II.

General Principles of Pharmacology

 Sources and Nature of Drug Dosage Form
 Prescription Writing
 Rational Use of Drugs & Drug Laws
 Pharmacokinetics (Absorption, Distribution,
Metabolism and Excretion of Drugs)
 Pharmacodynamics (Mode of Action of Drugs)

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RUDs: Definition
The rational use of drugs requires that:

1. Patients receive medications appropriate to

their clinical needs,
2. In doses that meet their own individual
requirements
3. For an adequate period of time, and
4. At the lowest cost to them and their
community.

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In other words:
• Correct drug
• Appropriate indication
• Appropriate drug considering efficacy, safety, suitability for
the patient, and cost
• Appropriate dosage, administration, duration
• No contraindications
• Correct dispensing, including appropriate information for
patients
• Patient adherence to treatment

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 Prescription: Types of Irrational Drug Use
• Under-prescribing
• Incorrect prescribing (injections vs. oral ..)
• Over-prescribing
• Self-medication
• Multiple prescribing (polypharmacy)
• Failure to prescribe in accordance with clinical guidelines;
• Inappropriate use of antimicrobials, often in inadequate dosage, for non-
bacterial infections;
• “False” Evidence-based medical practice (EBM)
• Promotion of Non essential drugs: Drugs in Essential Medicines List
Adequate to take care of the majority of the health needs of the population.
4
 A multi-disciplinary team work is required
to achieve Rational Drug Use !!!

Counselor /
Pharmacist
Treatment
supporter

Doctor
Nurse
Community

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 RUDs means minimal Adverse drug events!
• 4-6th leading cause of death in
the USA
• 4-6% of hospitalisations in the
USA
• commonest, costliest events
include bleeding, cardiac
arrhythmia, confusion,
diarrhoea, fever, hypotension,
itching, vomiting, rash, renal
failure

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 The Solution
• Rational use of Drugs
– Generic Prescribing
– Adoption of essential drugs list (EDL)
– Adoption of Standard Treatment Guidelines
(STGs) to discourage “Luxury drugs”

• Rational use of medicines could be greatly

improved if a fraction of the resources spent on
medicines were spent on improving use.
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 Pharmacokinetics

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Pharmacology is divided into two parts:

1. Pharmacodynamics
What the drug does to the body?

2. Pharmacokinetics
– What the body does to the drug?

Pharmacokinetic parameters allow the clinician to design and

optimize treatment regimens, including decisions as to:
 Route of administration
 Amount and frequency of each dose
 Duration of treatment.
9
Pharmacokinetics
• Are studies of the
– Absorption
– Distribution
– Metabolism
– Excretion of drugs

Pharmacodynamics
• Are studies of
- Mechanisms of drug action (MOA)
- Pharmacological effects
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 :pharmacokinetic properties 4

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 I. ABSORPTION OF DRUGS
• Definition: Absorption is the transfer of a drug from its site of
administration to the bloodstream via one of several
mechanisms. (except for drugs that are applied directly to
the target tissue)

• The rate and efficiency of absorption depend on:

1. Factors in the environment where the drug is absorbed
2. the drug’s chemical characteristics
3. route of administration (which influence its
bioavailability).

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 Absorption: Rate & Extent

 Rate: how rapidly does the drug get from its site of
administration to the general circulation ?

 Extent: How much of the administered dose enters

the general circulation ? ( % bioavailability = F)

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 Types of ABSORPTION
• Passive diffusion: Conc. gradient is the driving force, No
energy required
• Facilitated diffusion: Appears to depend on an oscillating
carrier protein, Depends on conc. Gradient, No energy
required, For a few drugs movement occurs faster than
predicted
• Active transport: Can proceed against a conc. Gradient,
Requires energy, can become saturated
• Exocytosis & Endocytosis: Mainly for drugs with MW > 1000
–E.g. hormones, growth factors, immunoglobulins, Vitamin
B12

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C. Bioavailability

• Bioavailability is the fraction of administered unchanged

drug that reaches the systemic circulation.

• For example
– if 100 mg of a drug are administered orally
– 70 mg of this drug are absorbed unchanged
– the bioavailability is 0.7, or 70 percent.

Why is it important to determine bioavailability?

