Pharmacology 1 Lecture Notes PDF

PHARMACOLOGY 1 All automatic FACULTY OF DENTISTRY 1 Autonomic nervous system 2 Nervous System (N.S) 3 Nervous System (N.S) 4 5 6 7 8 9 10 11 12 13 14 15 The Autonomic Nervous System (A.N.S)...

PHARMACOLOGY 1 All automatic FACULTY OF DENTISTRY 1 Autonomic nervous system 2 Nervous System (N.S) 3 Nervous System (N.S) 4 5 6 7 8 9 10 11 12 13 14 15 The Autonomic Nervous System (A.N.S) 16  Parasympathetic nervous system Sympathetic nervous system Cranio-sacral Originate from cranial nerves: Thoracolumbar ❶. 3rd → Occulomotor nerve. ❷. 7th → Facial nerve. These arise from thoracic (T1 Origin: ❸. 9th → Glossopharyngeal nerve. – T12) and lumbar (L1 – L3) segments of the spinal cord. ➍. 10th → Vagus nerve (80 – 90%). ❺. Sacral segment (S2 – S4) in spinal cord. REST & DIGEST FIGHT, FRIGHT &FLIGHT ❶. Conserving energy so ↓ metabolism. ❶. Utilizing energy Functions: ❷. Responsible for stress ❷. Maintain essential body functions. condition. ❸. Essential for survival. ❸. Not essential for surviva17l. 18 19 Autonomic Ganglia are sited at which information (action potentials) arising from the central nervous system (CNS) is transmitted to the periphery via synaptic neurotransmission. The information from the CNS can be amplified, inhibited (filtered), or, in the case of a simple relay, left unaltered. 20  Sympathetic Ganglia Parasympathetic Ganglia are located in two chains, one on each side of are located within the target organ. the vertebral bodies, and sometimes called These ganglia receive synapses from long the paravertebral ganglia. axons of pre-ganglionic neurons, The postganglionic nerves are long and travel and have short post-ganglionic axons to many of their targets within spinal nerves. because these ganglia are within the target organ. 21 22 23  AUTONOMIC NEUROTRANSMITTERS The functional differences between sympathetic and parasympathetic post- ganglionic neurons occur because they use different neurotransmitters. Two PNS neurotransmitters, acetylcholine, and norepinephrine have particular clinical importance. Both are synthesized and stored primarily in the nerve terminals until released by a nerve impulse 24  Acetylcholine Norepinephrine Released by parasympathetic post- The main transmitter produced and ganglionic neurons released by sympathetic post- ganglionic, except for the sympathetic released by the pre-ganglionic postganglionic neurons that innervate neurons, sympathetic and sweat glands and some of the blood parasympathetic. vessels in skeletal muscle are cholinergic Neurons that release this substance are called Neurons that release this substance are called cholinergic adrenergic or noradrenergic Drugs that mimic its actions are termed Drugs that mimic its actions are termed cholinomimetic or parasympathomimetic andromimetic or sympathomimetics Interact with choline receptors Interact with adrenoceptors 25  Sites of Ach release ❶. All preganglionic autonomic ganglia (For both Sympathetic & Parasympathetic). ❷. All postganglionic parasympathetic nerve endings. ❸. Somatic nerve of skeletal muscle (End Motor Plate) (Neuromuscular junction) (NMJ). ❹. Exceptions: Sympathetic nerve to Sweat glands, Adrenal medulla and B.V.’s of some Skeletal muscles. 26 27  Receptors of the ANS Usually, a particular receptor subtype for each division of the ANS will dominate in a certain gland or organ. In general, ✓ activation of some receptor subtypes leads to stimulation of the effector ✓ and activation of others to inhibition of the effector. 28  Adrenergic Receptors Epinephrine (EPI) released by the adrenal gland also binds to adrenergic receptors expressed on effectors. There are two main types of adrenergic receptors, namely, alpha and beta which have several subtypes. Activation of adrenergic receptors expressed on effectors by NE or EPI may result in stimulation or inhibition of the effector depending on the tissue involved. Odd subtypes of adrenergic receptors (alpha 1, beta 1, and 3) generally have stimulatory effects and even subtypes (alpha 2 and beta 2) have inhibitory effects. 29 30 31  Innervation of various organs by the sympathetic and parasympathetic nervous systems Many visceral organs are innervated by both divisions of the autonomic nervous system. In most instances, when an organ receives dual innervation, the two systems work in opposition to one another. In some tissues and organs, the two innervations exert an opposing influence on the same effector cells (e.g., the sinoatrial node in the heart), while in other tissues opposing actions come about because different effector cells are activated (e.g., the circular and radial muscles in the iris). 