Final Review

FINAL REVIEW I.

PHARMACOKINETICS - derived from two Greek words:

pharmakon = drug or poison kinesis =

motion - what the body does to drugs, includes metabolism and drug excretion A.

PROCESSES 1. absorption – movement of a drug from its site of administration into the

blood 2. distribution – drug movement from the blood to the interstitial space of tissues and from there into cells 3. metabolism – (biotransformation) enzymatically mediated alteration of drug structure 4. excretion – movement of drugs and their metabolites out of the body elimination – combination of metabolism plus excretion All four processes acting in concert determine the concentration of a drug at its sites of action. B. 1.

COMMONLY USED ROUTES OF ADMINISTRATION ENTERAL – via the gastrointestinal tract a.

Oral (PO)- per os = Latin phrase meaning by way of mouth i. Advantages: - easy, convenient, and inexpensive - safer than injection: inducing either emesis (vomiting) or catharsis (rapid emptying of the small intestine and bowel) or both before there has been sufficient time for absorption in the case of inappropriate administration - administering activated charcoal (compound that absorbs drugs while they are still in the GI tract) is another safeguard ii.

Disadvantages: - Variability makes it difficult to control the concentration of a drug at its sites of action, therefore making it difficult to control the onset, intensity and duration of responses - Inactivation can occur because the drug is destroyed by stomach acid, destroyed by digestive enzymes or undergo rapid inactivation by hepatic enzymes as they pass through the liver on their way from the GI tract to the general circulation - Patient Requirements = conscious, cooperative patients - Local Irritation of the GI tract can result in discomfort, nausea, and vomiting

2.

PARENTERAL – outside the gastrointestinal tract - by injection - pattern of all routes is unique because the barriers to absorption associated with each route are different a.

Intravenous (IV) i. Advantages: - Rapid Onset which is beneficial in emergencies - Control over levels of drug in the blood - Use of Large Fluid Volumes are permitted only through IV routes (some drugs are poorly soluble in water and must be dissolved in a large volume) - Use of Irritant Drugs can be administered only by IV route; when administered through a freely flowing IV line, these drugs are rapidly diluted in the blood, thereby minimizing the risk of injury ii. Disadvantages: - High Cost, Difficulty (set up takes time and special training; dependent on a healthcare professional), and Inconvenience (tethered to lines and bottles limits mobility) - Irreversibility can be dangerous: once the drug is in the body, it cannot be retrieved - to minimize this risk, IV drugs should be injected slowly in order for it to dilute in the largest volume of blood possible and concentrations that are unnecessary or even dangerous can be avoided - slow injection reduces the risk of toxicity to the central nervous system also - Fluid Overload - Infection - Embolism (blood vessel blockage at a site distant from the point of administration) - insertion of an IV needle can injure the venous wall, leading to formation of a thrombus (clot); embolism can result if the clot breaks loose and becomes lodged in another vessel - injection of hypotonic or hypertonic fluids can destroy red blood cells and the debris from these cells can produce embolism - injection of drugs that are not fully dissolved can cause embolism - Importance of Reading Labels before giving an IV drug, whereas solutions intended for subcutaneous administration are concentrated, solutions intended for intravenous use

are dilute; giving the right drug is not sufficient, you must also be sure that the formulation and concentration are appropriate for the intended route b.

Intramuscular (IM) i. Advantages: - can be used for administration of poorly soluble drugs - can be used to administer depot preparations (preparations from which the drug is absorbed slowly over an extended time) greatly reducing the number of injections required during long-term therapy ii.

Disadvantages: - discomfort and inconvenience - can cause local tissue injury and possible nerve damage (if the injection is done improperly) - less convenient than oral administration c.

Subcutaneous (SC or SQ) - no significant barriers to absorption - readily enters the blood by passing through the spaces between cells of the capillary walls - blood flow and drug solubility are the major determinants of how fast absorption takes place - advantages: suitability for poorly soluble drugs and depot preparations - disadvantages: discomfort, inconvenience, potential for injury - only real difference is the length of the needle – meds stay in circulation longer C.

EXITING THE VASCULAR SYSTEM Blood Brain Barrier – refers to the unique anatomy of capillaries in the CNS - tight junctions between the cells that compose the walls of most capillaries in the CNS are so tight that they prevent drug passage - a drug must be able to pass through cells of the capillary wall - only drugs that are lipid soluble or have a transport system can cross the blood brain barrier to a significant degree - barrier protects the brain from injury by potentially toxic substances - barrier can be a significant obstacle to therapy of CNS disorders - barrier is not fully developed at birth D.

SPECIAL CONSIDERATIONS IN DRUG METABOLISM First Pass Effect – refers to the rapid hepatic inactivation of certain oral drugs that are then carried through the small intestines through the liver and to the heart (nitroglycerine, insulin)

- when administered orally, drugs are absorbed from the GI tract and carried directly to the liver via the hepatic portal circulation - if the capacity of the liver to metabolize a drug is extremely high, that drug can be completely inactivated on its first pass through the liver - to circumvent the first pass effect, a drug that undergoes rapid hepatic metabolism is often administered parenterally - this permits the drug to temporarily bypass the liver, thereby allowing it to reach therapeutic levels in the systemic blood - once in the circulation, the drug is carried to its sites of action prior to passage through the liver; hence, therapeutic action can be exerted before the drug is exposed to hepatic enzymes Age - drug metabolizing capacity of infants is limited - the liver does not develop its full capacity to metabolize drugs until about 1 yr. after birth - the elderly can easily overdose because they don’t have the same liver function anymore

II.

