INTRODUCTION TO PHARMACOLOGY HISTORY Early drug plants, animals & minerals 2700 BB earliest recorded drug use found

found i n Middle East & China 1550 BC Egyptians created Ebers Medical Papyrus Castor oil laxative Opium pain Moldy bread wounds & bruises Galen (131-201 AD) Roman physi cian; initiated common use of prescriptions 1240 AD introduction of apothecary s ystem (Arab doctors) 1st set of drug standards & measurements (grains, drams, mi nims), currently being phased out 15th century apothecary shops owned by barber, surgeons, physicians, independent merchants 18th century small pox vaccine (by Jenner) Digitalis from foxglove plant for strengthening & slowing of heartbeat V itamin C from fruits 19th century morphine & codeine extract from opium Introduc tion of atropine & iodine Amyl nitrite used to relieve anginal pain Discovery of anesthetics (ether, nitrous oxide) Early 20th century aspirin from salicylic ac id Introduction of Phenobarbital, insulin, sulforamides Mid 20th century 1940 Di scovery antibiotics (penicilline, tetracycline, streptomycin), antihistamines, c ortisone 1.

1950 discovery antipsychotic drug, antihypertensives, oral contraceptives, polio vaccine 2. DEFINITION & SUBDIVISIONS Drug chemical introduced into the body to cause some changes WHO def: any produc t/subs used to modify/explore physiologic system/pathologic states for the benef it of the patient Pharmacology study of the manner in which the function of livi ng system is affected by chemical agents/drugs Science concerned with history, s ources, physical & chemical properties of drugs & the way in which drug affects living system Subdivisions of pharmacology: 1. pharmacodynamics study of the biochemical & physiological effects of drugs & mechanisms of action what the drug does to the body 2. pharmacokinetics deals with the absorption, distribution, biotransformation & excretion of drugs what the body does to the drug 3. pharmacotherapeutics study of drugs used in the diagnosis, prevention, suppre ssion, & treatment of diseases deals with beneficial effects of the drugs (medic ines) 4. pharmacognosy study of drugs in their original unaltered state; origin of dru gs source of drugs ex: penicillin from penicillium (fungi) 5. Toxicology study of biologic toxins: study of poison & its effects deals with deleterious effects of physical & chemical agents (including drugs) in human Ph armacoeconomics study of relationship of drugs & economics

Pharmacovigilance science of collecting,researching, analyzing, & evaluating set of information about adverse drug effects. Receptor a component of the cell tha t interacts with drug, initiating a chain of biochemical events leading to drugs observed effects Human body works through complicated series of chemical reactio ns & processes Important aspects of nursing: understanding how drug ant on body to cause changes & apply that knowledge in clinical setting Patients take compli cated drug regimen & receive potentially toxic drug Some manage their own care a t home Nursing responsibilities regarding drug therapy: Administering drugs Asse ssing drug effects Intervening to make drug regimen more tolerable Provide patie nt teachings about drugs & drug regimen Knowing how drug works --- easier to han dle --- enhances drug therapy DRUG NOMENCLATURE 1. CHEMICAL NAME atomic/molecular structure of drug 2. GENERIC NAME/NON-PROPERTY NAME original designation given to the drug when the drug company applies for a pproval patents universally accepted & not capitalized; before drug becomes offi cial, used in all countries protected by law; not capitalized 3. TRADE/BRAND/PRO PRIETY NAME name given by the drug company that developed it followed by the sym bol R or TM, 1st letter is capitalized chemical name acetylsalicylic acid generi c name aspirin trade name aspilet

