Antimuscarinic Agents

Antimuscarinic Agents
Atropine 654-2 Anisodamine Scopolamine Smooth muscle relax weak similar Glands secrete potent Eye mydriasis Cardiovascular tachycardia CNS excite Sedation hypnosis LD50mg/kg 98 115 155

Antimuscarinic agents
Atropine 654-2 Anisodamine Scopolamine application Gastrointestinal spasm Ophthalmologic disorders Arrhythmia Infectious shock Organophosphates poisoning Preanesthetic treatment Motion sickness Parkinsonism

Categories of Autonomic Pharm
Sympathetic Adrenergic Parasympathetic Cholinergic Adrenaline Rush Agonist Antagonist

Chapter 10: Adrenoceptor- Activating Drugs
Autonomic Drugs Chapter 10: Adrenoceptor- Activating Drugs “Fight & Flight”

Adrenoceptor-Activating Drugs
Drugs that activate adrenoceptors and exert their effects mimic adrenaline, which will increase the sympathetic nervous system response

Similar Terminologies: - Adrenoceptor Stimulants - Adrenergic Agonists - Sympathomimetics (mimic, imitate) - Adrenergics / Adrenomimetics - Adrenaline Receptor Agonists/Stimulants

Classification By mechanism of action - direct: bind directly to receptor - indirect: inhibit CA transporter inhibit storage of NE - mixed: both direct and indirect NE

Indirect-acting agonists

Classification By their spectrum of action depending on the type of primary receptors - alpha (α) - beta (β) - both (α、 β)

① Ad or Ep ② Dopamine, DA ③ Ephedrine α, β-receptors activating drugs α-receptors activating drugs β-receptors activating drugs NA or NE Metaraminal (Aramine) Phenylephrine(neosnephrine) Methoxamine ① β-R agonist: isoprenaline ② β1-selective agonist: dobutamine ③ β2-selective agonist: salbutamol

Adrenoceptors (potency of Ad, NE, and other adrenoceptor agonists) α- adrenoceptor α1 (α1A, α1B, α1D) , α2 β- adrenoceptor β1, β2, β3 Dopamine Receptor only activated by dopamine

Direct-Acting Adrenoceptor Agonists Catecholamines - Dopamine (DA) - NE (NA) Natural - AD (EP) Isoprenaline Noncatecholamines - Ephedrine - Conidine - Midodrine - Phenylephrine Synthetic

Basic structure of catecholamine

Basic structure of catecholamine a. the benzene ring – Catechol moiety b. the amino group c. the α-carbon Ethylamine d. the β-carbon

Structure-Activity relationship β α

General Properties of Catecholamine Rapidly inactivated - gut, liver (MAO & COMT) Low oral bioavailabilities Short plasma half life Ad. parenterally

α- Adrenoceptors α1-R: S.M: contraction - vascular S.M - iris dilator muscle - lower urinary S.M (sphincter of bladder, urethra, & prostate) Exocrine glands: secretion CNS: excitation M-R Iris dilator muscle α1-R

α- Adrenoceptors α2-R: Presynaptic neurons: autoreceptor, NE Tissues - ocular: aqueous humor - adipose: inhibition of lipolysis - intestinal: secretion - endocrine tissue: insulin Blood platelets: aggregation

NA (NE) Chemistry: unstable Pharmacokinetics: - intravenous infusion - not across BBB - short duration of action, metabolized by MAO and COMT - excretion by urine

NA (NE) Postganglionic 10%-20% of catecholamine Direct-acting Activate α(α1 &α2 ) -R strongly and β1 weakly

NE (NA) Cardiovascular Effects Vascular S.M contraction Total Peripheral Resistance Stroke Volume Coronary Flow Skin, renal, intestinal, hepatic blood flow SBP DBP Compensatory vagal reflex HR or Unchanged

NE (NA) Other Effects Not prominent in human Large dose: metabolic effects similar to those produced by Ad

Clinical Uses of NE Early phase of neurogenic shock eg. extreme pain, being shocked blood vessels dilated hypotension b. Hypotension caused by drug toxication (α-R blockers) c. Upper digestive tract bleeding, orally

Adverse Effects of NE Local tissue marked ischemia and necrosis, procaine or phentolamine can be used to relieve them Acute renal dysfunction

Contraindications of NE Hypertension, atherosclerosis, coronary heart disease, oliguria, and anuria

Metaraminol or Aramine Chemistry: stable Direct and Indirect acting Long duration of action, metabolized by MAO and COMT

Metaraminol or Aramine Both iv. infusion and im. Produce tachyphylaxis Less side effects than NA Used to treat hypotensive states as a substitute for NA

Isoprenaline: synthetic β(β1, β2 , β3 – adrenoceptor agonist Chemistry: unstable Inhalation as aerosol or sublingual Absorbed fast Not across BBB

β- Adrenoceptors β1-R: Positive chronotropic effect Positive inotropic effect Positive dromotropic effect Renin secretion from renal juxtaglomerular cells

β- Adrenoceptors β2-R: S.M: relax - bronchial, uterine, vascular S.M of skeleton: mediate potassium uptake Liver: mediate glycogenolysis BG Renin secretion from renal juxtaglomerular cells

β- Adrenoceptors β3-R: produce lipolysis: release of fatty acids

Isoprenaline: synthetic Duration of action longer than Ep Most are destroyed by COMT, few by MAO Excretion by urine Pharmacodynamics: extremely potent β-R(β1, β2) agonist, having little effect on α-R

