Department of Pharmacology1
Basic pharmacological terminology
Drug classification
Mechanisms of drug effects
Basics of pharmacokinetics
Literature
Pharmacology. Edited by Michelle Alexia Clark. 5th ed. Baltimore: Wolters Kluwer
Health/Lippincott Williams & Wilkins, 2012. xii, 612. ISBN 9781451113143.
In IS: Pharmacology for students of bachelor’s programmes at MF MU (special part)
Basic pharmacological terminology
A synthesis of several biomedical sciences….
Pharmacology
…but unique in its own right
Pharmacology, definition, aims
„pharmacon“ + „logos“ / „logia“
Scientific discipline dealing with
INTERACTIONS BETWEEN SUBSTANCES..
introduced into the organism from the environment
..AND THE LIVING ORGANISM
on all levels of complexity:
molecular
cellular
organ
organism as a whole
Pharmacologists study science at every level
DRUG
„substance or mixture of substances, suppopsed to be
administered to the humans or animals for prevention,
treatment or diagnosis of diseases or its symptomes or for
physiological function adjustment“
Drugs are administered for
- Prevention,
- Diagnosis,
- Treatment of disseases
What Pharmacology is NOT...
❖ Pharmacy
This is a separate profession responsible for the
preparation and dispensation of medication.
❖ Pharmaceutical Science
Basic Pharmacology
General principles
Systems Pharmacology
General principles
Principles which predestinate the interactions of the drug and body
- General Pharmacokinetics
- General Pharmacodynamics
Two important and interrelated areas:
Pharmacokinetics (PK)
Deals with the fate of the drug in the body
– processes of
Absorption,
Distribution
Metabolism
Excretion …“ADME“
„What the body makes with the drug“
Pharmacodynamics (PD)
deals with the mechanism of action (e.g.
receptor sites, molecular level of action..)
„How does it work“
Systems Pharmacology
Is focused on individual organ systems and its
pharmacotherapy
e.g.
Autonomic drugs
Psychoactive drugs
Drugs used in cardiovascular diseases….
Systems Pharmacology
❖ Neuropharmacology: study of the effect of drugs on
components of the nervous system (brain, spinal cord, nerves)
Example: treatment of Alzheimer‘s disease
❖ Cardiovascular Pharmacology: study of the effects of drugs
on heart, vasculature, kidney, nervous and endocrine systems
that participate in cardiovascular function.
Example: treatment of high blood pressure (hypertension)
Branches of Pharmacology
Clinical pharmacology
• deals with different drugs and their varied clinical usage
• interdisciplinary branch, which integrates basic and
experimental Pharmacology with the clinical and
complementary branches
AIM: to study and evaluate the effect of the drug using
objective methods (EBM)
Sub-branches of clinical pharmacology:
Clinical Pharmacokinetics, clin. Pharmacodynamics,
Rational prescribing, Clinical toxicology
Toxicology
the study of the toxic effects of chemicals on living organisms
study of symptoms, mechanisms, treatments and detection of poisoning
experimental (in vitro, in vivo)
clinical - poisoning prophylaxis, diagnosis, treatment
forensic toxicology…
Pharmacogenetics
deals with the influence of genetic variation on Pharmacokinetics and
Pharmacodynamics
study of the drug response in patients by correlating gene expression or singlenucleotide
polymorphisms with a drug's efficacy or toxicity
consequences can be either quantitative or qualitative
Biochemical and molecular pharmacology
detail study of the mechanism of action at molecular level
Chronopharmacology
Study of the action of the drugs with respect to the biorhythm
(antiasthmatics, glukocorticoids, statins, etc. )
Pharmacovigilance
Pharmacological science relating to the detection, assessment, understanding and
prevention of adverse effects
collecting, monitoring, researching and evaluating information from healthcare providers
and patients on the adverse effects of medication
Drug safety monitoring
AIM: to minimize the risk of adverse effects
Pharmacoepidemiology
- study of the effect of drugs on populations; questions dealing with the influence of genetics are
particularly important
risks and benefits of the therapy using epidemiological methods
Approach of the health specialists (GP, pharmacist)
patient (compliance)
society (drug abuse, marketing, financial resources…)
Pharmacoeconomy
- rationalize the use of sources in health care
- Compares the costs of therapeutic approaches by the pharmacoeconomical
analyses
The goal is not „to decrease total money spent in health care“ , but to use the
sources effectively
Experimental pharmacology
Biological experiment
in vitro – isolated structures or organs,
cell cultures, microorganisms
- regulatory factors we have to satisfy:
☺ ethical (replacement, refinement, reduction)
☺ small amounts of drugs
☺ use of human cells
 elimination of systhemic reaction of the whole body
Biological experiment
in silico – use of IT, especially computer modelling (f-kinetics), databases
Biological experiment
in vivo – whole animal
- systhemic effects
- we record toxicity, possible adverse and alergic effects
- impact on memory and other cognitive faculties, learning abilities,
depression
Drug classification
Drug names
Chemical name
according to the IUPAC (International Union of Pure and Applied Chemistry)
nomenclature rules
e.g.: N-acetyl-para aminophenol
Generic name (non-proprietary)
INN (International Non-proprietary Name)
not registered, supposed to be used internationally
has to be printed on the packing of the drug (under the registered trade name)
for the universal terminological identification of the medicines
formed from the chemical name (shortness) accordingly with the rules (WHO)
each drug has its own CAS No (Chemical Abstracts Sevice Number)
e.g. paracetamol
Trade name (proprietary)
registered, patent-protected ®
has to be acompanied with the INN
e.g. Panadol, Coldrex, Paralen
Officinal name
latin name in Pharmacopoeia (e.g. Paracetamolum)
usually very similar to INN
has to be prescribed on Rx formulary in case of individually prescribed
medicines
established name for a drug substance is usually found in the originating
country's Pharmacopeia
Paracetamolum
…
Drug names
Some drug-family names
-olol beta receptor antagonists
-caine local anaestethics
-tidine histamine receptor antagonists
-dipine calcium channel blockers of
dihydropyridine type
-statin inhibitors of HMG CoA transferase
„GENERICS“
Drug which is produced and distributed after ending of patent protection - mostly manufactured by
other company which has not developed the original drug (the same active substance!)
Mostly cheaper than original preparation
Assumed to be identical in dose, strength, route of administration, safety, efficacy, and intended use
Bioequivalent trials are needed before registration
Registration procedures are much easier than in orig. preparation
Drug patents give 10 years of protection, but they are applied for before clinical trials begin, so the
effective life of a drug patent tends to be between 7 and 12 years
DOSE
A specified quantity of a therapeutic agent, prescribed to be taken at one time
or at stated intervals.
If administered in the body, desintegrates, solutes, and distribute across
the barriers in the body compartments. Than it is measured like
„concentration“
DOSIS SINGULA - single dose
DOSIS PRO DIE - daily dose
- for 24 h !!
DOSIS CHRONICA
- (adjusted) dose in the chronic treatment (long-term)
DOSE
on Rx !
Basics of pharmacokinetics
Basic principles of pharmacokinetics
Pharmacokinetics is aimed on this processes:
absorption
distribution
biotransformation
excretion of drugs
and their relation to pharmacologic (therapeutic or toxic) effects
Pharmacokinetics
absorption A
distribution D
metabolism M
excretion E
- processes of ADME
“ADME“
elimination
invasion
Administration of drug
Absorption
depot
binding
receptor
free
drug
free
drug
free
drug
Biotransformation
organs
drug bound to proteins
or blood cells
receptor
depot
binding
metabolite free
metabolite
metabolite
bound to protein
or blood cell
free
metabolite
TISSUES BLOOD CIRCULATION
ORGANS OF
EXCRETION
EXCRETION
Absorption – routes of administration
̶ penetration of dissolved drug from the site of administration to blood
(systemic circulation) – necessary for general effect– systemic effect
̶ Local effect:
̶ on skin, mucosas or ventricles
̶ absorption is undesirable – possible AE
̶ ie. local corticoids, local anesthetics
Speed and extent of absorption are described by P-kinetic parameters:
C max max. concentration of drug in plasma after single dose
T max time, when drug reach cmax (speed)
F bioavailability (extent)
Concentration of drug
Time
Bioavailability- F
how much from the administered dose get to circulation
extravascular administration - 0-100% (resp. 0-1)
intravenous (intravascular) - 100% = 1
̶ if F is < 20 % = 0 - 0,2 – it not worth to administer the drug by this way
(some of them are administered through that - SET, bisfosfonates)
̶ the measure of bioavailability is the area under the curve (AUC)
𝐅 =
𝐀𝐔𝐂 𝐩𝐨
𝐀𝐔𝐂𝐢𝐯
http://icp.org.nz/icp_t6.html
AUC – area under the curve
Time
Presystemic elimination
First pass effect
http://icp.org.nz/icp_t6.html?htmlCond=1
Other factors influencing drug absorption
̶ gender, weight, plasmatic volume, speed of gastric discharging
̶ age - pH, bile, enzymes
̶ pathophysiological defect – diseases of liver, inflammation ...
