Adrenergic Drugs Lecture Notes PDF

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 Li...

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-adrenoceptors b-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;b 1 ; b 2; b3) a2; Clonidine, Brimonidine Dopamine (D1; a1; B1 ) b 1; Dobutamine Isoprenaline (B1 ; b 2; b3) b 2; Salbutamol, Terbutaline, Ephedrine (a ; b) Ritoderine  Direct acting adrenergic agonists ADRENALINE Receptor Non-selective a1; a2; (predominate at high doses ) B 1 ; b 2; 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) (b 1 ) Blood pressure  systolic (b1)  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) Action SMC; GIT  motility (b2) / contract sphincter (a1) 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 locally: - combined with local anesthetics to  absorption & side effects of local anesthetics + ↑duration of action +  bleeding from incision 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 b 2 are better Systemically: 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. -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. cal actions skeletal muscles and coronaries.  BP [ systolic & diastolic]. this stimulates Bronchodilatation. 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 indications - in spinal anesthesia (Hypotension (Spinal 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. has prolonged duration Overview Metabolized by -Released from postganglionic of action, since it’s Not adrenergic fibres COMT, thus has a inactivated by COMT short duration Administration Given parentally by infusion IV Orally Receptor D1 > b1 > a1 (in order) Selective b1–agonist. selective a1 D1: Low dose On heart: Myadritic action (a1 ) vasodilatation of mesenteric, +ve Inotropic with  increased both coronary, renal blood little chronotropic systolic & diastolic vessels. Thus improves effect. as it blood pressure blood flow to viscera increases cardiac (hypertension) due to diuresis (increase excretion output, with little vasoconstriction (a1 ) of urine) Increased blood flow increase in heart 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 Decrease BP Adverse effects: counterbalance + β1: intermediate dose Hypertension. no α1 +ve inotropic Thus, another drug is more No vasodilatation of +ve chronotropic effects preferable to produce renal blood vessels. Increase BP hypertension that doesn’t (No effect on α1: high dose last for long. This drug is dopaminergic Vasoconstriction Midodrine. It peaks in 20 receptors ) hypertension min, duration 30 min only. - 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 B 2 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) Antihypertensive drug: prematur decrease intra- Formoterol Indica- used in essential e labor) 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 Indirect acting: (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 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 Dual acting: 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) 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 According Lack catechol ring (Lipid soluble) Non-selective E.g. Ephedrine, Amphetamine, Phenylephrine, Adrenaline (α1 , α2 , β1 , β2 , β3 ) to action 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. α1 Contraction. Adrenal medulla. NN Secretion of catecholamines. 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. α1 Ejaculation. β3 Penis, seminal vesicles. Fat cells. 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. Adrenaline Β≥α Cardiac arrest (IV) Nasal stuffiness. Headache, tremors. local hemostatic. Closed-angle glaucoma. Administration: parenteral & by inhalation local anesthetics. Sever vasoconstriction (α1), Reflex bradycardia, Hypertensive state noradrenaline α > β1  force of contraction but  H.R. 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. Dobutamine β𝟏 > β2 > α1 Administration: IV Cardiac decompensation. Direct / Non-ctecholamine / Selective Hypotension, tachycardia , Admin.: Orally / ADRS: Hypertension. Midodrine & Local Hemostatic, with Local α1 (Midodrine) peaks in 20min, duration 30min, it’s anesthesia. / Mydriasis. Phenylephrine 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 ‫‪QUIZ‬‬ ‫‪THANK YOU FOR CHECKING OUR WORK‬‬ ‫‪THE PHARMACOLOGY TEAM‬‬ ‫عبدالرحمن السياري‬ ‫أمل العمران‬ ‫لولوه الصغير‬ ‫خالد الزهراني‬ ‫شماء السعد‬ ‫شادن العمران‬ ‫عبدهللا الجنيدل‬ ‫أحمد المصعبي‬ ‫رهف بن عبّاد‬ ‫ساره الحسين‬ ‫مهند الزيد‬ ‫سارة الخليفة‬ ‫لمى الزامل‬ ‫معاذ باعشن‬ ‫كوثر الموسى‬ ‫ساره المطوع‬ ‫عبدالعزيز الشعالن‬ ‫فاطمة الدين‬ ‫منيرة السلولي‬ ‫محمد السحيباني‬ ‫عصام الوهيبي‬ ‫ديمه الراجحي‬ ‫أحمد اليحيى‬ ‫‪For any correction, suggestion or any useful information do not‬‬ ‫‪hesitate to contact us: [email protected]‬‬