LUSAKA APEX MEDICAL UNIVERSITY
School of
Department of
Name:
Winnie
Computer No.:
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Class:
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Course Code:
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Lecturer:
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Assignment No.:
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Due date:
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Assignment outline
i.
Abstract.
ii.
Applications of pharmacokinetics to the clinical settings.
iii.
The pharmacodynamics concept.
iv.
Factors affecting the metabolism rate and metabolism itself.
v.
Mechanisms of renal drug excretion.
vi.
Pharmacokinetic calculations.
Abstract
Pharmaceuticals number among the most important therapeutic measures for restoring and
maintaining health. Without pharmaceuticals, medicine would be restricted to revelations of
disease conditions, with no hope for the restitution of the patients’ health.
However, regardless of how much natural substances and mainstream drugs have contributed to
helping in bringing remedial help to patients in times of old and to-date, it is important to see to it
that pharmacokinetic and pharmacodynamics profiles of these drugs are understood in order to
achieve effective and rational therapy.
In order to ensure an effective therapy with little or no significant side effects, precise knowledge
about the Active Pharmaceutical Ingredients and the form in which the drug is administered is
vital. This therefore implies that, without the pharmacokinetic and pharmacodynamics knowledge
of drug substances; the administration of drugs would be restricted to blind theraping of the
patients, without the clear understanding of the therapeutic active ingredients contained in a
medicinal substance, what it will do, how long it will take to have an effect, how it is absorbed,
what route to use to use when administering, in what form should it be and at what intervals should
it be repeated.
To this effect the aim of this assignment will be, to evaluate the importance of pharmacokinetics
and pharmacodynamics, and their applications and importance to the clinical settings. Another
important pharmacodynamics parameter to be independently evaluated in this assignment is the
concept of genetic polymorphism under acetylation genetic polymorphism which affects the
normal pharmacokinetic and pharmacodynamics of drugs..
Q.1. Clinical Pharmacokinetics
Clinical pharmacokinetics is concerned with the rational, safe, and effective use of drugs. It studies
the factors that determine the time course of the plasma concentration of a drug and its variability.
The factors that affect the time course of drug concentrations in plasma produced by repetitive
administration include the dosing rate, total clearance, biologic half-life, and systemic availability
of the drug. A clinical pharmacokinetics service can monitor drug concentrations in biologic fluids,
design individualized drug-dosing regimens, and carry out pharmacokinetic diagnostic work-ups
to help determine the reasons for a patient's unusual response to drug therapy. The Knowledge of
the pharmacokinetics of a drug bears the ideal goal to mold the drug and dosing regimen to the
unique characteristics of each patient in a manner tailored to the individual patient.
To apply pharmacokinetics to a practical sense, let us evaluate the drug packaging.
Pharmacokinetic information contained in the drug package insert can be an important tool when
there is a need to adapt the dosage regimen to particular clinical scenarios (e.g. renal impairment,
change in bacterial susceptibility, hepatic impairment and other factors).
Pharmacokinetic information is most useful when the range of doses (or concentrations) in which
the drug exhibits linear pharmacokinetics is known. Linear pharmacokinetics implies direct
proportionality between dose and exposure. For example, under linear kinetics, a 20 mg/kg dose
provides two-fold the exposure (but not necessarily the pharmacological effect) of a 10 mg/kg
dose. Some drugs exhibit linear pharmacokinetics within a wide range of doses and concentrations,
while others do not.
Therefore, when examining the pharmacokinetic information in the drug insert we can start by
determining the Pharmacokinetic linearity and range. Under nonlinear pharmacokinetics, there is
no proportionality between dose and exposure, and therefore dose adjustment becomes a much
more difficult task.
To validate this concept we evaluate the pharmacokinetics of time dependent and concentration
dependent antibiotics.
Concentration dependent antibiotics are a type of antibiotics, which eradicate pathogenic
bacteria by first achieving high concentration at the site of binding. These antibiotics show
optimum response in killing bacteria (bactericidal) when their concentration is either equal or
greater than 10 times above the MIC (minimum inhibitory concentration) at the site of infection
for certain target micro-organism.
