General Pharmacology

Objectives
I. Pharmacokinetics
Absorption
Bioavailability
Distribution
Drug metabolism
Excretion
II. Combined action of drugs

Pharmacokinetics
Pharmacokinetics
(from Greek pharmakon - medicine, kineo - move)
Pharmacokinetics is the part of pharmacology that deals with compound absorbtion, distribution in the body, storage, metabolism and exretion.
What a body does to a drug

Pharmacokinetics
Based on the hypothesis that
the action of a drug requires
presence of a certain concentration
in the fluid surrounding the target tissue.
In other words, the magnitude of response (desirable or undesirable) depends on the concentration of the drug at the site of action

Pharmacokinetics
Drug Movement in the Body
Absorption
Distribution
Metabolism
Excretion
ADME
profile

Pharmacokinetics
and Pharmacodynamics
TISSUES
BLOOD PLASMA
depot
depot
metabolism
site of drug action
(receptors)
metabolites and conjugates
adsorption
excretion
free substance
bound substance
metabolites conjugates

Absorption
The usage of drugs starts with their administration into the organism or application onto body surface
The route of administration defines the speed of onset of effect, its intensity and duration and, in certain cases, the drug activity
There are several known absorbtion mechanisms
Step 1 in ADME profile

Absorption

Absorption

Absorption of drugs from the gastrointestinal tract through the skin, respiratory and vascular walls
is connected with several known mechanisms.
Types of transport:
passive transport
(simple diffusion, facilitated diffusion, ultrafiltration)
active transport
pinocytosis
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Absorption

Passive diffusion: substances move from the area with high concentration to the area with low concentration
(small neutral molecules, oxygen)
Facilitated diffusion: involves transport systems (specific carriers)
functioning without energy consumption,
along the concentration gradient (adenilyc nucleotides)
Active transport: can occur against the concentration gradient and with energy consumption. Involves transport systems that are selective to certain compounds and saturable
(Na+ and K+ ions, sugars, aminoacids)
Pinocytosis: involves formation of a vesicle filled with fluid and large molecules of transported substances. The vesicle migrates via the cytoplasm to the opposite side of the cell where the vesicle content is expelled from the cell
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Absorption

Absorption

Passive transport

Membranes and Absorption

Facilitated transport

Active transport

Pinocytosis

Factors that influence the absorption

Bioavailability
bioavailability is the proportion of the initial drug dosage that reaches blood plasma (systemic circulation) without changes
after i.v injection - 100% bioavailability
In bioavailability assessment,
the area under the curve (AUC) is usually measured
Says nothing about effectiveness
Systemic effect of a substance
develops only after its entrance into the bloodstream from which it moves to tissues

Bioavailability

Bioavailability
Not
absorbed
Destroyed
by gut wall
to
systemic
circulation
Destroyed
by liver
Dose
Destroyed
in gut

Distribution Step 2 in ADME profile
After absorption, drug enters the blood, than different organs and tissues
The majority of drugs are distributed unevenly
Distribution into the body compartments
Plasma 3.5 litres (heparin, plasma expanders)
Extracellular fluid 14 litres, (tubocurarine, charged polar compounds)
Total body water 40 litres (ethanol)
Drugs more easily penetrate into most organs with intensive blood circulation (heart, liver, kidneys)

THE BODY COMPARTMENTS

Distribution of drugs in the body
In the body drugs partially bind to other molecules and form extracellular and cellular depots
Plasma proteins (especially albumins) are the most important extracellular depots
Only free drug fraction can move through the membrane, render a pharmacological effect, undergo biotransformation and excretion
Binding of drugs to proteins may be reduced in liver and kidney diseases, sepsis, burns, gastritis, enteritis, protein deficiency, and due to the drug interaction (if two drugs get bound with the same proteins)

Distribution

Important for clinical pharmacology
It is the presumed volume of liquid in which a drug can be distributed (assuming that drug concentrations in plasma and other liquid media of the body is equal)
Distribution
The apparent volume of distribution
Plasma 3.5 litres
Extracellular fluid 14 litres
Total body water 40 litres
Vd =
Total amount of drug in the body
Drug concentration in plasma
Liphophilic compounds with wide distribution have high value of Vd
Drugs that only circulate in blood
have low value of Vd

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Distribution
Biological barriers
substantially influence drug distribution
There are such biological barriers:
capillary wall
cell membranes
blood-brain barrier
placental barrier
blood-brain barrier
blood
brain
astrocyte
endothelium
basal membrane

Biotransformation of drugs (drug metabolism)
is the process of drugs (xenobiotics) conversion into metabolites that are easily dissolved in water and can be excreted by the kidneys.
Many enzymes participate in drug biotransformation, the most important among them are microsomal enzymes of the liver, they do not have substrate specifity
Non-microsomal enzymes are localized in the liver and in the intestines, lungs, kidneys, blood, placenta and others.
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Metabolism Step 2 in ADME profile
Most drugs undergo biotransformation in the body
Drug metabolism determines drug dosage regimen.

