Introduction To Pharmacology 2nd Year PDF

Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani The nervous system is divided into two anatomical divisions: the central nervous system (CNS), which is composed of the brain and spinal cord. And The peripheral nervous system is subdivided...

Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani The nervous system is divided into two anatomical divisions: the central nervous system (CNS), which is composed of the brain and spinal cord. And The peripheral nervous system is subdivided into the efferent and afferent divisions. The efferent portion of the peripheral nervous system is further divided into two major functional subdivisions: the somatic and the ANS. The somatic efferent neurons are involved in the voluntary control of functions such as contraction of the skeletal muscles essential for locomotion. The ANS, regulates the everyday requirements of vital bodily functions without the conscious participation of the mind. The autonomic nervous system consists of 1. Sympathetic neurons 2. Parasympathetic neurons 3. Enteric neurons Function of sympathetic nervous system 1. Increase heart rate 2. Increase blood pressure 3. mobilize energy stores 4. bronchodilation 5. mydriasis 6. decrease blood flow to skin and GIT 25 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani 7. Fight-or-flight response Function of parasympathetic nervous system 1. Regulates GIT and renal excretion and hemostasis 2. Decrease heart rate 3. Decrease blood pressure 4. Bronchospasm 5. Miosis 6. Rest-and-digest Function of the enteric plexuses 1. Located in gut 2. Regulated motility and secretion 3. Have the ability to stimulate itself Efferent neurons The ANS carries nerve impulses from the CNS to the effector organs through two neurons: the preganglionic neurons and the postganglionic neurons Location of autonomic nervous system The sympathetic and the parasympathetic neurons originate in the CNS and emerge from two different spinal cord regions. The preganglionic neurons of the sympathetic system come from the thoracic and lumbar regions (T1 to L2) of the spinal cord, and they synapse in two cord-like chains of ganglia that run close to and in parallel on each side of the spinal cord. The parasympathetic preganglionic fibers arise from cranial nerves and the sacral region (S2 to S4) of the spinal cord The synapse in ganglia near or on the effector organs. The enteric nervous system functions independently of the CNS and controls the motility, exocrine and endocrine secretions, and microcirculation of the GI tract. 26 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Innervation by the autonomic nervous system 1. Dual innervation: Most organs in the body are innervated by both sympathetic and parasympathetic nerve. But single system usually predominates in controlling the activity of a given organ. For example parasympathetic (vagus) nerve slows the heart rate, and sympathetic increases the heart rate, but vagus predominant control heart rate 2. Organs receiving only sympathetic innervation: adrenal medulla, kidney, pilomotor muscles, and sweat glands Chemicals and signaling Neurotransmitters Communication between nerve cells, other nerve cells or effector organs, occurs through the release of specific chemical. The release of neurotransmitter from preganglionic cell cause excitation of the postganglionic cell or effector organ Types of neurotransmitters 1. Noradrenalin \ Norepinephrine (adrenalin\ epinephrin ) 2. Acetylcholine 3. Dopamine 27 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani 4. Serotonin 5. Histamine 6. Glutamate 7. GABA Acetylcholine and norepinephrine are the primary chemical signals in the autonomic nervous system Nerves that release Acetylcholine are called cholinergic nerves Nerves that release noradrenalin or noradrenalin are called adrenergic nerve nerves. Acetylcholine mediates the transmission of nerve impulses in preganglionic cells in both the sympathetic and parasympathetic nervous