Time dependent antibiotics are antibiotics whose killing response is dependent on time they
spend at the action site. Higher concentration of such drugs does not result in greater killing of
organism. “The inhibitory effect can be effective because their concentration exceeds the MIC
for the microorganism.
The implication is that if these pharmacokinetic properties of the antibiotics are not understood
the antibiotics therapy will not be very effective with the risk of resistance emanating if they are
treated with common respect..
Clinical pharmacodynamics as a contrast to pharmacokinetics is concerned with the rational, safe
and effective use of drugs. It studies the relationship between drug exposure and
pharmacological or toxic effect. Pharmacodynamics studies often allow defining exposure
targets that are optimally related to the desired level of pharmacological effect [e.g. a range of
AUC-(Area Under the Curve)-values that optimizes the probability of bacterial eradication
during an infection].
Q.2. Acetylation genetic polymorphism
One of the major causes of inter-individual variation of drug effects is genetic variation of drug
metabolism. Genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups
in the population that differ in their ability to perform certain drug biotransformation reactions.
Polymorphisms are generated by mutations in the genes for these enzymes, whose consequences
may include decreased, increased, or absent enzyme expression or activity by multiple molecular
mechanisms. Moreover, the variant alleles exist in the population at relatively high frequency.
Genetic polymorphisms have been described for most drug metabolizing enzymes.
The acetylation polymorphism concerns the metabolism of a variety of arylamine and hydrazine
drugs, as well as carcinogens by the cytosolic N-acetyltransferase 2 (NAT2). Seven mutations of
the NAT2 gene that occur singly or in combination define numerous alleles associated with
decreased function. The debrisoquine-sparteine polymorphism of drug oxidation affects the
metabolism of more than 40 drugs. The poor metabolizer phenotype is caused by several “loss of
function” alleles of the cytochrome P450 CYP2D6 gene. On the other hand, “ultra-rapid”
metabolizers are caused by duplication or amplification of an active CYP2D6 gene. Intermediate
metabolizers are often heterozygotes or carry alleles with mutations that decrease enzyme activity
only moderately.
A classical clinical example is acetylation genetic polymorphism of alcohol (Ethanol).
Ethanol metabolism involves several enzymes. Among them; alcohol dehydrogenase, catalase,
aldehyde dehydrogenase and cytochrome p450-2E1 enzymes. Whereas alcohol dehydrogenase
metabolizes the bulk of ethanol within the liver, cytochrome P4502E1 and catalase, also
contributes to the production of acetaldehyde from ethanol oxidation. In turn, acetaldehyde is
metabolized by the enzyme aldehyde dehydrogenase.
In humans, the genetic polymorphisms of the enzymes alcohol dehydrogenase and aldehyde
dehydrogenase are also associated with alcohol drinking habits and the incidence of alcohol
abuse. From human genetic studies, it has been concluded that blood acetaldehyde accumulation
induces unpleasant effects that prevent further alcohol drinking. To be specific the Chinese for
example metabolise ethanol differently. They are fast acetylators with higher plasma concentration
of acetaldehyde within a short period. However, this comes with Flushing and palpitations due to
the higher levels of blood acetaldehyde.
Q.3. Pharmacodynamics
Pharmacodynamics is a terminology derived from two greek words Phamakon;- meaning drug
and dynamis:- meaning propelling power. In its simpler terms, it is what the drug does to the body.
This includes physiological and biochemical effects and activity of drugs and their mechanism of
action at organ system/subcellular/or macromolecular levels. It is therefore, the Interactions of
drugs with cellular proteins, such as receptors or enzymes, to control changes in physiological
function of particular organs, cell membranes or in the intracellular fluids.
Pharmacodynamic Concept
A. Receptors and Receptor Sites
Drug actions are mediated through the effects of drug molecules on drug receptors in the body.
Most receptors are large regulatory molecules that influence important biochemical processes
(including enzymes involved in glucose metabolism) or physiologic processes (eg,
neurotransmitter receptors, neurotransmitter reuptake transporters, and ion transporters).
