How drugs work:

Mechanism of action of
drugs
MBBS program
Alli-oluwafuyi AbdulMusawwir Ph.D.
09-01-2020
Recommended texts
• Goodman and Gilman: Pharmacokinetics and Pharmacodynamics
• Rang and Dale: How drugs act: General (Chapter 2) and molecular
aspects (Chapter 3).
• Basic and Clinical Pharmacology 14th Edition (Katzung): Chapters 1 & 2
Carbachol
• Carbachol is a semisynthetic carbamic ester analog of the endogenous
parasympathetic neurotransmitter, acetylcholine.
• Carbachol is clinically used for disorders of the GI where smooth
muscle activity is impaired without obstruction eg paralysis of stomach
or bowel.
• GI smooth muscles express the muscarinic cholino(re)captor.
• Activation of this receptor results in the contraction of smooth muscle.
• Carbachol binds to this receptor to activate it thereby causing
muscular contraction.
Insulin
• Insulin is a peptide hormone secreted largely from the pancreatic
beta cells in response to glucose.
• Insulin is used in diabetes mellitus to bring down blood glucose.
• Insulin brings down blood glucose by binding to insulin receptors (IR)
that are expressed on liver, adipose tissue and skeletal muscle (SM).
• In the SM, insulin binding to the IR results in downstream cellular
biochemical events that results in the translocation of cytoplasmic
glucose transporters to the membrane where they facilitate entry of
glucose into the cells thereby bringing a reduction in plasma glucose.
Losartan
• Losartan is an antihypertensive agent.
• Losartan binds to and antagonizes the angiotensin receptor (AT1).
• Angiotensin is an endogenous octapeptide that binds to AT1 receptor
expressed on vascular smooth muscles.
• Binding and activation of this receptor results in vasoconstriction
which may result in/contribute to hypertension.
• Preventing the binding of angiotensin to its receptor reduces basal
vasoconstriction (or induces relative vasodilatation) which results in
lowering of blood pressure.
Sildenafil
• Several cells including endothelial cells express guanylyl cyclase (GC) enzyme
which catalyzes the conversion of GTP into cGMP.
• cGMP activates a protein kinase G (PKG) which (de)phosphorylates several
proteins which results in reduced intracellular calcium levels.
• Since calcium triggers contraction, PKG-mediated reduction in cytosolic calcium
results in vasorelaxation.
• Intracellular phosphodiesterase is an enzyme that inactivates cGMP by
converting it to GMP. Preventing this conversion prolons the action of cGMP.
• Sildenafil is a phosphodiesterase inhibitor used to prolong erection.
• Nitrates (Nitroglycerin) are NO-donors. They are metabolized by intracellular
enzymes generating NO which activates GC.
Aspirin
• Aspirin is a drug used for its analgesic and anti-inflammatory effects.
• Aspirin irreversibly binds and inhibits the cyclo-oxygenase (COX-
1/COX-2) enzyme.
• This enzyme catalyzes the production of prostaglandins from
arachidonic acid substrates.
• Prostaglandins act on blood vessels increasing permeability to
cytokines and chemokines that orchestrate the inflammatory process.
• Preventing the production of prostaglandins limits inflammation.
Cisplatin
• Cancer cells are characterized by uncontrolled growth and results in
diminished health and death.
• Cisplatin is an anticancer drug that prevents cellular growth.
• Cisplatin is activated by oxidation in cells and the oxidative products
bind to the Nitroen atoms of guanine in the DNA.
• When proteins that ensure DNA integrity detects this addition, they
attempt to repair by excising the amended base. Due to the several
cuts, the repair enzymes fail to correct all amended bases triggering
apoptosis – automatic cell death
Diazepam
• Diazepam is a sedative agent.
• It binds to the GABAA receptor just like the endogenous
neurotransmitter GABA though at a different site.
• The GABA receptor is a receptor-controlled chloride ion channel
• Binding of GABA or diazepam to the receptor results in a
conformational change in the receptor which opens up the chloride
channel allowing influx of cl- which hyperpolarizes the neuron
reducing its activity.
Amlodipine
• Amlodipine is a commonly used antihypertensive agent.
• It binds to and blocks the L-type calcium channel in smooth muscle
and cardiac cells
• The calcium channel allows calcium entry which is vital to both
cardiac muscle contraction and blood vessel constriction
• The inhibition of the channel reduces Ca entry and thus results in
reduced cardiac contraction and vasodilation
Edetate calcium disodium
• Lead poisoning is common and exerts multisystemic effects inhibiting
enzymes, interfering within essential cations and generates oxidative
stress which may culminate in organ damage/death.
• Intravenous edetate calcium disodium can be used to treat lead
poisoning
• This drug chelates freely dissolved iron in plasma and tissue fluids.
Mannitol
• Osmosis is the movement of water molecules from a region of low
solute concentration to a region of high solute concentration.
• Mannitol is a prototypical osmotic diuretic.
• When administered, it is filtered by the glomerulus but not
reabsorbed causing water to be retained in the tubules thereby
promoting water diuresis.
• It can be used to reduce intracranial pressure and renal toxin removal.
• To be used as diuretic it must be given intravenously. Oral mannitol
results in diarrhea (by similar mechanisms).
Paclitaxel
• Paclitaxel is an antineoplastic agent.
• Mammalian cells divide by mitosis which involves formation of 2
daughter cells.
• Cell division requires microtubule formation which allows
chromosomal division.
• Paclitaxel binds avidly to microtubules resulting in tubulin
polymerization.
• Tubulin polymer cannot function in chromosomal division thereby
inhibiting cell division
Levonogestrel
• Levonogestrel is a component of oral contraceptive
• It is an analog of estrogen.
• It binds to cytoplasmic estrogen receptors which upon activation
translocate to the nucleus where it functions as a transcription factor
mediating the transcription of several proteins.
Canagliflozin
• Canagliflozin is an antidiabetic agent that reduces blood glucose.
• It binds to the sodium-glucose transporter (SGLT2).
• SGLT2 is expressed in the nephron where it mediates the reabsorption
of sodium and glucose via cotransport mechanisms.
• Canagliflozin binds to this ransporter such that it cannot bind glucose.
• Glucose is therefore lost in urine. Continous loss of filtered glucose in
urine results in lowering of blood glucose in diabetes patients.
Folic Acid
• Pregnant women are given folic acid supplements to prevent neural
tube defects in fetus.
• Folic acid is activated by reduction.
• Reduced folic acid serve as cofactors in biochemically important
cellular reactions. For instance, folate transfers one carbon atom to
dUMP to form dTMP – a critical DAN precursor.
• Similarly, folate is involved in conversion of homocysteine to
methionine – a critical myelin sheath precursor.
Immunos
• Monoclonal antibodies: omalizumab
• Anakinra: natural IL-1 antagonist.
• Decoy receptors: rilonacept.
• Reslizumab: binds and neutralizes IL-5 thereby suppressing
production and survival of eosinophils.
Class work
Write an essay on how drugs work? 5 minutes
Principles
• Some principles on how drugs work
What are Drugs?
• Ligands that are used or intended to be used for their biologic effects
(therapeutic or toxic) or abilities to explore/exploit physiological
systems.
Nature of drugs
• Physical state at room temperature
• Solid: Acetaminophen,
• Liquid: Ethanol
• Gases: Nitric oxide
• Organic compounds: usually weak acids or bases
• Carbohydrates
• Proteins
• Lipids
• Oligonucleotides:
• Inorganic
• Metals: Iron, Silver
• Non-metals: Ca,
Nature of drugs
• Drug sizes
• Upper MW cutoff: 900 daltons (MW 1000)
• To allow diffusion across membranes
• Most drugs are close to MW 100
• To allow specificity
• Li: 7, Ca:40 etc
Implication of shape for drug action
What do drugs bind to?
• Receptors. Targets. Other ligands. Or Nothing.