systems. Acetylcholine also mediates the transmission of nerve impulses in postganglionic cells in parasympathetic nervous systems, adrenal glands and sweat gland (sympathetic nervous system). Norepinephrine mediates the transmission of nerve impulses in postganglionic cells in sympathetic nervous systems. Type of receptors 28 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Acetylcholine stimulates either muscarinic or nicotinic receptor Noradrenalin simulate either α or β receptor Exercise ( do it at home ) Compare between sympathetic and parasympathetic nervous system according to the following Sympathetic Parasympathetic Nerve Origin From CNS Location Of Ganglion Type Of Neurotransmitter Type Of Receptor Length Of The Fiber Cholinergic agonist (Parasympathomimetic) The preganglionic fibers terminating in the adrenal medulla, the autonomic ganglia (both parasympathetic and sympathetic), and the postganglionic fibers of the parasympathetic division use ACh as a neurotransmitter Neurotransmission in cholinergic neurons involves six sequential steps: 1) synthesis: acetayl CoA + choline choline acetylase Acetaylcholine + CoA 2) storage : presynaptic vesicles 3) release: excitation of presynaptic nerve increase Ca influx release of vesicles to the synaps 4) binding of ACh to a receptor (Muscarinic or nicotinic ) 5) degradation : cholinesterase break down acetylcholine to choline + acetate, ( true cholinesterase found in CNS and RBC while pseudocholinesterase, is found in the plasma) 6) recycling/ uptake : Choline is recycled to form ACh 29 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Cholinergic receptors 1. Muscarinic receptor : ( G-protien ) M1, M2, M3 found on ganglia of the peripheral nervous system and on the autonomic effector organs, such as the heart, smooth muscle, brain, and exocrine glands. These receptors are selectively stimulated by muscarine and blocked by atropine 30 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Receptor Location Effect M1 gastric parietal cells Increase gastric acid secretion M2 cardiac cells and smooth muscle Bradycardia M3 bladder, exocrine glands, and Urination, miosis , increase glandular secretion smooth muscle increase contraction of smooth muscle M4 &M5 CNS 2. Nicotinic receptors: ( ion channel ) Nn and Nm Nicotine at low concentration stimulates the receptor, whereas nicotine at high concentration blocks the receptor. Receptor Location Effect Nn CNS, the adrenal Stimulation of adrenal gland and medulla, autonomic stimulation of ganglion and postganglionic ganglia nerves. High dose cause tachycardia and increase blood pressure Nm neuromuscular junction Contraction of skeletal muscles (NMJ) in skeletal muscles DIRECT EFFECTS OF AUTONOMIC NERVE ACTIVITY Organ Parasympathetic Receptor Eye Radial muscle + Circular muscle Miosis (pupil becomes narrower) M3 Ciliary muscle Contraction (for near vision) M3 Heart Sinoatrial node SA node (pacemaker of ↓in heart rate M2 heart) Ectopic pacemakers Contractility Decreases (atria) M2 Blood vessels Skeletal muscle vessels Endothelium (drug effect) releases M3&M5 (NO) Lungs Bronchiolar smooth muscle Contracts M3 Gastrointestinal tract 31 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Smooth muscle Walls Contracts M3 Sphincters Relaxes M3 Secretion Increases M3 Genitourinary smooth muscle Bladder wall Contracts M3 Sphincter Relaxes M3 Uterus, pregnant No effect Penis, seminal vesicles Erection M Parasympathomimetic drugs 1. Direct a. Choline esters i. Acetylcholine ii. bethancol iii. Methacholine iv. carbachol b. Alkaloids i. Pilocarpine ii. Muscrine iii. Nicotine iv. Libeline 32 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani 2. Indirect a. Reversible i. Physostigmine ii. Neostigmine iii. Tacarine iv. danepezil b. irreversible : organophosphorus compounds Direct-acting cholinergic agonists Acetylcholine lacks therapeutic importance because is is rapidly Inactive orally by cholinesterase and cannot cross membranes Activate both M and N receptors Action