ANS & CV Pharmacology - Autonomic Nervous System Pharmacology

Autonomic Nervous System Pharmacology 1  NS CNS PNS Brain Spinal Cord SNS ANS Sympathetic Parasympathetic Enteric NS NS NS...

Autonomic Nervous System Pharmacology 1  NS CNS PNS Brain Spinal Cord SNS ANS Sympathetic Parasympathetic Enteric NS NS NS 2 Autonomic NS  Operates involuntarily on reflex control  Functions to maintain the constancy of the internal environment (homeostasis)  Innervates three types of effector cells 1. Smooth muscle 2. Cardiac muscle 3. Exocrine glands Somatic NS innervates skeletal muscle  Voluntary control of skeletal muscle 3  Anatomical differences: ANS-vs-SNS Neurons between CNS and effector cells  Two neurons in ANS  Only one neuron in somatic NS Synaptic junctions in ANS occur in ganglia which lie out side the cerebrospinal axis while no such structures occur in somatic NS. While efferent neurons in somatic NS are myelinated, generally postsynaptic autonomic neurons are nonmyelinated. 4 5  Autonomic Nervous System Has three divisions  Sympathetic nervous system (thoracolumbar)  Parasympathetic nervous system (craniosacral)  ¿¿¿Enteric nervous system??? 6 Physiology of the ANS The ANS controls smooth muscle, exocrine secretions, and rate & force of the heart Sympathetic and parasympathetic systems have opposing actions in some situations (e.g. control of heart rate), but not in others (e.g. salivary glands).  Sympathetic activity increases in stress ('fight or flight‘), whereas PNS activity predominates ‘rest & digest’. Both systems exert a continuous physiological control of specific organs under normal conditions 7 Fight or flight vs. rest and digest ORGAN SYMP. PARASYMP. Heart  rate and force  rate and force Blood vessels mostly constriction no effect (dilates some skeletal muscle arterioles and some veins) Airway smooth muscle dilatation constriction GI tract  motility  motility Male sex organs ejaculation erection Eye (pupil) dilatation constriction Sailvary glands secretion secretion Liver glycogenolysis no effect 8  Sympathetic vs Parasympathetic Location of cell body of preganglionic neuron  From brain stem and sacral segment of the spinal cord in Parasympathetic  From thoracic and lumbar segments of the spinal cord in Sympathetic Location of ganglia  Close to effector cell in parasympathetic  Generally close to vertebral column in sympathetic Ratio of preganglionic to postganglionic neurons  Almost one to one in parasympathetic  One to more than 20 in sympathetic 9 10 Autonomic Neurotransmitters  Neurotransmission in the PNS occurs at three major sites:  Autonomic ganglia  Autonomic neuroeffector junctions  All somatic motor end plates on skeletal muscle.  Acetylcholine and norepinephrine (noradrenaline) are the major autonomic neurotransmitters. 11 Neurotransmitters at different peripheral sites 12  Acetylcholine (Ach)  Neurotransmitter at All autonomic ganglia All parasympathetic neuroeffector junction (NEJ) Some sympathetic NEJ (those innervating sweat glands) All somatic neuromuscular junctions.  Cholinergic neurons: Neurons that release Ach  Cholinoreceptors: receptors with which Ach interacts  Cholinomimetic drugs are those that mimic Ach on interaction with cholinoreceptors or also called parasypatomimetics  Cholinoreceptor antagonists are drugs that antagonize the effects of Ach 13  Norepinephrine (NE) and epinephrine (Epi)  NE is the neurotransmitter at sympathetic postsynaptic neurons except those innervating sweat glands  Adrenergic neurons: that release NE and/or Epi  Adrenoceptors: receptors with which NE or Epi interacts.  Adrenomimetic (sympathomimetic): drugs that mimic NE/ Epi on interaction with adrenoceptors  Adrenoceptor antagonists are drugs that antagonize the effect of NE/ Epi 14 Neurohumoral Transmission 15  Steps in Neurohumoral transmission  Synthesis of the transmitter  Storage of the transmitter  AP triggered release of the transmitter  Interaction of the released transmitter with receptors on the effector cell membrane and the associated change in the effector cell  Rapid removal of the transmitter from the vicinity of the receptors  Recovery of the effector cell to the state that preceded transmitter action 16  Presynaptic modulation  Presynaptic release of transmitters depends on the transmitter themselves and chemicals released by other tissues into the synapse.  Example Ach inhibits its own release and NE inhibits Ach and its own release.  Heterotropic inhibition is when a neurotransmitter affects the release of another.  Homotropic inhibition is when a transmitter, by binding to a presynaptic autoreceptors, affects its own release from the nerve terminal 17 18  Drugs acting on the cholinergic system 19  Cholinergic transmission Synthesis of Acetylcholine  Choline is taken up from extracellular sites by a carrier mediated, sodium dependent, transport. This can be blocked by hemicholiniums.  Choline -Acetlytransferase (ChAT) effects acetylation of Choline with acetyl-coA 20  Vesicular storage of Ach  Synthesized Ach (and ATP, Ca2+, and Mg2+) is actively transported by vesicular transporter into vesicles in nerve terminals (The process is inhibited by vesamicol)  Release of Ach on arrival of action potential at the nerve terminal causes opening of voltage gated Ca2+ channels ↑ IC Ca2+ → fusion of vesicular membrane with the surface membrane → Ach exocytosis into the synaptic space (inhibited by botulinium toxin) 21 Termination Ach action Ach is rapidly inactivated in the synapse by the action of Acetylcholinesterase 22 Nicotinic and Muscarinic Cholinoreceptors Nicotinic receptors  They are ligand-gated ion channels and fall into b1 a1 e three main classes: ganglionic (Nn g a1 ), muscle b2 b4 a4 b2 a3 b4 (Nm b2 a4 ) and CNS ( b4 a3 ) subtypes  Mediate fast excitatory synaptic transmission at neuro-mascular junction, autonomic ganglia, adrenal medulla and various sites in the CNS. 23  Muscarinic receptors  Are G-protein coupled receptors found on tissues innervated by postganglionic parasympathetic neurons and on sweat glands hormone signal outside GPCR plasma membrane agga cytosol AC GDP bbGTP GTP GDP ATP cAMP + PPi  They are five types: M1, M2, M3, M4, and M5 24 M1 (Neural)  Found mainly in the CNS, peripheral neurons and gastric parietal cells. They are selectively blocked by pirenzepine. M2 (Cardiac)  Found in the heart & presynaptic terminals of peripheral and central neurons. Selectively blocked by gallamine. M3 (Glandular)  Occur on exocrine glands, smooth muscles, endothelial cells and CNS M4 and M5  Found in the CNS  N.B. All mAChRs are activated by acetylcholine and blocked by atropine. 