COMMON SOURCES /4 MAJOR SOURCES (ORIGINS) OF DRUGS: 1. Animal sources from organs, organ secretion or organ cells Used to replace hu man chemical not produces because of disease or genetic problems Thyroid drugs & growth hormones preparations from animal thyroid & hypothalamus tissue (many of these preparations are now created synthetically safer & purer) Insulin from pa ncreas of animals (hog, cattle, sheep): thru genetic engineering cld produce hum an insulin by altering E. coli bacteria making it a better product without impur ities that come with animal products 2. vegetable/plant sources roots, bark, sap , leaves, flowers, seeds of medicinal plants digitalis from wildflower, purple f oxglove, dried leaves of plant active principles of plants alkaloids alkaline in reaction, bitter in taste, powerful in physiologic activity o atropine & scopol amine o morphine sulfate, cocaine, quinine, nicotine, caffeine o procaine glycos ides digitalis resin soluble in alcohol; example colonic irritant found in laxat ive cascara gums used in bulk-type laxatives: some used in certain skin preparat ions for their soothing relief oils castor oil, oil of wintergreen 3. Mineral sources from free elements, both metallic & non-metallic usually in f orm of acids bases, salts found in food

 Dilute HCI control/prevent indigestion Calcium, aluminum, fluoride, iron, gold, potassium 4. synthetic sources many drugs developed synthetically after chemical in plants , animals, or environment have been screened for signs of therapeutic activity m ore potent, more stable, less toxic steroids arthritis & other diseases sulfonam ides/chemotherapeutic agents kill microorganism slow their growth meperidine HCI (Demerol)

DRUG CLASSIFICATION A. by action Anti infectives antiseptics, disinfectants, sterilants Antim ls, metabolic, diagnostic materials, vitamins & minerals Vaccine & serums, antif ungals, antihistamines, antineoplastics, antacids B. By body system CNS (+)/(-) actions of neural pathways & centers: Phenobarbita l ANS governs several bodily functions so that drugs that affect ANS will at the same time affect other systems functions GIT acts on mascular & glandular tissu es: leperamide RESPIRATORY SYSTEM act on resp. tract, tissues, cough center, sup press, relax, liquefy & stimulate depth & rate of respiration Urinary system act on kidney & urinary tract Circulatory system act on heart, blood vessels, blood ; metoprolol KINDS OF DRUGS Prescription/legend drug can be dispensed if with prescription order; with speci fic name of drug & dosage regimen to be used by patient

non-prescription drug can be dispensed over the-counter/without prescription orde r for self treatment of variety of complaints vitamin supplements, cold/cough re medies, analgesics, antacids, herbal products cautions in use of OTC drugs: 1. d elay in professional diagnosis & treatment of serious/potentially serious condit ion may occur 2. symptoms may be masked making the diagnosis more complicated 3. clients health care provider/pharmacist should be consulted before OTC preparati ons are taken 4. labels/instructions should be followed carefully 5. ingredients in OTC drug may interact with prescribed drug 6. inactive ingredients may resul t in adverse reactions 7. potential for overdose 8. multiple medication users ar e at risk as more medications are added to therapy regimen 9. interactions of me dications are potentially dangerous Investigational drug new drugs undergoing cl inical trails Illicit/street drug used/distributed illegally for non-medical pur poses to alter mood of feeling **when drug is taken by mouth, it undergoes 3 pha ses: 1. pharmaceutic/dissolution 2. pharmacokinetics 3. pharmacodynamics I. PHARMACEUTIC/DISSOLUTION Drug goes into solution so that it can cross the biologic membrane Not found in drug administered parenterally 1st phase of drug action of agents taken by mouth

Additive enhances absorbability of drugs EXCIPIENTS: filters & inert substances Allows drugs to take on particular size & shape Enhance drug dissolution potassi um (K) --- losartan K (cozaar); sodium (Na) ---cloxacillin Na (Prostaphlin-A) 2 phases: Disintegration breakdown into smaller parts Dissolution futher breakdown into smaller parts in GIT absorption; dissolved into liquid rate limiting: time it takes drug to disintegrate & dissolve to become available for body to absorb it factors affecting dissolution form of drug (LIQUID VS. SOLID) liquid more ab sorbed than solid, already in solution, rapidly available for GI absorption Gast ric ph (acid vs alkaline) acidic media (ph=1.2) faster disintegration & absorpti on Age young vs elderly inc ph. Dec absoption Enteric coated drugs resist disint egration in gastric acid Disintegration occurs only in alkaline environment (int estine) Should not be crushed Presence of food interfere with dissolution & abso rption, enhance absorption of other drugs, may be protectants of gastric mucosa I. PHARMACOKINETICS action of body to the drug: Study of absoption (taken into t he body), distribution (moved into various tissues), metabolism/biotransformatio n (changed into a form that can be excreted) & excretion (removed from the body) of drugs What happens to the drug when it enters the body kinetics movement: deal s with drugs actions as it moved through the body