If drug-receptor binding results in activation of the receptor, the drug is termed an agonist; if
inhibition results, the drug is considered an antagonist.
The extent of receptor activation, and the subsequent biological response, is related to the
concentration of the activating drug (the 'agonist'). This relationship is described by the dose–
response curve, which plots the drug dose (or concentration) against its effect. This important
pharmacodynamic relationship can be influenced by patient factors (such as age, disease and
others) and by the presence of other drugs that compete for binding at the same receptor (such as
receptor 'antagonists'). Some drugs acting at the same receptor (or tissue) differ in the magnitude
of the biological responses that they can achieve (this is to imply their 'efficacy') and the amount
of the drug required to achieve a response (their 'potency'). Drug receptors can be classified on the
basis of their selective response to different drugs. Constant exposure of receptors or body systems
to drugs sometimes leads to a reduced response ('desensitization').
However, at the cellular level, drug binding is only the first in what is often a complex sequence
of steps:
When the drug binds to the receptor, they form a drug receptor complex; [Drug (D) + receptoreffector (R)→ drug-receptor-effector complex].
The complex leads to the activation of intracellular coupling molecules then effector molecules
and subsequently an effect is produced; [D R D-R complex→activation of coupling molecule→
effector molecule→effect]
B. Drug-Receptor Bonds
Drugs bind to receptors with a variety of chemical bonds. These include very strong covalent bonds
(which usually result in irreversible action), somewhat weaker electrostatic bonds (Such as
between a cation and an anion), and much weaker interactions (such as, hydrogen, van der Waals,
and hydrophobic bonds).
Q.4. Factors affecting metabolism rate
They include; sex, ethnicity, age, pregnancy, disease state and idiosyncratic reactions.
1. Sex
It must be understood even from a modest perspective, how and when we use drugs can result in
unwanted and unexpected outcomes. This is because males and females differ in their response to
drug treatment. These differences can be critical in response to drug treatment. It is therefore
essential to understand those differences to appropriately conduct risk assessment and to design
safe and effective treatments.
From the understanding that the main enzymes involved in drug metabolism belong to the
cytochrome P450 (CYP) group. It is plausible that sex-related disparities in pharmacokinetics arise
due to variations in the regulation of the expression and activity of CYP isoenzymes, most probably
through endogenous hormonal influences.
This implies that at a given dose a drug reaches higher free drug concentrations or remains longer
in the body in females than in males. Alternatively, females may be more sensitive to drugs than
males. In this instance, free drug concentrations and duration in the body would be similar in men
and women but women would respond to a greater extent. Yet, another plausible explanation
might be attributed to behavior; if women take a greater number of medications than men they can
increase the incidence of adverse events resulting from drug interactions.
2. Disease state
The course of action of a drug is dependent upon the normal functioning of a number of organs,
which combine to absorb, distribute, metabolize and excrete the drug at a characteristic rate. A
pathological condition of any of these organs may disturb not only their individual contribution to
the course of the drug action, but as a secondary effect, those of other organs.
Numerous studies of the effect of diseases of the cardiovascular system, gastrointestinal tract, liver
and kidney have shown that organ dysfunction may be reflected in a changed rate and/or extent of
absorption, apparent volume of distribution, plasma protein binding, plasma half-life and plasma
and hepatic clearance.
3. Age
Age is a great determinant of the metabolism of drugs. This is because in the case of paediatrics,
most of their important organs that are involved in drug metabolism and excretion such as the liver
and the kidney are not yet fully developed. In old age adults, senescence has caught up with them
and affected most their vital organs involved in the metabolism and excretion of drugs, including
the liver and the kidney.
Metabolism is slowed for most drugs, partly by a reduced hepatic blood flow (with GFR declining
slowly from 20 years of age, falling by 25% at 50 years old and falling by 50% at 75 years old)
and reduced capacity of the microsomal enzyme system. The ability to conjugate compounds
(phase II reactions) is substantially unchanged with age. Hepatic function tends also to be
diminished by other illnesses or malnutrition. The reduction of hepatic oxidation of drugs is most
apparent in drugs such as diazepam, which have a long half-life and active metabolites. Therefore,
if doses are not tapered toxicities can arise.