• Most drugs interact with binding sites on macromolecules

• When such interactions results in alteration of a biochemical or physiological effect, such a
macromolecule is referred to as RECEPTOR
• Otherwise, such are inert binding sites . Examples?

• receptors already exist for several physiological effects

• Drugs only make use of these.
Receptor-linked
ion channel
G-protein coupled receptor
Enzyme-linked receptor
Nuclear Receptors
Ligand gated channels
Drugs bind receptors at specific sites
Binding at the GLP-1 receptor
How do they bind?

•Chemical forces
•Van der waal
•Hydrogen forces
•Covalent
•Electrovalent
Drugs have affinity for receptors

• The strength of the reversible interaction between a drug

and its receptor, as measured by their dissociation constant,
is defined as the affinity of one for the other.
• This feature is largely dependent on chemical structure.
• Hence, altering the chemical structure of an endogenous or
known molecules with specific affinity can result in several
other molecules with differing affinities.
Structure-activity relationship

• Codeine is 1000 times less potent than

morphine because of a singular difference
• Proton for methyl
What happens after binding?

• Usually induce conformational changes

which results in downstream biochemical
effects and ends with the physiological
effect.
Drugs form drug-receptor complexes that
are not static
Drugs either activate or prevent activation of
receptors
How do we know a drug’s target?
• Affinity for a receptor (or Potency)
Drug Bacterial Cancer DHFR Plasmodium
DHFR DHFR
Methotrexate 10 M 1 µM 100 mM

Trimethoprim 1 nM 100 mM 1mM

Pyrimethamine 100 mM 50 mM 10 nM
Where are these receptors located?
• Host or parasite
• Cell membrane
• Cytoplasm
• Mitochondrion
• Ribosomes
• Storage vesicles

• Nucleus
Drug concentration

•Drugs achieve a therapeutic

concentration to bring about an effect.
• Concentration-effect curves
• Dose-response curves
• The dose affects the concentration which
affects the response
Relationship amongst dose, concentration and
effect
Dose Concentrati Effect
(Diazepam) on (mmol/l)
50 mg/kg 2.0 No effect
100 mg/kg 3.5 Calm, docile
150 mg/kg 4.0 Somnolence
250 mg/kg 5.1 Death
How do drug effects get terminated?
Multiple effects
• What happens when the receptors of a drug are not located in one
place?
• Use H1 receptors and chlorpheniramine as example.

• Drugs sometimes have unintended effects.

• Receptors located elsewhere
• Off-targets
How do drugs works?
• Drugs bind and modulate receptors.
• Drugs bind and inhibit enzymes
• Drugs bind and damage DNA
• Drugs bind and close/open ion channels
• Drugs bind and chelate ions
• Drugs alter osmosis
• Drugs bind and alter structural proteins
• Drugs bind and alter activity of transport proteins
• Drugs replace hormones, ions and essential micronutrients (cofactors)