BASIC PRINCIPLES

Pharmacology. Defined as a science that deals with the

study of substances that activate or inhibit the normal body
processes upon their interaction with living systems.

Medical pharmacology: is dealing with prevention,

diagnosation and treatment of diseases.
Have therapeutical effect in patients or toxic effect on parasites.

Toxicology: is branch of pharmacology that dealing with harmful

effects of substances on living systems.

pharmacon (from Greek: pharmakos) which originally denoted a

magical substance or drug.
 PRINCIPLES OF THERAPY

- CURATIVE antibiotics

- SUPRESSIVE drugs for treatment

of hypertension,
diabetes etc.

- PREVENTIVE malaria,
anticoncipients
 THE NATURE OF DRUGS
• Natural, semisynthetic and synthetic
• Agonists, antagonists.
• Endogenous: synthesise within the body
(hormones, transmitters)
or xenobiotics (xenos= stranger) out the body.
• Poisons are drugs synthesized by plants, animals
or of metals origin such as lead and arsenic.
• Solid, liquid (nicotine) or gases (nitrous oxide)
• SHOULD BE TRANSPORTED,
INACTIVATED/EXCRETED
CHARACTER OF THE PHARMACONS

• Physical properties
- solid, liquid, gas (may decide the
route of
administration)
- organic compounds;
proteins, carbohydrates, fats
- weak acids/bases
• Size of the molecules
- mol wt: 7-59 000; the majority 100-
1000
 DRUG-RECEPTOR BONDS
Electrostatics ( strong between charged ionic molecules,
weaker (H bond) and very weak (van der Waals : dipol
interactions) are most common. Covalent
(phenoxybenzamine, alkylating agents)
Hydrophobic
DRUG-BODY INTERACTIONS
Pharmacodynamic: The actions of the drugs on the body or on
microorganisms or parasites within or on the body .
Pharmacokinetic: The actions of the body on the drugs. Is a
branch of pharmacology dealing with the fate of drugs
administered externally to a living organism.
DRUG-RECEPTOR INTERACTIONS
K+1 β
A+ R AR AR* RESPONSE
K-1 α

K+1
B+ R BR NO RESPONSE
K-1

A= Agonist
B= Antagonist
AGONIST : is a drug when binds to receptors
alters their activities and leads to a biological
response.
Types of agonists:
- Full agonist
- Partial agonist (Buprenorphine at µ, Pindolol at β-receptors)
- Mixed (agonist + antagonist; Nalorphine antagonist at µ and
partial at κ )
ANTAGONIST: Binds to receptors without
causing biological response.

Types of antagonists:
- Competetive antagonism (reversible or irreversible)
- Noncompetetive antagonists
(reversible or irreversible)
- Physiological antagonism ( Histamine ↔ Omeprazole;
glucocorticoids ↔ Insulin)
- Chemical antagonism (Heparine↔ protamine sulfate)
- Pharmacokinetic antagonism (warfarin↔Phenobarbital)
 TARGETS(CÉLPONTOK) FOR
DRUG ACTION
A drug is a chemical that affects normal
bodily function.

TARGET PROTEINS:
- RECEPTORS (RECEPTOR FAMILIES)
- ENZYMES
- ION CHANNELS
- CARRIERS
RECEPTORS AGONISTS ANTAGONISTS
Nicotine ACh Acetylcholine Tubocurarine
receptor Nicotine α-Bungarotoxine
β-adrenoceptor NE, Isoprenaline Propranolol
Opioid (µ-receptor) Morphine, DAMGO Naloxone,
Naltrexone
Oestrogen Ethinylestradiol Fulvestrant
breast cancer in
receptor
postmenopausal women
ION CHANNELS BLOCKERS MODULATORS
Voltage-gated Na Local anaesthetics Veratridine
channels Tetrodotoxin
Renal tubule Na Amiloride Aldosterone
channels
Voltage-gated Divalent cations Dihydropyridines
Ca-channel Cd2+
Voltage-gated K 4-Aminopyridine
channels
ATP-sensitive K ATP Cromakalim
channels Sulphonylureas

GABA-gated Picrotoxin Benzodiazepines

chloride channels
ENZYMES INHIBITORS FALSE SUBSTRATES
Acetylcholinestrase Neostigmine
Organophosphate
Choline Hemicholine
acetyltransferase
Cyclooxygenase Asprine
Dopa Carbidopa Methyldopa
decarboxylase
Thymidine kinase Aciclovir
HIV protease Saquinavir
Revers Didanosine
transcriptase Zidovudine
CARRIERS INHIBITORS FALSE
SUBSTRATES
Choline carrier Hemicholine
(nerve terminal)
Noradrenaline Tricyclic
uptake 1 antidepressants
Cocaine
NE uptake Reserpine
(vesicular)
Na+/K+/Cl- co- Furosemide
transporter (loop
of Henle)
Na+/K+ pump Cardiac glycoside
Proton pump Omeprazole
(stomach)
 TYPES OF DOSE RESPONSE
CURVES