25  Signal Transduction M1, M3, M5 (odd numbered)  Activation results in increased Phospholipase C activity (and hence IP3 and DAG mediated effects)  Excitatory effects result on activation M2, M4 (even numbered)  Activation results in inhibition of adenylate- cyclase activity while M2 mediates K+ channel opening  Inhibitory effects result on activation 26 Cholinergic Agonists 27  1. Choline Esters  Acetylcholine  Ester of acetic acid and choline  Choline group contains a quaternary ammonium gp that confers high polarity (hydrophilicity)  Cholinesterases (AchE and Pseudo-ChE) catalyze hydrolysis of Ach to acetate and choline and this is the only means of termination of transmitter action of Ach  The therapeutic usefulness of ACh is limited by:-  Lack of selectivity as an agonist for different types of cholinoreceptors  Its rapid degradation by cholinesterases 28  Derivatives of Ach (Methacholine, carbachol and bethanechol)  Are too hydrophilic to cross membranes 29  Methacholine  Is structurally b-methylated Ach which renders the drug more selective to muscarinic receptors and resistant to cholinesterase activity  Increased potency and duration of action relative to Ach  Carbachol  Differs from Ach only in the substitution of a carbamoyl group for the terminal methyl group of Ach  This renders carbachol completely resistant to degradation by cholinesterase  Its receptor selectivity is not improved for muscarinic Vs nicotinic  Bethanechol  Combines the addition of a methyl group and the substitution of the terminal carbamoyl group  It is selective agonist of muscarinic receptors and is resistant to degradation by cholinesterases 30  2. Naturally occurring alkaloids Naturally occurring alkaloids: pilocarpine, muscarine, nicotine, lobeline Pilocarpine, nicotine, lobeline are tertiary amines and can readily cross membranes, while muscarine, a quaternary ammonium cpd does not cross membranes 31 Pharmacological Effects of Cholinergic Agonists 32  Parasympathetic activation produces effect by two mechanisms  Released Ach interacts with muscarinic receptors on effector cell membrane  The Ach also interacts with presynaptic muscarinic receptors to inhibit release of transmitters Circulating cholinergic agonists act in the same way to modulate parasympathetic & sympathetic systems 33 Effect on Cardiovascular system  Vasodilation  Mediated by NO production up on activation of M3 receptors on endothelial cells.  Decrease in cardiac rate (-ve chronotropic)  Decrease in the rate of conduction in SA node and AV conduction systems (-ve dromotropic)  Decrease in the force of cardiac contraction (-ve inotropic) 34  Gastrointestinal tract  Increased intestinal tone and peristaltic activity  Stimulation of salivation and acid secretion (M1)  Relaxation of most sphincters Genitourinary tract  Stimulation of the detrusor muscle and relaxation of the trigone and sphincter muscles of the bladder, thus promoting voiding  The human uterus is not notably sensitive to muscarinic agonists 35  Respiratory system  Contraction of bronchial smooth muscle (bronchoconstriction)  Stimulation of glands of the tracheobronchial mucosa→secretion Exocrine glands  Stimulation of secretion (lacrimation, salivation, sweating) 36  Eye  Contraction of two important muscles in the eye  Circular muscle (constrictor pupillae) in the iris  Smooth muscles of the ciliary body that controls the thickness of the lens  Decrease in intraocular pressure due to two reasons  Ciliary muscle contraction puts tension on trabecular meshwork, opening its pores and facilitating outflow of aqueous humor into the canal of Schlemm  Contraction of the iris sphincter pulls the peripheral iris away from the trabecular meshwork, thereby opening the path for aqueous outflow. 37 38  Clinical Use The therapeutic use of cholinomimetics is limited by the paucity of drug selectivity for specific subtypes of muscarinic receptors This lack of specificity combined with the broad- ranging effects of muscarinic stimulation on different organ systems makes the therapeutic use of cholinomimetic drugs a challenge 39  Glaucoma  Pilocarpine is the first choice among cholinomimetics. It can be applied as gel in chronic open-angle glaucoma and as drop in emergency cases of angle-closure glaucoma.  Carbachol is sometimes effective in treating cases of open-angle glaucoma that are resistant to pilocarpine. 40  Surgery of the Eye  Ach is used in cases where miosis is required for a short period of time (10 min).  Carbachol is used for operations necessitating miosis for longer than 10 minutes Diagnosis of Bronchial Hyper-reactivity  Methacholine is indicated for the diagnosis of bronchial airway hyper-reactivity in subjects who do not have clinically apparent asthma 41  Urinary and GI Smooth muscle dysfunction  Urinary Retention To treat postsurgical non obstructive bladder dysfunction associated with the retention of urine  GI atony Treatment of postoperative ileus (atony or paralysis of the stomach or bowel following surgical manipulation) and congenital megacolon  Bethanechol most widely used for the purpose 42  Alzheimer’s disease  Found to have a development of cholinergic deficits.  Oxotremorine has been developed as a muscarinic agonist which is able to pass through the BBB and act centrally. It is not available for clinical use yet. Contraindications  Major contraindications are: asthma, hyperthyroidism, coronary insufficiency, and acid-peptic disease. Adverse Reactions ADR include sweating, abdominal cramps, sensation urinary bladder, difficulty in visual accommodation, headache, and salivation. 43 Cholinesterase Inhibitors (Indirectly acting Cholinomimetics Drugs) 44 Cholinesterase Inhibitors AcetylCholinesterase (AchE) inhibitors are indirectly acting cholinergic agonists. Inhibition of AchE slows or prevents the degradation of Ach released at synapses prolonging the activation of cholinoreceptors produced by synapticaly released Ach. Some of the AchE inhibitor drugs have intrinsic nicotinic activity (quaternary ammonium cpds) Cholinomimetic effect of AChE inhibitors is more selective than the effect of directly acting cholinomimetics, because the inhibitors of AChE increase the activation of cholinoreceptors only at active cholinergic synapses 45  Types of Cholinesterases Acetylcholinesterase (TRUE)  Present in nerve synapses and NMJ and RBCs  The primary substrate is Ach Butyrylcholinesterase (PSEUDO)  Present in the plasma and in lots of tissues  Metabolises Ach and other drugs 46  ChE inhibitors AchE inhibitors are broadly classified into two 1. Reversible  Non-covalent inhibitor drugs: simple alcohols bearing a quaternary ammonium’ eg, edrophonium.  Carbamic acid esters of alcohols bearing quaternary or tertiary ammonium groups (eg, neostigmine). 2. Irreversible  Organic derivatives of phosphoric acid (organophosphates, eg, echothiophate). Are generally irreversible. 47  Nature of interaction with AchE Non-covalent inhibitors  Bind electrostaticaly & by hydrogen bonds to the anionic active site, preventing access of Ach (2-10 min)  Edrophonium, ambenenium, tacrine and donepezil (with longer activity and more lipophilicity) Carbamate esters  Same hydrolysis pattern same as for Ach but form carbamoylated enzyme, which is more resistant to hydration, and enzyme takes longer time to regenerate (in the order of 30 minutes to 6 hours)  Physostigmine, neostigmine, pyridostigmine, rivastigmine 48 Revesrible ChEI’s 49  Organophosphates Undergo binding and hydrolysis, resulting in a phosphorylated active site. The phosphorus- enzyme bond is extremely stable (hundreds of hours). Phosphorylated enzyme complex may undergo aging, which involves breaking of one of the oxygen-phosphorus bonds further strengthening the phosphorus-enzyme bond. Sarin, Tabun, Soman, Malathion, Parathion, Echothiophate are some of the drugs. 