PHARMACODYNAMICS

Pharmacodynamics – study of the biochemical and physiologic effects of drugs and the molecular mechanisms by which those effects are produced (study of what drugs do to the body and how they do it) Maximal Efficacy – largest effect that a drug can produce - indicated by the height of the dose-response curve - a drug with very high maximal efficacy is not always more desirable than a drug with lower efficacy Relative Potency – potency refers to the amount of drug we must give to elicit an effect - a potent drug is one that produces its effects at low doses affinity – the strength of the attraction between a drug and its receptor - drugs with high affinity can bind to receptor when present in low concentrations, therefore, are effective in low doses - very potent intrinsic activity – the ability of a drug to activate the receptor following binding and is reflected in its maximal efficacy agonists – drugs that mimic the body’s own regulatory molecules - molecules that activate receptors

- neurotransmitters, hormones, and all other endogenous regulators of receptor functions - in terms of modified occupancy theory, these drugs have both affinity and high intrinsic activity affinity allows the agonist to bind to receptors intrinsic activity allows the bound agonist to “activate” or “turn on” receptor function antagonists – drugs that block the actions of endogenous regulators - employed most commonly in the treatment of overdose - have virtually no effects on their own on receptor function - in terms of modified occupancy theory, these drugs have affinity for a receptor but with no intrinsic activity Classes: a. Noncompetitive (Insurmountable) Antagonists – bind irreversibly to receptors and inhibition of these agents cannot be overcome – no matter how much agonist may be available -irreversibility does not mean effects last forever; effects wear off as the receptors to which they are bound are replaced (life cycle) - intensity of response is proportional to the total number of receptors occupied - if sufficient antagonist is present, agonist effects will be blocked completely - rarely used therapeutically b. Competitive (Surmountable) Antagonists – bind reversibly to receptors and the inhibition they cause is surmountable - produce receptor blockade by competing with agonists for receptor binding - if competitive antagonist and an agonist have equal affinity for a particular receptor, the receptor will be occupied by whichever agent is present in the highest concentration

III.

ORIENTATION

TO

PHARMACOLOGY

DRUG – defined as any chemical that can affect living processes and have therapeutic applications PHARMACOLOGY - defined as the study of drugs and their interactions with living systems - encompasses the study of the physical and chemical properties of drugs as well as their biochemical and physiologic effects THERAPEUTICS – also known as pharmacotherapeutics

- defined as the use of drugs to diagnose, prevent, or treat disease or to prevent pregnancy - medical use of drugs A.

PROPERTIES OF AN IDEAL DRUG: - there is no such thing as a perfect drug 1. Effectiveness – an effective drug is one that elicits the responses for which it is given. - effectiveness is the most important property a drug can have ***IF A DRUG IS NOT EFFECTIVE, IT SHOULD NOT BE USED*** 2. Safety – a safe drug is one that cannot produce harmful effects – even is administered in very high doses and for a very long time - there is no such thing as a safe drug - pharmakon – Greek word meaning poison 3. Selectivity – one that elicits only the response for which it is given - there is no such thing as a selective drug: All medications cause side effects 4.

Reversible Action – it is important that effects be reversible - we want drug actions to subside within an appropriate time 5. Predictability – since each patient is unique, the accuracy of certain predictions cannot be guaranteed 6. Ease of Administration – an ideal drug should be simple to administer, the route should be convenient, and the number of doses per day should be low a. Benefits: - it can enhance patient adherence - it can decrease errors in drug administration 4. Freedom from Drug Interactions – when taking two or more drugs, those drugs can interact with one another in that they either augment or reduce drug responses - possible impact of drug interactions must be considered 5. Low Cost – an ideal drug would be easy to afford 6. Chemical Stability – some drugs lose effectiveness during storage; others which are stable on a shelf can rapidly lose effectiveness when put into a solution - losses in efficacy result from chemical instability 7. Possession of a Simple Generic Name – generic names are usually complex and difficult to remember and pronounce - as a rule, the trade name for a drug is simpler than its generic name

IV.