of acetylcholine 1. CVS decrease heart proper 2. BP: small dose hypotension,large dose hypertension 3. GIT:increase secretion and motility 4. Lung:bronchoconstriction , secretion 5. UT:contration of wall and relax of sphincter 6. Eye:miosis 7. Skeletal muscle: stimulation of NMJ Bethanechol Not hydrolyzed by cholinesterase Stimulate muscarinic receptors only Action : stimulate GIT secretion and motility Stimulate urination Uses : atonic bladder, postoperative urinary retention Adverse effect: sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani 32 Methacholine Not effective orally, don’t cross BBB Not hydrolyzed by cholinesterase Stimulate muscarinic receptors only Used: in atrial tachycardia Adverse effects : heart block ,hypotension, Bronchoconstriction Carbachol Effective orally Not hydrolyzed by CHE Stimulates M&N receptors Action : stimulates the depress CVS and GIT , miosis Uses : glaucoma Adverse effects: eye drops have no adverse effects Degree of effect Choline Ester by ACE Muscarinic Receptors Nicotinic Receptors Extremely affected Highly affects Highly affects Acetylcholine ++++ +++ +++ Slightly affected Extremely affects No effect Methacholine + ++++ - Not affected Moderately affects Highly affects Carbachol - ++ +++ Not affected Moderately affects No effect Benthanechol - ++ - Pilocarpine Not hydrolyzed by CHE penetrate BBB Action: : miosis and contraction of the ciliary muscle. increase sweat, tears, and saliva Uses: glaucoma counteract atropine effect on eye Adverse effects: blurred vision, night blindness, profuse sweating and salivation. Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani 33 Indirect-acting cholinergic agonists: anticholinesterase agents (reversible) Anticholinesterases (anti-ChEs) are agents which inhibit ChE, protect ACh from hydrolysis. Reversible inhibitors reacts slowly with cholinesterase enzyme while irreversible inhibitors reacts extremely slowly. Pharmacological action: CNS: stimulation of ganglion, persistent stimulation is followed by block of nerves CVS: bradycardia and hypotension (M-receptors) Skeletal muscle: contraction followed by paralysis (Nm) Physostigmine Mechanism of action : reversible inhibition of cholinesterase Action : stimulates M,Nn and Nm receptors and cross BBB The effect last for 30-120 min Uses: bladder and GIT atony, atropine poisoning Adverse effects: convulsions, Bradycardia and paralysis of skeletal muscle. Neostigmine Mechanism of action : reversible inhibition of cholinesterase Action : stimulates M, Nn and Nm receptors BUT DONT cross BBB More potent than physostigmine on skeletal muscles The effect is intermediate and last for 30-120 min Uses; myasthenia gravis paralytic ileus urine retention antidone for D-tubocurarine Adverse effects: salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani 34 Autonomic nervous 2nd Dr/Butheina Myasthenia gravis An autoimmune disorder due to development of an bodies directed to nico nic receptors (Nm) → weakness and easy fa gability on repeated ac vity, with recovery a er rest. Treatment is usually started with neos gmine , atropine , Cor costeroids Pyridostigmine and ambenonium Mechanism of action : reversible inhibition of cholinesterase durations of action are intermediate (3 to 6 hours and 4 to 8 hours, respectively) uses : chronic management of myasthenia gravis Adverse effects: similar to neostigmine. Tacrine, donepezil, rivastigmine, and galantamine : Used to treat Alzheimer’s disease  35 Indirect-acting cholinergic agonists: anticholinesterase agents (irreversible) Organophosphorus compound (OPC) Commonly used as agricultural insecticides Bind covalently to cholinesterase (Irreversibly) then leads to Aging of enzymes. New enzyme must be formed ( how long?) How OPC poisoning occur 1. Inhalation 2. Contaminated crops 3. Accidental 4. Intention 5. war Sign and symptoms of POC poisoning are DUMBELS 1. Diarrhea 2. Urination 3. Miosis 4. Bronchoconstriction 5. Excitation 6. Lacrimation 7. Salivation & sweat Treatment of POC poisoning 