Adrenergic, Cholinergic, Histamines Categories of Action Smooth Muscle Effects Metabolic Effects o Smooth muscle activation, including o increase

e in rate of muscle and liver activation of blood vessel vasculature glycogenolysis (skin, kidney). o increase in free-fatty acid release from fat o Activation of glands (salivary and sweat). Endocrine o Smooth muscle inhibition, including o Regulation/modulation of insulin, pituitary, inhibition of smooth muscle of the gut, and renin secretion bronchioles, and skeletal muscle vascular Central Nervous System Effects smooth muscle. o Respiratory stimulation Cardiac Effects o CNS stimulation o increased heart rate (positive chronotropic o Appetite attenuation effect) Presynaptic Effects o increased contractility (positive inotropic o Presynaptic effects: modulation of release effect) of norepinephrine or acetylcholine Blood Pressure Potent vasopressor o Systolic pressure increases to a greater extent than diastolic (diastolic pressure may decrease) pulse pressure widens o Epinephrine increases blood pressure by:

1 1 1 1 1 1

enhancing cardiac contractility (positive inotropic effect): 1-receptor effects

increasing heart rate (positive chronotropic effect): 1-receptor effects. vasoconstriction a1 receptor effects precapillary resistance vessels of the skin, kidney, and mucosa veins 2 If epinphrine is administered relatively rapidly, the elevation of systolic pressure is likely to activate the baroreceptor system resulting in a reflex-mediated decrease in heart rate. A principal mechanism for arterial blood pressure control is the baroreceptor reflex. The reflex is initiated by activation of stretch receptors located in the wall of most large arteries of the chest and neck. A high density of baroreceptors is found in the wall of each internal carotid artery (just above the carotid bifurcation i.e. carotid sinus) and in the wall of the aortic arch. As pressure rises and especially for rapid increases in pressure: baroreceptor input to the tractus solitarius of the medulla results in inhibition of the vasoconstrictor center and excitation of the vagal (cholinergic) centers resulting in 1. a vasodilatation of the veins and arterioles in the peripheral vascular beds. 2. negative chronotropic and inotropic effects on the heart. (slower heart rate with reduced force of contraction)

Vascular Effects Epinephrine has significant effects on smaller arteriolar and precapilliary smooth muscle. Acting through alpha1 receptors, vasocontrictor effects decrease blood flow through skin and kidney. o Even at doses of epinephrine that do not affect mean blood pressure, substantially increases renal vascular resistance and reduces blood flow (40%). o Renin release increases due to epinephrine effects mediated by 1-receptors associated with juxtaglomerular cells. Acting through 2-receptors, epinephrine causes significant vasodilation which increases blood flow through skeletal muscle and splanchnic vascular beds.

Uterus

If an a receptor blocker is administered, epinephrine 2-receptor effects dominate and total peripheral resistance falls as does mean blood pressure--this phenomenon is termed "epinephrine reversal". Cardiac Effects Epinephrine exerts most of its effects effects on the heart through activation of 1-adrenergic receptors. o 2- and a receptors are also present. o Heart rate increases o Cardiac output increases o Oxygen consumption increases Direct Responses to Epinephrine o increased contractility o increased rate of isometric tension development o increased rate of relaxation o increased slope of phase-4 depolarization o increased automaticity (predisposes to ectopic foci Smooth Muscle Epinephrine has variable effects on smooth muscle depending on the adrenergic subtype present. o GI smooth muscle is relaxed through activation of both alpha and -receptor effects. o In some cases the preexisting smooth muscle tone will influence whether contraction or relaxation results following epinephrine. o During the last month of pregnancy, epinephrine reduces uterine tone and contractions by means of 2receptor activation. This effect provides the rationale for the clinical use of 2-selective receptor agonists: ritodrine and terbutaline to delay premature labor. alpha1; beta2 Pregnant: contraction (alpha1); relaxation (beta2); Non-pregnant: relaxation variable (beta2)