32  Blood Vessels Sympathetic Parasympathetic regulate the tension produced no parasympathetic innervation by vascular smooth muscle of most vessels, blood pressure except the erectile tissues of Via action on alpha-adrenoceptors sexual organs 33  The Heart Sympathetic Parasympathetic accelerate the heart rate slow the heart (Bradycardia) Heart Rate (tachycardia) Acetylcholine muscarinic receptors noradrenaline Receptor : beta-1 adrenoceptors positive inotropic effect do not innervate the ventricles, Ventricular Increase stroke volume cholinergic drugs can have a negative inotropic effect because ventricular Output muscle has muscarinic receptors. 34 35  Respiratory Tract Sympathetic Parasympathetic Airways dilate the airways, produce bronchoconstriction Smooth mediated by beta-2 adrenoreceptors mediated by muscarinic Muscle receptors Mucus Secretion No effect Increase mucus secretion Pulmonary blood vessels vasoconstrict vasodilate 36 37  Gastrointestinal Tract Sympathetic Parasympathetic Stimulatory on smooth muscle Gastric Motility Inhibitory on gastric smooth muscle ( increase motility) Gastric Decrease the acid secretion Increase the acid secretion Secretion sphincters Stimulatory (contract) Inhibitory (relax) 38 39 40  Sympathetic nervous system Sympathetic acting drugs Adrenergic receptors: Are classified into Alpha (α) and Beta (β) adrenergic receptors. Alpha (α) adrenoceptors Subtype Actions ▪ VC of blood vessels α1 receptors ▪ CONTRACT radial muscle →mydriasis ▪ Contraction of sphincter (GIT) ▪ Relaxation of non-sphincter parts (GIT) All α1 receptors are excitatory ▪ Glycogenolysis & (leads to contraction) EXCEPT on GIT (is inhibitory). 41 α2 receptors ↓ Presynaptic NE synthesis and release → ↓ Sympathetic outflow. 42  Cholinergic Receptors There are two main subtypes of cholinergic receptors-; ✓ Nicotinic ✓Muscarinic. They are named after alkaloids found in tobacco and certain mushrooms respectively. The alkaloid nicotine specifically activates nicotinic cholinergic receptors, while muscarine activates muscarinic cholinergic receptors, and ACH activates both types. 43  To distinguish nicotinic receptors in neurons from nicotinic receptors found in the neuromuscular junction, we use the terms nicotinic neural (NN or N2) cholinergic receptors and nicotinic muscle (NM or N1) cholinergic receptors respectively. Muscarinic receptors (M) are located on cells of all parasympathetic effectors and on cells of some sweat glands innervated by the sympathetic nervous system. There are several subtypes of muscarinic receptors (M1-M5) which may be stimulatory or inhibitory. 44 45  Synthesis, Storage, Release, and Removal of Acetylcholine 47 1)Muscarinic receptors (Stimulate by muscarine &Ach) Subtype Location Actions M1 ▪ Brain ▪ Central excitation ▪ Gastric parietal cells ▪ ↑ Gastric acid secretion M2 ▪ Cardiac muscle ▪ ↓ heart rate and force of ▪ Smooth muscle contraction ▪ Bladder ▪ Smooth muscle contraction M3 ▪ Smooth muscles ▪ Glandular secretion e.g. saliva, ▪ Exocrine glands sweat ▪ GIT M4 ▪ CNS M5 ▪ CNS 48 2) Nicotinic receptors ▪ Nicotine (or acetylcholine) initially stimulates and then blocks the receptor. A)NN receptor (nicotinic neural) B) NM receptor (nicotinic muscular) 1. Adrenal medulla Found in Skeletal muscle 2. Autonomic ganglia (Symp & (Neuromuscular junction) parasym) (Motor end plate) 3. CNS Antagonist → Hexamethonium Antagonist → Tubocurarine 49  Muscarinic actions Heart (M2) 1)Cardiovascular ▪ ↓ Heart rate (-ve Chronotropic) system ▪ ↓ Force of atrial contraction (-ve Inotropic effect) ▪ ↓ Conduction velocity in AV node (-ve Dromotropic effect) Blood vessels (M3) Generalized VD (mediated by NO from endothelial lining of vascular smooth muscle) So ↓ F.O.C, HR, conduction , VD →Hypotension 50  All smooth muscle (M3) →Contraction Except vascular smooth muscle 2) Smooth muscle a) GIT →↑ Peristaltic activity b) Bladder → Contraction of detrusor muscle c) Lung → Bronchoconstriction ▪ ↑ Salivation 3) Glandular ▪ ↑ Lacrimal secretions (M3) ▪ ↑ Sweating ▪ ↑ Bronchial secretions 51 Termination of ACh Action 52 53  Synthesis, Storage, Release, and Removal of Norepinephrine 55 The mechanisms of termination of the adrenergic action 56 ❶ Adrenergic uptake mechanisms: 57  ❷ Enzymatic degradation mechanisms MAO COMT Mono-Amine Oxidase enzyme. Catechol-O-Methyl Transferase enzyme. Methylation of released catecholamines in Oxidative amination of re-captured synapses to → HMMA (4-hydroxy-3-methoxy catecholamines in the nerve endings (NE, mandelic acid) (Vinylmandelic acid) (VMA) → Dopamine, and serotonin). To be excreted into urine. Present in neuronal mitochondria in the Present in synaptic cleft. nerve terminals. Urinary VMA level is a very important diagnostic test for pheochromocytoma → Due to severe ↑↑ NE and E → ↑↑ VMA levels. 