- Graded-dose response curve

Null dose response curves
Cummalative
- Quantal
 DOSE-RESPONSE
RELATIONSHIPS
• Potency: Potencies or activities of
compounds are Expressed by EC50 or
IC50 (in vitro); ED50 or ID50 (in vivo) and
defined as the amount of agonist needs to
produce 50% effect.
• Efficacy: is the magnitude of the response
resulted upon the interaction of agonists
with the receptors.
Relations between drug concentration and drug effect (panel A) or receptor-bound
drug (panel B). The drug concentrations at which effect or receptor occupancy is half-
maximal are denoted EC50 and KD, respectively. (2001 The McGraw Hill Companies, Inc.)
Experimental demonstration of spare receptors, using different concentrations of an irreversible
antagonist. Curve A shows agonist response in the absence of antagonist. After treatment with a low
concentration of antagonist (curve B), the curve is shifted to the right; maximal responsiveness is preserved,
however, because the remaining available receptors are still in excess of the number required. In curve C,
produced after treatment with a larger concentration of antagonist, the available receptors are no longer "spare";
instead, they are just sufficient to mediate an undiminished maximal response. Still higher concentrations of
antagonist (curves D and E) reduce the number of available receptors to the point that maximal response is
diminished. The apparent EC50 of the agonist in curves D and E may approximate the KD that characterizes the
binding affinity of the agonist for the receptor. (2001 The McGraw Hill Companies, Inc.)
Spare receptors increase sensitivity to drug. In panel A, the free concentration of agonist is equal to the KD
concentration; this is sufficient to bind 50% of the four receptors present, resulting in the formation of two
agonist-receptor complexes. (Note: When the agonist concentration is equal to the KD, half the receptors will be
occupied. Remember that B/Bmax = C/[C + KD].) Agonist occupancy of these two receptors changes their
conformation so that they bind to and activate two effector molecules, resulting in a response. Because two of
four effectors are stimulated by agonist-receptor complexes, the response is 50% of maximum. In panel B, the
receptor concentration has been increased tenfold (not all receptors are shown), and the KD for binding of agonist
to receptors remains unchanged. Now a very much smaller concentration of free agonist (= 0.05 ´ KD) suffices to
occupy two receptors and consequently to activate two effector molecules. Thus, the response is 50% of
maximum (just as in panel A), even though the agonist concentration is very much lower than the KD. (2001 The
McGraw Hill Companies, Inc.)
Changes in agonist concentration-effect curves produced by a competitive antagonist
(panel A) or by an irreversible antagonist (panel B). In the presence of a competitive
antagonist, higher concentrations of agonist are required to produce a given effect; thus the
agonist concentration (C') required for a given effect in the presence of concentration [I] of an
antagonist is shifted to the right, as shown. High agonist concentrations can overcome inhibition
by a competitive antagonist. This is not the case with an irreversible antagonist, which reduces the
maximal effect the agonist can achieve, though it may not change its EC50. (2001 The McGraw
Hill Companies, Inc.)
Panel A: The percentage of receptor occupancy resulting from full agonist (present at a single concentration) binding to receptors in the presence of
increasing concentrations of a partial agonist. Because the full agonist (filled squares) and the partial agonist (open squares) compete to bind to the same
receptor sites, when occupancy by the partial agonist increases, binding of the full agonist decreases. Panel B: When each of the two drugs is used alone
and response is measured, occupancy of all the receptors by the partial agonist produces a lower maximal response than does similar occupancy by the
full agonist. Panel C: Simultaneous treatment with a single concentration of full agonist and increasing concentrations of the partial agonist produces
the response patterns shown in the bottom panel. The fractional response caused by a single concentration of the full agonist (filled squares) decreases
as increasing concentrations of the partial agonist compete to bind to the receptor with increasing success; at the same time the portion of the response
caused by the partial agonist (open squares) increases, while the total response—ie, the sum of responses to the two drugs (filled triangles)—gradually
decreases, eventually reaching the value produced by partial agonist alone (compare panel B). (2001 The McGraw Hill Companies)
 Graded dose-response
curves for four drugs,
illustrating different
pharmacologic potencies
and different maximal
