Introduction to the course Clinical Pharmacy

Clinical Pharmacy - a Definition §It is a health specialty, which describes the activities and services of the clinical pharmacist to develop and promote the rational and appropriate use of medicinal products and devices. §Clinical Pharmacy includes all the services performed by pharmacists practising in hospitals, community pharmacies, nursing homes, home-based care services, clinics and any other setting where medicines are prescribed and used. §The term "clinical" does not necessarily imply an activity implemented in a hospital setting. It describes that the type of activity is related to the health of the patient(s). This implies that community pharmacists and hospital pharmacists both can perform clinical pharmacy activities.

How does clinical pharmacy differ from pharmacy? §the discipline of pharmacy embraces the knowledge on synthesis, chemistry and preparation of drugs §clinical pharmacy is more oriented to the analysis of population needs with regards to medicines, ways of administration, patterns of use and drugs effects on the patients. §The focus of attention moves from the drug to the single patient or population receiving drugs.

Clinical Pharmacy - Overall Goal The overall goal of clinical pharmacy activities is to promote the correct and appropriate use of medicinal products and devices. These activities aim at: §maximising the clinical effect of medicines, i.e., using the most effective treatment for each type of patient §minimising the risk of treatment-induced adverse events, i.e., monitoring the therapy course and the patient's compliance with therapy §minimising the expenditures for pharmacological treatments born by the national health systems and by the patients, i.e., trying to provide the best treatment alternative for the greatest number of patients.

Clinical pharmacy activities may influence the correct use of medicines at three different levels: before, during and after the prescription is written. 1. Before the prescription §Clinical trials §Formularies §Drug information §Clinical pharmacists have the potential to implement and influence drug-related policies, i.e., making decisions on which drugs deserve to be marketed, which drugs should be included in national and local formularies, which prescribing policies and treatment guidelines should be implemented. §Clinical pharmacists are also actively involved in clinical trials at different levels: participating in ethical committees; study monitoring; dispensation and preparation of investigational drugs.

2. During the prescription §Counselling activity §Clinical pharmacists can influence the attitudes and priorities of prescribers in their choice of correct treatments. §The clinical pharmacist monitors, detects and prevents harmful drug interaction, adverse reactions ad medication errors through evaluation of prescriptions' profiles. §The clinical pharmacist pays special attention to the dosage of drugs which need therapeutic monitoring. §Community pharmacists can also make prescription decisions directly, when over the counter drugs are counselled.

3. After the prescription §Counselling §Preparation of personalised formulation §Drug use evaluation §Outcome research §Pharmacoeconomic studies §After the prescription is written, clinical pharmacists play a key role in communicating and counselling patients. §Pharmacists can improve patients' awareness of their treatments, monitor treatment response, check and improve patients' compliance with their medications. §As members of a multidisciplinary team, clinical pharmacists also provide integrated care from 'hospital to community' and vice versa, assuring a continuity of information on risks and benefits of drug therapy.

Pharmacology is the study of drugs (chemicals) that alter functions of living organisms. CLINICAL PHARMACOLOGY is the use of drugs to prevent, diagnose, or treat signs, symptoms, and disease processes. When prevention or cure is not a reasonable goal, relief of symptoms can greatly improve quality of life and ability to function in activities of daily living.

Drugs given for therapeutic purposes are usually called medications. Medications may be given for various reasons. In many instances, the goal of drug therapy is to lessen disease processes rather than cure them. To meet this goal, drugs may be given for local or systemic effects. Drugs with local effects, such as sunscreen lotions and local anesthetics, act mainly at the site of application. Those with systemic effects are taken into the body, circulated through the bloodstream to their sites of action in various body tissues, and eventually eliminated from the body. Most drugs are given for their systemic effects. Drugs may also be given for relatively immediate effects (eg, in acute problems such as pain or infection) or long-term effects (eg, to relieve signs and symptoms of chronic disorders). Many drugs are given for their long-term effects.

DRUG NAMES Individual drugs may have several different names, but the two most commonly used are the generic name and the trade name (also called the brand or proprietary name). The generic name (eg, amoxicillin) is related to the chemical or official name and is independent of the manufacturer. The generic name often indicates the drug group (eg, drugs with generic names ending in “cillin” are penicillins). The trade name is designated and patented by the manufacturer. For example, amoxicillin is manufactured by several pharmaceutical companies, some of which assign a specific trade name (eg, Amoxil, Trimox) and several of which use only the generic name. In drug literature, trade names are capitalized and generic names are lowercase unless in a list or at the beginning of a sentence. Drugs may be prescribed and dispensed by generic or trade name.