Epinephrine is a significant respiratory tract bronchodilator. Bronchodilation is caused by 2-receptor activation mediated smooth muscle relaxation. This action can antagonize other agents that promote bronchoconstriction. 2-receptor activation also decreases mast cell secretion. This decrease may be beneficial is management of asthma also. Pulmonary Adrenergic Effects Cholinergic Tracheal and bronchial beta 2 Relaxation contraction muscle decrease secretion; Bronchial glands alpha1, beta2 stimulation increased secretion Metabolic Effects Insulin secretion: inhibited by a2 adrenergic receptor activation (dominant) Insulin secretion: enhanced by 2 adrenergic receptor activation Pancreas Adrenergic Acini Islets (beta cells) Islets (beta cells) alpha alpha2 beta2 Effects decreased secretion decreased secretion increased secretion Cholinergic secretion -----------------

Glucagon secretion: enhanced by adrenergic receptor activation of pancreatic islet alpha cells. Glycolysis- stimulated: by adrenergic receptor activation Liver Adrenergic Liver alpha1; beta2 Effects Cholinergic glycogenolysis and ----------gluconeogenesis Free fatty acids, increased: by adrenergic receptor activation on adipocytes--activation of triglyceride lipase Adipose Tissue Fat Cells alpha2; beta3 lipolysis (thermogenesis) --------Calorigenic effect (20% - 30% increase in O2 consumption): caused by triglyceride breakdown in brown adipose tissue. Electrolytes Epinephrine may activate Na+-K+ skeletal muscle pumps leading to K+ transport into cells. Stress-induced epinephrine release may be responsible for relatively lower serum K+ levels preoperatively compared postoperatively.

Mechanistic basis: "Preoperative hypokalemia" can be prevented by nonselective beta-adrenergic receptor antagonists {but not by cardio-selective beta1 antagonists}. Possible "preoperative hypokalemia" may be associated with preoperative anxiety which promotes epinephrine release-therapeutic decisions based on preinduction serum potassium levels to take into account this possible explanation

Adverse Effects-Agonists Excessive cardiovascular stimulation Skeletal muscle tremor (tolerance develops, unknown mechanism) due to 2 adrenergic receptor activation Overusage may be a factor in morbidity and mortality in asthmatics. Alpha1 Selective Adrenergic Agonists Alpha1 selective adrenergic agonists activate a adrenergic receptors in vascular smooth muscle producing vasoconstriction. o Peripheral vascular resistance is increased. o Blood pressure may be increased, causing a reflex reduction heart rate o a1 adrenergic agonists are used clinically in management of hypotension and shock. o Phenylephrine (Neo-Synephrine) and methoxamine (Vasoxyl) are direct-acting vasoconstrictors. o Mephentermine (Wyamine) and metaraminol (Aramine) act both by direct receptor activation and by promoting epinephrine release. Smooth muscle tone is determined by modulation of myosin light-chain kinase activation. o Myosin light-chain kinase phosphorylates myosin--a step that initiates myosin-actin interaction. (by contrast in skeletal or cardiac muscle Ca2+ interaction with troponin is central to initiation of muscle contraction) o Increases in intracellular Ca2+ with Ca2+ calmodulin complex formation results in activation of myosin lightchain kinase. Alpha1 receptor activation causes Ca2+ influx In some cells, 1 receptor activation causes IP3 production, which releases sequested Ca2+.

Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms (Muscarinic Receptor Coupling Mechanisms) Five types of cholinergic receptors have been identified by molecular cloning methods. The possibility of multiple forms was suggested by the pharmacology of piprenzipine which is an effective antimuscarinic in blocking gastric acid secretion, but was not effective in blocking other responses to muscarinic agonists. The five muscarinic receptor subtypes, M1 - M5, are associated with specific anatomical sites. For example: o M1 -ganglia; secretory glands o M2 - myocardium, smooth muscle o M3 , M4 :smooth muscle, secretory glands Nicotinic Muscle Receptor Antagonists Tubocurarine alpha-bungarotoxin Tissue Neuromuscular Junction Responses Membrane Depolarization leading to muscle contraction Molecular Aspects Nicotinic (muscle) receptor's cation ion channel opening

Nicotinic Neuronal Receptor Antagonists Tissue Autonomic Ganglia Mecamylamine (Inversine) Adrenal Medulla CNS Responses Molecular Aspects Depolarization: Nicotinic (muscle) receptor's postsynaptic cell activation cation ion channel opening Catecholamine secretion unknown

Muscarinic Type M1 Antagonist Atropine Pirenzepine (more selective) Tissue Autonomic Ganglia Responses Molecular Aspects Depolarization (late EPSP) Stimulation of Phospholipase C (PLC): activation of inositol-1,4,5 triphosphate (IP3 ) and diacylglycerol Unknown (DAG) leading to increased cytosolic Ca2+

