BLOOD AND ITS COMPONENTS – blood • • – composed of plasma and a variety of cells transports nutrients and wastes

Blood components • 55% plasma: 7 to 8% dissolved substances (sugars, amino acids, lipids & vitamins), ions, dissolved gases, hormones – most of the proteins are plasma proteins: provide a role in balancing osmotic pressure and water flow between the blood and extracellular fluid/tissues most common plasma proteins: albumin, globulins, clotting proteins (fibrin)

interstitial fluid • bathes the cells of the body –

Physical Characteristics of Blood • • • • • Thicker (more viscous) than water and flows more slowly than water Temperature of 100.4 degrees F pH 7.4 (7.35-7.45) 8 % of total body weight Blood volume – – – 5 to 6 liters in average male 4 to 5 liters in average female hormonal negative feedback systems maintain constant blood volume and osmotic pressure  

Blood Plasma Composed of approximately 90 percent water Includes many dissolved substances     Nutrients, Salts (metal ions) Respiratory gases Hormones Proteins, Waste products

FORMED ELEMENTS OF BLOOD • • Red blood cells ( erythrocytes ) White blood cells ( leukocytes ) – granular leukocytes • • • – neutrophils eosinophils basophils

Functions of Blood • Transportation – • O2, CO2, metabolic wastes, nutrients, heat & hormones

Regulation – – helps regulate pH through buffers helps regulate body temperature • • – coolant properties of water vasodilatation of surface vessels dump heat •

agranular leukocytes • • lymphocytes = T cells, B cells, and natural killer cells monocytes

helps regulate water content of cells by interactions with dissolved ions and proteins

Platelets (special cell fragments)

Protection from disease & loss of blood

 Neutrophils   Multilobed nucleus with fine granules Act as phagocytes at active sites of infection  Eosinophils   Large brick-red cytoplasmic granules Found in repsonse to allergies and parasitic worms Erythropoiesis: Production of RBCs • Erythrocyte formation. and can be used to identify a tissue.Erythrocytes (Red Blood Cells)   The main function is to carry oxygen Anatomy of circulating erythrocytes      • • • Reticulocytes escape from bone marrow into the blood WHITE BLOOD CELLS Biconcave disks Essentially bags of hemoglobin Anucleate (no nucleus) Contain very few organelles – – Leukocytes (white blood cells or WBCs) are nucleated cells and do not contain hemoglobin. called erythropoiesis. Proerythroblast starts to produce hemoglobin Nucleus is ejected & a reticulocyte is formed – orange in color with traces of visible rough ER •  Basophils  Have histamine-containing granules • • • Involved in inflammatory and allergy reactions . occurs in adult red bone marrow of certain bones. They are called major histocompatibility antigens (MHC). are unique for each person (except for identical siblings). and neutrophils based on the straining of the granules. Leukocytosis is a high white blood cell count Leukopenia is low white blood cell count Granulocytes HAEMOGLOBIN    • Iron-containing protein Binds strongly. but reversibly. The main stimulus for erythropoiesis is hypoxia. Agranular leukocytes do not have cytoplasmic granules and include the lymphocytes and monocytes. as do erythrocytes. Two principal types are: Granular leukocytes include eosinophils. to oxygen Each hemoglobin molecule has four oxygen binding sites Production of abnormal hemoglobin can result in serious blood disorders such as thalassemia and sickle cell anemia. Outnumber white blood cells 1000:1 Contain oxygen-carrying protein hemoglobin that gives blood its red color Anemia – not enough RBCs or not enough hemoglobin • – • • Polycythemia too many RBCs • • Leukocytes have surface proteins. basophils. which differentiate into macrophages (fixed and wandering).

4 micron cell fragment with no nucleus HEMOSTASIS • A clot is a gel consisting of a network of insoluble protein fibers (fibrin) in which formed elements of blood are trapped. cancer cells & some bacteria • Natural killer cells – – attack many different microbes & some tumor cells destroy foreign invaders by direct attack •    • Platelets Derived from ruptured multinucleate cells (megakaryocytes) Needed for the clotting process Normal platelet count = 300. Blood clotting involves a cascade of reactions that may be divided into three stages: formation of prothrombinase (prothrombin activator). 2 . and conversion of soluble fibrinogen into insoluble fibrin.000/mm3 Disc-shaped.Agranulocytes  Monocytes     • Largest of the white blood cells Function as macrophages Important in fighting chronic infection • thrombin. fungi. transplanted organs. conversion of prothrombin into • . Platelet Plug Formation Platelets store a lot of chemicals in granules needed for platelet plug formation – alpha granules • – clotting factors Lymphocytes   Nucleus fills most of the cell Play an important role in the immune response dense granules Steps in the process – (1) platelet adhesion (2) platelet release reaction (3) platelet aggregation • B cells – – destroy bacteria and their toxins turn into plasma cells that produces antibodies • T cells – attack viruses.