̶ body constitution (BW/LBM)
̶ diet
- acceleration/ decceleration
- chemical incompatibilities
- GIT functionality
Distribution
̶ Penetration of drug from blood to tissues, dynamic proces where we are interested in:
speed of distribution- depends on:
bindings
membrane penetration
organ perfusion
Volume of distributionVd
̶ hypothetic, theoretical volume
̶ rate between amount of drug in organism and plastmatic concentration
𝐕𝐝 =
𝐃 . 𝐅
𝐂 𝟎
𝐥
http://icp.org.nz/icp_t3.html?htmlCond=0
The apparent volume of distribution, Vd, is defined as the volume that would contain the
total body content of the drug at a concentration equal to that present in the plasma
Vd = hypothetical volume,
Final value of Vd can be even 50000 liters (antimalarial drugs).
What does this value tell us:
We can assess distribution of the drug in the body.
Distribution
Assessment of the effect of hemodialysis and hemoperfusion
̶ drugs with higher Vd can not be eliminate from the body by these technics
Biotransformation - metabolism
̶ Predominantly in liver, but also in other organs and parts of body
Enzymatic processes
̶ bioactivation (prodrug)
cyclophosphamide – phosphoramide
̶ biodegradation
Biotransformation - metabolism
1. Phase:
̶ oxidation, hydrolysis → drug is still partly lipophilic
̶ cytochromes P450, dehydrogenases
2. Phase:
̶ conjugation → molecules becomes hydrophilic
Metabolites
- effective („more/less“)
- inneffective
- toxic
CYP 450
CYP 2D6
30%
CYP 1A2
2%
CYP 2C9
10%
ostatní
3%
CYP 3A4
55%
CYP 3A4
CYP 2D6
CYP 2C9
CYP 1A2
others
Inducers of CYP450
• dexametazon
• fenobarbital
• rifampicine
• fenytoin
• St. John´s worth (Hypericum perforatum)
• Maidenhair Tree (Ginkgo biloba)
Inhibitors of CYP450
• antidepressants (fluoxetin, fluvoxamin, paroxetin)
• chinin, chinidin
• chloramphenicol, erytromycine
• ketokonazol, itrakonazol
• grapefruit juice
Excretion
kidneys
bile
lungs
Saliva, skin, hair, milk…
Excretion by kidney
̶ MW < 60.000 D (MW of albumin = 68.000 D)
̶ glomerular filtration
̶ tubular secretion
̶ organic acids
furosemide
thiazide diuretics
penicilins
glukuronids
̶ organic bases
morfin
̶ tubular reabsorption
diazepam
alkalization
natrium hydrogencarbonate
acidification
ammonium chloride
Excretion by liver
̶ Substances permeate through 2 membranes of hepatocytes –
basolateral and apical (canalicular)
̶ Metabolites are excreted primary by pasive diffusion, further by
active transport (glucuronides, bile acids, penicillins, tetracyclines,
etc.)
̶ Metabolites can be deconjugated by bacterial enzymes in intestine
→ release of lipophilic molecule → re-absorption
= ENTEROHEPATIC CIRCULATION
Basics of pharmacodynamics
(mechanisms of drug actions)
Mechanism of drug actions
non-specificspecific
receptor non-receptor
I. Non-specific drug effects
…through by the general physical-chemical properties of
substances - no specific chemical and structural
configuration of drugs is needed
- influencing pH
- oxidating and reducing agents
- protein precipitation
- adsorbents / detergents
- chelating agents
a. based on osmotic properties ▪
e.g. salinic laxatives (magnesium sulphate, lactulosa)
▪ osmotic diuretics (mannitol)
b. influencing acid-base balance
▪ Antacids
̶ aluminium hydroxide
̶ magnesium carbonate
̶ calcium carbonate
̶ sodium bicarbonate
▪ pH modifiers (blood, urine)
- Sodium bicarbonate, ammonium chloride
c. based on oxido – reducing properties
▪ e.g. 3% hydrogen peroxide, boric acid, fenols
▪ chlorhexidine act as antiseptics
d. chelates (chelating agents)
▪ ethylenediaminetetraacetic acid (EDTA) is a chelating agent,
it can form bonds with a metal ion
II. Specific drug effects
➢ binding to receptors
➢ affecting ion channels
➢ affecting enzymes
➢ affecting transporters
A. RECEPTORS
B. ION CHANNELS
C. ENZYMES
D. CARRIERS
Agonist
Antagonist
Direct
Signal
Transduction
No effect
Endogenous mediator blocked
Ion channels
Open/closed
Enzymes
Activation/inhibition
n channel modulation
DNA transcription
Blockers
Modulators
Flow is blocked
Increasing or decreasing
probability of opening
Inhibitor
False substrate
Prodrug
Reaction is inhibited
Abnormal metabolites
Active substance
normal
transport
Inhibitor Transport is blocked
Rang and Dale Pharmacology, 2017
A. Receptor – effector system
= complex of processes
extracelullar signal -------------> intracell. signal cascade-------->
effector (own effect)
✓ receptor = protein, which interacts ligands
– involved in signal transduction
✓ effector = enzyme, ionic channel etc. change in the
activity leads to the effect of drug
✓ ligand (signal molecule) = molecule able to bind to specific
receptor
– endogenous - neurotransmitters, hormones
– exogenous - xenobiotics, drugs
Receptor – effector system
̶ Affinity
✓ the ability of the ligand to bind to the receptor
̶ Instrinsic activity
✓ ability to evoke an effect after binding to
receptor
̶ !!!the presence of sufficient number of receptor for the induction of
pharmacological effect is essential as well as sufficient amounts of
receptor ligand!!!