4. Ethnicity
Genetic factors or pertinently intra-species genetic variations are responsible for alterations in drug
dosage and/or drug effect. These may be related to gene-related alterations in drug metabolism or
alterations in tissue/receptor sensitivity. These variations can lead to genetic tolerance, intolerance
or idiosyncratic-reactions in susceptible individuals.
Genetic tolerance renders individuals less responsive to normal/ or higher doses of drugs,
intolerance makes individuals to respond excessively to normal or lower dosage, and idiosyncratic/
reaction refer to qualitatively or quantitatively abnormal reaction to a single dose of drug that may
endanger patient survival (the phenomenon is called idiosyncrasy).
On one end of acetylators are the fast and slow acetylators. This is as a result of the variations in
hepatic and jejunal acetyltransferase activity. Resistance to warfarin (for example), a mediated
anticoagulant effect due to reduced binding affinity of hepatic vitamin K epoxide reductase, that
normally activates vitamin K, which leads to bleeding tendencies. Hemolytic anemia occurs as a
response to oxidant drugs or oxidant drug metabolites due to either deficient glucose-6-phosphate
dehydrogenase or glutathione synthetase in RBCs. Porphyria is response to certain drugs
(barbiturates, sulfa-drugs, griseofulvin, oral contraceptives and others) due to increased delta-ALA
synthetase activity. Prolonged apnea with succinylcholine due to atypical pseudo-cholinesterase
in plasma; high hepatotoxicity with drugs such as paracetamol and nitrofurantoin due to deficient
hepatic glutathione synthetase increased ethanol toxicity due to atypical alcohol dehydrogenase
activity. Thus, individuals within a given species may react variably to drug effect and drug dosage.
5. Pregnancy
The dynamic physiological changes that occur in the maternal-placental-fetal unit during
pregnancy influence the pharmacokinetic processes of drug absorption, distribution and
elimination. Pregnancy-induced maternal physiological changes may affect gastrointestinal
function and hence drug absorption rates.
Ventilatory changes may influence the pulmonary absorption of inhaled drugs. As the glomerular
filtration rate usually increases during pregnancy, renal drug elimination is generally enhanced,
whereas hepatic drug metabolism may increase, decrease or remain unchanged. A mean increase
of 8L in total body water alters drug distribution and results in decreased peak serum
concentrations of many drugs. Decreased steady-state concentrations have been documented for
many agents as a result of their increased clearance.
Pregnancy-related hypoalbuminaemia, leading to decreased protein binding, results in increased
free drug fraction. However, as more free drug is available for either hepatic biotransformation or
renal excretion, the overall effect is an unaltered free drug concentration. Since the free drug
concentration is responsible for drug effects, the above mentioned changes are probably of no
clinical relevance.
The placental and fetal capacity to metabolize drugs together with physiological factors, such as
differences in acid-base equilibrium of the mother versus the fetus, determine the fetal exposure
to the drugs taken by the mother. As most drugs are excreted into the milk by passive diffusion,
the drug concentration in milk is directly proportional to the corresponding concentration in
maternal plasma. The milk to plasma (M : P) ratio, which compares milk with maternal plasma
drug concentrations, serves as an index of the extent of drug excretion in the milk. For most drugs
the amount ingested by the infant rarely attains therapeutic levels.
6. Idiosyncratic reactions.
The term idiosyncratic drug reaction (IDR) has been used in various ways and has no clear
definition, but the term in this assignment will be used to designate an adverse reaction that does
not occur in most patients treated with a drug and does not involve the therapeutic effect of the
drug.
Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they
also markedly increase the uncertainty of drug development. The major targets are skin, liver, and
bone marrow. Clinical characteristics suggest that Idiosyncratic Drug Reactions are immune
mediated, and there is substantive evidence that most, but not all, Idiosyncratic Drug Reactions
are caused by chemically reactive species.