1. Prophylaxis 2. Treatment a. Wash the skin b. Wash the stomach c. Maintain airway d. Atropine e. CHE reactivators ( Oximes) CHE reactivators ( Oximes) Pralidoxime Should be given ½ -1 hr after exposure, Maxi 12 hrs before enzyme aging Cannot pass BBB has no effect on CNS manifestation Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Parasympatholytic Antimuscarinic drugs Block the action of Ach on autonomic nervous system Classification according to body systems affected 1. Hyoscine 2. Ipratropium 3. Atropine 4. Oxybutynin 5. Benztropine Atropine Belladonna alkaloid Mechanism of action: block muscarinic receptor centrally and peripherally Pharmacological action GIT : decrease motility ,decrease secretions , antispasmodic CVS: at high dose tachycardia (block M2) Low dose bradycardia due to block of presynaptic M1 Eye: mydriasis, cycloplegia Smooth muscle: relaxation (block M3), bronchodilation Glands; decrease gland secretion , decrease lacrimation , dryness of the mouth (xerostomia) Pharmacokinetics Absorbed from GIT , metabolized in liver and excreted by the kidney , t1\2 is 4 hours but local administration to the eye last for many hours 36 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Therapeutic uses 1. Fundal examination, examination of error of refraction 2. Treatment of bradycardia 3. Spasm, colic 4. Paranesthesia 5. Motion sickness 6. Treatment of organophosphorus poisoning Adverse effects dry mouth, blurred vision, “sandy eyes,” tachycardia, urinary retention, and constipation. CNS : confusion, hallucinations, and delirium physostigmine, treat atropine toxicity Scopolamine (hyoscine ) Mechanism of action: block muscarinic receptor centrally and peripherally Pharmacological Actions Motion sickness Sedation and blocking short-term memory At high dose euphoria Abuse Therapeutic uses: 1. Motion sickness 2. Postoperative nausea and vomiting Pharmacokinetics and adverse effects: These aspects are similar to atropine Ipratropium Mechanism of action: block muscarinic.Do not enter the systemic circulation or the CNS, their effects only local in the pulmonary system Given by inhalation Therapeutic uses: 1. chronic obstructive pulmonary disease (COPD) 2. Asthma Tropicamide and cyclopentolate 37 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Antimuscrinic agent used as ophthalmic solutions for mydriasis and cycloplegia Benztropine and trihexyphenidyl Benztropine and trihexyphenidyl Antimuscrinic agent used to treat Parkinson’s disease Oxybutynin, solifenacin, tolterodine, and trospium atropine- like drugs are used to treat overactive bladder Neuromuscular-Blocking Agents These drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors Nm on the skeletal muscle They are similar to Ach chemically Types Neuromuscular-Blocking 1. Nondepolarizing blockers (competitive): antagonist 2. Depolarizing blockers (noncompetitive): agonists Uses: During surgery facilitate tracheal intubation and muscle relaxation Nondepolarizing (competitive) blockers Tubocurarine Atracurium Cisatracurium Pancuronium Rocuronium Vecuronium Mechanism of action: a. At low doses: Nondepolarizing agents competitively block ACh at the nicotinic receptors Nm without stimulating it prevent depolarization of the muscle cell membrane and inhibit muscular contraction. Administration of cholinesterase inhibitors decrease their action 38 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani b. At high doses: Nondepolarizing agents can block the ion channels of the motor endplate further weakening of neuromuscular transmission, thereby reducing the ability of cholinesterase inhibitors to reverse their actions Actions Small muscles are paralyzed first. Face and eye are most susceptible followed by the fingers, limbs, neck, and trunk then intercostal muscles are affected and, lastly, the diaphragm. The muscles recover in the reverse manner. Pharmacokinetics Injected intravenously not effective orally Do not cross the blood–brain barrier These drugs are not metabolized Excreted