - combined with local anesthetics to  absorption & side effects of local anesthetics

+ ↑duration of action +  bleeding from incision locally: locally: • In acute asthma. Given S.C. or by inhalation in emergency to produce bronchodilatation Indication (b2) + mucosal edema (due to vasoconstriction by a1) . Note: Selective b2 are better • Drug of choice in Anaphylactic shock (Hypersensitivity reactions), given S.C. it is the physiological antagonist of histamine. Effects:  BP & bronchodilation.

• Cardiac arrest (I.V). to restore cardiac rhythm in patients with cardiac arrest. Systemically: -Tachycardia, palpitation, arrhythmias, angina pains. - Headache, weakness, tremors, anxiety and restlessness. ADRs - Hypertension  cerebral hemorrhage and pulmonary edema. - Coldness of extremities  tissue necrosis and gangrene if extravasation - Nasal stuffiness & rebound congestion if used as decongestant - Congestive heart disease (CHD), hypertension, peripheral arterial disease. Contraindi - Hyperthyroidism. Thyroxine causes CVS abnormalities, adrenaline will therefore make it worse. cations - Ischemic heart disease (angina), Arrhythmia & Myocardial infarction - Closed-angle glaucoma: ciliary relaxation (due to mydriasis)  filtration angle   IOP

Direct acting adrenergic agonists

NORADRENALINE Isoprenaline A naturel catecholamine, non-selective agonist • Synthetic direct acting catecholamine Overview Adrenergic neurons release • show no presynaptic uptake nor norepinephrine as the primary breakdown by MAO which lead to neurotransmitter. longer action.

only administered by I.V , • Used mainly in cardiac arrest may cause necrosis using IM or SC (Parenteral). Adminis- • Rarely in acute attack of asthma (inhalation). mainly on α adrenoceptors (α1, α2, β1, non-selective b agonist Receptor weak action on β2). It Acts on β1, β2, β3 • Severe vasoconstriction (α1). Note: Norepinephrine causes greater β1 vasoconstriction than epinephrine, • + inotropic effect, because it does not induce compensatory • + chronotropic effect vasodilation via β2 receptors on blood • increase cardiac output (CO). vessels supplying skeletal muscles. The weak β2 activity of norepinephrine also β2 Pharmacologi explains why it is not useful in the • Vasodilatation of blood vessels of treatment of asthma or anaphylaxis. skeletal muscles and coronaries. cal actions • Bronchodilatation . •  BP [ systolic & diastolic]. this stimulates the baroreceptors, inducing a rise in vagal • Relaxation of uterus. activity (parasympathatic system)  • Hyperglycemia reflex bradycardia • Increase force of contraction β1 but β3 decrease H.R. (CO not much changed) lipolysis

Topically: as a local haemostatic with local anesthetic to reduce tachycardia & Uses: irritability, but as side effect, may produce • Used mainly in cardiac arrest necrosis & sloughing of the skin. (Parenteral). Systemically: hypotensive states : • Rarely in acute attack of asthma for - in spinal anesthesia (Hypotension (Spinal indications bronchodilation (inhalation). shock) – commonly occurs due to Contraindications: sympathetic nervous system blockade) In hyperthyroidism & Congestive heart - in septic shock (hypotension) if fluid disease replacement and inotropics fail

Direct acting adrenergic agonists

DOPAMINE DOBUTAMINE Phenylephrine • Synthetic • Synthetic non - Natural catecholamine & CNS catecholamine catecholamine transmitter. • Overview • Metabolized by has prolonged duration -Released from postganglionic Not COMT, thus has a of action, since it’s adrenergic fibres inactivated by COMT short duration Administration Given parentally by infusion IV Orally

