Pharmacology

Ideal Drug  Effectiveness  Safety  Selectivity  Reversible  Predictability  Ease of administration  Freedom from drug interactions

Ideal Drug  Low cost  Chemical Stability  Possession of a simple generic name

Therapeutic Objective  Maximum benefit with minimum harm  The intensity of the response to a drug is directly related to the concentration of the drug at its site of action

Intensity of Drug responses  Administration – dosage and route  Pharmacokinetics  Pharmacodynamics  Individual variation

Nursing Responsibilities  Last line of defense against errors!!!!!!!!!  Patient education  Utilize the nursing process

Drug Legislation  1906 – drugs should be free of adulterants  1938 – testing for toxicity  1962 – proof of effectiveness  1970 – Controlled Substance Act – Scheduled drugs  1997 – Food and Drug Administration Modernization Act

New Drug Development  Preclinical testing – prior to testing on humans  Clinical testing  I – normal volunteers – except maybe patients who have disease  II and III – patients  IV – released for general use

 Be neither the first to adopt the new nor the last to abandon the old!

Drug Names  Chemical  Generic Name  Trade Name  OTC drugs

Pharmacokinetics  Drug movement throughout the body  Absorption – movement of drug from its site of administration into blood  Dissolve – must dissolve before being absorbed  Surface area – the larger the faster  Blood flow – most rapid where blood flow is high  Lipid solubility - the higher the faster  pH partitioning

Absorption - Routes  IV – no barriers to absorption  Intramuscular – good for poorly soluble drugs, “time released”  Subcutaneous – again no significant barriers  Oral – must pass through cells of epithelium, enteric coating  Safer but highly variable absorption – enteric, sustained-release, tablets

Routes of Drug Administration Routes of Drug Administration

Drug Absorption  Absorption is the process by which a drug enters the bloodstream without being chemically altered or  The movement of a drug from its site of application into the blood or lymphatic system

Drug Absorption  Factors which influence the rate of absorption –types of transport –the physicochemical properties of the drug –protein binding –routes of administration –dosage forms –circulation at the site of absorption –concentration of the drug

Drug Absorption  The rate at which a drug reaches it site of action depends on: –Absorption - involves the passage of the drug from its site of administration into the blood –Distribution - involves the delivery of the drug to the tissues

Drug Absorption  Mechanisms of solute transport across membranes –passive diffusion –filtration and bulk flow –endocytosis –ion-pairing –active transport –Drug Absorption animationDrug Absorption animation

Ion Trapping cont: Body fluids where a pH difference from blood pH will favor trapping or reabsorption: stomach contents small intestine breast milk aqueous humor (eye) vaginal secretions prostatic secretions

Ion Trapping: Kidney: Nearly all drugs filtered at the glomerulus: Most drugs in a lipid-soluble form will be absorbed by passive diffusion. To increase excretion: change the urinary pH to favor the charged form of the drug: Weak acids: excreted faster in alkaline pH (anion form favored) Weak bases: excreted faster in acidic pH (cation form favored)

Lipid-Water Partition Coefficient –The ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid or organic solvent (representing the membrane); and an aqueous buffer, pH 7.4 (representing the plasma)

Lipid-Water Partition Coefficient  The higher the lipid/water p.c. the greater the rate of transfer across the membrane – polarity of a drug, by increasing ionization will the lipid/ water p.c. – polarity of a drug, suppression of ionization will the lipid/ water p.c.

Routes of Drug Administration The route of administration (ROA) that is chosen may have a profound effect upon the speed and efficiency with which the drug acts ImportantInfo

 The possible routes of drug entry into the body may be divided into two classes : –Enteral –Parenteral

Enteral Routes  Enteral - drug placed directly in the GI tract: –sublingual - placed under the tongue –oral - swallowing (p.o., per os) –rectum - Absorption through the rectum

Sublingual/Buccal Some drugs are taken as smaller tablets which are held in the mouth or under the tongue.  Advantages –rapid absorption –drug stability –avoid first-pass effect

Sublingual/Buccal  Disadvantages –inconvenient –small doses –unpleasant taste of some drugs

Oral  Advantages –Convenient - can be self- administered, pain free, easy to take –Absorption - takes place along the whole length of the GI tract –Cheap - compared to most other parenteral routes

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Oral  Disadvantages –Sometimes inefficient - only part of the drug may be absorbed –First-pass effect - drugs absorbed orally are initially transported to the liver via the portal vein –irritation to gastric mucosa - nausea and vomiting

Oral  Disadvantages cont. –destruction of drugs by gastric acid and digestive juices –effect too slow for emergencies –unpleasant taste of some drugs –unable to use in unconscious patient

First-pass Effect  The first-pass effect is the term used for the hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation. The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally

First-pass Effect cont. Magnitude of first pass hepatic effect: Extraction ratio (ER) ER = CL liver / Q ; where Q is hepatic blood flow (usually about 90 L per hour. Systemic drug bioavailability (F) may be determined from the extent of absorption (f) and the extraction ratio (ER): F = f x (1 -ER)

First-pass Effect

1. unconscious patients and children 2. if patient is nauseous or vomiting 3. easy to terminate exposure 4. absorption may be variable 5. good for drugs affecting the bowel such as laxatives 6. irritating drugs contraindicated Rectal