50 Irreversible ChEI’s 51 Pharmacological effects of AchE inhibitors 52  The anti-ChE agents potentially can produce 1. Stimulation of muscarinic receptor responses at autonomic effector organs 2. Stimulation, followed by depression or paralysis, of all autonomic ganglia and skeletal muscle (nicotinic actions) 3. Stimulation, with occasional subsequent depression, of cholinergic receptor sites in the CNS 53  Effects on autonomic cholinergic synapses ↑ed secretions from salivary, lacrimal, bronchial and gastrointestinal glands, increased peristaltic activity, bronchoconstriction, bradycardia and hypotension, pupillary constriction, fixation of accommodation for near vision, fall in intraocular pressure. Large doses can stimulate, and later block, autonomic ganglia, producing complex autonomic effects 54 Effects on neuromuscular junction Low (therapeutic) concentrations  Prolonged and intensified actions of physiologically released Ach (ed strength of contraction) At higher concentrations  Fibrillation of muscle fibbers With marked inhibition  Depolarizing neuromuscular blockade occurs and that may be followed by a phase of 55 nondepolarizing blockade  Effects on the CNS Tertiary compounds, such as physostigmine, and the non-polar organophosphates penetrate the BBB freely and affect the brain. Initial excitation, which can result in convulsions, followed by depression, which can cause unconsciousness and respiratory failure. Effects are mediated via the muscarinic receptors in the CNS 56 Neurotoxicity of organophosphates Many organophosphates can cause a severe type of peripheral nerve demyelination, leading to slowly developing weakness and sensory loss. This seems to result from inhibition of an esterase (not cholinesterase itself) specific to myelin. 57 Cholinesterase Reactivation Dephosphrylation of enzyme can be effected by strong nucleophilic cpds like the oximes (pralidoxime, obidoxime) Used in organophosphate poisoning but they should be used with in few hours following exposure. Once aging has occurred reactivation of cholinesterase is practically impossible. 58  Clinical use Myasthenia Gravis  Autoimmune disease in which the No of functional nicotinic receptors on skeletal muscle es, with consequent  in the sensitivity of muscle to ACh.  Anticholinesterase used in diagnosis and therapy are: Pyridostigmine, neostigmine, ambenenium 59  Smooth Muscle Atony  Non-obstructive paralytic ileus & atony of the urinary bladder, which may result from surgery.  Neostigmine is most commonly used, and it can be administered subcutaneously or intramuscularly Antimuscarinic toxicity  Toxicities with antimuscarinic drugs (atropine and scopolamine) and others with significant anticholinergic effect  Physostigmine has been used in such acute toxicities 60  Alzheimer’s Disease Functional changes in AD appear to result primarily from the loss of cholinergic transmission in the neocortex Tacrine, donepezil, rivastigmine, and galanthamine are cholinesterase inhibitors approved in AD. Produce modest but significant improvement in the cognitive function of patients with mild to moderate AD but do not delay the progression of the disease. 61  Glaucoma  Long-lasting AChE inhibitors, such as demecarium, echothiophate, and physostigmine are effective in treating open-angle glaucoma though are largely replaced by less toxic drugs Reversal of Neuromuscular Blockade  Used post operatively to reverse effects of Non- depolarising muscle relaxants  Neostigmine, pyridostigmine, and edrophonium are used for this purpose. 62  Unwanted effects Acute toxicity result from accumulation of Ach  First muscarinic stimulation, followed by nicotinic receptor stimulation and then desensitization of nicotinic receptors. Excessive inhibition leads to cholinergic crisis  Gastrointestinal distress, respiratory distress, CV distress (bradycardia or tachycardia, A-V block, hypotension), Visual disturbance, Sweating, loss of skeletal motor function, CNS symptoms (agitation, dizziness, and mental confusion).  Death usually results from paralysis of skeletal muscles required for respiration but may also result from cardiac arrest. 63  ANTICHOLINERGIC DRUG PHARMACOLOGY 64  These are drugs that selectively antagonize the actions of Ach or other cholinergic agonists at muscarinic (muscarinic blockers) and/or at nicotinic (nicotinic blockers) receptors. 65  MUSCARINIC BLOCKERS Chemistry  All of the antimuscarinic compounds are amino alcohol esters with a tertiary amine or quaternary ammonium group  Tertiary amines can cross membranes (including BBB) Antimuscarinic are competitive antagonists of the binding of Ach to muscarinic receptors 66 67 Pharmacological effects of Atropine & Scopolamine 68  CVS Heart  At lower dose = bradycardia  At higher dose = tachycardia  Generally blocks the effect of parasympathetic influence on the heart Blood vessels  Minimal effect due to the minor role cholinergic innervation in determining smooth muscle tone  Produces flushing due to vasodilation 69  GIT  Inhibits salivation at low doses  Inhibits gastric acid secretion and GI motility Urinary bladder  Inhibits excitatory effect of parasympathetic stimulation on detrusor muscle  Respiratory tract  Inhibits bronchial secretion  Relaxation of bronchial smooth muscle  Inhibits mucous secretion and mucociliary clearance 70  Eye Block contraction of the iris sphincter and the ciliary muscle, which results in  Dilation of pupil (mydriasis), causing photophobia  Loss of accomodation (cycloplegia), causing inability to focus on nearby objects 71  CNS Typical doses of atropine (0.2–2 mg) have minimal central effects Intermediate doses (2–10 mg), memory and concentration may be impaired More than 10 mg doses confusion, excitment, hallucinations, ataxia, and possibly coma. 72 Clinical Use 73  Cardiovascular use  Carotid sinus syncope  Sinus or nodal bradycardia associated with excessive vagal tone in acute myocardial infarction As preanaesthetic medication  To reduce excessive salivary and bronchial secretion induced by certain inhalational aneasthetics 74  Anticholinesterase poisoning  Atropine interferes with muscarinic effects and not the nicotinic ones Use in ophthalmology  Produce mydriasis (due to dilation of the pupil)  Produce cycloplegia(due to relaxation of ciliary muscles) 75  Use in GI disorders  Pirenzepine, telenzepine: more selective to M1 and are used in acid-peptic diseases  As adjunctive therapy in the treatment of irritable bowel syndrome and diarrhea  GI hypermotility (spasmolytics hyoscine, atropine methonitrate) 76  Uses in Urology  Propantheline , oxybutynin, dicyclomine, used for uninhibited bladder syndrome, bladder spasm, enuresis, and urge incontinence.  