Amoxicillin

Metronidazole

Ranitidin

Testing and Clinical Trials The testing process begins with animal studies to determine potential uses and effects. The next step involves FDA review of the data obtained in the animal studies. The drug then undergoes clinical trials in humans. Most clinical trials use a randomized, controlled experimental design that involves selection of subjects according to established criteria, random assignment of subjects to experimental groups, and administration of the test drug to one group and a control substance to another group.

PHARMACOKINETICS Pharmacokinetics involves drug movement through the body (ie, “what the body does to the drug”) to reach sites of action, metabolism, and excretion. Specific processes are absorption, distribution, metabolism (biotransformation), and excretion. Overall, these processes largely determine serum drug levels, onset, peak and duration of drug actions, drug half-life, therapeutic and adverse drug effects, and other important aspects of drug therapy. PHARMACODYNAMICS Pharmacodynamics involves drug actions on target cells and the resulting alterations in cellular biochemical reactions and functions (ie, “what the drug does to the body”). As previously stated, all drug actions occur at the cellular level.

. ENTRY AND MOVEMENT OF DRUG MOLECULES THROUGH THE BODY TO SITES OF ACTION, METABOLISM, AND EXCRETION

ABSORPTION is the process that occurs from the time a drug enters the body to the time it enters the bloodstream to be circulated. Onset of drug action is largely determined by the rate of absorption; intensity is determined by the extent of absorption. Numerous factors affect the rate and extent of drug absorption, including -dosage form, -route of administration, -blood flow to the site of administration, -GI function, -the presence of food or other drugs, and other variables. Dosage form is a major determinant of a drug’s bioavailability (the portion of a dose that reaches the systemic circulation and is available to act on body cells). An intravenous drug is virtually 100% bioavailable; an oral drug is virtually always less than 100% bioavailable because some is not absorbed from the GI tract and some goes to the liver and is partially metabolized before reaching the systemic circulation.

Most oral drugs must be swallowed, dissolved in gastric fluid, and delivered to the small intestine (which has a large surface area for absorption of nutrients and drugs) before they are absorbed. Liquid medications are absorbed faster than tablets or capsules because they need not be dissolved. Drugs injected into subcutaneous (SC) or intramuscular IM) tissues are usually absorbed more rapidly than oral drugs because they move directly from the injection site to the bloodstream. Absorption is rapid from IM sites because muscle tissue has an abundant blood supply. Drugs injected intravenously (IV) do not need to be absorbed because they are placed directly into the bloodstream.

Oral drugs Some patients have difficulty swallowing tablets or capsules; some dislike the taste. In these cases, crushing of medication for powdered delivery (to be mixed with food or beverages) should be considered. But not all medications are suitable for crushing. Generally, meds that should not be crushed fall into one of these categories:

Drugs that should not be crushed §Sustained-release tablets, which can be composed of multiple layers for different drug release times, as can beads within capsules. Some of the more common prefixes or suffixes for sustained-release, controlled-release, controlled-delivery, extended-release, prolonged-release, slow-release products include: 12-hour, 24-hour, CC, CD, CR, ER, LA, Retard, SA, Slo-, SR, XL, XR, or XT. §Enteric-coated tablets, which are formulated because certain drugs can be irritating to the stomach or are degraded by stomach acid. By enteric-coating tablets or capsule beads, the drug’s release can be delayed until it reaches the small intestine. Prefixes include EN- and EC-.

Sustained-release tablets Advantages Extended-release products offer 3 potential benefits: §sustained blood levels §attenuation of adverse effects §improved patient compliance.