Receptor D1 > b1 > a1 (in order) Selective b1–agonist. selective a1 • On heart: D1: Low dose • Myadritic action (a ) +ve Inotropic with 1 • vasodilatation of mesenteric, •  increased both little chronotropic coronary, renal blood systolic & diastolic effect. as it vessels. Thus improves blood pressure increases cardiac blood flow to viscera (hypertension) due to output, with little • diuresis (increase excretion vasoconstriction (a ) increase in heart 1 of urine) Increased blood flow • reflex Bradycardia due to the kidney enhances the rate to  BP Pharmacologic glomerular filtration rate and • On BP: Hardly any

al actions causes diuresis. effect; β1 & β2 Adverse effects: • Decrease BP counterbalance + Hypertension. β1: intermediate dose no α1 Thus, another drug is more • +ve inotropic • No vasodilatation of preferable to produce • +ve chronotropic effects renal blood vessels. hypertension that doesn’t • Increase BP (No effect on last for long. This drug is α1: high dose dopaminergic Midodrine. It peaks in 20 • Vasoconstriction receptors ) min, duration 30 min only. • hypertension - Drug of choice in treatment • Given parentally by - systemically: of shocks (hypotension); septic, infusion for short Vasopressor agent in Hypovolemic (after fluid term management hypotension & terminates replacement), cardiogenic. of Cardiac atrial tachycardia by its It increases the BP by β1 decompensation reflex bradycardia action. receptor but without causing after cardiac -Topically: renal impairment (D1) surgery, in acute • Haemostatic, with Local indications -so it’s preferred to be used in myocardial anesthesia. shocks, because it protects the infarction • Mydriatic (in kidney from renal failure which (AMI) & heart ophthalmic solutions to could be caused by failure [AHF]. facilitate eye vasoconstriction- • It does not increase examination) - Can be given in acute heart oxygen demand • Nasal decongestant failure (HF) but Dobutamine is which made it topically, nasal drops in better. preferred. allergic rhinitis, cold

Direct acting adrenergic agonists

Clonidine Brimonidine Salbutamol Terbutaline Ritordine

Over- Synthetic Synthetic Imidazoline view Imidazoline non catecholamines

Orally, Administ Orally or Orally or patch inhalation or ration injection parentral

Presynaptic a2 agonist Receptor a2 agonist selective B2 agonists Remember: this receptor inhibits NE release • Acts centrally (α2) at nucleus tractus solitarius used in Bronchodilat Pharma- to decrease sympathetic glaucoma as it or for acute Bronchodila Tocolytic cological outflow to heart & reduces attacks of tor & (relaxatio action vessels. formation of asthma & Tocolytic n of • Inhibit sympathetic aqueous COPD. (delay uterus to vasomotor centers. humor and N.B. premature treat therefore Salmeterol & labor) prematur Antihypertensive drug: decrease intra- Formoterol e labor) Indica- used in essential ocular are longer tions hypertension to lower BP. pressure (IOP) acting

NOTE: Any selective drug given in high dose turns to be NON-SELCTIVE.

Nasal & Ocular decongestants: Phenethylamines Imidazoline Drug Phenylephrine Pseudoephedrine Nephazoline Oxymetazoline Indications Used for treatment of nasal stuffiness Side Can cause nasal rebound. effects Other nasal decongestants that are mentioned earlier: adrenaline + phenylephrine

Indirect & dual acting adrenergic agonists

AMPHETAMINE mechanism of It acts indirectly by releasing NE from presynaptic stores at adrenergic action terminals. It depletes vesicles from stored NE and thus cause Tachyphylaxsis (reduction of response after repeated administration) Administration & Absorbed orally, because it is a Synthetic non-catecholamine. metabolism Not destroyed by MAO (longer duration) , excreted mostly unchanged (increased excretion by acidification of urine). Selectivity Acts on α & β similar to epinephrine but has CNS stimulant effects CNS effects mental alertness, wakefulness, concentration & self-confidence ADRS - depression & fatigue on continued use - euphoria ( a feeling or state of intense excitement and happiness

Indirect acting: acting: Indirect which is what cause its addiction & abuse in use) - lose appetite & decrease weight - increase energy expenditure extra information Not used therapeutically anymore, because it induces psychic & physical dependence & psychosis is an Indirect Adrenergic stimulants that inhibits the uptake of Cocaine norepinephrine so it increases its availability in synapse