Also concerned with a drugs onset of action, peak concentration level, & duration of action 4 processes involved: I. Absorption route of drug takes from the time it enters the body until it is absorbed in circulating fluids Movement of drug molecules f rom site of administration to circulatory system Movement of drug particles from GIT to body fluids involve 3 processes Passive absorption (diffusion) movement from higher concentration o No energy required: occurs when smaller molecules di ffuse across membrane o Stops when drug concentration on both sides of the membr ane is equal o Major process through which drugs are absorbed into the body Acti ve absorption needs carrier (enzymes or protein) to move against a concentration gradient o Energy is required: from lower concentration to higher concentration o Used to absorb electrolytes (i.e. sodium, potassium) & some drugs (levodopa) Pinocytosis engulfs the drug to carry it across the membrane o Transport fat-sol uble vitamins (vit.A,D,E,K) Factors affecting absorption: Drug solubility lipid soluble drugs pass readily through GI membrane, Water soluble drugs need an enzy me or protein

Local condition at site of absorption weak acids less ionized in stomach - - - readily pass through the SI Pain / stress / solid foods / fatty or hot foo ds slows down gastric emptying time Drug concentration drugs can take several ho urs/days to reach peak concentration levels (slow rate: rectal administration or sustained release drugs) Circulation at site of absorption poor circulation ham pers absorption (i.e. shock) The more blood vessels, the faster the absorption E xercise decrease blood flow to GI slows absorption Application of heat/massage i ncreases blood flows at site Muscles area selected for IM administration: Blood flows faster through deltoid muscle (upper arm) vs gluteal muscle (buttocks) Glu teal muscle can accommodate larger volume of drug than deltoid muscle 3. Metabol ism biotransformation: essential for termination of a drugs biologic activity so can be easily excreted Sites of metabolism o Liver main organ for drug metabolis m Through the drug metabolizing enzymes (microsomal enzymes, non-microsomal enzy mes) 1st pass effect hepatic 1st pass some drugs do not directly go into circula tion but pass thru intestinal lumen to liver via portal vein - - drug metabolize d in liver into inactive form - - decrease

amount of active drugs - - - increase recommended dose for oral drugs o Plasma o Kidneys o Membranes of intestine Process by which body changes a drug from its dosage form to a more watersoluble form that can then be excreted Can be metabol ized in several ways: o Most drugs metabolized into inactive metabolites (produc ts of metabolism), which are then excreted o Other drugs converted to active met abolites capable of exerting their own pharmacologic action May undergo further metabolism or may be excreted from body unchanged Prodrugs some drugs administer ed as inactive drugs which dont become active until theyre metabolized o Permits t he body to inactive a potent drug before it accumulates & produces toxic effects Phases of drug metabolism: o Phase 1: endoplasmic reticulum; introduce/expose a functional group on the parent compound (i.e. alkylation, alipathic hydroxylati on, oxidation, deamination, hydrolysis, microsomal oxidases) Cytochrome p450 ind ucer inc drug metabolism, dec bioavailability Cytochrome p450 inhibitor dec drug metabolism, inc levels of drug prolonged effect & inc toxicity o Phase 2 conjug ation reactions that lead to formation of covalent linkage between parent compou nd with glucoronic acid, sulfate, Lidocaine extensive 1st pass not given orally