unchanged in urine or plasma Vecuronium and rocuronium are deacetylated in the liver and excreted unchanged in bile. Atracurium releases histamine and is metabolized to laudanosine, which can provoke seizures Adverse effects: minimal side effects Drug interactions a. Cholinesterase inhibitors: overcome the action of nondepolarizing neuromuscular blockers b. Halogenated hydrocarbon anesthetics: enhance neuromuscular block c. Aminoglycoside antibiotics: enhance neuromuscular block d. Calcium channel blockers: enhance neuromuscular block. Depolarizing agents Succinylcholine Mechanism of action Bind to the nicotinic receptor Nm and acts like ACh Unlike ACh, which is instantly destroyed by AChE, the depolarizing agent persists at high concentrations in the synaptic cleft, remaining attached to the receptor for a relatively longer time and providing constant stimulation of the receptor. Phase I : depolarization of the receptor transient twitching of the muscle Phase II: resistance to depolarization due to continues stimulation flaccid paralysis 39 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Actions Succinylcholine initially produces brief muscle fasciculations that cause muscle soreness followed by paralysis Uses 1. Endotracheal intubation during the induction of anesthesia 2. Electroconvulsive shock treatment Pharmacokinetics: Injected intravenously Rapid hydrolysis by plasma pseudocholinesterase Adverse effects 1. malignant Hyperthermia 2. Apnea 3. Hyperkalemia Adrenergic agonist (sympathomimetic) Adrenergic neurons release norepinephrine NE as the primary neurotransmitter. Adrenergic drugs act on adrenergic receptors, located either presynaptically on the neuron or postsynaptically on the effector organ. Neurotransmitter of the adrenergic neurons 1. Synthesis : Tyrosine tyrosine hydroxylase DOPA DOPA DOPA decarboxylase dopamine Dopamine dopamine β-hydroxylase NE NE phenylethanolamine N-methyl transferas epinephrine Epinephrine MAO /COMT vanillyl mandelic acid ( VMA) 2. storage 40 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani 3. Release of norepinephrine 4. Binding to receptors: Adrenergic receptors ( α and β) 5. Degradation : metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase enzyme (MAO) 6. Reuptake : by norepinephrine transporter (NET) Adrenergic receptors (adrenoceptors) 1. α-Adrenoceptors: α1 and α2 α receptors, the potency and affinity is epinephrine ≥ norepinephrine >> isoproterenol. 41 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani a. α1 Receptors: (G protein ) found in postsynaptic cells. b. α2 Receptors: found on sympathetic presynaptic nerve endings causes feedback inhibition of norepinephrine. The α1 and α2 receptors are further divided into α1A, α1B, α1C, and α1D and into α2A, α2B, and α2C 2. β-Adrenoceptors: β 1, β 2, β 3 potency is isoproterenol > epinephrine > norepinephrine β1 receptors have approximately equal affinities for epinephrine and norepinephrine, whereas β2 receptors have a higher affinity for epinephrine than for norepinephrine. Major effects mediated by α- and β-adrenoceptors receptor Location effect α1 Arterioles Vasoconstriction Veins Increased peripheral resistance Sphincters Increased blood pressure Iris Mydriasis Increased closure of internal sphincter of the bladder α2 Presynaptic neurons Inhibition of norepinephrine release GIT, Veins, adipose Inhibition of acetylcholine release tissue Inhibition of insulin release β1 Heart Kidney adipose Tachycardia tissue Increased lipolysis Increased myocardial contractility Increased release of renin β2 Arterioles ,Veins Vasodilation Bronchus Decreased peripheral resistance Liver ,Pancreas Bronchodilation Uterus Increased muscle and liver glycogenolysis Iris Increased release of glucagon Relaxed uterine smooth muscle Heart Sinus β 1 Increase Automaticity and AV β 1 Increase Conduction velocity, automaticity Increase Condu β 1 Contractility, automaticity ction pathwa y Myofbrils 42 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Vascular β 2 