EPHEDRINE Overview Plant alkaloid, synthetic, non-catecholamine, dual (mixed) acting

Spectrum of Action Non selective , Acts on α & β Pharmacokinetics Absorbed orally, not destroyed by MAO or COMT  prolonged action

Mechanism of • Directly: direct action on receptors  down regulation of receptors action • Indirectly: Release NE from adrenergic nerve endings Lead to depletion of stores then tachyphylaxsis Action • facilitation of neuromuscular transmission & retention of urine • it has CNS stimulant effects (less than amphetamine)

Dual acting: Dual ADRS • Drugs of abuse by athletes and prohibited during games, thus No more therapeutically used • Bi folded effect: activation fallowed by dropping; Because it depletes vesicles of stored NE it cause tachyphylaxsis Pseudoephedrine Dual acting , acts on CNS & has less pressor effects compared to ephedrine.

Used as nasal & ocular decongestant & in flu remedies

Mind map

Drugs on the Autonomic nervous system

Cholinergic drugs Adrenergic drugs Act on the PNS Act on the Sympathetic Nervous System (SNS) Adrenergic Depressants Types Catecholamine (Antagonist) According to Have catechol ring (polar) E.g. Adrenergic stimulants chemistry Natural: Adrenaline, Noradrenaline, Dopamine (Sympathomimetic) Synthetic: Isoprenaline, Dobutamine

According to spectrum of action Non-catecholamine Non-selective According Lack catechol ring (Lipid soluble) to action E.g. Ephedrine, Amphetamine, Phenylephrine, • Adrenaline (α1, α2 , β1 , β2 , β3) Methoxamine, Salbutamol, Ritodrine. • Noradrenaline (α1, α2 , β1) • Dopamine ( D1, α1,β1) Direct • Isoprenaline (β1, β2 , β3 ) Indirect Dual • Amphetamine (α & β) Direct stimulation of  NA release from Direct & indirect Receptors • Ephedrine (α & β) adrenergic receptors. E.g. Epinephrine, NE, presynaptic adrenergic stimulation of Adrenergic Phenylephrine… nerve ending. adrenergic receptors. α1, α2, β1 , β2 , β3, Selective E.g. Amphetamine E.g. Ephedrine, Dopamine receptors • Phenylephrine (α1) Or inhibit NA uptake. pseudoephedrine. • Clonidine – Brimonidine ( α2) E.g. Cocaine & • Dobutamine ( β1) antidepressants. • Salbutamol, Terbutaline, Ritoderine (β2) Organ R. Response Organ R. Response Eye: Heart: • Radial m. α1 • Contraction (mydriasis) • SA node β1 •  HR. (Chronotropic) • Circular m. --- • AV node β1 •  velocity (Dromotropic) • Ciliary m. β2 • Relaxation • Contractility β1 •  force (Inotropic) Lung: GI: • Bronchial m. β2 • Relaxation. • Sphincter. α1 • Contraction (retention) • Motility & tone. α, β2 •  Blood vessels: Secretory glands: • Most (except Sk. m.) α1 • Contraction. • Sweat. α1 • Localized secretion. • Skeletal m. β2 • Relaxation. • Intestinal. α2 • Inhibition. • Bronchial. -- • Lacrimal. α •  Secretion (moderate) GU: Metabolism: • Urinary sphincter. α • Contraction. • Adrenal medulla. N • Secretion of catecholamines. 1 N

• Bladder wall. β2 • Relaxation (retention) • Kidney. β1 •  Renin release.

• Uterus, pregnant. α1;β2 • Contraction ; Relaxation. • Skeletal m. β2 • Glycogenolysis, contractility.

• Uterus, nonpregnant. β2 • Relaxation. • Pancreas. α2 •  Insulin release.

• Ejaculation. • Penis, seminal vesicles. α1 • Fat cells. β3 • Lipolysis.