glutathione or acetate (glucoronidation, sulfation, acetylation); synthetic reac tions Factors affecting biotransformation: o Genetic some people metabolize drug s rapidly, other more slowly o Physiologic Liver diseases (cirrhosis), heart fai lure dec circulation in liver Infants immature livers dec rate of metabolism o Area of absorbing surface to which a drug is exposed (+) chemical agents may d estroy the drug o Types of transport diffusion, active, pinocytosis o Routes of administration skin absorption slower than IM Absorption with in seconds/minutes : sublingual, IV, by inhalation route Slower rate absorption: oral, IM SC routes o Bioavailability consideration of highest importance in drug effectiveness & s afety Subcategory of absorption % of administered drug does that reaches systemi c circulation Oral route <100%(usually 20-40%); IV route = 100% Factors that alt er bioavailability: Drug form (tablet, capsule) Route of administration GI mucos a & motility Food & other drugs (+) food - - - pord of gastric acid inc drug abs orption (i.e. azole) Changes inliver metabolism, liver disorder dec liver function inc bioavailability II. distribution process by which drug becomes available to body fluids & tissues

the ways a drug is transported from the site of administration to the site of ac tion (transportation) factors affecting distribution: o size of the organ o bloo d flows drug is quickly distributed to organs with large supply of blood (heart, liver, kidneys) distribution to other internal organs, skin, fat, muscle is slo wer o solubility lipid soluble drugs can also cross the blood-brain barrier & en ter the brain o Binding as drug travels trough the body, it comes in contract wi th proteins (albumin). The drug can remain free or bind to protein. Portion of d rug bound to protein is inactive, no therapeutic affect Free/unbound portion act ive - - - - (+) pharmacologic response Highly protein bound drug - > 89% of drug is bound to protein Diazepam, piroxicam, valproic acid

Moderately highly protein bound drugs (61-89% bound protein) Erythromycin, pheny toin

Moderately protein bound drugs 30-60% Aspirin, lidocaine, pindolol, theophyliine

Low protein-bound drugs - < 30% bound to protein (amikacin, amoxicillin) DISTRIBUTION PROTEINBINDING BLOOD FLOW BODY TISSUE AFFINITY PHARMACOLOGIC EFFECT

Elderlies dec liver size, blppd flow, enzyme production - - - slows metabolism E nvironment cigarette smoke may affect rate of some drugs o Stressful environment prolonged illness, surgery, injury

III. Excretion/elimination removal of drug from the body: drug is changed into i nactive form & excreted by the body Routes: o Kidney main organ for drug elimina tion: leaves the body through urine tract Factors affecting drug excretion o Uri ne ph normal: 4-5.8 Acid urine promotes elimination of weak base drugs i.e. cran berry juice dec urine ph - - - (-) elimination of aspirin alkaline urine (+) eli mination of weak acid drug overdose aspirin - - - give Nabicarbonate inc urine p h - - - (+) excretion of drug Free/unbound/water soluble drugs filtered in kidne y Protein bound drug cannot be filtered in kidney (+) kidney dose dose must be d ecreased

o Lungs, exocrine (sweat, salivary, mammary) glands, skin, intestinal

o glomerular filtration rate (GFR) dec GFR - - - drug excretion slowed/impaired can result to drug accumulation extent of filtration directly proportional to GF R & to fraction of unbound drug to plasma ratio of clearance = fu x GFR - - - cl eared by filtration ratio of clearance < fu x GFR - - - cleared tubular reabsorp tion ratio of clearance > fu x GFR - - - cleared by tubular secretion o creatini ne clearance most accurate test to determine renal function creatinine excreted in kidney dec renal GFR inc serum creatinine level & dec urine creatinine cleara nce 12-24 hrs urine collection & blood sample Normal 85-135 ml/min; elderly 60ml /min Renal clearance ife/elimination o be eliminated G) o Long t = amount of substance removed from the blood by the kidneys Half-l half-life (t ) time it takes for one half of drug concentration t o Short t = 4-8 hrs: given several times a day (i.e. penicillin > 12 hrs: given 2x or 1x / day (digoxin)

II. PHARMACODYNAMICS refers to action of drug to dy in response to the drug Effects of drugs on the al functions & mechanisms of action Interactions living systems & foreign chemicals including drugs

the body What happens to the bo cells biological & physiologic between chemical components of that enter these system