CNS

Muscarinic Type M2 Tissue (Heart) SA node Atrium AV node Ventricle Responses decreased phase 4 depolarization; hyperpolarization decreased contractility; decreased AP duration decreased conduction velocity decreased contractility Molecular Aspects K+ channel activation through gamma Gi subunits; Gi -mediated inhibition of adenylyl cyclase which decreases intracellular Ca2+ levels. (Gi can inhibit directly Ca2+ channel opening)

Pharmacological Effects of Cholinomimetics Cardiovascular: Four major effects Vasodilation: This effect is mediated by muscarinic receptor activation and is especially prominent in the salivary gland and intestines. 1. 2. The vascular response is due to endothelial cell nitric oxide (NO) release following agonist interactions with endothelial muscarinic receptors. Increased NO activates guanylate cyclase which increases cyclic GMP concentrations. Subsequent activation of a Ca2+ ion pump reduces intracellular Ca2+. Reduction in intracellular Ca2+ causes vascular smooth muscle relaxation. Ca2+ complexes with calmodulin activating light-chain myosin kinase o Increased cGMP promotes dephosphorylation of myosin light-chains. o Smooth-muscle myosin must be phosphorylated in order to interact with actin and cause muscle contraction.

3. 4. 5.

Vasodilation may also occur due to ACh inhibition of N.E. release from post-ganglionic sympathetic fibers. Damaged endothelium can result in ACh causing vasoconstriction by direct action on vascular smooth muscle. Negative chronotropic effect (Decrease in heart rate) o Decreases phase 4 (diastolic depolarization) As a result, it takes longer for the membrane potential to reach threshold. o Mediated by M2 muscarinic receptors Decreased SA nodal and AV nodal conduction velocity o Excessive vagal tone may induce bradyarrhythmias including partial or total heart block (impulses cannot pass through the AV node to drive the ventricular rate; in this case, the idioventricular or intrinsic ventricular rate must maintain adequate cardiac output) o Transmission through the AV node is especially dependent on Ca2+ currents. ACh decreases calcium currents in the atrioventricular node. Negative inotropism (decreased myocardial contractility) o more prominent in atrial than ventricular tissue. o due to a decrease in ICa2+ inward current o in the ventricle, adrenergic tone dominates; at higher levels of sympathetic tone, a reduction in contractility due to muscarinic stimulation is noted. Muscarinic stimulation reduces the response to norepinephrine by opposing increases in cAMP in addition to reducing norepinephrine release from adrenergic terminals Effect of muscarinic receptor activation on cardiac currents o increase in I K (Ach) in atrial muscle and in SA and AV nodal tissue o decrease in slow, inward calcium (ICa2+) current (decreased atrial contractility; decreased AV nodal conduction) o decrease in diastolic depolarizing current (If)--decreases heart rate, because it takes longer for the membrane potential to reach threshold (less depolarizing If current) Gastrointestinal and Urinary Tracts o Muscarinic agonists increase intestinal peristalsis, tone, and contraction amplitude. o Carbachol and bethanecol (not ACh or methacholine) stimulate the urinary tract by increasing ureteral peristalsis and by contraction of the urinary bladder detrusor muscle. Histamine