It is important for calculating drug dosages for non-intravenous
routes of administration.
15
Determination of bioavailability:

16
Factors influencing the oral bioavailability of drugs :

1. Decomposition in acidic gastric juices

2. Decomposition by hydrolytic gut enzymes (eg, proteases,
lipases)
3. Degradation by gut microorganisms
4. Food in the gut may alter absorption rate and amount (eg.
interact or form a complex)
5. Metabolism by gut wall enzymes
6. Metabolism by liver enzymes prior to reaching the systemic
circulation (1st pass metabolism)
7. Others: solubility, chemical stability & nature of the drug
formulation:

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 II. DRUG DISTRIBUTION

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 DRUG DISTRIBUTION
• Drug distribution is the process by which a
drug reversibly leaves the blood-stream and
enters the interstitium (extracellular fluid) and
then the cells of the tissues.

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20
• The delivery of a drug from the plasma to the
interstitium primarily depends on:

A. cardiac output and regional blood flow

B. capillary permeability
C. the tissue volume
D. the degree of binding of the drug to
plasma and tissue proteins
E. the relative hydrophobicity of the drug.

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D. Volume of distribution:

• The volume of distribution (VD), = apparent volume

of distribution
• is defined as:
– the distribution of a medication between plasma
and the rest of the body.

– Apparent volume into which a drug

homogeneously distributes in the body.

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• If VD is big the drug is more diluted
than it should be (in the blood plasma),
meaning more of it is distributed in tissue (i.e.
not in plasma).

• The half-life (t1/2): is the time taken for the

plasma concentration to fall to half its original
value.

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Effect of drug binding on
volume of distribution. Drug A
diffuses freely between the 2
compartments and does not
bind to macromolecules
(heavy wavy lines) in the
vascular or the extravascular
compartments of the
hypothetical organism in the
diagram. With 20 units of the
drug in the body, the steady-
state distribution leaves a
blood concentration of 2
units. Drug B, on the other
hand, binds avidly to proteins
in the blood. At equilibrium,
only 2 units of the total are
present in the extravascular
volume, leaving 18 units still
in the blood. In each case, the
total amount of drug in the
body is the same (20 units),
but the apparent volumes of
distribution are very different.
Drug C is avidly bound to
molecules in peripheral
tissues, so that a larger total
dose (200 units) is required to
achieve measurable plasma
concentrations. At
equilibrium, 198 units are
found in the peripheral
tissues and only 2 units in the
plasma, so that the calculated
volume of distribution is
greater
24 than the physical
volume of the system.
:Effect of Vd on drug half-life .4

• A large Vd has an important influence on the half-life

of a drug, because drug elimination depends on the
amount of drug delivered to the organs of
metabolism per unit of time.

• If the Vd for a drug is large, most of the drug is in the

extraplasmic space and is unavailable to the
excretory organs.

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 III. METABOLISM

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• The process of elimination begins as soon as the drug
enters the body.

• Three major routes of elimination:

1) hepatic metabolism
2) elimination in bile
3) elimination in urine.

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• Elimination causes the plasma
concentration of a drug to
decrease exponentially.

• A constant fraction of the drug

is eliminated in a unit of time.

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• Metabolism leads to products with increased polarity, which
will allow the drug to be eliminated.

• Clearance (CL) estimates the amount of drug cleared from the

body per unit of time.

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30
 Reactions of drug metabolism

• Lipid-soluble agents must first be metabolized into

more polar (hydrophilic) substances in the liver using
two general sets of reactions, called Phase I and
Phase II.

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 Site of Biotransformation

Tissue: Cellular
Liver Endoplasmic reticulum
Kidneys Cytosol
GI tract Mitochondria
Lungs Nuclear Envelope
Skin Plasma membrane

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Phase I – introduce/unmask a functional group
A. Cytochrome P450-dependent
– Hydroxylations – propranolol, ibuprofen
– Oxidative dealkylation – morphine, caffeine
– Oxidation – thioridazine,
– Deamination – amphetamine, diazepam
B. Cytochrome P450-independent
– Dehydrogenation – ethanol
– Reductions – chloramphenicol
– Hydrolysis – aspirin

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1. Phase I:

• Phase I reactions convert lipophilic molecules into more

polar molecules by:
introducing or unmasking a polar functional group, such as –
OH or –NH2.
• Phase I reactions are catalyzed by the cytochrome P450
system (microsomal mixed-function oxidases)

• Pharmacologic activity after phase I metabolism may:

– Increase
– Decrease
– Same
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CytP450 - Specificity:

• Many different P450 isoforms.

• They can modify a large number of
structurally diverse substrates.
• An individual drug may be a substrate for
more than one isozyme.
• Four isozymes are responsible for the vast
majority of P450-catalyzed reactions.
• CYP3A4/5
• CYP2D6
• CYP2C8/9
• CYP1A2

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 :Cyt P450 - Genetic variability

• P450 enzymes exhibit considerable genetic variability

among individuals and racial groups.