Parenteral Routes –Intravascular (IV, IA)- placing a drug directly into the blood stream –Intramuscular (IM) - drug injected into skeletal muscle –Subcutaneous - Absorption of drugs from the subcutaneous tissues –Inhalation - Absorption through the lungs

Intravascular Absorption phase is bypassed (100% bioavailability) 1.precise, accurate and almost immediate onset of action, 2. large quantities can be given, fairly pain free 3. greater risk of adverse effects a. high concentration attained rapidly b. risk of embolism c. OOPS factor or

Intramuscular 1. very rapid absorption of drugs in aqueous solution 2.repository and slow release preparations 3.pain at injection sites for certain drugs

Subcutaneous 1. slow and constant absorption 2. absorption is limited by blood flow, affected if circulatory problems exist 3. concurrent administration of vasoconstrictor will slow absorption

1.gaseous and volatile agents and aerosols 2.rapid onset of action due to rapid access to circulation a.large surface area b.thin membranes separates alveoli from circulation c.high blood flow Particles larger than 20 micron and the particles impact in the mouth and throat. Smaller than 0.5 micron and they aren't retained. Inhalation

Inhalation cont.  Respiratory system. Except for IN, risk hypoxia.  Intranasal (snorting) Snuff, cocaine may be partly oral via post- nasal dripping. Fairly fast to brain, local damage to septum. Some of the volatile gases also appear to cross nasal membranes.  Smoke (Solids in air suspension, vapors) absorbed across lung alveoli: Nicotine, opium, THC, freebase and crack cocaine, crystal meth.Particles or vapors dissolve in lung fluids, then diffuse. Longer action than volatile gases. Tissue damage from particles, tars, CO.  Volatile gases: Some anaesthetics (nitrous oxide, ether) [precise control], petroleum distillates. Diffusion and exhalation (alcohol).  Lung-based transfer may get drug to brain in as little as five seconds.

Topical Mucosal membranes ( eye drops, antiseptic, sunscreen, callous removal, nasal, etc.) Skin a. Dermal - rubbing in of oil or ointment (local action) b. Transdermal - absorption of drug through skin (systemic action) i. stable blood levels ii. no first pass metabolism iii. drug must be potent or patch becomes to large

 intravenous seconds  intraosseous seconds  endotracheal 2-3 minutes  inhalation 2-3 minutes  sublingual 3-5 minutes  intramuscular minutes  subcutaneous minutes  rectal 5-30 minutes  ingestion minutes  transdermal (topical) variable (minutes to hours) Route for administration -Time until effect-

Time-release preparations  Oral - controlled-release, timed-release, sustained-release –designed to produce slow,uniform absorption for 8 hours or longer –better compliance, maintain effect over night, eliminate extreme peaks and troughs

Time-release preparations  Depot or reservoir preparations - parental administration (except IV), may be prolonged by using insoluble salts or suspensions in non-aqueous vehicles.

Distribution  Blood flow to tissues  Exiting the vascular system once it has been delivered – pass through pores in capillary wall

Protein - binding  Drugs can bind with proteins  Parts of drugs will be bound during any given time period  Impedes drug’s ability to reach sites of action, metabolism, or excretion

Metabolism  LIVER  Enzymatic alteration of drug structure

Consequences of metabolism  Accelerated renal excretion – kidney cannot excrete highly lipid soluable  Drug inactivation  Increased therapeutic action  Activation of prodrugs  Increased or decreased toxicity

Considerations in Metabolism  Age  Induction of drug metabolizing enzymes  First-pass effect – Nitroglycerin  Nutritional status  Competition between drugs

Excretion  KIDNEY  Glomerular filtration – blood to tubular urine  Tubular reabsorption  Active tubular secretion – pumps for organic acids and organic bases – to urine

Monitoring drug levels  Plasma drug levels Therapeutic range

Drug Half-life  Time requires for the amount of drug in the body to decrease by 50%  Will determine dosing requirements  Goal - plateau

Dosing  Loading doses – when plateau must be achieved quickly  Routine smaller doses – maintenance doses

 Peak and trough levels

 Maximal efficacy – largest effect a drug can produce  Potency – one that produces its effects at lower dosages

Receptors  Drugs bind to receptors to produce effects  Reversible

 All that drugs can do is mimic the physiological activity of the body’s own molecules  Block the physiological activity of the body’s own molecules

Agonists  Mimic the body’s own regulatory molecules

Antagonists  Drugs that block the actions of endogenous regulators

Partial agonists  Mimic the actions but with reduced intensity

Drug Interactions  Can have varying effects  Direct chemical or physical – IV preparation

Drug – Food Interactions  Frequently decreased rate of absorption  Grapefruit juice can inhibit metabolism  “with food” – with or shortly after meal  “empty stomach” – one hour prior to meal or two hours after

Adverse drug reactions  Side effect  Toxicity  Allergic reaction  Idiosyncratic effect  Iatrogenic disease  Physical dependence  Carcinogenic effect

 Teratogenic effect – induce birth defect  Ways to minimize

Variation in drug responses  Age  Body composition  Gender  Pathophysiology  Tolerance  Placebo effect  Genetics  Variability in absorption – bioavailability – oral – ability to reach circulation  Compliance

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