Introduction Autacoids is a general term that refers to a number of compounds such as: histamine, serotonin, endogenous peptides, prostaglandins, and leukotrienes o The formal definition of autacoids is "self-remedy, referring to the action of local hormones Chemistry and Pharmacokinetics o The formation of histamine occurs by the removal of a carboxyl group (decarboxylation) from amino acid L-histidine o One of the important issues associated with formation of a biologically active compound is the mechanism that accounts for the compounds inactivation. Histamine is active biologically, but the first step for its inactivation involves the addition of a methyl group (CH3) followed by a chemical oxidation. o Most of the time very little histamine is excreted unchanged because of these metabolic steps. One exception would be the case of neoplastic disease (cancer). For instance, significant histamine is excreted unchanged in the presence of these diseases: (a) systemic mastocytosis, (b) gastric carcinoid syndrome or (c) urticaria pigmentosa. Tissue Distribution: o The primary site for histamine localization is the mast cell granules (or basophils) Mast cells are important in that they release histamine in response to potential tissue injury Other sites include the central nervous system where histamine may function as a neurotransmitter and the fundus of the stomach (enterochromaffin-like cells) which are major acid secretagogues [They promotes accretion by activation of acid-producing mucosal parietal cells] Histamine: Storage and Release o Immunologic Release: The most important mechanism for histamine release is in response to an immunological stimulus. In Mast cells, if sensitized by surface IgE antibodies, degranulate when exposed specific antigen. Degranulation means liberation of the contents of the mast cell granules, including histamine. Degranulation is involved in the immediate (type I) allergic reaction. Release regulation is present in most mast cells. Histamine Modulation is associated with the inflammatory responses. Following local injury, histamine first produces a local vasodilation (reddening of the area) followed by an the release of acute inflammation mediators. Inflammatory cells are involved in this process and include neutrophils, eosinophils, basophils, monocytes & lymphocytes. In o Mechanical/Chemical Release: A second type of release occurs following chemical or mechanical injury to mast cells. In these injuries caused degranulation as noted above including again histamine release. Common drugs such as morphine or tubocurarine can displace histamine from granule storage sites. Pharmacodynamics-- Mechanism of Action -- Histamine mediates its effects by interacting with receptors. In o Receptor Types include H1, H2,and H3 types. We will focus our attention on the first two types (H1,H2) Receptor Subtype Localization Endothelium, brain, smooth muscle mass and cells, gastric mucosa, cardiac muscle, brain presynaptic: brain, mesenteric plexus (other neurons) Receptor coupling receptor activation causes and increased IP3, DAG (diacylglycerol) production receptor activation causes an increase in cAMP production G protein coupled Antagonists (partially selective) N/A

H1

H2

ranitidine (Zantac), cimetidine (Tagamet) N/A

H3

Receptor subtypes --H1, H2, and H3: o intracellular G protein interactions H1:endothelial and smooth muscle cell localization o H1 receptor activation causes can increase in phosphoinositol hydrolysis and an increase in intracellular calcium. H2 gastric mucosa, cardiac muscle cells, immune cell localization: o H2 receptor activation causes an increase in cyclic AMP. H3: primarily presynaptic

activation causes a decrease in transmitter release {transmitters: histamine,acetylcholine, norepinephrine, serotonin)

Organ System Effects: Histamine Cardiovascular: 11 increased pacemaker rate o Systolic and diastolic blood pressure: (positive chronotropism) Vasodilation of arterioles and precapillary 2 Gastrointestinal tract: Histamine promotes sphincters account for histamine's intestinal smooth muscle contraction which is an H1 vasodilating effects. Vasodilation may be receptor mediated effect due in part to nitric oxide liberation. 3 Bronchiolar smooth muscle activation by o Following from the reduced blood pressure, histamine causes bronchodilation (H1 receptor mediated ) the heart rate increases by autonomic reflex 1 It is not surprising that inhaled histamine is a mechanisms and by direct action. diagnostic, provocative test for bronchial hyperreactivity o Both H1 and H2 receptors involved in (asthma or cystic fibrosis) cardiovascular responses. 4 Nerve Endings: Sensory nerve endings are o Histamine-associated edema:H1 receptor stimulated by histamine, especially those endings effects (postcapillary vessels) which mediate pain and itching. increase in vessel permeability due to 1 These effects are H1 receptor mediated effect and separation of endothelial cells, represent part of the local reaction to insect stings (urticarial allowing transudation of fluid and responses) molecules as large as small proteins. 5 Secretory tissue: responsible for urticaria 1 Histamine cause the stimulation of release by (hives) secretory tissues. For example, a significant increase in endothelial cell separation: gastric acid secretion is caused by histamine. Other secondary to histamineexamples of increased release include gastric pepsin. induced calcium influx causing 2 Mechanism of Action: Considering the gastric parietal intracellular actin/myosincells, histamine interacts with H2 receptors and initiates a mediated contraction second messenger response which proceeds by (1.) o Direct cardiac effects: Increasing adenylyl cyclase activity which (2.) Results in an increase in the second messenger, cyclic AMP which (3.) 11 increased contractility Causes an increase in intracellular calcium levels. The (positive inotropism) increase in calcium triggers release. This releasing characteristic of calcium applies broadly in physiology.