ADRENOCEPTOR BLOCKERS • Pharmacologic antagonists -Divided into primary subgroups based on the receptor selectivity • Alpha and beta blockers -Differ in their effects and clinical application – – Cause baroreceptor reflex-mediated tachycardia as a result of the drop in mean arterial pressure (MAP) Tachycardia maybe exaggerated. and terazosin are used in hypertension – Used together with tamsulosin for urinary hesitancy and prevention of urinary retention with benign prostatic hyperplasia TOXICITY – Main manifestation is orthostatic hypotension – For nonselective agents. RAUWOLSCINE – Prototype – Selective alpha2 competitive blockers – Used primarily in research application EFFECTS NONSELECTIVE BLOCKERS – Most important effects are on the CVS system – Reduction in cardiovascular tone – Reduction of both arterial and venous pressure (decrease in BP) EPINEPHRINE REVERSAL – Predictable result of the use of an agonist in a patient who has received an alpha-blocker – Reversal in the BP effect of large doses of epinephrine – From pressor response (alpha receptors) to a depressor response (beta receptors) – Not observed with phenylephrine or NE because they lack sufficient beta2 effects SELECTIVE ALPHA1 BLOCKERS – Block alpha1 receptors much more effectively – Cause much less tachycardia than the nonselective blockers when reducing BP CLINICAL USES NONSELECTIVE ALPHA BLOCKERS – Limited clinical application – Presurgical treatment of pheochromocytoma – Phenoxybenzamine is used during the preparatory phase – Phentolamine during surgery – Severe hypertension caused by overdose with drugs of abuse such as amphetamine. doxazosin. cocaine. or phenylpropanolamine SELECTIVE ALPHA BLOCKERS – Prazosin.alpha2 receptors on adrenergic terminals in the heart which normally reduce the release of NE are also blocked ALPHA BLOCKING DRUGS • All active by – Oral route – Parenteral route CLASSIFICATION/PHARMACOKINETICS/MOA IRREVERSIBLE LONG-ACTING PHENOXYBENZAMINE – Prototype – Only slightly alpha1 selective – Short elimination half life IRREVERSIBLE LONG-ACTING PHENOXYBENZAMINE – Long duration of action (48 hours) – Binds covalently to its receptors REVERSIBLE SHORT-ACTING PHENTOLAMINE – Prototype – Nonselective (alpha1=alpha2) – Duration of action • Oral (2-4 hours) • IV (20-40 minutes) ALPHA1 SELECTIVE PRAZOSIN – Prototype – Selective reversible alpha1 blocker – Duration of action 8-24 hours – Doxasozin. marked reflex tachycardia . terazosin and tamsulosin – ALPHA2 SELECTIVE YOHIMBINE.

can cause some bronchodilatation LOCAL ANESTHETIC ACTIVITY – ”Membrane stabilizing ability” – Disadvantage when a beta-blocker is used topically in the eye because it decreases protective reflexes and increases the risk of corneal ulceration .– – Nausea and vomiting when taken orally Exaggerated orthostatic hypotensive response to the first dose of alpha1selective agents – – – – Acebutolol Labetalol Metoprolol Propranolol BETA BLOCKING DRUGS • Competitive pharmacologic antagonists • Propranolol is the prototype • Developed for chronic oral use • Bioavailability and duration of action vary widely • Usually classified into subgroups (Table in Katzung) CLASSIFICATION/SUBGROUPS/MECHANISMS RECEPTOR SELECTIVITY – Beta1 receptor selectivity – Beta1 block>beta2 block – Advantage when treating patients with asthma • Beta1 receptor selectivity – Acebutolol – Atenolol – Esmolol – Metoprolol Nonselective beta-blockers – Nadolol – Propranolol – Timolol Combined alpha and beta-blockers – Labetalol – Carvedilol – Optically active ESMOLOL • Short-acting ester • Used only parenterally NADOLOL • Longest acting beta-blocker ACEBUTOLOL. ATENOLOL and NADOLOL • Less lipid soluble • Enter the CNS to a lesser extent EFFECTS 1. CNS – Sedation – Fatigue – Sleep alteration – Depression – Psychosis • • PARTIAL AGONIST ACTIVITY – ”Intrinsic sympathomimetic activity” – Pindolol – Acebutolol – May be an advantage in treating patients with asthma – At maximum dose. RESPIRATORY – Worsen the asthma 3. EYE – Decrease intraocular pressure – Decrease production of aqueous humor 4. CVS – Decrease BP – Antagonize renin secretion – (-) inotropic effect – (-) chronotropic effect 2. METABOLIC AND ENDOCRINE – Reduce insulin secretion – Caution for insulin dependent DM CLINICAL USES – Open-angle glaucoma – Hypertension – Angina – Arrhythmias – Chronic heart failure – Pheochromocytoma TOXICITY 1. RESPIRATORY – Bronchoconstriction – Increase airway resistance 3. CVS – Bradycardia – AV blockade – Heart failure 2.