Kidneys D1 Vasodilatation and diuresis (increase excretion of urine).

adrenergic drugs summary

Drug Receptors Function/Administration/ADRS/Contra. Uses Direct / Catecholamine / Non-selective ADRS/Contra.: • Status asthmatics (S.C./Inhalation) • Tachycardia/CHD, Hypertension, angina. • Allergic reactions (S.C.) • Tissue necrosis/peripheral arterial disease. • Cardiac arrest (IV) Adrenaline Β ≥ α • Nasal stuffiness. Headache, tremors. • local hemostatic. • Closed-angle glaucoma. Administration: parenteral & by inhalation • local anesthetics. Sever vasoconstriction (α1), Reflex bradycardia, • Hypertensive state  force of contraction but  H.R. noradrenaline α > β1 • local hemostatic. Administration: Only IV

Long effect./ Contra.: Hyperthyroidism & CHD. • Cardiac arrest (Parenteral) Isoprenaline β > α Administration: inhalation • Acute asthma (Inhalation)

Dopamine D1 > β1 > α1 Has diuretic action /Admin.: parentally by infusion Treatment of shock • Acute heart failure. β > β > α Administration: IV Dobutamine ퟏ 2 1 • Cardiac decompensation. Direct / Non-ctecholamine / Selective • Hypotension, tachycardia , Admin.: Orally / ADRS: Hypertension. Midodrine & • Local Hemostatic, with Local α (Midodrine) peaks in 20min, duration 30min, it’s Phenylephrine 1 anesthesia. / Mydriasis. better since it’s short it doesn’t cause severe tachycardia. • Decongestant (nasal & ocular)

Clonidine α2 Synthetic, imidazoline. Admin.: Orally or as patch Hypotension

Brimonidine α2 Is an imidazoline. Admin.: ocular route Glaucoma

Salbutamol β2 Admin.: Orally, by inhalation or parenteral Bronchodilator: Asthma and COPD

Terbutaline β2 Admin.: S.C Bronchodilator, Tocolytic

Ritodrine β2 Admin.: Orally, or by injection. Tocolytic for premature labor Non-ctecholamine / Non-selective ADRS: Tachyphylaxis, euphoria, weight loss. Indirect Amphetamine CNS: mental alertness, wakefulness, concentration & self- Admin.: Orally. confidence followed by depression & fatigue on continued use. Abused in sports. (Not used anymore) Dual Ephedrine ADRS: Tachyphylaxis, urine retention Nasal & Ocular decongestant Direct Phenylephrine Methoxamine Nephazoline Oxymetazoline Otrivine Uses: treatment for nasal stuffiness / ADRS: Can cause nasal rebound. Dual Pseudoephedrine

CNS & pressor effects compared to ephedrine / works the same way as the “Nasal & Ocular Decongestants drugs” and for flu

Drugs Summary

Agents specifically indicated for hypotension: Midodrine, Phenylephrine, Norepinephrine Agents specifically indicated for cardiogenic shock (Acute Heart Failure): Dobutamine, Dopamine, Epinephrine Agents specifically indicated for shock: Dopamine, Norepinephrine Agents specifically indicated for cardiac arrest: Dobutamine, Epinephrine, Norepinephrine Agents specifically indicated for bronchial asthma: Salbutamol, Salmeterol, Formoterol, Terbutaline, Isoprenaline Agents specifically indicated for premature labour : Ritodrine, Terbutaline Agents specifically indicated for nasal decongestion: Pseudoephedrine, Naphazoline, Oxymetazoline, Phenylephrine Agents specifically abused in sports: Ephedrine, Amphetamine Drugs that are used as hemostatics along with local anesthatics: (α1) agonists: Epinephrine, Norepinephrine, Phenylephrine THANK YOU FOR CHECKING OUR WORK QUIZ THE PHARMACOLOGY TEAM

لولوه الصغير أمل العمران عبدالرحمن السياري خالد الزهراني شادن العمران شماء السعد عبدهللا الجنيدل ساره الحسين رهف بن عبّاد أحمد المصعبي لمى الزامل سارة الخليفة مهند الزيد معاذ باعشن كوثر الموسى ساره المطوع عبدالعزيز الشعالن منيرة السلولي فاطمة الدين محمد السحيباني ديمه الراجحي عصام الوهيبي أحمد اليحيى

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