58 Sympathomimetic drugs 59  The general effects of sympathomimetic drugs Heart 1) ↑ Contractility (+ ve Inotropic effect) 2) ↑ Heart rate (+ ve Chronotropic effect) β1 receptor 3) ↑ Conductivity (+ ve Dromotropic effect) Blood α1 V.C of B.V of skin and mucous membrane, kidney, GIT vessels β2 V.D of B.V of skeletal muscle, liver Respiratory β2 Bronchodilatation system Sphincter part α Contract GIT Non sphincter part α &β Relaxes 60  Drug Receptor Effect Adrenaline α1, α2, β1, β2 , Low doses → β2 (affinity) effects predominate → VD of vascular (Epinephrine system β3 High doses → α1 (affinity) effects predominate → VC of vascular system Noradrenaline α1, α2, β1 > β2 VC of most vascular beds including kidney (α1)→↑PR ▪ ↑ Systolic and diastolic blood pressures ▪ NE causes greater VC than E (because NE not cause β2 VD compensation) Isoprenaline Nonselective β1, β2 Heart ↑ all cardiac Properties agonist B.V V.D of coronary & skeletal muscles (β2 ) Blood pressure → Hypotension Bronchodilatation (β2 ) Oxymetazoline α1 & α2 agonist - Relief of Nasal decongestant - Relief of redness of the eyes associated with swimming, cold, or contact lens (ophthalmic drops) 61  - Used as Nasal decongestant & Mydriatic Selective α 1 agonist - Induces reflex bradycardia when given parenterally Phenylephrine stimulate α1 receptors in arterioles →↑BP →↑ PR Methoxamine Selective α1 agonist Relief attacks of supraventricular tachycardia (Because of its effects on the vagus nerve) Activate central α2 receptors →↓ Sympathetic VMC → ↓ Selective α2 Agonist sympathetic Clonidine outflow to the periphery →↓BP Selective α 2 agonist ocularly ↓IOP in open-angle glaucoma Brimonidine Selective α2 Agonist 1) ↓ Aqueous humor production 2) ↑ Aqueous humor outflow 62  Selective ß2 agonists (little effect on heart) Short acting bronchodilator Long-acting bronchodilator Salmeterol (Slower onset of action) Salbutamol Terbutaline, Formoterol Pirbuterol Administered by metered dose inhaler. Single dose inhalation Bronchodilation with less cardiac ▪ Sustained bronchodilation over 12 stimulation hrs ▪ Drug of choice for nocturnal asthma ▪ These drugs are highly efficacious when combined with a corticosteroid 63 Sympatholytic drugs (Sympathetic depressants) 64 65  1)α receptor antagonist A) Non-selective α antagonists Block α1 in B.V → VD (Artery & Vein)→↓ Peripheral resistance Phenoxybenzamine (PR) → hypotension → Reflex tachycardia b) Blocks presynaptic α2 in the heart resulting in more NE release →Stimulate β1 on heart →↑COP Reversible non-selective competitive α1 & α2 blocker Phentolamine Produces postural hypotension 66 B) α 1 Selective antagonists Prazosin, Terazosin, VD of arterial and venous smooth muscle→↓ PR →↓ Doxazosin Arterial BP Tamsulosin & Alfuzosin Tamsulosin has the least effect on blood pressure because it has higher selectivity to α1A receptors found on the smooth muscle of the prostate C) α 2 selective antagonists (Yohimbine) Naturally alkaloid readily enters the CNS. ↑ Blood pressure and HR Enhance motor activity and produce tremors 67  ΙΙ. β - Blockers A) Non -selective β blockers Heart (β1 receptor blocker)→ ↓ COP a) ↓Contractility (- ve Inotropic effect). b) ↓Heart rate (- ve Chronotropic effect). c) ↓ Conductivity (- ve Dromotropic effect). Propranolol Blood vessels →Peripheral vasoconstriction ▪ Blockade of β receptors prevents β2 – mediated vasodilation → VC → ↓ blood flow to the periphery →coldness of extremities (α1 effect). Bronchi Blocking β2 receptors in the lungs of susceptible patients →contraction of the bronchi Nadolol has a very long duration of action (14 – 24 h). Timolol & ▪ Timolol is used for Nadolol 1) Topically in eyes for treatment of chronic glaucoma (↓aqueous humor production) 2) Hypertension 3) Congestive heart failure 4) Acute MI 68  B) Cardio Selective β1 – antagonists Esmolol are useful in hypertensive patients with impaired Metoprolol. pulmonary function Atenolol. Acebutolol Betaxolol & Bisoprolol 69  Adrenergic neuron blockers Guanethidine It inhibits the release of noradrenaline from sympathetic nerve ending, it depletes catecholamine stores Reserpine It depletes catecholamines(NE and dopamine) and serotonin ( 5HT ) central and peripheral. It blocks the ability of vesicles to store these biogenic amines by interfering with vesicular uptake 70  Centrally acting drugs (α2 agonist) α-methyl dopa –Central mechanism: through stimulation of α2 receptors →↓ sympathetic out flow →↓HR , ↓COP,↓TPR →↓BP –↑ presynaptic α2 receptors →↓NA Clonidine It act directly on α2 receptors so inhibit sympathetic outflow from C.N.S., and inhibit noradrenaline release 71 Parasympathomimetic drugs 72 Parasympathomimetic 73 Parasympatholytic drugs 74 75 PHARMACOLOGY 1 Lec10 FACULTY OF DENTISTRY 1 Parasympathomimetic drugs 2  These are drugs which produce actions similar to that of ACh, CHOLINERGIC either by : DRUGS Directly interacting with cholinergic (Parasympathomimetic) receptors (Cholinergic Agonists) or by increasing availability of Ach at these sites (anticholinesterases). 