Tolterodine, a nonselective muscarinic antagonist, exhibits functional specificity for blocking muscarinic receptors in the bladder 77  Respiratory Disorders  Ipratropium in chronic obstructive lung diseases Parkinsonism  There is an apparent excess of cholinergic activity in the striatum of patients suffering from this disorder. Benztropine mesylate, biperiden, procyclidine, and trihexyphenidyl hydrochloride Prevention of motion sickness  Anticholinergic activity in the vestibular nuclei and reticular formation may account for their effect  Scopolamine is used for the purpose 78  Antimuscarinic poisoning lower doses  Signs of peripheral muscarinic blockade large doses  CNS effects (e.g., headache, restlessness, ataxia, and hallucinations) Mostly can be managed by removing unabsorbed drug, treating symptoms, and providing supportive therapy. Use of physostigmine in life-threatening effects (seizures, severe hypertension, hallucinations, or lifethreatening arrhythmias) 79  Side Effects Constipation, dry mouth, hypohidrosis (decreased sweating), mydriasis (dilated pupils), urinary retention, precipitation of glaucoma, decreased lacrimation, tachycardia, 80 Nicotinic Pharmacology Neuromuscular Blockers 82  Drugs can block neuromuscular transmission  Presynaptically by inhibiting Ach synthesis or release  Postsynaptically by binding to nicotinic receptors 1. Non-depolarising blocking agents: which act by blocking acetylcholine receptors or the ion channel 2. Depolarising blocking agents, which are antagonists at acetylcholine receptors. 83 Depolarizing Blockers Produce a two phased block (same mechanism of block as nicotine )  Phase I: Depolarization block (block can not be reversed, may even be prolonged, by anti-ChE drugs)  Phase II: Desensitization block (Block can be reversed by anti-ChE drugs) Succinylcholine is the only therapeutically useful drug in this group. Though not in clinical use decamethonium has also same activity. 84  Clinical Uses The principal advantage of succinylcholine is its rapid onset and ultra-short action. IV administration produces flaccid paralysis in less than 1 minute and lasts about 10 minutes. Suitable for short term procedures such as endotracheal intubation, setting of fractures, and prevention of injury during 85  Untoward Effects Bradycardia (preventable by atropine) Hyperkalemia  May lead to cardiac arrythmia and arrest Increased intraocular pressure Malignant hyperthermia in susceptible patients Muscle pain (due to the fasciculations) 86 Non-Depolarizing Blockers Include Tubocurarine, Atracurium, Mivacurium, Pancuronium, Vecuronium, Rocuronium, and Rapacuronium Are all reversible antagonists of Ach at NMJ d-tubocurarine is the prototype drug in this group. 87 Pharmacological Effects 88  Skeletal muscles With appropriate dose of nondepolarizing drugs, motor weakness progress to a total flaccid paralysis  Small rapidly moving muscles (those of the eyes, jaw and larynx) - relax 1st  Muscles of the limbs and trunk – follow  Then, the intercostals muscles and finally the diaphragm are paralyzed  Recovery occurs in reverse order Transient apnea usually occurs at the time of maximal effect 89  CNS  These drugs are quaternary ammonium compounds  Have no significant CNS effects at therapeutic doses 90  Autonomic ganglia and Muscarinic sites  d-tubocurarine causes partial blockade at autonomic ganglia and adrenal medulla  Pancuronium shows less ganglionic blockade but has some vagolytic action(tacycardia).  Atracurium, vecuronium, doxacurium, pipecuronium, mivacurium, and rocuronium are more selective 91  Histamine Release Tubocurarine causes release of histamine from mast cells which is responsible for the bronchospasm, hypotension, excessive bronchial and salivary secretion. Succinylcholine, mivacurium, doxacurium, and atracurium also cause histamine release, but to a lesser extent. The ammonio steroids, pancuronium, vecuronium, pipecuronium, and rocuronium, have even less tendency to release histamine. 92  Classification On chemical nature  Natural alkaloids and their congeners d-tubocurarine, alcuronium. They are seldom used Have longer period of activity, have ganglionic and muscarinic blocking activity and cause release of histamine from mast cells.  Ammonio steroids Pancuronium, pipecurium, rocuronium, vecuronium  Benzylisoquinolines Atracurium, doxacurium, mivacurium 93  Ammonio steroids Less tendency to induce release of histamine from mast cells. Block muscarinic receptors and produce tachycardia (vagolytic activity) Vecuronium and rocuronium do not produce tachycardia. 94  Therapeutic Uses To obtain relaxation of skeletal muscle during surgical anaesthesia, in various orthopedic procedures, such as the correction of dislocations and the alignment of fractures, and also to facilitate endotracheal intubation To prevent trauma during electroshock therapy Control of muscle spasms 95  Drug interactions Have been documented with certain general anaesthetics, certain antibiotics, Ca2+ channel blockers, and anti-ChE compounds. 96  Untoward effects Include prolonged apnea, cardiovascular collapse, those resulting from histamine release, and, rarely, anaphylaxis Malignant Hyperthermia  The clinical features include contracture, rigidity, and heat production from skeletal muscle resulting in severe hyperthermia, accelerated muscle metabolism, metabolic acidosis and tachycardia 97  Adrenergic Pharmacology 98  Synthesis of NE Tyrosine enters neurons by active transport, converted, in the cytosol, by the enzyme tyrosine hydroxylase to dihydroxyphenylalanine (dopa), which is then converted to dopamine by aromatic L–amino acid decarboxylase, (dopadecarboxylase). The dopamine is actively transported into storage vesicles, where it is converted to NE by dopamine hydroxylase. 99  Synthesis of NE (Cont’d) In noradrenergic neurons, the end product is NE In the adrenal medulla the enzyme phenylethanolamine N-methyltransferase, converts NE to Epi. Adrenal medulla contains approximately four times as much Epi as NE. The enzyme is absent in noradrenergic neurons 100 101  Hydroxylation of tyrosine is the rate limiting process and is activated following sympathetic stimulation. 102  Vesicular Storage of NE Dopamine hydroxylase is located only within the vesicles, There is a tendency for NE to leak from the vesicles into the cytosol, where it is destroyed by a mitochondrial enzyme, monoamine oxidase (MAO). However, most of the NE that leaks out of the vesicle is rapidly uptaken in to storage vesicles by an active transport system. 103  Vesicular Storage of NE (cont’d) Ensures regulated release of transmitters  Decreases intraneuronal metabolism  Decreases leakage of NE to the extracellular sites 104  Release of NE Action potential triggered exocytotic release of NE containing vesicles. This is the same process as the release of Ach. Neuropeptide Y and ATP are also released along with NE. 105 Removal of NE from the synapse Termination of its transmitter role Three processes contribute to this process 1. Transport back into the noradrenergic neuron (reuptake, uptake1) [87%] 2. Dilution by diffusion out of the junctional cleft (8%) and uptake into extraneuronal sites (extraneuronal uptake or ENT, uptake2) (5%) 3. Metabolic transformation  By MAO and COMT (catechol O-methyl transferase) 106  Adrenoceptors Can broadly be divided into two: a-AR & b-AR: – comparative potency; a-AR : EPI ≥ NE >>isoproterenol b-AR: isoproterenol > EPI ≥ NE – a-AR: constitutes a1 & a2 subtypes a1A, a 1B, and a 1D a 2A, a 2B, and a 2C – b-AR: constitutes b1 , b2 & b3 subtypes Are all GPCR 107  b-AR – Couple to Gs and activate adenylyl cyclase ( cAMP  activation PKA  activation of target proteins). – β1-mainly heart (+ve inotropic and chronotropic) – β2-receptors: bronchodilatation, vasodilatation, relaxation of visceral smooth muscle – selective β2 agonists relax smooth muscle with minimal effect on heart – selective β1 antagonists: a useful blocking effect on the heart minimal effect in bronchial smooth muscle – β3-receptors: lipolysis. 