• Variations in P450 activity may alter a drug’s efficacy

and the risk of adverse events.

• Genetic polymorphism

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Drug-Drug interactions at a level of metabolism

A. CytP450 - Inducers:
• Enzyme synthesis initiated within 24 h of exposure, increasing
over 3 –5 days

• Environmental Factors:
– Cigarette smoking
– Some drugs: as Rifampicin

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 The effect of smoking on theophylline metabolism

38
B. CytP450 - Inhibitors
Omeprazole is a potent inhibitor of three of the
CYP isozymes responsible for warfarin
metabolism.

If the two drugs are taken together, plasma

concentrations of warfarin increase, which
leads to greater inhibition of coagulation and
risk of hemorrhage and other serious bleeding
reactions.
39
• Natural substances may also inhibit drug metabolism.

– grapefruit and its juice inhibits CYP3A4

• Examples on drugs that are substrate s for this
enzyme
– Nifedipine
– Clarithromycin
– Simvastatin

40
2. Phase II (conjugation of endogenous molecule with drug)
1. If the metabolite from Phase I metabolism is sufficiently polar, it can be
excreted by the kidneys.
2. many Phase I metabolites are too lipophilic

conjugation with an endogenous substrate

glucuronic acid, sulfuric acid, acetic acid and an amino acid

polar, more water-soluble compounds

most often therapeutically inactive.

A notable exception is morphine-6-glucuronide ,

which is more potent than morphine.

41 .The highly polar drug conjugates may then be excreted by the kidney or in bile
Outcomes of metabolism:

1. abolishes activity and terminates drug action

2. Can promote activity of prodrug.
3. No change in activity
4. Produce toxic metabolites

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 DRUG CLEARANCE BY THE
KIDNEY

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A. Renal elimination of a drug

• Elimination of drugs via the kidneys into urine involves the

three processes:

1. Glomerular filtration:
• The glomerular filtration rate (125 mL/min) is normally
about 20 percent of the renal plasma flow (600 mL/min).
• Passage of drugs into the glomerular filtrate depends on:
– glomerular filtration rate
– protein binding of the drugs.

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2. Proximal tubular secretion:

• Occurs by two active transport systems:

– one for anions
– one for cations
• They show low specificity
• Can transport many compounds
• Competition between drugs for these carriers can occur
within each transport system.
• Example: Penicillins and probenecid
• [Note: Premature infants and neonates have an incompletely
developed tubular secretory mechanism and, thus, may
retain certain drugs in the glomerular filtrate.]
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46
:Distal tubular reabsorption .3

• The drug, if uncharged, may diffuse out of the nephric lumen,

back into the systemic circulation.

• Manipulating the pH of the urine to increase the ionized form

of the drug in the lumen may be done to minimize the
amount of back-diffusion and, hence, increase the clearance
of an undesirable drug.

• As a general rule: “ion trapping.”

– weak acids can be eliminated by alkalinization of the urine
– elimination of weak bases may be increased by acidifcation
of the urine.
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4. Role of drug metabolism:

• To minimize this reabsorption, drugs are modified primarily in

the liver into more polar substances using two types of
reactions:
– Phase I reactions, which involve either
• the addition of hydroxyl groups or
• the removal of blocking groups from hydroxyl, carboxyl, or amino
groups
– Phase II reactions that use conjugation with
• sulfate, glycine, or glucuronic acid to increase drug polarity.

• The conjugates are ionized, and the charged molecules cannot

back-diffuse out of the kidney lumen.
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49
 CLEARANCE BY OTHER ROUTES

• Other important routes of drug clearance

• Intestines
• Bile
• Lungs
• milk in nursing mothers
• The feces are primarily involved in elimination:
– of unabsorbed orally ingested drugs or
– drugs that are secreted directly into the intestines or in bile.
• The lungs are primarily involved in the elimination of:
– anesthetic gases (for example, halothane and isofurane).

50
 B. Clinical situations resulting in changes in drug half-
life

• When a patient has an abnormality that alters the

half-life of a drug, adjustment in dosage is required.

• It is important to be able to predict in which patients

a drug is likely to have a change in half-life.

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• The half-life of a drug is increased by
1) diminished renal plasma flow or hepatic blood flow, for
example, in cardiogenic shock, heart failure, or
hemorrhage
2) decreased ability to extract drug from plasma, for
example, as seen in renal disease
3) decreased metabolism, for example, when another drug
inhibits its biotransformation or in hepatic insufficiency,
as with cirrhosis.

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• The half-life of a drug may decrease by
1) increased hepatic blood flow
2) decreased protein binding
3) increased metabolism.

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