efficacies.
Quantal dose-effect
plots. Shaded boxes
(and the accompanying
curves) indicate the
frequency distribution
of doses of drug
required to produce a
specified effect; ie, the
percentage of animals
that required a
particular dose to
exhibit the effect. The
open boxes (and the
corresponding curves)
indicate the cumulative
frequency distribution
of responses, which are
lognormally distributed.
 RECEPTOR FAMILIES
• Intracellular receptors: the ligand must get into the cells.
e.g. ( nitric oxide (NO), corticosteroids,
mineralocorticoids, sex steroids, vitamin D and thyroid
hormone). The observed response needs 30 minutes or
more.
• Ligand-Regulated Transmembrane Enzymes Including
Receptor Tyrosine Kinases (insulin, epidermal growth
factor EGF, platelet-derived growth factor PDGF, atrial
natriuretic factor ANF, transforming growth factor-β TGF
β, other trophic hormones).
• Ligand-Gated ion chanels. The response very fast (few
ms)
e.g. Nicotinic, GABA receptors
• G Protein-coupled receptors (response second to mins)
Known transmembrane signaling mechanisms:
1: A lipid-soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor (which may
be an enzyme or a regulator of gene transcription);
2: the signal binds to the extracellular domain of a transmembrane protein, thereby activating an enzymatic
activity of its cytoplasmic domain;
3: the signal binds to the extracellular domain of a transmembrane receptor bound to a protein tyrosine kinase,
which it activates;
4: the signal binds to and directly regulates the opening of an ion channel;
5: the signal binds to a cell-surface receptor linked to an effector enzyme by a G protein. (R, receptor; G, G
protein; E, effector [enzyme or ion channel].) (2001 The McGraw Hill Companies)
 Mechanism of glucocorticoid action.
The glucocorticoid receptor polypeptide
is schematically depicted as a protein
with three distinct domains. A heat-shock
protein, hsp90, binds to the receptor in
the absence of hormone and prevents
folding into the active conformation of
the receptor. Binding of a hormone ligand
causes dissociation of the hsp90 stabilizer
and permits conversion to the active
configuration.
Mechanism of activation of the EGF receptor, a representative
receptor tyrosine kinase. The receptor polypeptide has extracellular
and cytoplasmic domains, depicted above and below the plasma
membrane. Upon binding of EGF (circle), the receptor converts from
its inactive monomeric state (left) to an active dimeric state (right), in
which two receptor polypeptides bind noncovalently in the plane of
the membrane. The cytoplasmic domains become phosphorylated (P)
on specific tyrosine residues (Y) and their enzymatic activities are
activated, catalyzing phosphorylation of substrate proteins (S). /2001
The McGraw Hill Companies, Inc./
Cytokine receptors, like receptor tyrosine
kinases, have extracellular and intracellular
domains and form dimers. However, after
activation by an appropriate ligand, separate mobile
protein tyrosine kinase molecules (JAK) are
activated, resulting in phosphorylation of STAT
molecules. STAT dimers then travel to the nucleus,
where they regulate transcription.
(2001 The McGraw Hill Companies)
 The nicotinic
acetylcholine receptor, a
ligand-gated ion channel.
The receptor molecule is
depicted as embedded in a
rectangular piece of plasma
membrane, with
extracellular fluid above
and cytoplasm below.
Composed of five subunits
(two a, one b, one g, and
one d), the receptor opens a
central transmembrane ion
channel when acetylcholine
(ACh) binds to sites on the
extracellular domain of its a
subunits.
(2001 The McGraw Hill
Companies, Inc. )
• G-PROTEIN-COUPLED RECEPTORS
• Consist of extracellular N-terminal and intracellular C-terminal domain connected
by a single peptide chain passing the plasma membran seven times and thus forms
the extra and intracellular loops. The third intracellular loop is the region to which
G-proteins are coupling.
• G-proteins consists of three subunits α, β and γ. GTP and GDP bind to α-
subunit. At rest GDP is binding to α (GDP-αβγ, trimer). Upon attachment of agonist to
receptor α catayses the conversion of GDP to GTP ( then α-GTP complex dissociates from
βγ-complex and interacts with a target protein, eg enzyme Adenylate cyclase). The GTPase
activity of the α-subunit is enhanced when α-GTP complex binds to the target protein and
thus results in hydrolysis of GTP to GDP.
• α-GTP and βγ complexes are the active forms of G-proteins.
• Main classes of G-protein: Gs, Gi, Gq
• Cholera toxin acts only on Gs→ persistent activation
• Pertussis toxin acts on Gi
• Targets For G-proteins: second messengers (adenylate
↑cAMP production) ;
cyclase switch on by Gs (↑
Phospholipase C (generates IP3 and DAG) ; Ion channels
(Ca2+, K+). e.g. adrenaline, acetylcholine, dopamine,
serotonin, opioids.
 • PIP2