108  a1A is predominant receptor that causes vasoconstriction in many vascular beds a1B is the most abundant subtype in the heart a1D predominant receptor that causes vasoconstriction in the aorta 109  a2-AR  Mainly inhibit adenylate cyclase activity  Activate G protein-gated K+ channels (which may be Ca2+ dependent or Ca2+ independent), membrane hyperpolarization  Inhibit voltage gated Ca2+ channels  a2A inhibition of NE release from nerve endings and suppresses sympathetic outflow from the brain  a2B mediates vasoconstriction  a2C inhibits the release of catecholamines from adrenal medulla 110 Sympathomimetic drugs 111  Actions of catecholamines & sympathomimetic agents can be classified into seven broad types: 1. Excitatory action on certain types of smooth muscle (blood vessels supplying skin, kidney, and mucous membranes) & on gland cells (salivary, sweat glands) 2. Inhibitory action on certain types of smooth muscle (wall of the gut, bronchial tree, blood vessels supplying skeletal muscle) 3. Cardiac excitatory action 112 4. Metabolic actions (increased rate of glycogenolysis in liver and muscle and lipolysis from adipose tissue 5. Endocrine actions, such as modulation of secretion of insulin, renin, and pituitary hormones 6. Actions in the CNS, such as respiratory stimulation, an increase in wakefulness and psychomotor activity, and a reduction in appetite 7. Prejunctional actions that either inhibit or facilitate the release of neurotransmitters 113 CLASSIFICATION OF SYMPATHOMIMETIC DRUGS Direct acting  Act directly on one or more of the adrenergic receptors Indirect acting  Increase the availability of NE or Epi in synapses Release or displace NE from sympathetic nerve varicosities Block transport of NE into sympathetic neurons Blocking the metabolizing enzymes, MAO or COMT. Mixed acting  Indirectly release NE & directly activate receptors 114  Structure Activity Relationship (SAR) The NE molecule can be modified in several ways – Increasing the bulkiness of substituents on the N-atom: (adrenaline, isoprenaline and salbutamol); ↑ potency as β-agonists and less susceptible to uptake 1 and MAO. – Addition of an α-methyl group (α-methylnoradrenaline, metaraminol) increases α2-adrenoceptor selectivity and also renders compounds resistant to MAO, though they remain susceptible to uptake1. – Removal of the side-chain -OH group (dopamine) greatly reduces interaction with α- and β-adrenoceptors. 115  SAR (Cont’d) – Modification of the catechol -OH groups renders compounds resistant to COMT and uptake1 (salbutamol & many β-AR antagonists), but retains receptor activity. – Removal of one or both -OH groups (tyramine, amphetamine, ephedrine) abolishes affinity for receptors, but are substrates for uptake1. – Extension of the alkyl side-chain, with isopropyl substitution on the N-atom, and modification of catechol -OH groups (propranolol, oxprenolol, etc.) produce potent β-AR antagonists. 116  Endogenous catecholamines 117  Epinephrine: pharmacological effects Blood Pressure  Potent vasopressor  Rapid IV injection of pharmacological dose BP rises to a peak that is proportional to the dose As the response wanes, mean BP falls before returning to control level  Small dose (0.1 g/kg rapid IV infusion) causes fall in BP 118  Blood pressure (cont’d)  Slow IV infusion (10-30 g/min) or SC (0.5- 1.5mg) Moderate  in systolic BP (due to  in cardiac output) Peripheral resistance es (due to dominant b2), hence diastolic BP es 119  Vascular Effects  Constriction of cutaneous, mucosal and renal blood vessels (a1 mediated)  Dilatation of blood vessels supplying skeletal muscle (b2 mediated)  Epinephrine + a-AR antagonists ed TPR and ed MAP  Epinephrine + b-AR antagonists Pressor effect 120  Cardiac effects  ed heart rate and altered rythm  Cardiac systole: shorter and stronger  ed cardiac output  Cardiac work and oxygen consumption es  ed cardiac efficiency 121  Smooth muscle effects  GI smooth muscle Relaxation due to both a- & b-AR mediated effects Reduced intestinal tone and frequency and amplitude of spontaneous contraction Stomach is relaxed while pyloric and ileo-cecal sphincter are contracted  Uterine smooth muscle b2 mediated inhibition of uterine tone and contraction during the last month of pregnancy and parturition. 122  Smooth muscle effects (cont’d)  Urinary bladder Relaxation of detrusor muscle (b mediated) Contraction of trigone and sphincter muscle (a mediated) 123  Respiratory effects  Strong bronchodialator  Also have b2-mediated inhibition of release of inflammatory mediators from mast cells  Decreases bronchial secretion and congestion of mucosa (a-mediated) CNS effects  Too polar to cross the BBB 124  Metabolic effects  Inhibition of insulin secretion Predominant a2-mediated inhibition b2-mediated activation of release  ed glucose uptake by peripheral tissues  b-mediated activated glycogenolysis  free fatty acid level (b3-mediated lipolysis) Effects on the eye  Mydriasis, ed intraocular pressure 125  Pharmacokinetics Orally not effective SC: slow absorption (due to vasoconstriction) More rapid absorption through IM IV used only in emergency conditions Inhalational aerosol to produce local effect Metabolism is via hepatic MAO and COMT 126  Adverse effects, contraindications Restlessness, throbbing headache, tremor, palpitations, cerebral hemorrhage, cardiac arrhythmias Angina may be induced in coronary artery disease Contraindicated in patients taking b-AR blockers 127  Therapeutic uses Has limited clinical use Anaphylactic shock Prolong action of local anesthetics Restore cardiac rythm in patients with cardiac arrest Topical hemostatic agent To lower intraocular pressure 128  Norepinephrine Effects differ with Epi in ratio of their effectiveness in stimulating a & b Epinephrine and NE are equipotent at b1 NE is has little action on b2 NE is less potent than Epi on most a receptors 129  CVS  IV infusion of 10g/min ed systolic, diastolic and pulse pressures Increased total peripheral resistance Cardiac output may be unchanged or reduced Small doses do not cause reversal of BP typical of that of epinephrine No fall in blood pressure with the use a-AR blockers 130  Pharmacokinetics Orally ineffective Poor absorption from subcutaneous sites 131  Dopamine: pharmacological effects CVS  Dopamine exerts its cardiovascular actions by 1. Releasing NE from adrenergic neurons 2. Interacting with a-and b-ARs, and 3. Interacting with specific dopamine receptors  Low rates of dopamine infusion  D1-mediated vasodilation in renal, coronary and intercerebral vascular beds with little effect on other blood vessels or on the heart.  ed GFR, renal blood flow, Na+ excretion (appropriate in management of such states as CHF) 132  CVS (cont’d)  Higher rate of infusion b1-mediated +ve ionotropy Releases NE from nerve terminals ed systolic BP  Even higher levels  Activates a1-ARs and cause a more generallized vasoconstriction Clinical uses Treatment of severe congestive failure Treatment of cardiogenic and septic shock. 