Vasodilation smooth muscle Bronchial β 2 Bronchodilation smooth muscle Kidneys β1 Increase Renin release Liver α1,β 2 Increase Glycogenolysis and gluconeogenesis Adipose β3 Increase Lipolysis tissue Skeletal β2 Increased contractility Potassium uptake; muscle glycogenolysis Dilates arteries to skeletal muscle Tremor 43 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Eye- β2 Relaxation ciliary muscle GI β 2 Decrease Motility tract Organ Receptor Effect Heart Sinus and AV β1 Increase Automaticity Conduction pathway β 1 Increase Conduction velocity, automaticity Increase Myofbrils β1 Contractility, automaticity Vascular smooth muscle β 2 Vasodilation Bronchial smooth muscle β 2 Bronchodilation Kidneys β1 Increase Renin release Liver α1,β 2 Increase Glycogenolysis and gluconeogenesis Adipose tissue β3 Increase Lipolysis Skeletal muscle β2 Increased contractility Potassium uptake; glycogenolysis Dilates arteries to skeletal muscle Tremor Eye-ciliary β2 Relaxation muscle GI tract β2 Decrease Motility Gall bladder β2 Relaxation Urinary bladder β2 Relaxation detrusor muscle Uterus β2 Relaxation 44  Autonomic nervous 2nd Dr/Butheina ADRENERGIC AGONISTS Sympathomimetic A. Catecholamines Sympathomimetic amines ( epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines. 1. High potency ; show the highest potency in directly activating α or β receptors. 2. Rapid inactivation: metabolized by COMT , and MAO 3. Poor penetration into the CNS B. Noncatecholamines (phenylephrine, ephedrine, and amphetamine) They are not inactivated by COMT and are poor substrates for MAO Greater access to the CNS Mechanism of action 1. Direct-acting agonists: These drugs act directly on α or β receptors 2. Indirect-acting agonists: These agents may block the reuptake of norepinephrine or cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron Direct-Acting Adrenergic Agonists Epinephrine / adrenalin Stimulate with both α (high dose = vasoconstriction) and β (At low doses = vasodilation) receptors. Pharmacological Actions Cardiovascular: increase contractility of the myocardium (positive inotrope: β1 action) increases its rate of contraction (positive chronotrope: β1 action) increase oxygen demands on the myocardium increase renin release β1 constricts arterioles in the skin, mucous membranes, and viscera α dilates vessels in liver and skeletal muscle β2 decreased Renal blood flow increase systolic blood pressure, β2 45 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Respiratory: bronchodilation (β2 action) Hyperglycemia: increased glycogenolysis in the liver (β2 effect) increased release of glucagon (β2 effect) decreased release of insulin (α2 effect) Lipolysis Uses: 1. Bronchospasm 2. Anaphylactic shock 3. Cardiac arrest 4. Local anesthetic Pharmacokinetics given intramuscular, subcutaneously or intravenously (In emergency situations) It is rapidly metabolized by MAO and COMT and excreted in urine Adverse effects 1. CNS : anxiety, fear, tension, headache, and tremor 2. Cardiac arrhythmias/ tachycardia 3. Pulmonary edema Norepinephrine/ noradrenalin More potent on α-adrenergic receptor Pharmacological action 1. Cardiovascular Vasoconstriction: rise in peripheral resistance (α1 effect). Increase systolic and diastolic blood pressures 2. Baroreceptor reflex: Norepinephrine increases blood pressure vagal activity bradycardia, Uses: shock Pharmacokinetics: Given IV, duration of action is 1 to 2 minutes 46 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani It is rapidly metabolized by MAO and COMT, and inactive metabolites are excreted in the urine. Adverse effects These are similar to epinephrine If extravasation it can cause tissue necrosis Isoproterenol stimulates both β1 - and β2 receptors, no action on α receptors. Pharmacological Action increasing heart rate, contractility, and cardiac output increase systolic blood pressure slightly, but it greatly reduces mean arterial and diastolic blood pressures dilates the arterioles of skeletal muscle (β2 effect) decreased peripheral resistance bronchodilation (β2 effect) Use: rarely used in atrioventricular (AV) block Adverse effects: similar to epinephrine Dopamine Activate α (high doses) and β (low doses) receptors Activate D1 and D2 dopaminergic receptors vasodilation Pharmacological Actions Cardiovascular: increase heart rate and contraction β1 receptors vasoconstriction.