3 Action of Acetylcholine 4  Heart (M2) 1)Cardiovascul ▪ ↓ Heart rate ar system ▪ ↓ Force of atrial contraction ▪ ↓ Conduction velocity in AV node Blood vessels (M3) Generalized VD (mediated by NO from endothelial lining of vascular smooth muscle) ↓ F.O.C, HR, conduction , VD →Hypotension All smooth muscle (M3) →Contraction 2) Smooth Except for vascular smooth muscle a) GIT →↑ Peristaltic activity muscle b) Bladder → Contraction of detrusor muscle c) Lung → Bronchoconstriction ▪ ↑ Salivation ▪ ↑ Lacrimal 3) Glandular ▪ ↑ Sweating secretions (M3) ▪ ↑ Bronchial secretions 5 Nicotinic receptors ▪ Nicotine (or acetylcholine) initially stimulates and then blocks the receptor. A)NN receptor (nicotinic neural) B) NM receptor (nicotinic muscular) 1. Adrenal medulla Found in Skeletal muscle 2. Autonomic ganglia (Symp. & (Neuromuscular junction) parasym.) (Motor end plate) 3. CNS Antagonist → Hexamethonium Antagonist → Tubocurarine 6 7 Direct Acting Cholinergic Agonists All of the direct-acting cholinergic drugs have longer durations of action than acetylcholine 8  Bethanechol It is structurally related to Ach. Muscarinic agonist. It is not hydrolyzed by acetylcholinesterase Actions Primarily affects the urinary and GIT a) Contraction of detrusor muscle s sphincter relaxed → Expulsion of urine. b) Directly stimulate muscarinic receptors → ↑ GIT motility 9  Therapeutic application (Uses) 1) Atonic bladder in Postpartum, Postoperative, Non-obstructive urinary retention. 2) Neurogenic atony 3)Megacolon (an abnormal dilation of the colon) Adverse effects 1)Nausea, abdominal pain and diarrhea 2) Bronchospasm 3)Sweating & Salivation 4)Flushing & ↓ Blood pressure 10 Glaucoma 11  Carbachol Carbachol has both → Muscarinic s Nicotinic actions. It is not hydrolyzed by acetylcholinesterase. ❑ Action Because of nicotinic action → Can cause the release of epinephrine from the adrenal medulla. Locally into the eye mimics the effects of acetylcholine → Miosis. ❑ Uses  It is rarely used therapeutically due to : a)Receptors non-selectivity b)Relatively long duration of action 12 13 Used as an Exception in the eye as a Miotic agent to treat glaucoma Contraction of the constrictor pupillae muscle (circular muscle) → Miosis → ↓ intraocular pressure (IOP) Adverse effects At doses used ophthalmologically → Little or no side effects Due to lack of systemic penetration. 14 15 16  Cholinomimetic Alkaloids Pilocarpine Stable to hydrolysis by acetylcholinesterase. It exhibits muscarinic activity and is used primarily in ophthalmology. Actions 1) Eye (Topically it produces ) a)Miosis b)Contraction of the ciliary muscle. 17 2) Exocrine glands Potent stimulators of secretions (secretagogues) such as sweat, tears, and saliva. 3) Smooth muscle →↑ Motility of the bowel →Defecation ↑ Urine excretion 18  Uses 1. It is the drug of choice in lowering of IOP of glaucoma. 2. Treatment of Xerostomia (due to sialagogue effect) Adverse effects ✓ Pilocarpine can enter the brain and cause CNS disturbances. ✓ It stimulates profuse sweating and salivation 19  Cevimeline Selective M3 agonist in lacrimal and salivary glands. Has a sialagogue effect. Used in the treatment of: a) Xerostomia after head and neck radiation b) Sjogren's syndrome (The main symptoms are dry eyes and mouth). Has fewer side effects than pilocarpine 20  Bronchial asthma. Peptic ulcer Contraindications of choline esters Angina pectoris (can reduce coronary flow due to hypotension). Never given I.M. or I.V. (produce sever bradycardia and hypotension and atropine is the antidote). 