and dopamine – Endogenous adrenoceptor agonists • Rapidly metabolized by COMT and MAO • Inactive when given by the oral route • Short duration of action • When given IV. norepinephrine.• SYMPATHOMIMETICS Adrenomimetics BETA Further subdivided into subgroups as -Beta1 -Beta2 -Beta3 EPINEPHRINE • Single prototype with effects at all receptors • Alpha1 and alpha2 • Beta1. MODE OF ACTION DIRECT-ACTING SYMPATHOMIMETICS • • Bind to and activate the adrenoceptors Result to sympathetic stimulation INDIRECT-ACTING SYMPATHOMIMETICS • • • Displacement of stored cathecolamines in the synapse Tyramine. SPECTRUM OF ACTION • Classified as: ALPHA Further subdivided into subgroups as -Alpha1 -Alpha2 .beta2 and beta3 PHENYLEPHRINE • Separate prototype • Alpha ISOPROTERENOL • Separate prototype • Beta • Synthetic cathecolamine • Similar to the endogenous transmitters • Not readily taken up into the nerve ending DOPAMINE • Constitute a third class of adrenoceptors • Drugs mentioned have little effect on Dopamine • May act as a potent dopamine receptor Agonist itself CATHECOLAMINES • Epinephrine. they do not enter the CNS in significant amounts AMPHETAMINES • Not a cathecolamine • Resistant to MAO • Resistant to COMT • Orally active • Enter the CNS • Longer effects PHENYLETHYLAMINE • Presence of OH groups at carbons 3 and 4 • Degraded by cathecol-o-methyl transferase (COMT) • Removal of OH will: – Make it resistant to COMT • Constitute a group of drugs used for – – – Cardiovascular Respiratory Other conditions • Subdivided into – Mode of action • Direct-acting • Indirect-acting Spectrum of action • Alpha • Beta • Dopamine receptor affinity – A. tricyclic antidepressants • • MONOAMINE OXIDASE (MAO) • • Present in the mitochondria in the adrenergic nerve endings Inactivates portion of dopamine and norepinephrine in the cytoplasm MONOAMINE OXIDASE INHIBITORS • May increase the stores of these transmitters and other amines in the nerve endings B. amphetamine Inhibit the reuptake of cathecolamines by nerve terminals Cocaine.