Isoprenaline: synthetic Cardiac Effects β1-R Chronotropic Effects (HR ) Cardiac output Cardiac Stimulation Dromotropic Effects (cardiac impulse conduction velocity ) Inotropic Effects (contractility ) Oxygen Consumption

Isoprenaline: synthetic Blood Vessels: ① A potent vasodilator β2-R Total Peripheral Resistance DBP ② The blood flow of coronary artery

Isoprenaline: synthetic Smooth Muscles: ① Bronchial SM: Relaxation β2-R Bronchodilation ② GI S: Relaxation

Isoprenaline: synthetic Inhibit antigen induced release of histamine Metabolism increases Blood Glucose

Isoprenaline: synthetic Clinical uses Bronchial asthma: control acute attack, sublingual or inhalation c. Serious atria-ventricular conduction blocking: sublingual or intravenous infusion

Isoprenaline: synthetic Clinical uses Cardiac arrest: intraventricular injection Infectious shock: - central venous pressure - cardiac output - peripheral resistance

Isoprenaline: synthetic Side effects: palpitation, sinus tachycardia, provoke serious arrhythmias, flushing

Isoprenaline: synthetic Contraindication: coronary artery disease, hyperthyroid

Dobutamine: synthetic Selective β1-agonist No effect by orally administration, should be given intravenously Positive inotropic action stronger than chronotropic action Treatment for acute cardiogenic shock or heart failure

Dobutamine: synthetic Adverse effects: blood pressure , palpitation, headache, ventricular arrhythemia Contraindication: myocardial disease with hypertrophy, atria fibrillation,

α,β-adrenoceptor agonists Adrenaline or Epinepherine Dopamine, DA Ephedrine

Adrenaline or Epinepherine (Ad or Ep) Chemistry: unstable Pharmacokinetics: - iv, im or sc. infusion - not across BBB - short duration of action, metabolized by MAO and COMT - excretion by urine

Ad (Ep) Adrenal Medulla Direct-acting Activate both α(α1, α2 and β(β1, β2 ) receptors strongly

Ad (Ep) Cardiac Effects (β1, β2 -R) Marked positive chronotropic effect on both normal and abnormal pacemaker activity Strong positive inotropic effect on intrinsic contractility

Ad (Ep) Cardiac Effects (β1, β2 -R) Promote conduction of heart Cardiac output Oxygen consumption Relax coronary arteries

Ad (Ep) Vascular Effects (α1, β1, β2 -R) Chief action: smaller arterioles and precapillary sphincters Low dose: activate β2-R on the smooth muscles relaxation Large dose: strongly activate α1-R on the smooth muscles peripheral vascular resistance

Ad (Ep) Vascular Effects (α1 ,β1, β2 -R) d. Blood pressure low dose: SBP increased, DBP normal or decreased (heart β1-R and peripheral β2-R) large dose: markedly increase BP (peripheral α1-R and β1-R of juxtaglomerular cells, excretion renin)

Ad (Ep) Other Effects Smooth muscles bronchial SM: relaxation, β2-R (+), strong GI tract tone decreased, β1-R (+)

Ad (Ep) Other Effects Metabolism ① lipolysis , β3-R (+) ② glycogenolysis in liver , BG markedly, αand β2-R (+), ③ plasma potassium ion when stress or exercise, β2-R (+)

Ad (Ep) Other Effects counteract the effects of histamine and other mediators released from mast cells and basophils during immediate hypersensitivity reactions

Clinical Uses of EP Cardiac arrest Anaphylactic shock: sc or im Bronchial asthma: sc or im Local application: local anesthesia (1:250000), stop bleeding

Adverse Effects of EP BP marked elevation, cerebral hemorrhage or pulmonary edema Severe angina or myocardial infarction Sinus tachycardia or serious ventricular arrhythmias

Contraindications of EP hypertension, sclerosis of cerebral artery, ischemic heart disease, congestive heart failure, hyperthyroidism, and diabetes, use with care for old patients.

Dopamine (DA) Pharmacokinetics precursor of NA and Ad intravenous infusion, destroyed by MAO & COMT rapidly t1/2=1-2 min can’t across BBB

DA: Pharmacodynamics Low concentration: activates DA1-R in renal, coronary artery and mesentery vascular beds vasodilation Large dose: activate β1-R and α-R vasoconstriction, including renal blood vessels, BP

DA: Pharmacodynamics Release of NA from nerve endings Infusion of low dose: glomerulus filtration rate, renal blood flow and sodium ions excretion

DA: Clinical Uses: Treatment of various shock Acute renal dysfunction and heart failure, combination of dopamine and diuretics

DA: Adverse Effects: If infused very fast, it may induce tachycardia, arrhythmia, headache and hypertension

Ephedrine: plant alkaloid Activate both αand β-Rs Direct acting Indirect acting: enhances the release of NA from adrenergic nerve endings

Ephedrine: plant alkaloid Stable chemistry property, has effect after oral administration Sympathomimetic action less than ad. But longer duration than that of ad Marked excitement effects of CNS, because it can across BBB Produce tachyphylaxis rapidly

Ephedrine: Clinical Uses: Bronchial asthma, light symptoms Nasal decongestant Prevent hypotension induced by peidermal anesthesia or subarachnoid anesthesia Relieve symptoms of allergic reaction on the skin and mucous membrane

Ephedrine Adverse Effects: anxiety, insomnia, tachyphylaxis

Ephedrine Contraindication: hypertension, atherosclerosis, hyperthyroidism, and coronary heart disease

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