21 Lec 11 & lab 12  ANTICHOLINESTERASES Anticholinesterases (anti-ChEs) are agents which inhibit ChE, protect ACh from hydrolysis—produce cholinergic effects in vivo and potentiate ACh both in vivo and in vitro. Some anti- ChEs have additional direct action on nicotinic cholinoceptors. Anti-ChEs are either esters of carbamic acid or derivatives of phosphoric acid. In carbamates R1 may have a nonpolar tertiary amino N, e.g. in physostigmine, rendering the compound lipid soluble. In others, e.g. neostigmine, R1 has a quaternary N+—rendering it lipid insoluble. All organophosphates are highly lipid soluble except echothiophate which is water soluble. Pharmacological actions The actions of anti-ChEs are qualitatively similar to that of directly acting cholinoceptor stimulants. However, relative intensity of action on muscarinic, ganglionic, skeletal muscle and CNS sites varies among the different agents. Lipid-soluble agents (physostigmine and organophosphates) have more marked muscarinic and CNS effects; stimulate ganglia but action on skeletal muscles is less prominent. The centrally acting anti-ChEs produce a generalized alerting response; cognitive function may improve in Alzheimer’s disease. Lipid-insoluble agents (neostigmine and other quaternary ammonium compounds) produce more marked effect on the skeletal muscles (direct action on muscle endplate cholinoceptors in addition to potentiation of ACh.), stimulate ganglia, but muscarinic effects are less prominent. They do not penetrate CNS and have no central effects.  Uses 1.Glaucoma Open angle (chronic simple) glaucoma: Miotics increase the tone of the ciliary muscle which pulls on and improves the outflow facility of trabecular meshwork. 2. To reverse the effect of mydriatic: After refraction testing. 3. To prevent/break adhesions between iris and lens/cornea: A miotic is alternated with a mydriatic. 4. Myasthenia gravis: It is an autoimmune disorder due to development of antibodies to the muscle endplate nicotinic receptors resulting in weakness and easy fatigability. Neostigmine and its congeners improve muscle contraction by preserving ACh as well as by directly depolarizing the endplate Anticholinesterase poisoning Anticholinesterases are easily available and extensively used as agricultural and household insecticides; accidental as well as suicidal and homicidal poisoning is common. Treatment 1. Termination of further exposure to the poison—fresh air, wash the skin and mucous membranes with water, gastric lavage according to need. 2. Maintain patent airway, positive pressure respiration if it is failing. 3. Supportive measures—maintain BP, hydration, control of convulsions with judicious use of diazepam. 4. Specific antidotes— (a) Atropine It is highly effective in counteracting the muscarinic symptoms, but higher doses are required to antagonize the central effects. It does not reverse peripheral muscular paralysis which is a nicotinic action. (b) Cholinesterase reactivators Oximes are used to restore neuromuscular transmission in case of organophosphate anti-ChE poisoning. They provide more reactive OH groups which react with phosphorylated enzyme to form oxime phosphonate and release free cholinesterase. Pralidoxime is the most commonly used oxime ANTICHOLINERGIC DRUGS (Muscarinic Receptor Antagonists, Atropinic, Parasympatholytic)  PHARMACOLOGICAL ACTIONS (Atropine as prototype) It blocks all subtypes of muscarinic receptors 1. CNS Atropine has an overall CNS stimulant action. However, these effects are not appreciable at low doses which mainly produce peripheral effects because of restricted entry of atropine into the brain. 2. CVS Heart most prominent effect of atropine is tachycardia. It is due to blockade of M2receptors on SA node through which vagal tone decreases HR. BP Since cholinergic impulses are not involved in maintenance of vascular tone, atropine does not have any consistent or marked effect on BP 3. Eye The autonomic control of iris muscles and the action of mydriatics as well as miotics  Indirect Acting Cholinergic Agonists  Anticholinesterases A. Reversible Anticholinesterases B. Irreversible Anticholinesterases ↑ Lifetime of Ach (Endogenously) at the cholinergic nerve endings → accumulation of Ach in the synaptic space at M &N receptors of 1) ANS 2) Neuromuscular junctions  Physostigmine Neostigmine a) Reversible indirect-acting Pyridostigmine Cholinergic Agonists Edrophonium Donepezil, Rivastigmine and galantamine 1)Physostigmine 2) Neostigmine Natural Synthetic Pass BBB →Stimulate cholinergic site more polar →not pass BBB → NO CNS side in CNS effect Duration of action (2- 4 hrs) Moderate duration of action (30min-2hrs) Wide range of effects on → Its effect on skeletal muscle ✓ M & N receptor (ANS) >Physostigmine ✓ Nicotinic receptors of NMJs Can stimulate contractility → Paralysis Therapeutic applications Therapeutic applications 1)Intestinal or bladder atony 1)Treatment of myasthenia gravis 2)Glaucoma 2)Stimulate bladder & GIT 3)Atropine (Anticholinergic) overdose 3)Used as an antidote for Tubocurarine Adverse effects Adverse effects 1) CNS (↑ Doses → Convulsions) Generalized cholinergic stimulation 2)Heart → Bradycardia & ↓COP causes 3)Accumulation of ACh at NMJs → 1) Salivation, Diarrhea, Nausea Skeletal muscle paralysis. 