Course Coordinator
Rebaz Fayaq Hamarawf
Department of Pharmacy, Kurdistan Technical institute
Lecture-5
May 03, 2021
As mentioned before, the term Distribution means the process by
which the drug reaches the site of action (active site on the receptor).
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
2
As we mentioned before, the term "drug" means any Substance used
in the diagnosis, cure, mitigation, treatment, or prevention of
disease in human, animals or plants…
When A drug inhaled, injected, smoked, consumed, absorbed via one
of the drug administration routs causes a physiological change in the
body (pharmacological response).
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
3
For a drug (ligand) to have an action, it should interact(bind) with
one of the receptor molecules in a specific positon to form drugreceptor complex. The ligand binds to the ligand-binding site on the
receptor protein causes activation or inhibition of the receptor. A
ligand may be any molecule (drug) , from organic and inorganic
minerals
to
organism-created
proteins,
hormones,
and
neurotransmitters.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
4
A receptor is a protein which binds to a specific molecule. The
molecule it binds is known as the ligand. Most of the receptors are
found on the macromolecules. Macromolecules such as:
1. Proteins (mainly enzymes, receptors and transport proteins)
2. Lipids
3. Carbohydrates
4. Nucleic acids (DNA and RNA) are the main molecular targets for
drugs.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
5
The area of the macromolecule where the interaction takes place is
called the binding site; which is a pocket or canyon at the surface
of the macromolecule.
Many drug receptors are the same as those used by endogenously
produced ligands. Such as Cholinergic agents interact with the same
receptors as the neurotransmitter acetylcholine and most
metalloenzymes.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
6
Lock and Key Hypothesis “ The drug molecule must fit into the
receptor AND produce its action like a key fits into the lock
AND opens it also” This is known as Intrinsic Activity
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
7
Intrinsic activity is a measure of the ability of a drug that is bound
to the receptor to generate an activating stimulus and produce a
change in cellular activity. Both agonists and antagonists can bind
to a receptor.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
8
Receptor: a binding site located on the surface/inside the
effector macromolecule cell that serves to recognize the signal
molecule/drug (Ligand) and initiate the response to it, but has
no other function itself.
Efficacy: potential maximum therapeutic response that a drug
can produce.
Potency: amount of drug needed to produce an effect.
Ligand: a molecule which binds selectively to a receptor or site.
Affinity: the ability to bind with the receptor.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
9
Agonist: activates a receptor to produce an effect similar to that
of the physiological signal molecule.
Partial Agonist: activates a receptor to produce a submaximal
effect - but antagonizes the action of a full agonist.
Inverse Agonist: activates a receptor
to produce an effect in the opposite
direction to that of the agonist.
Antagonist: prevents the action of an
agonist on a receptor or the
subsequent response but does not
have an effect of its own.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
10
Active site
The active site is the three-dimensional clefts region (crevices or
pockets) occupying small region in big enzyme or protein molecules
The active site consists of amino acid and non-amino acids residues
that form temporary bonds with the substrate as a ligand (binding
site).
Enzymes are flexible structures, while the active site change the
shape to fit with substrate.
Active site
 Site of reaction catalysis.
 Only substrates of specific size,
shape, solubility, and charge can
bind.
 Basis of enzyme specificity
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
11
Drug-target interactions can be grouped into two types:
1- Permanent (Irreversible): covalent bonding (strength of 200-400 KJ/mol).
2- Reversible: by different types of interactions.
 A drug combine with a receptor and may initiate a sequence of effects
 The ability of drug to combine with the receptor to form the drug-receptor
complex is defined as affinity.
 The ability of drug to initiate the effect is termed as intrinsic activity.
 Agonist is the drug possess both affinity as well as intrinsic activity.
 Antagonist is the drug possess affinity but not intrinsic activity.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
12
A biological response is produced by the interaction of a drug
with a functional or organized group of molecules on a
macromolecule like protein, known as active site of the receptor.
This interaction would be expected to take place by using the same bonding
forces as are involved when simple molecules interact.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
13
Simply an antagonist is a drug that binds to the receptor
without activating the receptor
Antagonists block the action of
agonists simply by getting in the way
of the agonist, preventing the agonist
from binding to the receptor and
producing the drug effect.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
14
Competitive antagonism (Reversible/irreversible) is present when
increasing concentrations of the antagonist progressively inhibit the
response to the agonist.
Noncompetitive antagonism (Irreversible) is present when, after
administration of an antagonist, even high concentrations of agonist
cannot completely overcome the antagonism
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
15
A drug is said to be an antagonist when it binds to a
receptor and prevents (blocks or inhibits) a natural
compound or a drug to have an effect on the receptor.