Receptor – effector system
Receptor classification
Lokalizace
✓ membránové
✓ cytoplazmat.
✓ organelové
✓ auto/heterore
ceptory
Transdukce
✓ metabotropní
✓ iont. kanály
ligandové
✓ kinázové
✓ regulující DNA
Ligandů
✓ Achol
✓ Aminy
✓ AMK
✓ peptidy
Type 1
Receptors connected
with ion channels
Type 2
G-protein coupled
receptor
Type 3
Receptor tyrosin
kinases
Type 4
Intracellular
(nuclear) receptors
Place Membrane Membrane Membrane Intracellular
Efector Ion channel Channel or enzyme Enzyme Gene transcription
Binding direct G-protein direct DNA mediated
Examples
Nicotin-cholinergic
receptor,
GABA receptor
Muscarin-cholinergic
adrenoreceptors
Inzulin, growth factor,
cytokin receptor
Steroids, thyroid
hormon receptors
Structure
Oligomer composed by
subunits surrounding
center of the channel
Monomer (or dimer)
containing 7
transmembrane helical
domains.
Single
transmembrane
helical domain
interconencted with
extracelular kinase
Monomer structure
with separate
receptor and DNA
binding domain
4 main type of receptors
Rang and Dale Pharmacology, 2012
Ligand classification
(intrinsic activity)
AGONISTS
Full agonist Partial agonist
- IA = 1 - dualist
- IA in a range from 0‹ to ›1
Ligand classification
Antagonists
✓ IA = 0
✓ Blocks agonist binding to receptor
Inverse agonist
✓ IA = -1
✓ Stabilizesthe receptor in the constitutive activity
Relation between dose and effect
Receptor-effector system
Spectrum of ligands
Antagonism
competitive reversible
non-competitive irreversible
at the receptor level
at the function level
Antagonism
Competitive
✓ ligands compete for the same binding site
✓  c of antagonist decreases agonist effect and inversely
✓ the presence of antagonist incerases the amounts of
agonist needed to evoke the effect
Non-competitive
✓ allosteric antagonism
✓ irreverzible bounds
✓  c of agonist does not interrupt the effect of antagonist
Regulation of receptor function
Receptor desensitization
̶ reducing the sensitivity of the receptors after repeated agonist exposure
̶ Tachyphylaxis – acute drug „tolerance“
̶ reduced sensitivity to the active substance evolving quickly (minutes) → distortion of
the signal cascade
̶ the reactivity of the organism returns to the original intensity after the elimination of
the substance
̶ Example of tachyphylaxis – ephedrine
̶ Tolerance – reduced sensitivity to the active substance, arising from the repeated
administration of the drug (days – weeks) → down-regulation, internalization of the
receptors
̶ to achieve the original effect required increasingly higher doses of drug
̶ the original reactivity of the organism returns to a certain period of time after
discontinuation of the drug
̶ Example of tolerance – opioids administration
Regulation of receptor sensitivity and counts
Hypersensitivity
✓incerase of receptor sensitivity/counts after chronic
anatagonist exposure
Rebound phenomenom
after discontinuation of long-term administered drugs return to
its original state or ↑ intensity of the original condition
(hypersensitivity of receptors to endogenous ligands → up-
regulation)
Example: chronic administration of β blockers
Regulation of receptor sensitivity and counts
B. Non-receptor mechanism of action
Interaction with „non-receptor“ proteins
̶ 1. enzyme inhibition
̶ 2. block of ion channels
̶ 3. block of transporters
1. Enzyme inhibition
▪reversible
▪ acetylcholinesteraze– physostigmine
▪irreversible:
▪ cyklooxygenase – ASA (aspirin)
▪ aldehyddehydrogenaze– disulfiram
2. Ion channels
▪ Calcium channel blockers (nifedipin, isradipin…)
▪ Natrium channel blockers – local anesthetics
3. “Carriers“
▪ Proton pump inhibitors (PPIs) – omeprazol