2) Abdominal pain, Bronchospasm N.B Myasthenia Gravis It is auto-immune disease. Caused by antibodies that bind to nicotinic receptors of skeletal muscle Characterized by weakness of skeletal muscles. E.g. ✓ Eye muscle (ptosis) ✓ Limb muscle ✓ Respiratory muscle 3) Pyridostigmine Used in the chronic management of myasthenia gravis Duration of action is longer than that of neostigmine (3-6 h). Adverse effects of these agents are similar to those of neostigmine. 4) Edrophonium Prototype short-acting agent. More rapidly absorbed Short duration of action (10 -20 mins). I.V injection of edrophonium → Rapid ↑ in muscle strength. Atropine is used as an antidote for edrophonium overdose and toxicity. 5) Donepezil, Rivastigmine and Galantamine Used to delay the progression of Alzheimer's disease Patients with Alzheimer’s disease have a deficiency of cholinergic neurons in CNS. B)Irreversible indirect-acting cholinergic Agonists (Irreversible anticholinesterase) They are used as: 1) Insecticides: Parathion and malathion. 2) War gas: Tabun, sarin, 3) Metrifonate is an oral antibilharzial drug. They covalently bind to serine OH at the active site of AChE The enzyme is permanently inactivated O Restoration of acetylcholinesterase requires the synthesis of a new enzyme. Cholinesterase reactivation Pralidoxime (PAM) can reactivate inhibited acetylcholinesterase. Displaces the organophosphate and regenerates the enzyme. Treatment must be within hrs. O Because the phosphorylated enzyme slowly changes to a form that cannot be reversed. Parasympatholytic Cholinergic antagonists (Anticholinergic drugs) 1)Muscarinic antagonists 2)Ganglionic blockers 3)Neuromuscular blocking drugs  Bind to cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects  Muscarinic antagonists 1) Natural belladonna alkaloids - Atropine -Scopolamine -Ipratropium 2) Synthetic atropine substitutes - Tropicamide - cyclopentolate  These drugs block the cholinergic sympathetic that are innervating sweat glands.  They do not block nicotinic receptors therefore the antimuscarinic drugs have little or no action at skeletal neuromuscular junctions or autonomic ganglia. 1)Atropine Tertiary amine belladonna alkaloid. A high affinity for muscarinic receptors, where it binds competitively preventing acetylcholine from binding to those sites. Acts both centrally and peripherally. Topically in the eye, the action may last for days (3 days) Pharmacological action of atropine 1)Eye A) Mydriasis (Dilation of the pupil) → passive mydriasis (Unresponsiveness to light) Block the Block M3 in circular muscle →↓ Gq (IP3) pathway →↓ contraction →Mydriasis cholinergic activity B) Cycloplegia (Inability to focus for near vision) Block M receptor in ciliary muscle →Cycloplegia C) ↑ IOP In patients with narrow (Close) angle glaucoma Mydriasis →Close angle →↓aqueous humor drainage →↑ IOP 2) Cardiovascular a) Small doses → Stimulation of cardioinhibitory center in the medulla → Bradycardia (↓HR) b) High doses Block M2 receptors on SA node → Tachycardia (↑HR) blood pressure is unaffected Arterial c) but at toxic levels Atropine will dilate the cutaneous blood vessels especially blush area (Atropine flush) 3) Respiratory system 4)GIT Block M3 receptor → →↓ Gq (IP3) pathway →↓ contraction →↓ Activity of the GIT → relaxation → antispasmodic effect. 5) Urinary bladder a) Relaxation of bladder wall (detrusor muscle) b) Contraction of sphincter → Urine retention  Used in enuresis (involuntary voiding of urine) → children ▪ α adrenergic agonist with fewer side effects may be more effective 6) Secretions Atropine blocks the salivary glands → drying effect (Xerotomia) ▪ ↓ Sweat secretion → ↑ body temperature  Therapeutic uses of atropine 1)Mydriatic for retinal examination 2)Antispasmodic 3) Nocturnal enuresis 4) Hyperhidrosis 5) Vomiting and motion sickness (Scopolamine is better) 6) Antidote for cholinergic agonists e.g. Organophosphorus poisoning 7)Pre-anesthetic medication → (Antisialagogue) ↓ salivary and bronchial secretions and prevent bronchospasm. Stimulate the RC (counteracts the inhibitory effects of some anesthetics and morphine). Protect heart from bradycardia induced by some general anesthetics. Prevent vomiting.  Adverse effects of atropine 1)Dry mouth 2)Tachycardia 3)Blurred vision 4)Constipation 5)CNS include a)Confusion, restlessness and delirium b)May progress to depression, collapse of the circulatory and respiratory systems and death. Contraindications of atropine 1)Glaucoma 2)Fevers 3)Constipation and paralytic ileus 4)Senile hypertrophy of prostate. 