Transcript GENERAL PRINCIPLES OF CLINICAL PHARMACOLOGY

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 extendedrelease 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.
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.
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
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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
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Age
Body Weight
Genetic and Ethnic Characteristics
Gender (еxcept 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.