An antagonist has no activity.
Types of Antagonism:
1.
2.
3.
4.
Chemical antagonism
Physiological/Functional antagonism
Pharmacokinetic antagonism
Pharmacological antagonism
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
16
Antagonist effectively reduces the concentration of the active
drug at its site of action (at the receptor). Either by increased
metabolic degradation, decreased absorption or increased
excretion.
ACalcium
&
tetracycline,
Cholestyramine
&
warfarin/digoxin
DPhenylbutazone & warfarin
M- ↑ Phenobarbital/rifampicin & warfarin, rifampicin & OCP
↓ciprofloxacin/chloramphenicol/erythromycin
&
theophylline.
E- ↓ Probencid/aspirin/sulfonamides/thiazides/indomethacin &
penicillin/zidovudine, NSAIDS & methotrexate/ furosemide
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
17
 Receptors: come in many types, but they can be divided into two
categories: intracellular receptors, which are found inside of the cell
(in the cytoplasm or nucleus), and cell surface receptors, which are
found in the plasma membrane.
 Ion Channels: are located within the membrane of all excitable cells,
and of many intracellular organelles. Is narrow, water-filled tunnels
that allow only ions of a certain size and/or charge to pass through.
 Enzymes: are biological molecules (typically proteins) that
significantly speed up the rate of virtually all of the chemical
reactions that take place within cells.
 Transporters: are membrane proteins involved in the uptake or efflux
of drugs by several tissues such as the intestine, liver, kidney and
brain.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
18
The distribution of Sodium and potassium ions across the cell
membrane is unequal: Na is extracellular cation, while K is
intercellular cation.
Sodium is very soluble and easily absorbed from the stomach and
small intestine. reabsorb or eliminate it in order to maintain stable
blood sodium levels. Absorption of potassium from the diet is
passive and does not require any specific mechanism.
Aldosterone, a hormone made and secreted by the adrenal cortex,
acts on the kidneys to regulate sodium metabolism and tends to
promote potassium excretion.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
19
The Sodium-Potassium Pump
The process of moving sodium and potassium ions across the cell membrane is an
active transport process involving the hydrolysis of ATP to ADP provide the
necessary energy.
It involves an enzyme referred to as Na+/K+-ATPase. This process is responsible for
maintaining the large excess of Na+ outside the cell and the large excess of K+ ions
Mg2+
on the inside.
3Na+ic + 2K+ec + ATP4- + H2O
3Na+ec + 2K+ic + ADP3- + HPO42- + H+
It accomplishes the transport of three Na+ to the outside of
the cell and the transport of two K+ ions to the inside.
The sodium-potassium pump
moves toward an equilibrium
state with the relative
concentrations of Na+ and
K+ shown at left.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
20
Mechanisms for Membrane Transport
Passive Transport: moves ions down the concentration
gradient, requiring no energy source.
◦ Ionophores and Ion Channels are Passive
Active Transport: moves ions against the concentration
gradient, requiring energy from ATP hydrolysis
◦ Ion Pumps are Active
 Choice of Transport Mechanism
◦ Charge
◦ Size
◦ Ligand Preference
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
21
Mechanisms for Membrane Transport
 Ionophores: special carrier molecules that wrap around metal ions
so they can pass through the membrane by diffusion.
 Ion Channels: large, membrane-spanning molecule that form a
hydrophilic path for diffusion.
 Ion Pumps: molecules using energy to transport ions in one
direction through a membrane.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
22
The Sodium-Potassium Pump
Examples of Ionophores
Nonactin and tetranactin: is a macrotetrolide that forms complexes
with alkali cations, such as potassium and sodium.
Nonactin
Tetranactin
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
23
Lithium Salts
Ions Channels and Lithium Carbonate
Lithium carbonate is used in the treatment of manic depression (bipolar disorder
or mania), is a serious change from the way a person normally thinks or behaves, to
carry out day to day tasks.
Lithium carbonate tablets are taken usually 1 to 2 g per day to maintain a plasma
lithium concentration of 0.5 -1.0 mmol/dm3.
Toxicity are observed at about 2.0 mmol/dm3. leading to course tremor of the hand,
polyurea, vomiting and diarrhea.
The mechanism of action of lithium salts in bipolar disease
is unknown: The following hypotheses are proposed:
A- Li+ enhances the effect of the neurotransmitter serotonin.
B- Li+ target second messenger systems.
C- Interferes with transport of Na+ and K+ ions.
Pharmaceutical Chemistry
Rebaz F. Hamarawf
Lecture 4 / KTI
24
End of Lecture Five
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