133  Adverse effects, contraindications Nausea, vomiting, tachycardia, anginal pain, headache, hypertension, and peripheral vasoconstriction. Extravasation of large amounts of dopamine cause necrosis. Contraindicated or used at a much reduced dosage if patient has received a MAO inhibitor. Careful adjustment of dosage also is necessary in patients who are taking tricyclic antidepressants. 134 b-AR AGONISTS 135  Isoproterenol Non-selective b receptor agonist with very low affinity for a receptors Pharmacological Effects  CVS ed peripheral vascular resistance ed Diastolic BP while systolic BP may remain unchanged or rise ed cardiac output 136  Pharmacological Effects (Cont’d)  Smooth muscles Relaxation especially those of the GI and bronchial Metabolized primarily by COMT (relatively resistant to MAO & is uptaken in to sympathetic neurons to a lesser extent than Epi & NE) Toxicity and Adverse effects  Palpitations, tachycardia, headache, and flushing are common and arrhythmias 137  Therapeutic Uses  Management of bronchospasm (inhalation)  In emergencies to stimulate heart rate in patients with bradycardia or heart block and asthma (I.V.) 138  Dobutamine Relatively b1 selective, but also acts on a1 Actions are not due to  Release of NE from sympathetic neurons  Activation of dopamine receptor Dobutamine possesses a center of asymmetry  (-)-isomer is a potent agonist at a1 receptors  (+)-isomer is a potent a1 receptor antagonist, which can block the effects of (-)-dobutamine.  Both isomers appear to be full agonists at b1. 139  Pharmacological Effects  CVS  More prominent inotropic than chronotropic effects compared to isoproterenol  Administration at 2.5 to 15 mg/kg/min  es cardiac contractility and cardiac output.  TPR is not greatly affected.  HR es only modestly. 140  Adverse Effects  Hypertension, tachycardia, Atrial fibrillation (especially if there is preexisting condition), ventricular ectopic activity, Increase in the size of a myocardial infarct by increasing myocardial oxygen demand. Therapeutic use  Treatment of Cardiogenic shock 141 Selective b2-AR Agonists 142  Adverse effects associated with activation of b1 are avoided Some strategies have improved therapeutic use of these drugs in asthma  Placing -OH groups at positions 3 and 5 of the phenyl ring or substituting another moiety at position 3. Not substrates for COMT  Bulky substituents on the amino group contribute to potency at b-AR with ed activity at a-AR ed metabolism by MAO  Administration in aerosol form 143  Terbutaline  Not a substrate for methylation by COMT.  Effective orally, subcutaneously, or by inhalation.  Effects observed rapidly on inhalation or parenteral administration  Therapeutic use  Long-term treatment of obstructive airway diseases and acute bronchospasm,  Emergency treatment of status asthmaticus (Parenteral)  Control premature labor 144  Albuterol  Pharmacological properties and therapeutic indications are similar to those of terbutaline  Produces significant bronchodilation within 15 min, & effects persist for 3 to 4 hours (Inhalation) 145  Metaproterenol  Resistant to methylation by COMT & a substantial fraction (40%) is absorbed in active form after oral administration. It is also used by inhalation  Less selective to b2 than albuterol or terbutaline  Therapeutic use Long-term treatment of obstructive airway diseases, asthma, and for treatment of acute bronchospasm. 146  Salmeterol  Has slow onset but prolonged duration of action (>12 hours) and has 50X greater selectivity for b2 receptors than albuterol.  It also may have antiinflammatory activity.  Salmeterol or formoterol are the agents of choice for nocturnal asthma in patients who remain symptomatic despite antiinflammatory agents and other standard management.  NB prophylaxis of exercise induced asthma is by ------------------------ FORMOTEROL 147  Ritodrine  b2 receptor agonist developed specifically for use as a uterine relaxant.  Use: To arrest premature labor (intravenously). 148  Other less commonly used b2 agonists: Isoetharine (acute bronchoconstriction), Bitolterol, Formoterol (long acting~12hrs, used in COPD, prophylaxis of excerise induced bronchospasm) 149 Selective a1-AR Agonists 150  Phenylephrine  Causes marked arterial vasoconstriction  Used as a nasal decongestant and as a mydriatic  Not a catechol derivative, hence not a substrate for COMT (acts longer than the catecholamines) 151  Other drugs: – Mephentermine (prevent hypotension durin spinal anaestheasia), Metaraminol, Midodrine (Rises in BP are associated with both arterial and venous smooth muscle contraction- advantageous in the treatment of patients with autonomic insufficiency and postural hypotension) 152 Selective a2-AR Agonists 153  Clonidine Activates central a2-ARs (and probably immidazoline1 receptors) to reduce sympathetic outflow to the periphery. Also activates peripheral presynaptic a2-ARs Stimulates parasympathetic outflow IV infusion:  Acute rise in BP (mediated through a2-ARs in vascular smooth muscle)  More prolonged hypotensive response (decreased sympathetic outflow from the CNS) 154  Well absorbed orally and has bioavaillability of about 100% Adverse effects  Dry mouth, sedation, sexual dysfunction, marked bradycardia, Rebound hypertension following abrupt withdrawal of clonidine therapy. Therapeutic use  Treatment of mild to moderate hypertension 155  Apraclonidine  When applied topically, it reduces intraocular pressure with minimal or no effects on CVS.  It does not cross the BBB.  Therapeutic use: Short-term adjunctive therapy in glaucoma To control or prevent elevations in intraocular pressure after laser iridotomy 156  Brimonidine  Similar in actions and use as Apraclonidine  Unlike Apraclonidine, it can cross the BBB and can produce hypotension and sedation, although these CNS effects are slight compared to those of Clonidine. 157  Guanfacine  Is more selective for a2 than is Clonidine.  The drug has a large volume of distribution (4 to 6 litter/kg). Has relatively longer half-life than Clonidine  Guanfacine and Clonidine appear to have similar efficacy for the treatment of hypertension.  Adverse effects, including rebound hypertension, are milder and occur less frequently with Guanfacine. 158  Guanabenz  Guanabenz and guanfacine are closely related chemically and pharmacologically.  Guanabenz has a half-life of 4 to 6 hours and is extensively metabolized by the liver.  Adverse effects are similar to those associated with clonidine use. 159  a-methyldopa  Methyldopa, an analog of DOPA, is decarboxylated to a-methyldopamine which is then actively transported to vesicles where it is b-hydroxylated to the a2-AR agonist a-methylnorepinephrine.  Use: treatment of hypertension (it is the preferred agent during pregnancy)  Adverse effects: sedation, dry mouth, bradycardia, hepatotoxicity, hemolytic anemia 160  Indirect acting sympathomimetics 161  Includes such drugs as amphetamine and its congeners, tyramine, ephedrine Have weak actions on AR but sufficiently resemble NE to be transported into nerve terminals by uptake 1. Inside the nerve terminals, they are taken up into vesicles, displace the NE which escapes into the cytosol 162 163  Actions  Include bronchodilatation, raised arterial pressure, peripheral vasoconstriction, increased heart rate and force of myocardial contraction, and inhibition of gut motility.  