( very high doses) α1 receptors Renal and visceral: Dopamine dilates renal and splanchnic arterioles D receptors Uses: 1. cardiogenic and septic shock 2. hypotension and severe heart failure Adverse effects: nausea, hypertension, and arrhythmias Fenoldopam D1 receptors agonist. It is used to treat severe hypertension Dobutamine 47 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani β1 receptor agonist. used to increase cardiac output in acute heart failure Phenylephrine Simulate α1 receptorsvasoconstriction and induces reflex bradycardia Uses 1. Hypotension 2. Nasal decongestant 3. Induce mydriasis Clonidine Agonist of presynaptic α2 receptors Uses 1. hypertension 2. addiction withdrawal symptoms ( opiates, tobacco smoking, and benzodiazepines) Adverse effects lethargy, sedation, constipation, and xerostomia Abrupt discontinuance must be avoided to prevent rebound hypertension. Salbutamol (Albutero)l and terbutaline Short-acting β2 agonists (SABA) used in asthma and uterine relaxant to suppress premature labor adverse effects : tremor, tachycardia , arrhythmia, restlessness, apprehension, and anxiety Salmeterol Long acting β agonists (LABAs) that are β2 selective Used in the prophylaxis of asthma Indirect-acting adrenergic agonists Cause the release, inhibit the reuptake, or inhibit the degradation of epinephrine or norepinephrine Amphetamine Mechanism of action : increase the release of catecholamines such as dopamine and norepinephrine from nerve terminals 48 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Pharmacological effects CNS : o alertness, increased concentration, euphoria, talkativeness, anti fatigue. o followed by deterioration , anxiety, restlessness, tremor, dysphoria and agitation. o respiratory center stimulation o decrease appetite o weak anticonvulsant, analgesic and antiemetic actions CVS : mild elevation of blood pressure Tolerance and psychological dependence occurs Uses of amphetamine  Hyperkinetic syndrome (attention deficit disorder)  Fatigue and depression  Narcolepsy  obesity Adverse effects  Acute effect : tremors, irritability and insomnia  Convulsion and coma at high doses  Cardiac stimulation  Chronic effect : weight loss ,schizophrenia  Abstinence syndrome: prolong sleep, fatigue, extreme hunger, long lasting depression Cocaine Mechanism of action Inhibiting dopamine, NE and 5HT transporter (DAT, NET, SERT) Pharmacological action Increase in heart rate and blood pressure due to stimulation of vasomotor centre Arousal, improved alertness, sense of self-confidence and well-being. Chronic used : involuntary motor activity, stereotyped behavior, paranoia and irritability Nausea and vomiting Have no tolerance Uses : Cocaine is used rarely as local aesthesia 49 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Mixed-action adrenergic agonists Ephedrine and pseudoephedrine Mechanism of action : release stored norepinephrine from nerve endings directly stimulate both α and β receptors poor metabolized by COMT and MAO eliminated in urine pharmacological action : Raises systolic and diastolic blood pressures Bronchodilation Mild CNS stimulation Use Pseudoephedrine nasal and sinus congestion Ephedrine hypotension ADRENERGIC ANTIGONISTS Sympatholytic α – blockers Phenoxybenzamine Mechanism of action : nonselective α1 and α2 receptors blocker (irreversible and noncompetitive) Pharmacological action Decreased peripheral resistance provokes a reflex tachycardia. But the block presynaptic inhibitory α2 receptors in the heart increased cardiac output Reverse the α agonist actions of epinephrine. For example, the vasoconstrictive action but not the vasodilation caused by stimulation