•phospholipase C

IP3 DAG

Activation of protein
Release of intracellular
kinase C
Ca2+

PIP2= Phosphatidylinositol
biphosphate
The guanine nucleotide-dependent activation-inactivation cycle of G proteins. The agonist
activates the receptor (R), which promotes release of GDP from the G protein (G), allowing entry of
GTP into the nucleotide binding site. In its GTP-bound state (G-GTP), the G protein regulates
activity of an effector enzyme or ion channel (E). The signal is terminated by hydrolysis of GTP,
followed by return of the system to the basal unstimulated state. Open arrows denote regulatory
effects. (Pi, inorganic phosphate.) /2001 The McGraw Hill Companies/
Transmembrane topology of a typical serpentine receptor. The receptor's amino (N) terminal is extracellular (above the
plane of the membrane), and its carboxyl (C) terminal intracellular. The terminals are connected by a polypeptide chain that
traverses the plane of the membrane seven times. The hydrophobic transmembrane segments (light color) are designated by
roman numerals (I-VII). The agonist (Ag) approaches the receptor from the extracellular fluid and binds to a site surrounded
by the transmembrane regions of the receptor protein. G proteins (G) interact with cytoplasmic regions of the receptor,
especially with portions of the third cytoplasmic loop between transmembrane regions V and VI. The receptor's cytoplasmic
terminal tail contains numerous serine and threonine residues whose hydroxyl (-OH) groups can be phosphorylated. This
phosphorylation may be associated with diminished receptor-G protein interaction. (2001 The McGraw Hill Companies, Inc. )
Possible mechanism for desensitization of the β−αδρενοχεπτορ.
αδρενοχεπτορ. Τηε υππερ παρτ οφ τηε φιγυρε δεπιχτσ τηε ρεσπονσε
το α β−αδρενοχεπτορ αγονιστ (ορδινατε) ϖερσυσ τιµε (αβσχισσα). Τηε βρεακ ιν τηε τιµε αξισ ινδιχατεσ πασσαγε
οφ τιµε ιν τηε αβσενχε οφ αγονιστ. Τεµποραλ δυρατιον οφ εξποσυρε το αγονιστ ισ ινδιχατεδ βψ τηε λιγητ−
χολορεδ βαρ. Τηε λοωερ παρτ οφ τηε φιγυρε σχηεµατιχαλλψ δεπιχτσ αγονιστ−ινδυχεδ πηοσπηορψλατιον (Π) βψ
β−αδρενοχεπτορ κινασε (β−αδρενεργιχ ρεχεπτορ κινασε, βΑΡΚ) οφ χαρβοξψλ τερµιναλ ηψδροξψλ γρουπσ (−ΟΗ)
οφ τηε β−αδρενοχεπτορ. Τηισ πηοσπηορψλατιον ινδυχεσ βινδινγ οφ α προτειν, β−αρρεστιν (β−αρρ), ωηιχη
πρεϖεντσ τηε ρεχεπτορ φροµ ιντεραχτινγ ωιτη Γσ. Ρεµοϖαλ οφ αγονιστ φορ α σηορτ περιοδ οφ τιµε αλλοωσ
δισσοχιατιον οφ β−αρρ, ρεµοϖαλ οφ πηοσπηατε (Πι) φροµ τηε ρεχεπτορ βψ πηοσπηατασεσ (Π∋ασε), ανδ
ρεστορατιον οφ τηε ρεχεπτορ∋σ νορµαλ ρεσπονσιϖενεσσ το αγονιστ. 2001 Τηε ΜχΓραω Ηιλλ Χοµπανιεσ
The cAMP second
messenger pathway.
Key proteins include hormone
receptors (Rec), a stimulatory
G protein (Gs), catalytic
adenylyl cyclase (AC),
phosphodiesterases (PDE)
that hydrolyze cAMP, cAMP-
dependent kinases, with
regulatory (R) and catalytic (C)
subunits, protein substrates
(S) of the kinases, and
phosphatases (P'ase), which
remove phosphates from
substrate proteins. Open
arrows denote regulatory
effects.

The McGraw Hill Companies,

Inc. 2001.
 The Ca2+-
phosphoinositide
signaling pathway.
Key proteins include
hormone receptors (R), a G
protein (G), a
phosphoinositide-specific
phospholipase C (PLC),
protein kinase C (PK-C),
substrates of the kinase (S),
calmodulin (CaM), and
calmodulin-binding enzymes
(E), including kinases,
phosphodiesterases, etc.
(PIP2, phosphatidylinositol-
4,5-bisphosphate; DAG,
diacylglycerol. Asterisk
denotes activated state. Open
arrows denote regulatory
effects.)
2001 The McGraw Hill
Companies, Inc.
Possible relations between the therapeutic and toxic effects of
a drug, based on different receptor-effector mechanisms.
The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration)
and pharmacodynamic (concentration-effect) components. Concentration provides the link between
pharmacokinetics and pharmacodynamics and is the focus of the target concentration approach to
rational dosing. The three primary processes of pharmacokinetics are absorption, distribution, and
elimination.