ADVERSE DRUG REACTIONS (ADR) - any noxious, unintended, and undesired effect that occurs at normal drug doses, excludes undesired effects that occur when dosage is excessive (defined by the World Health Organization)

- can range in intensity from annoying to life threatening - when drugs are used properly, many ADR can be avoided or at least kept to a minimum - adverse effects are most common in the elderly and very young - adverse events are more common in patients receiving multiple drugs Side Effect – a nearly unavoidable secondary drug effect produced at therapeutic doses - intensity is dose dependent and generally predictable - response can develop soon after the onset of the drug use or as long as weeks or months later - ex. Antihistamines causing drowsiness Toxicity – an adverse drug reaction caused by excessive dosing Allergic Reaction – an immune response - once the immune system has been sensitized to a drug, re-exposure to that drug can trigger an allergic response - intensity is largely independent of dosage - very few medications cause severe allergic reactions; in fact, the most serious reactions are caused by just one drug family -- penicillins - reactions can range from mild itching to sever rash to anaphylaxis - reactions are determined primarily by the degree of sensitization of the immune system – not by drug dosage anaphylaxis – a life-threatening response characterized by bronchospasm, laryngeal edema, and a precipitous drop in blood pressure Idiosyncratic Effect – an uncommon drug response resulting from a genetic predisposition Iatrogenic Disease – a disease produced by a physician - derived from the Greek word iatros = physician and –genic = to produce - also used to denote a disease produced by drugs - nearly identical to idiopathic (naturally occurring) diseases - ex. Patients taking certain antipsychotic drugs may develop a syndrome whose symptoms closely resemble those of Parkinson’s disease Physical Dependence – a state in which the body has adapted to prolonged drug exposure in such a way that an abstinence syndrome will result if drug use is discontinued - develops during long term use - precise nature of the abstinence syndrome is determined by the drug involved - usually associated with “narcotics” (heroin, morphine, and other opioids); however, these are not the only dependence-inducing drugs

- patients should be warned against abrupt discontinuation of any medication without first consulting a knowledgeable health professional - people heal better when not in pain – DO NOT WITHHOLD MEDICATIONS DUE TO PHYSICAL DEPENDENCY Carcinogenic Effect – ability of certain medications and environmental chemicals to cause cancers - several drugs used to treat cancer are among the drugs with the greatest carcinogenic potential - unlikely that carcinogenic potential will be detected during preclinical and clinical drug trials - ex. Diethylstilbestrol (DES) – synthetic hormone with actions similar to estrogen was at one time used to prevent spontaneous abortion during high-risk pregnancies. It wasn’t until years later when vaginal and uterine cancers developed in females who had been exposed to this drug in utero. Teratogenic Effect – a drug-induced birth defect - capable of causing birth defects - ex. Accutane for acne

V.

INDIVIDUAL VARIATION

IN

DRUG RESPONSES

A.

BODY WEIGHT AND COMPOSITION - the absence of adjustments in dosage, body size can be a significant determinant of drug effects - response to a drug is determined in large part by the concentration of the drug at its sites of action - the higher the concentration, the more intense the response - when adjusting dosage to account for body weight, the clinician may base the adjustment on body surface area rather than on weight per se - surface area determinations account not only for the patient’s weight but also for how fat or lean the patient may be - dosage adjustments based on body surface area provide a more precise means of controlling drug responses than do adjustments based on weight alone B.

AGE - infants and elderly are especially sensitive to drugs - the very young have heightened drug sensitivity as a result of organ immaturity - the elderly have a heightened drug sensitivity due to organ degeneration - the elderly also have an increased severity of illness, the presence of multiple pathologies, and treatment with multiple drugs

C. GENDER - for most drugs, we don’t know much about gender-related differences because, until recently, essentially all drug research was done in men - clinicians must keep in mind that the information currently available may fail to accurately predict responses in female patients D. PATHOPHYSIOLOGY - abnormal physiology (someone that is sick) can alter responses to drugs E. TOLERANCE - decreased responsiveness to a drug as a result of repeated drug administration 1. Pharmacodynamic Tolerance - refers to the familiar type of tolerance associated with long-term administration of drugs such as morphine and heroin - requires increased drug levels to produce effects that could formerly be elicited at lower drug levels - MEC of a drug is abnormally high - thought to result from adaptive processes that occur in response to chronic receptor occupation 2. Metabolic Tolerance - tolerance resulting from accelerated drug metabolism - brought about by the ability of certain drugs (e.g., barbiturates) to induce synthesis of hepatic drug-metabolizing enzymes, thereby causing rates of drug metabolism to increase - because of increased metabolism, dosage must be increased to maintain therapeutic drug levels 3. Tachyphylaxis - form of tolerance that is a reduction in drug responsiveness brought on by repeated dosing over a short time - occurs quickly - not a common mechanism of drug tolerance - ex. Transdermal nitroglycerin – using a transdermal patch, effects are lost in less than 24 hours

VI.

PATIENT EDUCATION & COMPLIANCE PROMOTION

Issues to Address: • dosage size and timing • route and technique of administrations • duration of treatment • drug storage

•

nature and time course of desired and adverse responses

- techniques of administration that are difficult, a demonstration should be made, after which the parents should repeat the procedure to ensure they understand - with young children, spills and spitting out are common causes of inaccurate dosage - parents should be instructed to complete the full treatment Additional Compliance Promotional Tools: • selecting the most convenient dosage form and dosing schedule • suggesting mixing oral drugs with food or juice (when allowed) to improve palatability • providing a calibrated medicine spoon or syringe for measuring liquid formulations • taking extra time with young or disadvantaged parents to help ensure conscientious and skilled participation