of β2 Therefore, in the presence of phenoxybenzamine, the systemic blood pressure decreases in response to epinephrine Uses 1. Pheochromocytoma 2. Raynaud disease 50 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Adverse effects Postural hypotension Nasal stuffiness Nausea and vomiting Reflex tachycardia contraindicated in patients with coronary artery disease Phentolamine Mechanism of action: nonselective but competitive α1 and α2 receptors blocker Pharmacological action Postural hypotension caused by epinephrine reversal Reflex cardiac stimulation and tachycardia Arrhythmias and anginal pain Uses 1. Pheochromocytoma 2. hypertensive crisis contraindicated in patients with coronary artery disease Prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin Mechanism of action : selective competitive blockers of the α1 receptor. (α1 > α2) Action : Decrease peripheral vascular resistance Lower blood pressure Cause minimal changes in cardiac output, renal blood flow, and glomerular filtration rate Tamsulosin more selective on α1A receptors decreases tone in the smooth muscle of the bladder neck and prostate and improves urine flow has the least effect on blood pressure Develop tolerance First dose may produce orthostatic hypotensive response 51 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani Uses 1. Combination with other antihypertensive drugs 2. Benign prostatic hyperplasia Adverse effects: Dizziness, lethargy Nasal congestion Headache Orthostatic hypotension Sever hypotension when given with nitrates or PDE-5 inhibitors Inhibition of ejaculation Yohimbine Mechanism of action: is a selective competitive α2 -blocker Cause CNS sympathetic outflow and increase erectile function 52 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani β- BLOCKING AGENTS Types Nonselective β-blockers act at both β1 and β2 receptors : propranolol, Nadolol and timolol Cardioselective β antagonists primarily block β1 receptors: Acebutolol, atenolol Propranolol Mechanism of action : A nonselective β antagonist blocks both β1 and β2 receptors Pharmacological Actions: CVS: diminishes cardiac output (negative inotropic and chronotropic effect prevents β2 -mediated vasodilation in skeletal muscles, increasing peripheral vascular resistance Bronchoconstriction Disturbances in glucose metabolism Blocked action of isoproterenol uses: 1. Hypertension 2. Angina pectoris 3. Myocardial infarction 4. Migraine prophylaxis 5. Hyperthyroidism Pharmacokinetics Completely absorbed from GIT Metabolized by first-pass effect, and only about 25% of an administered dose reaches the circulation. The volume of distribution is (4 L/kg) Readily crosses the blood–brain barrier Metabolized, and most metabolites are excreted in the urine. Adverse effects 1. Bronchoconstriction 2. Arrhythmias: sudden stopped precipitating cardiac arrhythmias 3. Sexual impairment 4. Metabolic disturbances 5. CNS effects :depression, dizziness, lethargy, fatigue, weakness, visual disturbances, hallucinations, shortterm memory loss, 53 Introduction to Pharmacology – 2nd year Dr-Buheina Al-Amrani. Drug interactions Microsomal enzyme inhibitors: cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its antihypertensive effects. Use Hypertension in patients with moderate bradycardia Labetalol and carvedilol Mechanism of action: Antagonists of both α and β adrenoceptors Pharmacological action Peripheral vasodilation due to α blocking Carvedilol also decreases lipid peroxidation and vascular wall thickening Uses 1. Hypertension 2. Heart failure 3. Labetalol used in pregnancy-induced hypertension and hypertensive emergencies because Adverse effects 1. Orthostatic hypotension 2. dizziness Drugs Affecting Neurotransmitter Release Or Uptake Reserpine Mechanism of action : block the transport of (norepinephrine, dopamine, and serotonin) from the cytoplasm into storage vesicles. This causes the ultimate depletion of biogenic amines. was used for the management of hypertension but has largely been replaced with newer agents 54