Sustained blood levels §The size and frequency of dosing is determined by the pharmacodynamic and pharmacokinetic properties of the drug. The slower the rate of absorption, the less the blood concentrations fluctuate within a dosing interval. This enables higher doses to be given less frequently. For drugs with relatively short half-lives, the use of extended- release products may maintain therapeutic concentrations over prolonged periods

Attenuation of adverse effects §With conventional dosage forms, high peak blood concentrations may be reached soon after administration with possible adverse effects related to the transiently high concentration. An example is hypotension in patients taking rapid-release nifedipine products. The use of an extended-release product avoids the high initial blood concentrations which cause the sudden reduction in blood pressure and other significant haemodynamic changes such as reflex tachycardia.1,2 Another example is the transient nausea at sub-toxic concentrations which results from the local irritation caused by high intestinal concentrations of some conventional-release products such as theophylline.12

Improved patient compliance § Drugs with short half-lives often need to be given at frequent intervals to maintain blood concentrations within the therapeutic range. There is an inverse correlation between the frequency of dosing and patient compliance. A reduction in the number of daily doses offered by extended-release products has the potential to improve compliance.3 However, this advantage probably only occurs when conventional formulations need to be given 3 or more times a day.3

Sustained-release tablets Disadvantages §For many controlled-release products, the release rate can be altered by various factors including food and the rate of transit through the gut. There may be some differences in the release rate from one dose to another, but these have been minimised by modern formulations. §Extended-release products contain a higher drug load and thus any loss of integrity of the release characteristics of the dosage form has potential problems. While some extended-release products can be divided to provide half-doses, others should only be taken whole. Modified-release products should never be crushed or chewed as the slow-release characteristics may be lost and toxicity may result. This is particularly important in patients unable to swallow whole tablets, a problem commonly affecting the elderly. The larger size of extended-release products may cause difficulties in ingestion or transit through the gut. These problems may result in some drugs, e.g. Slow-K, causing local tissue damage in patients who have a pathological or drug-induced reduction in gut motility.

Oral drugs §Other medications have objectionable tastes and are sugar-coated to improve tolerability. If this type of medication is crushed, the patient would be subject to its unpleasant taste, which could significantly impair medication adherence. Additionally, both sublingual and effervescent medications should not be crushed because it will decrease the medication’s effectiveness.

Drug transport pathways. Drug molecules cross cell membranes to move into and out of body cells by directly penetrating the lipid layer, diffusing through open or gated channels, or attaching to carrier proteins.

Plasma proteins, mainly albumin (A), act as carriers for drug molecules (D). Bound drug (A–D) stays in bloodstream and is pharmacologically inactive. Free drug (D) can leave the bloodstream and act on body cells.

THE LIVER IS THE PRINCIPAL ORGAN OF DRUG METABOLISM. Other tissues that display considerable activity include the gastrointestinal tract, the lungs, the skin, and the kidneys. Following oral administration, many drugs (eg, isoproterenol, meperidine, pentazocine, morphine) are absorbed intact from the small intestine and transported first via the portal system to the liver, where they undergo extensive metabolism. This process has been called a first-pass effect. Some orally administered drugs (eg, clonazepam, chlorpromazine) are more extensively metabolized in the intestine than in the liver. Thus, intestinal metabolism may contribute to the overall first-pass effect. First-pass effects may so greatly limit the bioavailability of orally administered drugs that alternative routes of administration must be used to achieve therapeutically effective blood levels.

Pharmacodynamic Variables §Maximum Effect (аll pharmacologic responses must have a maximum effect (Emax). No matter how high the drug concentration goes, a point will be reached beyond which no further increment in response is achieved. §Sensitivity (the sensitivity of the target organ to drug concentration is reflected by the concentration required to produce 50% of maximum effect, the EC50. Failure of response due to diminished sensitivity to the drug can be detected by measuring—in a patient who is not getting better—drug concentrations that are usually associated with therapeutic response. This may be a result of abnormal physiology—eg, hyperkalemia diminishes responsiveness to digoxin—or drug antagonism—eg, calcium channel blockers impair the inotropic response to digoxin.

Pharmacodynamic Variables (cont’d) §Clearance is the single most important factor determining drug concentrations. Clearance is readily estimated from the dosing rate and mean steady-state concentration. Blood samples should be appropriately timed to estimate steady-state concentration.

SERUM HALF-LIFE Serum half-life, also called elimination half-life, is the time required for the serum concentration of a drug to decrease by 50%. It is determined primarily by the drug’s rates of metabolism and excretion. A drug with a short half-life requires more frequent administration than one with a long half-life. When a drug is given at a stable dose, four or five halflives are required to achieve steady-state concentrations and develop equilibrium between tissue and serum concentrations. Because maximal therapeutic effects do not occur until equilibrium is established, some drugs are not fully effective for days or weeks. To maintain steady-state conditions, the amount of drug given must equal the amount eliminated from the body. When a drug dose is changed, an additional four to five halflives are required to re-establish equilibrium; when a drug is discontinued, it is eliminated gradually over several half-lives.