5)Allergy to atropine.  2)Scopolamine ▪Tertiary amine belladonna alkaloid ▪Produces peripheral effects similar to those of atropine. ▪Greater action on the CNS & longer duration of action in comparison with atropine Actions ▪Most effective anti-motion sickness drug ▪Unusual effect of blocking short term memory (Amnesia) ▪It may produce euphoria and is subject to abuse. ▪In contrast to atropine oScopolamine produces sedation, but at higher doses can produce excitement. oLess potent than atropine in its effect on the heart, bronchial muscles and intestine  Therapeutic uses 1) Prophylaxis of motion sickness 2) Adjunct drugs in anesthetic procedures. Adverse effects →as atropine 3) ipratropium ▪ Inhaled ipratropium (quaternary derivative of atropine) is useful in treating asthma in patients who are unable to take adrenergic agonists. ▪ Because of its positive charge, it does not enter the systemic circulation or the CNS, isolating its effects to the pulmonary system. ▪ Also beneficial in the management of chronic obstructive pulmonary disease 4) Tropicamide and Cyclopentolate ▪ Used as ophthalmic solutions for retina examination ▪ Shorter duration than atropine O Tropicamide (6 hrs) and Cyclopentolate (24 hrs) Sympathomimetic drugs Lec 12  The general effects of sympathomimetic drugs C.V.S Heart (β1 receptor) 1)↑ Contractility (+ve Inotropic effect) 2 ) ↑ Heart rate (+ve Chronotropic effect) 3 ) ↑ Conductivity (+ve Dromotropic effect) Blood vessels 1) α1 → V.C of B.V of skin and mucous membrane, kidney, GIT 2) β2 → V.D of B.V of skeletal muscle, liver Respiratory β2 → Bronchodilatation system GIT ▪ Sphincter part → α → Contract ▪ Non sphincter part → α s β → Relaxes  Genitourinary  Bladder ▪ Sphincter → α1 →contract sphincter →urinary continence tract ▪ Detrusor muscle →β2 →relaxation  Men → α1 →prostatic smooth muscle contraction  Women →Uterus →α1 →Contraction β2 →Relaxation Eye α1 →Contraction of radial muscle (dilator pupillary muscle) →Active Mydriasis ▪ β →↑ Aqueous humor production Metabolic actions Hyperglycemia due to: a) ↑ Glycogenolysis in the liver (β2) b) ↑ Glucagon release (β2) c) ↓ Insulin release (α 2) ↑ Lipolysis (↑ free fatty acid in blood) (β3) β3 →↑Gs →↑CAMP→↑ lipase enzyme →hydrolyzes TGs →free fatty acid + glycerol  Direct sympathomimetic 1) Adrenaline (Epinephrine) Stimulate α1, α2, β1, β2 , β3  Low doses → β2 (affinity) effects predominate → VD of vascular system  High doses → α1 (affinity) effects predominate → VC of vascular system Pharmacokinetics  Absorption ▪ Ineffective orally →rapid destruction by digestive enzymes and liver metabolism ▪ Slow with S.C → because the drug causes local vasoconstriction. ▪ More rapid after I.M →due to vasodilatation (β2 effect).  Can be given I.V but must be used with caution to avoid cardiac arrhythmia (cardiac fibrillation).  Pharmacological action of adrenaline C.V.S Heart (β1 receptor) 1)↑ Contractility (+ve Inotropic effect) 2 ) ↑ Heart rate (+ve Chronotropic effect) 3 ) ↑ Conductivity (+ve Dromotropic effect) Blood vessels 1) α1 → V.C of B.V of skin and mucous membrane, kidney, GIT 2) β2 → V.D of B.V of skeletal muscle, liver Respiratory system β2 → Bronchodilatation GIT ▪ Sphincter part → α → Contract ▪ Non sphincter part → α s β → Relaxes  Genitourinary  Bladder ▪ Sphincter → α1 →contract sphincter →urinary continence tract ▪ Detrusor muscle →β2 →relaxation  Men → α1 →prostatic smooth muscle contraction  Women →Uterus →α1 →Contraction β2 →Relaxation Eye α1 →Contraction of radial muscle (dilator pupillary muscle) →Active Mydriasis ▪ β →↑ Aqueous humor production Metabolic actions Hyperglycemia due to: a) ↑ Glycogenolysis in the liver (β2) b) ↑ Glucagon release (β2) c) ↓ Insulin release (α 2) ↑ Lipolysis (↑ free fatty acid in blood) (β3) β3 →↑ lipase enzyme →hydrolyzes TGs →free fatty acid + glycerol  Therapeutic uses 1) Bronchospasm Adrenaline is the drug of choice in the treatment of acute asthma and anaphylactic shock when bronchoconstriction has resulted in diminished respiratory exchange). 2) Hypersensitivity reactions such as Anaphylaxis shock 3) Cardiac arrest to restore cardiac rhythm 4) Adrenaline is added to local anesthetics to Prolong their action, by producing VC at the site of injection. 