They have important central actions, which account for their significant abuse potential and for their limited therapeutic applications  These drugs are no longer used for their peripheral sympathomimetic effects 164  Amphetamine: CNS effects CNS effects mediated by release of biogenic amines from their storage sites in nerve terminals. Effects include alerting, anorexia, locomotor- stimulation With higher doses of amphetamine, disturbances of perception and overt psychotic behaviour occur  Ephedrine Mixed acting (causes release of biogenic amines from nerve terminals and also acts on both a- & b-AR) Has longer duration of action (resistant to metabolism by MAO and COMT) 166  Other drugs in this category include  Methamphetamine  Methylphenidate  Pemoline 167 Drugs that affect NE uptake Tricyclic antidepressants (e.g. desipramine)  Their major effect is on the CNS but also cause tachycardia and cardiac dysrhythmias Cocaine  Enhances sympathetic transmission, causing tachycardia and increased arterial pressure.  Its central effects of euphoria and excitement are probably a manifestation of the same mechanism acting in the brain. 168 AR Antagonists 169  Non-Selective a-AR Antagonists 170  Pharmacological effects CVS  a1-AR antagonists  Inhibits vasoconstriction induced by catecholamines  The fall in BP opposed by baroreceptor reflexes  a1-AR antagonist + phenylephrine  abolished pressor  a1-AR antagonist + NE  pressor response incompletely blocked (due to b1-mediated myocardial effects)  a1-AR antagonist + Epi  Depressor effect 171  Pharmacological effects (CVS, cont’d)  a2-AR Antagonists  release of NE from peripheral sympathetic neurons  sympathetic outflow from the CNS Hence cause  in BP 172 Phenoxybenzamine; Pharmacological effects CVS  ed peripheral resistance  ed cardiac output due to  Reflex sympathetic stimulation ed release of NE in sympathetic neuroeffector junction 173  Therapeutic Uses  Treatment of pheochromocytoma Treat patients in preparation for surgery Prolonged treatment in patients with inoperable or malignant pheochromocytoma Toxicity and adverse effects  Postural hypotension accompanied by reflex tachycardia, reversible inhibition of ejaculation. It is found to be mutagenic in experimental studies. 174  Phentolamine Therapeutic Use  Short-term control of hypertension in patients with pheochromocytoma  Relieve pseudo-obstruction of the bowel in patients with pheochromocytoma  Used in hypertensive crises (abrupt withdrawal of clonidine or ingestion of tyramine-containing foods during use of nonselective MAO inhibitors) 175  Toxicity and Adverse Effects  Hypotension, tachycardia, cardiac arrhythmias  Abdominal pain, nausea, and exacerbation of peptic ulcer-it should be used with caution in patients with coronary artery disease or a history of peptic ulcer. 176 a1-AR Selective Antagonists 177  Quinazoline derivatives (Prazosin, Terazosin and Doxazosin) Prazosin is the prototype drug It has about a 1000 fold greater affinity for a1-AR than that for a2-AR. has similar potencies at a1A, a1B, and a1D It is an inhibitor of cyclic nucleotide phosphodiesterases 178  Prazosine; Pharmacological properties Blocks a1-ARs in arterioles & veins  fall in TPR and venous return Does not increase heart rate  Does not affect a2-ARs and no increase in NE release and hence no tachycardia  It es cardiac preload and thus has little tendency to increase cardiac output and rate 179  Prazosin; Pharmacokinetics Well absorbed orally with bioavaillability of 50-70 %, extensivelly protein bound (95%) It has a duration of action of 7 to 10 hours in the treatment of hypertension 180  Terazosin and Doxazosin Have same activity as prazosin and differ in pharmacokinetic profiles  Terazosin is more hydrophilic with better bioavaillability (>90%). Duration of action extends to 18 hours, which enables once per day administration  Duration of action of doxazosin extends to 36 hrs. 181  Tamsulosine An a1-AR antagonist with some selectivity for a1A (and a1D) subtypes compared to a1B subtype Blockade of a1A receptors in prostate. It is efficacious in the treatment of BPH (benign prostatic hyperplasia) with little effect on blood pressure 182  Adverse effects First-dose effect; marked postural hypotension, (quinazolines) Impaired ejaculation (tamsulosine) 183  Therapeutic uses Treatment of hypertension (prazosin and congeners) Congestive heart failure Benign prostatic hyperplasia (especially tamsulosine) 184 Yohimbine Indolealkylamine alkaloid which is selective competitive antagonist of a2-AR It readily enters the CNS, and acts to increase BP and heart rate; it also enhances motor activity and produces tremors 185  b-AR Antagonists 186  Introduction Most are competitive antagonists of b-AR Useful in the treatment of hypertension, ischemic heart disease, CHF, and certain arrhythmias Propranolol: prototype drug in this group 187 Structural formulas of some b adrenergic receptor antagonists. 188  b-AR antagonists can be distinguished by  Relative affinity for b1 and b2 receptors Non-selective antagonists (propranolol, nadolol, timolol) b1-Selective antagonists (metoprolol, atenolol, acebutolol, bisoprolol, and esmolol): the selectivity is not absolute and is dose dependent  Intrinsic sympathomimetic activity (ISA)  Pindolol and acebutolol: activate b-AR partially in the absence of catecholamines – Counter productive to the response desired from a b-antagonist – Prevent profound bradycardia or negative inotropy in a resting heart  Differences in lipid solubility  Pharmacokinetic properties 189  Pharmacological effects CVS  Slow HR and decrease myocardial contractility   cardiac output  TPR Initial increase (blockade of vascular b2-AR and reflex stimulation of sympathetic activity) Returns to initial state or decreases with prolonged use   in BP 190  CVS (cont’d)  Reduce sinus rate, decrease the spontaneous rate of depolarization of ectopic pacemakers, slow conduction in the atria and in the AV node, and increase functional refractory period of the AV node.  