METABOLISM

Drug Metabolism

1. Metabolic transformation
occurs through oxidation, reduction, hydrolysis
In these reactions groups with active hydrogen atoms (oxy-, aminogroups)are formed
2. Conjugation
Functional groups of a drug get bound with endogenous compounds such as glucuronic residues, sulfur and amino acids. Also methylation and acetylation can take place.
Nb! Biotransformation can increase drug activity or toxicity
Prodrugs – active molecule is formed in the body
(sulphenamide is an active metabolite of omeprazole)
“Lethal synthesis“ – if the toxic metabolites are formed
(acetaldehyde is the toxic metabolite of ethanol)
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Metabolism Step 3 in ADME profile
There are two main types of drugs biotransformation

Biotransformation of drugs (drug metabolism)
METABOLISM
deactivation

Metabolic rate depends on genetic factors.
Induction and inhibition of metabolism enzymes influences the rate of metabolism of drugs.
Induction of metabolism enzymes – increase of their activity – acceleration of the drug metabolism
Inhibition of metabolism enzymes – decrease of their activity – retarding of the drug metabolism
While the use of drugs with inductors or inhibitors drug doses should be adjusted.
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Metabolism

Concentration of a drug in blood is variable
because of the changes in biotransformation processes
SUPRESSION OF METABOLISM
DRUG CUMULATION
INHIBITION
of enzymes that
provide metabolism
by other drugs
Side effects increase
Genetical
polymorphism
of enzymes
that provide metabolism
INDUCTION
of enzymes that
provide metabolism
by other drugs
Genetical
polymorphism
of enzymes
that provide metabolism
INTENSIFICATION OF METABOLISM
CONCENTRATION OF A DRUG
IN BLOOD IS LOW
Insufficient effect

Drugs and their metabolites are mainly eliminated with urine and bile
and sometimes with expiratory air, by salivary glands, sweat glands, gastric and intestinal glands, lacrimal glands, mammary glands (caution is needed when administering drugs to a nursing mother!)
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Excretion Step 4 in ADME profile

Important for clinical pharmacology
It shows the time necessary to decrease drug concentration in blood plasma by 50%
It is used to adjust doses of drugs and intervals between the times of their administration in order to achieve stable drug concentration
90% of the drug is eliminated during the period that equals 4 t1/2
t 1/2 is defined not only by the drug elimination from the body, but also by its biotransformation and storage
t1/2
The elimination half-life or «half-life»
Excretion

EXCRETION

Drug interactions
Based on the change in drugs pharmacokinetics
Based on the change in drugs pharmacodynamics
Pharmaceutical interaction

Synergism
(from Greek syn – together, ergos – work)
increase in effect of drugs used at
the same time (unidirectional effects)
Two types of drug synergism
- Summing up or additive effects
- Potentiation
Drug interactions
based on the change
in drugs pharmacodynamics

Summing up or additive effects
(combination of analgesics)
The mechanisms of actions of both drugs are similar
Summed effect represents the actual sum of effects of the individual drugs
Effect, %

Potentiation
(neuroleptanalgesia)
The drugs differ in mechanisms of action
The total effect exceeds the sum of effects of the individual drugs
Effect, %

Antagonism
(from Greek antagōnisma – struggle, conflict)
the ability of drug to decrease the effect
of the other one
Types of antagonism
direct (competitive)
the same target but the opposite effect
(contraction or relaxation of the same muscle)
- indirect (noncompetitive)
different targets and the opposite effect
Drug interactions
based on the change
in drugs pharmacodynamics

Antagonism Types of antagonism
- two-way and one-way antagonism
A blocker reliably eliminates the effects of a mimetic (activator)
but a mimetic (activator) usually is ineffective against a background of a blocker
Synergoantagonism
Occurs when some effects of the combined drugs
are intensified, and others are weakened
Drug interactions
based on the change
in drugs pharmacodynamics

Drug incompatibility
Incompatibility is the weakening, full loss or change in the pharmacotherapeutic effect, intensification of side or toxic effects
–Pharmacological incompatibility – in the body
Antagonistic combinations of drugs (activator + blocker) or drugs with food (nialamide + chocolate, iron compounds + milk and others)
Dangerous combinations of drugs (astemisole + itraconazole; cardiac glycosdes + calcium salts and others) or drugs with food (niphedipine + grapefruit and others) or drugs with herbal preparations (drugs decreasing blood coagulation + ginkgo or garlic)
Pharmaceutical incompatibility– during the production process, storage or mixing of the drugs in one syringe
physical
chemical
physico-chemical