5) Local hemostatic, to stop hemorrhage from the nasal mucosa  Adverse effects of adrenaline 1) CNS disturbance (not direct effect on CNS)→ Anxiety, tension, tremors and headache 2) Cardiac arrhythmia 3) Adrenaline can induce pulmonary edema (due to VC of Pulmonary B.V → edema 4) ↑ Doses of Adrenaline may cause a sharp rise in blood pressure → cerebral hemorrhage. Contraindications s interaction of adrenaline 1) Diabetes (Adrenaline ↑ release of endogenous stores of glucose →hyperglycemia) So in the diabetic →↑ Insulin dose 2) β blocker →Block β receptor only leaving α receptor unblocked So β blocker prevent adrenaline effects on β receptors →so adrenaline act only on α →VC →↑ PR →↑ BP  2) Noradrenaline (NA or NE) C.V.S → α1, α2, β1 > β2 1)Vasoconstriction ▪ VC of most vascular beds including kidney (α1)→↑PR ▪ ↑ Systolic and diastolic blood pressures ▪ NE causes greater VC than E (because NE does not cause β2 VD compensation) E→ stimulate α1 →VC s stimulate β2 →VD (Compensate α ) NE → stimulate α1→ VC not act β2 (NO compensation ) →cause more VC 2) Reflex Bradycardia α1 stimulation →VC→↑ BP →Stimulating baroreceptors →reflex stimulate to vagus → Reflex bradycardia → ▪ Sufficient to counteract the local actions of NE on the heart rate ▪ But doesn’t affect the positive inotropic effect of the drug Therapeutic uses  NA is used to treat shock C Severe hypotension →Because it ↑ Blood pressure o However, dopamine is better, because it does not ↓ blood flow to the kidney as NA.  It is never used for: 1) Asthma (Because NA not affects β2 receptors) 2) In combination with local anesthetics NE is a potent VC → extravasation (discharge of blood from vessel into tissue)  3) Isoprenaline (Isoproternol) Stimulates β1 s β2 receptors→ Nonselective C.V.S 1) Heart → ↑ all cardiac Properties 2) B.V → V.D of coronary s skeletal muscles (β2 ) B.V → V.D of coronary s skeletal muscles (β2 ) Blood pressure → Hypotension Respiratory Bronchodilatation (β2) system Therapeutic uses of isoprenaline 1) Heart block 2) Bronchial asthma  4) Dopamine Activates D1, β1 s α1 receptors C.V.S Stimulate β1 receptor ( heart) →↑ HR s FOC →↑ COP At high doses → stimulates α1 receptors in B.V→ V.C→↑ PR Renal Activate D1 receptors (renal artery) →VD → ↑ blood flow to the kidney  Drug of choice for D1 receptor  Given by I.V. infusion because T1/2 is short (about 2 min).  Binds to dopaminergic receptors (Gs) in mesenteric s renal vascular beds → →VD  5) Dobutamine (Selective β1 agonist)  Doesn’t stimulate dopaminergic receptors.  ↑ AV node conduction velocity with little change in heart rate.  Given by I.V infusion to treat congestive heart failure (CHF)  6) Oxymetazoline (α1 s α2 agonist ) Therapeutic uses 1) Nasal decongestant. 2)Relief of redness of the eyes associated with swimming, cold, or contact lens (ophthalmic drops)  7) Phenylephrine Selective α 1 agonist Used as Nasal decongestant C Mydriatic Induces reflex bradycardia when given parenterally (No direct effect on heart ). Adverse effects (Large doses) → 1) Hypertensive headache 2) Cardiac irregularities  8) Methoxamine (Selective α1 agonist) Direct acting, stimulate α1 receptors in arterioles →↑BP →↑ PR Therapeutic uses 1) Relief attacks of supraventricular tachycardia (Because of its effects on the vagus nerve). 2) Overcome hypotension during surgery involving halothane anesthetics  9) Selective α2 Agonists (Clonidine, Brimonidine ) ❑ Clonidine Activate central α2 receptors →↓ Sympathetic VMC → ↓ sympathetic outflow to the periphery →↓BP Therapeutic uses: 1) Essential hypertension (↓ BP because its action ON CNS). 2) ↓ withdrawal symptoms from opiates Adverse Effects Bradycardia, Dry mouth, Sedation ❑ Brimonidine  Selective α 2 agonist →ocularly →↓IOP in open angle glaucoma 1) ↓ Aqueous humor production 2) ↑ Aqueous humor outflow  10) Selective ß2 agonists (little effect on heart)  Smooth muscle → Relaxation (bronchioles s uterus ) Short-acting bronchodilator Long-acting bronchodilator Salbutamol Salmeterol (Slower onset of action) Terbutaline, Formoterol ▪ Administered by metered dose inhaler. Single-dose inhalation Sustained bronchodilation over 12 hrs ▪ Bronchodilation with less cardiac Drug of choice for nocturnal asthma stimulation These drugs are highly efficacious when combined with a corticosteroid B)Tocolytics (Uterine relaxant) Ritodrine ↓ Uterine contractions in premature labor.  B) Indirect acting adrenergic agonists 1)Amphetamine  Stimulates both α and β receptors  Acts indirectly by releasing catecholamine  Has marked CNS action Therapeutic uses of amphetamine a)Anorexigenic (↓Feeding center of hypothalamus) b)Analeptic (↑ stimulate R.C) c)Narcolepsy (sudden attach of sleep) d)Attention-deficit hyperactivity syndrome (ADHS) (Hyperactive children lacking the ability to be involved in any activity for longer than few minute) 2) Cocaine ▪ CNS stimulant ▪ Drug of abuse ▪ It inhibits neuronal reuptake of NE →Accumulate NE in synapse →↑ sympathetic activity as well as potentiation of action of EPI and NE