Decrease renin release 191  Activity As Antihypertensive Agents  Mechanisms responsible for this important clinical effect are not well understood b1-mediated release of renin from the juxtaglomerular apparatus is blocked Presynaptic b-mediated enhanced release of NE from sympathetic neurons is blocked 192  Nonselective b-AR antagonists  Inhibit vasodilation caused by isoproterenol  Augment pressor response to epinephrine Significant in patients with pheochromocytoma, in whom b receptor antagonists should be used only after adequate a receptor blockade has been established (This avoids uncompensated a receptor- mediated vasoconstriction caused by epinephrine) 193  Pharmacologic Pulmonary effects effects (cont’d)  b2-mediated increase in airway resistance  Little effect in individuals with normal pulmonary function  b1-selective antagonists or antagonists with ISA activity are less likely than propranolol to increase airway resistance  Celiprolol: b1 receptor selectivity and b2 receptor partial agonism Effects on the eye  Decrease in aqueous humor production   intraocular pressure 194  Metabolic effects  Modify the metabolism of CHOs and lipids. Catecholamines promote glycogenolysis and mobilize glucose in response to hypoglycemia  Block glycogenolysis   the release of free fatty acids from adipose tissue 195 Non-Selective b-AR Antagonists 196  Propranolol Interacts with b1- & b2-AR with equal affinity, lacks intrinsic sympathomimetic activity, and does not block a-ARs Highly lipophilic and is almost completely absorbed after oral administration. Undergoes extensive first pass effect (only about 25% reaches the systemic circulation) 197  Therapeutic use  Treatment of hypertension and angina  Treatment of supraventricular arrhythmias/tachycardias, ventricular arrhythmias/tachycardias, premature ventricular contractions, digitalis-induced tachyarrhythmias, myocardial infarction, pheochromocytoma 198  Nadolol  A long-acting antagonist with equal affinity for b1 and b2 receptors.  Has a relatively long half-life of 12 to 24 hours.  Therapeutic use: treatment of hypertension & angina pectoris. 199  Timolol  Potent, non-subtype-selective b antagonist.  Therapeutic use: Treatment of hypertension, congestive heart failure, migraine prophylaxis, and has been widely used in the treatment of glaucoma and intraocular hypertension. 200  Pindolol  Such drugs (b-blockers with partial agonistic activity) may be preferred as antihypertensive agents in individuals with diminished cardiac reserve or a propensity for bradycardia. Such drugs produce smaller reductions in resting heart rate and blood pressure 201 b1-Selective AR Antagonists 202  Metoprolol  b1-selective receptor antagonist, devoid of ISA and membrane-stabilizing activity.  Therapeutic Uses  For the treatment of hypertension, treatment of stable angina.  Effective in chronic heart failure Atenolol  b1-selective antagonist devoid of ISA and membrane stabilizing activity  Too hydrophilic to penetrate the CNS  Therapeutic Uses  Treatment of hypertension, in elderly patients with isolated systolic hypertension (in combination with a diuretic) 203  Esmolol  A b1-selective antagonist with a very short duration of action.  Has little if any ISA, and lacks membrane- stabilizing actions.  Administered IV is used when b blockade of short duration is desired or in critically ill patients in whom adverse effects of bradycardia, heart failure, or hypotension may necessitate rapid withdrawal of the drug.  Has a half-life of about 8 minutes  Onset and cessation of b receptor blockade which are rapid; peak effects occur within 6 to 10 minutes of administration, and there is substantial attenuation of b blockade within 20 204 minutes of stopping an infusion.  Acebutolol  Has some ISA and membrane-stabilizing activity.  Well absorbed, and undergoes significant first-pass metabolism to an active metabolite, diacetolol,  Therapeutic Uses Treatment of hypertension, ventricular arrhythmias Bisoprolol  A highly selective b1 receptor antagonist that does not have ISA or membrane-stabilizing activity  Therapeutic uses: For the treatment of hypertension, 205  b-AR Antagonists with Additional Cardiovascular Effects 206  These agents in addition to their competetitive b- antagonism have vasodilating effects  Labetelol (a1 antagonist and b2 partial agonist)  Carvedilol (membrane-stabilizing activity)  Bucindolol (a1 blocking as well as b2 & b3 agonistic properties)  Celiprolol (weak b2 agonistic activity)  Nebivolol  NO mediated vasodilation  Most selective b1 antagonist available clinically  Devoid of intrinsic sympathomimetic activity, inverse agonistic activity, and a1 receptor blocking properties 207  Adverse effects and precautions Cardiovascular System  b-AR blockade may cause or exacerbate heart failure in susceptible patients  Bradycardia which may cause life-threatening bradyarrhythmias in patients with partial or complete atrioventricular conduction defects  Cold extremities  Abrupt discontinuation of b-AR antagonists after long- term treatment can exacerbate angina and may increase the risk of sudden death 208  Adverse effects and precautions (cont’d) Pulmonary Function  A major adverse effect of b receptor antagonists  Drugs with selectivity for b1-AR or those with ISA at b2 AR may be somewhat less likely to induce bronchospasm Central Nervous System  Include fatigue, sleep disturbances, and depression 209 Adverse effects and precautions (cont’d) Metabolism  may delay recovery from insulin-induced hypoglycemia  Should d be used with great caution in patients with diabetes who are prone to hypoglycemic reactions  b1-selective agents may be preferable Overdosage  Hypotension, bradycardia, prolonged AV conduction times, and widened QRS complexes are common manifestations  Seizures and depression may occur.  Hypoglycemia is rare, and bronchospasm is uncommon in the absence of pulmonary disease. Drug Interactions  Aluminum salts, cholestyramine, and colestipol may decrease the absorption of b blockers  phenytoin, rifampin, and phenobarbital, as well as smoking 210 (inducers) may decrease plasma concentrations of b blockers  Therapeutic uses Cardiovascular diseases  Myocardial infarction Administered during the early phases of acute myocardial infarction and continued long-term may decrease mortality by about 25% Precise mechanism is not known  decreased myocardial oxygen demand, redistribution of myocardial blood flow, and antiarrhythmic actions 211  Cardiovascular diseases  Congestive Heart Failure The drugs improve myocardial function, improve life quality, and to prolong life reduce the mortality rate, reduction in the hospitalization of patients 212  Glaucoma  In the treatment of chronic open-angle glaucoma  carteolol, betaxolol, levobunolol, metipranolol, timolol, and levobetaxolol  Have little or no effect on pupil size or accommodation and are devoid of blurred vision and night blindness 213  Other drugs that block adrenergic transmission Guanethidine, guanadrel, bethanidine, debrisoquine Reserpine Ganglion blockers 214 Cardiovascular and Renal Pharmacology By Kaleab A. 215  Contents Anti hypertensive Antiangina Antiarrythemic (Reading Assignment ) Heart failur Diuratics 216 Hypertension A sustained increase in arterial blood pressure (140/90 mm Hg) [on repeated BP measurement] Is the most common cardiovascular disease Is a major risk factor for both coronary artery disease and cerebro-vascular accidents If left untreated hypertension leads to major end-organ damages » Renal failure » Stroke » Retinopathy » Congestive heart failure » Myocardial infarction 217 Classification of Hypertension Based on etiology  Primary (essential) hypertension 85-90% of all cases Unknown cause  Secondary hypertension 10-15% of all cases Identifiable causes, occurs secondary to other factors e.g. medical condition, drug indused (steroids, NSAIDs) 218 Risk factors 219  Blood Pressure (mm Classification Hg) Systolic Diastolic Normal < 120 < 80 Pre-hypertension 120 – 139 80 – 89 Hypertension, Stage 1 140 – 159 90 – 99 Hypertension, Stage 2  160  100 Hypertention crisis- BP>180/120 – Emergency-with EOD – Urgency-with out EOD Isolated systemic BP.....BP >140/