The propensity of a drug to cause an idiosyncratic reaction is dependent on its chemical
characteristics, but individual susceptibility is determined by patient-specific factors, in particular
the expression of immunologic receptors that display drug-derived antigens on the cell surface.
IDRs represent a major problem for drug development because, unless the incidence is very high,
they are usually not detected during clinical trials, and there are many examples where serious
IDRs have led to the withdrawal of a drug from the market.
Q.5.
Different Mechanism Of renal Drug Excretion
Although some drugs are excreted through extrarenal pathways, the kidney is the primary organ
of removal for most drugs; especially for those that are water soluble and not volatile. The three
principal processes that determine the urinary excretion of a drug are glomerular filtration, tubular
secretion, and tubular reabsorption (mostly passive back-diffusion). Active tubular reabsorption
also may have some influence on the rate of excretion for a limited number of compounds.
Glomerular Filtration
The ultrastructure of the glomerular capillary wall is such that it permits a high degree of fluid
filtration while restricting the passage of compounds having relatively large molecular weights.
This selective filtration is important in that it prevents the filtration of plasma proteins (e.g.,
albumin) that are important for maintaining an osmotic gradient in the vasculature and thus plasma
volume.
Several factors, including molecular size, charge, and shape, influence the glomerular filtration of
large molecules.
As the ultrafiltrate is formed, any drug that is free in the plasma water, that is, not bound to plasma
proteins or the formed elements in the blood (e.g., red blood cells), will be filtered as a result of
the driving force provided by cardiac pumping.
All unbound drugs will be filtered as long as their molecular size, charge, and shape are not
excessively large.
Passive Diffusion
An important determinant of the urinary excretion of drugs such as weak electrolytes) is the extent
to which substances diffuse back across the tubular membranes and reenter the circulation. In
general, the movement of drugs is favored from the tubular lumen to blood, partly because of the
reabsorption of water that occurs throughout most portions of the nephron, which results in an
increased concentration of drug in the luminal fluid. The concentration gradient thus established
will facilitate movement of the drug out of the tubular lumen, given that the lipid solubility and
ionization of the drug are appropriate.
Active Tubular Secretion
A number of drugs can serve as substrates for the two active secretory systems in the proximal
tubule cells. These transport systems, which actively transfer drugs from blood to luminal fluid,
are independent of each other; one secretes organic anions, and the other secretes organic cations.
The secretory capacity of both the organic anion and organic cation secretory systems can be
saturated at high drug concentrations. Each drug will have its own characteristic maximum rate of
secretion (transport maximum, Tm).
Some drugs that are not candidates for active tubular secretion may be metabolized to compounds
that
are. This is often true for metabolites that are formed as a result of conjugative reactions.
Active Tubular Reabsorption
Some substances filtered at the glomerulus are reabsorbed by active transport systems found
primarily in the proximal tubules. Active reabsorption is particularly important for endogenous
substances, such as ions, glucose, and amino acids, although a small number of drugs also may be
actively reabsorbed.
Conclusion
Pharmacokinetics and Pharmacodynamics answers very important clinical questions such as; is
compliance likely to be a problem? Are there any potential interaction with the patient's other
drugs? What if the "normal average" dosing regimen is not appropriate for this patient? Should
liver or renal impairment be taken into account? How do I tailor the dose to the changing bacterial
susceptibility in my patient? When both pharmacokinetic and pharmacodynamics information are
available, clinicians are better equipped to provide rational answers to these and other questions
as well as to calculate adjusted dosage regimens.
Knowing how to perform pharmacokinetic calculations is of paramount importance in dosage
adjustments for various conditions. Understanding pharmacogenomics and pharmacogenetic
polymorphisms is also paramount to quickly respond to any idiosyncratic drug reactions that may
occur in certain populations of patients.
The sum of the matter is that, possessing the knowledge of these pharmacokinetic and
pharmacodynamic parameters can help in rational treatment of patients with little risks, which
would otherwise turn to be fatal. They can be risks of toxicities in organ failures, or failure to
calculate the correct dosage for the correct age or just idiosyncratic adverse reactions to drugs.
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