Вioavailability is defined as the fraction of a given drug dose that reaches the circulation in unchanged form and becomes available for systemic distribution. The larger the presystemic elimination, the smaller is the bioavailability of an orally administered drug.

Сеll membrane contains receptors for physiologic substances such as hormones (H) and neurotransmitters (NT). These substances stimulate or inhibit cellular function. Drug molecules (Da and Db) also interact with receptors to stimulate or inhibit cellular function

Drug-Related Variables  Dosage  Route of Administration  Drug–Diet Interactions  Drug–Drug Interactions: Increased Drug Effects ( Additive effects, Synergism or potentiation, Interference by one drug with the metabolism or elimination of a second drug, Displacement of one drug from plasma protein-binding sites by a second drug increases the effects of the displaced drug) Decreased Drug Effects - Interactions in which drug effects are decreased are grouped under the term antagonism ( Example: naloxone (a narcotic antagonist) + morphine (a narcotic or opioid analgesic) > relief of opioidinduced respiratory depression. Naloxone molecules displace morphine molecules from their receptor sites on nerve cells in the brain so that the morphine molecules cannot continue to exert their depressant effects.

Agonists are drugs that produce effects similar to those produced by naturally occurring hormones, neurotransmitters, and other substances. Agonists may accelerate or slow normal cellular processes, depending on the type of receptor activated. For example, epinephrine-like drugs act on the heart to increase the heart rate, and acetylcholine-like drugs act on the heart to slow the heart rate; both are agonists.

Antagonists are drugs that inhibit cell function by occupying receptor sites. This prevents natural body substances or other drugs from occupying the receptor sites and activating cell functions. Once drug action occurs, drug molecules may detach from receptor molecules (ie, the chemical binding is reversible), return to the bloodstream, and circulate to the liver for metabolism and the kidneys for excretion.

Client-Related Variables  Age  Body Weight  Genetic and Ethnic Characteristics  Gender (е xcept during pregnancy and lactation, gender has been considered a minor influence on drug action).  Pathologic Conditions  Psychological Considerations

TOLERANCE AND CROSS-TOLERANCE Drug tolerance occurs when the body becomes accustomed to a particular drug over time so that larger doses must be given to produce the same effects. Tolerance may be acquired to the pharmacologic action of many drugs, especially opioid analgesics, alcohol, and other CNS depressants. Tolerance to pharmacologically related drugs is called cross-tolerance. For example, a person who regularly drinks large amounts of alcohol becomes able to ingest even larger amounts before becoming intoxicated—this is tolerance to alcohol. If the person is then given sedative-type drugs or a general anesthetic, larger-than-usual doses are required to produce a pharmacologic effect—this is cross-tolerance. Tolerance and cross-tolerance are usually attributed to activation of drug-metabolizing enzymes in the liver, which accelerates drug metabolism and excretion. They also are attributed to decreased sensitivity or numbers of receptor sites.

ADVERSE EFFECTS OF DRUGS Тhe term adverse effects refers to any undesired responses to drug administration, as opposed to therapeutic effects, which are desired responses. Some adverse effects occur with usual therapeutic doses of drugs (often called side effects); others are more likely to occur and to be more severe with high doses.  CNS effects may result from CNS stimulation (eg, agitation,confusion, delirium, disorientation, hallucinations,psychosis, seizures) or CNS depression (dizziness, drowsiness, impaired level of consciousness,sedation, coma, impaired respiration and circulation).  Gastrointestinal effects (anorexia, nausea, vomiting, constipation, diarrhea)  Hematologic effects (blood coagulation disorders, bleeding disorders, bone marrow depression, anemias, leukopenia, agranulocytosis, thrombocytopenia)

ADVERSE EFFECTS OF DRUGS  Hepatotoxicity (hepatitis, liver dysfunction or failure, biliary tract inflammation or obstruction)  Nephrotoxicity (nephritis, renal insufficiency or failure)  Hypersensitivity or allergy §Drug fever  Idiosyncrasy refers to an unexpected reaction to a drug that occurs the first time it is given.  Drug dependence §Carcinogenicity is the ability of a substance to cause cancer.  Teratogenicity is the ability of a substance to cause abnormal fetal development when taken by pregnant women. Drug toxicity (also called poisoning, overdose, or intoxication) results from excessive amounts of a drug and may cause reversible or irreversible damage to body tissues.