BRONCHI • Marked relaxation of the smooth muscles of the bronchi • Most efficacious and reliable for reversing bronchospasm D. brain – D1 . add OH – Direct-acting – Important in the storage of cathecolamines – – – • • TERBUTALINE ISOPROTERENOL beta2 > beta1 beta1 = beta2 ORGAN SYSTEM EFFECTS A.• • Prolong the duration of action Increase bioavailability Increase the ability to penetrate the CNS Alter the alpha carbon. add CH3 – Phenylisopropylamine – Ephedrine.Decrease cAMP – D2. beta3 – Increase cAMP DOPAMINE RECEPTOR ACTIVATION • Receptors found in renal vasculature. euphoria. paranoia and rarely convulsions B. • • • • HEART Well supplied with beta1 and beta2 receptors Beta1 predominate in some parts of the heart Both mediate increase heart rate and contraction Increase blood pressure alpha1 > alpha2 alpha1 activation alpha2 > alpha1 alpha2 activation MIXED (activates both alpha and beta) • NE alpha1 = alpha2 beta1 > beta2 • EPINEPHRINE alpha1 = alpha2 beta1 = beta2 BETASELECTIVE • DOBUTAMINE beta1 = beta2 . beta2. VASCULAR SYSTEM • Vasoconstriction • Dopamine causes vasodilatation in the splanchnic and renal vascular beds G. • • • EYE Pupillary dilator responds with mydriasis Accommodation is not significantly affected Facilitate outflow of aqueous humor with subsequent reduction of intraocular pressure ADRENOCEPTORS -G-protein coupled -Need a 2nd messenger to induce sympathetic effect ALPHA RECEPTOR ACTIVATION • Epinephrine > NE > isoproterenol • Alpha1 – Increase in phosphatidyl inositol (IP3) – Release of calcium • Alpha2 – Decrease cAMP BETA RECEPTOR ACTIVATION • Isoproterenol > epinephrine > NE • Beta1. like amphetamine. GUT • Contains alpha receptors in the bladder trigone and sphincter area • Bladder relaxation and sphincter contraction • Beta2 agonist causes uterine relaxation in pregnancy F. have stimulant effects Mild altering or reduction of fatigue. CNS • Do not enter the CNS effectively • Those that enter.More important in the brain ALPHA SELECTIVE • PHENYLEPHRINE • CLONIDINE C. and insomnia • Very high doses – Marked anxiety or aggressiveness. progressing to anorexia. GIT • Well endowed with both alpha and beta receptors • Located on the smooth muscles and neurons of the enteric nervous system • Activation of either receptors leads to the relaxation of the smooth muscles E. amphetamine • Resistant to hydrolysis by MAO • Indirect-acting • Long duration of action Alter the beta carbon.

METAPROTERENOL • Drugs of choice in the treatment of acute asthmatic attacks SALMETEROL • Long-acting • Recommended for prophylaxis E. METABOLIC AND HORMONAL EFFECTS • Beta1 increases renin secretion • Beta2 increases insulin secretion (gluconeogenesis) • Increases glycogenolysis in the liver and the resulting hyperglycemia is countered by insulin levels • Stimulate lipolysis CLINICAL USES A. ANAPHYLAXIS EPINEPHRINE • Drug of choice for the immediate treatment of anaphylactic shock • Rapid acting • Pressor agent • Used for cardiac arrest B. CVS 1. GUT RITODRINE. CNS PHENYLISOPROPYLAMINES (AMPHETAMINES) • Narcolepsy • Attention deficit disorder With appropriate control. weight reduction C. TERBUTALINE • Used to suppress premature labor • Cardiac stimulant effect may be hazardous to both mother and fetus EPHEDRINE • Long-acting oral sympathomimetic used to improve urinary incontinence in children and the elderly with enuresis • Mediated by the alpha receptors in the trigone of the bladder CATHECOLAMINES EPINEPHRINE • Pressor agent • Cardiac arrest • Anaphylactic shock NOREPINEPHRINE • Pressor agent ISOPROTERENOL • Cardiogenic shock DOBUTAMINE • Congestive heart failure • Inotropic effect DOPAMINE • Inotropic effect • Lower doses cause renal vasodilation • Higher doses cause vasoconstriction NON-CATHECOLAMINES PHENYLEPHRINE • Pressor agent • Mydriatic Decongestant METHOXAMINE • Pressor agent • IV form only MIDODRINE • Pressor agent • Orthostatic hypotension DRIXINE • OXYMETAZOLINE. Conditions in which a decrease in blood flow or increase in BP is desired • Alpha1 agonists are useful in situations in which vasoconstriction is needed • Local hemostatic • Decongestant effects • In spinal shock in which temporary maintenance of BP may help perfuse the brain. BRONCHI TERBUTALINE. ALBUTEROL. Conditions in which an increase in blood flow is desired • Beta1 agonists maybe useful in situations like – Acute cardiac failure – Some types of shock 2. heart and the kidneys F.H. XYLOMETAZOLINE • Topical decongestants . EYE PHENYLEPHRINE • Used topically to produce mydriasis • Used to reduce conjunctival itching and congestion caused by irritation and allergy D.

TERBUTALINE • Bronchial asthma RITODRINE • Inhibits premature labor COCAINE • Local vasoconstrictive • Anesthetic effect TYRAMINE • Derivative of tyrosine • Increase BP • Found in cheese and wine TOXICITY • Limited penetration to the brain • Little CNS toxicity when given systemically • In the periphery – Excessive vasoconstriction – Cardiac arrhythmias – Myocardial infarction – Pulmonary edema or hemorrhage .

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