Mechanism of action: means by which a drug produces alteration in function of th eir action Drug actions: a. To replace/act as substitute for missing chemicals b . To inc or stimulate certain cellular activities c. To depress/slow cellular ac tivities d. To interfere with functioning of foreign cells (i.e. invading microo rganisms/neoplasms) chemotherapeutic Agents Theories of Drug Actions a. Drug-rec eptors interaction certain portion of drug molecule (active site) selective comb ines with some molecular structure (reactive site) on the cell to produce a biol ogic effect Receptor site drugs act at specific areas on cedil memb.; react with certain chemicals to cause an effect with in cell lock & key theory specific chem ical (key) approaches a cell membrane & finds a perfect fit (the lock) at recept or site affects enzymes system within a cell produce certain effects Specificity selectivity theory Drug action may be: Agonists drugs that produce a response o insulin reacts with specific insulin receptor site to change cell membrane perm eability - - - (+) movement of glucose into cell competitive antagonist act with receptor sites to block normal stimulation producing no effect o curare use on spear in Amazon to paralyze prey & cause death: occupies receptor sites for Acet ylcholine (needed in muscle contraction & movement) - - - prevents nerve stimula tion causing paralusis

o noncompetitive antagonist - prevent reaction of another chemical with differen t receptor site on that cell b. drug-enzymes interaction interferes with enzyme systems that act as catalyst from various chemical reations enzyme systems casca de effect; one enzyme activating another - - - causing cellular reaction if sing le step in one of enzyme system is blocked normal cell function is disrupted ex: acetazolamide (diamox) diuretic that block carbonic anhydrase alters H+ & H2O e xchange systems in kidneys & eye c. nonspecific drug interaction act by biophysi cal means that do not affect cellular enzymatic reactions d. selective toxicity all chemotherapeutic agent would act only on 1 enzyme system needed for life of a pathogen or neoplastic cell & will nor affect healthy cells ex: penicillin unf ortunately most of it cause destruction of normal human cells Drug response may be: 1. primary always desirable / physiologic effects 2. secondary desirable or undesirable ex: diphenhydramine (benadryl) 1st effect: antihistamine, treat symp toms of allergy; 2: CNS depression - - - drowsiness desirable: when given at bed time: undesirable: when client is driving Classification of drug action: 1. rapi d few seconds to minutes (IV, SL, inhalation) 2. intermediate 1-2 hrs after admi nistration (IM, SC)

3. Delayed/slow several hrs after administration (rectal, oral) Parameters of Dr ug Action: 1. onset of action latent period: interval between time drug is admin istered & 1st sign of its effect time it takes to reach the minimum effective co ncentration (MEC) after a drug is administered time from drug administration to 1st observable effect _T0 T1) 2. duration of action period from onset until drug effect is no longer seen leng th of time the drug exerts pharmacologic effect (T1 T3) 3. peak action drug reaches its highest blood / plasma concentration (T0 T2) Ter mination of action point from onset at which drug effect is no longer seen Minim al effective concentration lowest plasma concentration that produces the desire effect Peak plasma level highest plasma concentration attained from a dose Toxic level plasma concentration at which a drug produces adverse effects Therapeutic range range of plasma concentration that produces the desire effect without tox icity (range between minimal effective concentration & toxic level) Loading dose bolus of drug given initially to attain rapidly a therapeutic plasma concentrat ion large initial dose; when immediate drug response is desired given to achieve a rapid MEC in the plasma i.e. digoxin - - - requires LD Maintenance dose amount of drug necessary to maintain a steady therapeutic plasm a concentration Dose response relationship between minimal vs. maximal amount of drug dosed needed to produce desired drug response i.e. some clients respond to lower drug dose while others need a high dose

Maximal efficacy (maximum drug effect) all drugs give a maximum drug effect (max imal efficacy) i.e. simvastatin 40mg vs rouvastatin 10mg Drug-response relationship: Biologic half-life (t1/2) = time required to reduce to amount of unchanged drug that is in the body short t1/2 drugs need to be admi nistered more often than one with a longer t1/2 Lethal dose (LD50) dose lethal t o 50% of animals tested Effective dose (ED50) dose required to produce therapeut ic effect on 50% animals tested Therapeutic index (TI) ratio between LD50 and ED 50; the closer the ratio is to 1, the greater the danger involved in giving the drug to humans estimates the margin of safety of a drug through the use of a rat io that measures the effective (therapeutic or concentration) dose (ED) in 50% o f persons/animals (ED50) & lethal dose in 50% of animals (LD50) TI=LD50/ED50 low therapeutic index: narrow margin of safety; might need to adjust drug dose & pl asma drug levels need to be monitored high therapeutic index: wide margin of saf ety less danger of producing toxic effects 4 Categories of Drug Action: 1. stimu lation/depression stimulation inc rate of cell activity/secretion from the gland depression dec cell activity & function of a specific organ 2. replacement replaces essential body compounds; i.e. insulin 3. inhibition/kil ling of organism interfere with bacterial cell growth ; i.e. antibiotics

4. irritation i.e. laxative irritate inner wall of colon - - - inc peristalsis - - inc defecation Drug potency relative amount of drug required to produce des ired response also used to compare a drug dose response curve graphical representation of relationship between dose of dru g & response it produces low dose low response dosage increased produce slight i ncrease response, as dose further increases, drug response increases markedly, a t certain point however, inc dose yield little or no inc in response - - - drug have reached Maximum Effectiveness Factors Affecting Dose Response Curve: nurse must be aware that human factor has tremendous influence on what actually happen s when it enter the body no 2 people react in exactly the same way to any given drug 1. weight heavier patient larger dose to get therapeutic effect (more tissu e to perfuse & inc receptor site in some reactive tissues) 3. toxicity 4. pharma cogenetics effect of a drug action that varies from a predicted drug response be cause of genetic factors or hereditary influence people have different genetic m akeup do not always respond identically to a drug dosage or planned drug therapy ex: African Americans do not respond as well as whites to some classes of antih ypertensive medications 5. route of administration dec weight dec dose older pat ients: less absorption, distribution between fewer plasma proteins & less effici ent perfusion: geriatric dosages nurse should monitor closely for desired effect s (may adjust dose) 2. age children (immune system for handling drugs) & older a dults

6. emotional factors 7. pre-existing disease state liver disease 8. drug history drug interaction synergistic/excretion 9. tolerance 10. cumulative effect 11. d rug- drug interaction 12. BMR inc BMR inc drug metabolism & excretion Drug Inter action 1. Additive effect 2 drugs with similar actions are taken for a doubled e ffect (desirable/undesirable) (1 + 1 = 2) Ibuprofen + paracetamol + added analge sic effect 2. Synergistic combined effect of 2 drugs is greater than sum of the effect or e ach drug given alone (1 + 1 = 3) Aspirin + codeine = greater analgesic effect 3. potentiation a drug that has no effect enhances the effect of a 2nd drug (0 + 1= 2) 4. Antagonistic one drug inhibits the effect of another drug (1 + 1 = 0) Tetracycline + antacid = dec absorption of tetracycline SIDE EFFECTS Physiologic effects not related to desired drug effects All drugs h ave side effects Desirable: diphenhydramine (Benadryl) at bedtime s/e: drowsines s Undesirable Result mostly from drugs that lack specificity Might be used interchangeably wit h adverse reactions Not a reason to discontinue drug therapy Nurses role: teach c lients to report any side effects

ADVERSE REACTIONS More severe than side effects Range of untoward effects (unint ended, occurring at normal doses) of drug that cause mild-severe side effects: a naphylaxis (cardiovascular collapse) Always undesirable Must always be reported & documented because they represent variances from planned therapy. TOXIC EFFECT /TOXICITY Can be identified by monitoring the plasma (serum) therapeutic range o f the drug Narrow TI (aminoglycoside & antibiotics) therapeutic range is monitor ed When drug level exceeds therapeutic range, toxic effects are likely to occur from overdosing or drug accumulation.