Pharmacodyanamics

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Dr. Shubham Dwivedi

What is Pharmacodynamics?

• What drugs do to the body when they enter

• Study of action-effect sequence of drugs and dose-effect relationship

• Definition.: It is the study of biochemical and physiological effects of drugs and their
mechanism of action at organ level as well as cellular level

• Also Modification of action of one drug by another drug “Effects of a drug on the
body”
Principles of drug action

-Do NOT impart new functions on any system, organ or cell

- Only alter the PACE of ongoing activity

• Stimulation
• Depression
• Irritation
• Replacement
• Cytotoxic Action
Mechanism of drug action

1. Physical Action
2. Chemical Action
3. Through Enzymes
4. Through Receptors
 Drug Action by Physical/Chemical properties
• Physical mass – Ispaghula (laxative)
•Physical form – Dimethicone (antifoaming)
•Smell - Volatile Oils
•Taste – Bitters
•Osmotic action – Mannitol, Mag. Sulfate
•Adsorption – Activated Charcoal
•Soothing-demulcent – Soothing agents like
calamine
•Oxidizing property – Pot. Permanganate
•Chelation – EDTA, dimercaprol
•Radioactivity - Iodine and others
•Radio-opacity – Barium sulfate
•Chemical properties – Chelating agents
(EDTA, dimercaprol)
•Scavenging effect – Mesna (with
cyclophosphamide)
•Acidifying agents & alkalinizing agents,
Antacids etc.
Majority of drugs interact with target biomolecules:

Usually a Protein

1. Enzymes
2. Ion Channels
3. Transporters
4. Receptors
Biomacromolecular targets of Drugs action
Four major types of biomacromolecular targets of drug action:
(A) Enzyme; (B) Transmembrane ion channel;
(C) Membrane bound transporter; (D) Receptor
Enzymes – drug targets

• All Biological reactions are carried out under catalytic influence of enzymes – major drug
target
• Drugs – increases/decreases enzyme mediated reactions
• In physiological system enzyme activities are optimally set

• Enzyme stimulation is less common by drugs – common by endogenous substrates

– Pyridoxine (cofactor in decarboxylase activity)
– Adrenaline stimulates hepatic glycogen phosphorylase (hyperglycaemia)

• Enzyme inhibition – common mode of DRUG action

Enzymes – Drug targets

• Nonspecific inhibition: Denature of proteins –strong acids, heavy metals,

alkalis, alcohol, phenols etc.

• Specific Inhibition: Many Drugs Inhibit Specific enzyme

Competitive enzyme inhibition

Equilibrium Type:

• Structurally similar competes with substrate

–binding sites
• Product not formed/non functional
• New equilibrium – kM increased,

Vmax unchanged
• Higher conc. of substrate
– ½ maximal reaction
• Sufficiently high conc. –Equal Vmax
Competitive Enzyme Inhibition – (equilibrium)
Examples
• Physostigmine Vs Acetylcholine (cholinesterase)

• Sulfonamides Vs PABA (folate synthetase)

• Moclobemide Vs Catecholamines (MAO-A)

• Captopril Vs Angiotensin 1 (ACE)

• Finesteride Vs Testosterone (5α-reductase)

• Carbidopa Vs Levodopa (dopa decarboxylase)

Competitive Enzyme Inhibition

Nonequilibrium type:

• Same catalytic site

• Form strong covalent Bond
• Normal substrate cannot displace

• Organophosphorous: compounds/Nerve gases

(cholinesterase)
• Methotrexate – 50,000 times DHFR than DHFA

• kM: increased but Vmax reduced

Non Competitive Enzyme Inhibition
Inhibitor reacts with an adjacent site not – catalytic site
• Alters the Enzyme – loses catalytic property
• kM unchanged and V max reduced

Examples:

• Acetazolmide – Carbonic anhydrase

• Aspirin – COX
• Omeprazole (PP) – HKATpase
• Digixin – Na_K_ATPase
• Theophylline – Phosphodiesterase
• Lovastatin – HMG-CoA reductase
 2. Ion Channel
Proteins take part in transmembrane signaling and regulates ionic composition

• Drugs also target these channels:

– Ligand gated channels

– G-protein operated channels
– Direct action on channels

• Examples:
BZD opens ligand gated GABAA Cl- channel,
Histamine binds GPCR and activates G-protein,
local anesthetics – directly blocks channel
• Many drugs modulate opening and closing of channels: Phenytoin,
Ethosuximide, Nifedepine, Quinidine Nicorandil and Amiloride, etc.
Transporters
•Substrates are translocated across membrane by binding to specific transporters (carriers)
– Solute Carrier Proteins (SLC)

• Pump the metabolites/ions in the direction of concentration gradient or against it

•Drugs can interact with these transport system

Examples:

ANS - Desipramine & cocaine (NET), Fluoxetine (SSRI), Amphetamine (DAT), Reserpine
(vesicular reuptake of NA), Hemicholinium (choline uptake) and Vesamicol (active
transport of Ach to vesicles);

Kidney: Probenecid (penicillin and uric acid – OAT ; org. acid transporter),Furosmide
(blocks Na+K+2Clcotransport), Thiazides block Na+Cl- symporter, Amphetamine (blocks
Dopamine reuptake),
Receptors

Many Drugs usually do not bind directly with enzymes, channels, transporters or
structural proteins, but act through specific macromolecules – RECEPTORS

Definition: It is defined as a macromolecule or binding site located on cell surface or

inside the effector cell that serves to recognize the signal molecule/drug and initiate the
response to it, but itself has no other function, e.g. Muscarinic (M type) and Nicotinic (N
type) receptors of Cholinergic system
Some Common Terms

•Agonist: An agent which activates a receptor to produce an effect similar to a that of the
physiological signal molecule, e.g. Muscarine and Nicotin
•Antagonist: an agent which prevents the action of an agonist on a receptor or the subsequent
response, but does not have an effect of its own, e.g. atropine and muscarine
•Inverse agonist: an agent which activates receptors to produce an effect in the opposite
direction to that of the agonist, e.g. DMCM in BDZ receptors (DMCM (methyl 6,7-
dimethoxy-4-ethyl-beta-carboline-3-carboxylate)
•Partial agonist: An agent which activates a receptor to produce submaximal effect but
antagonizes the action of a full agonist, e.g. opioids
•Ligand: (Latin: ligare – to bind) - any molecule which attaches selectively to particular
receptors or sites (refers only binding or affinity but no functional change)
Evidences of Drug action via receptors – Historical
1. Drugs exhibit structural specificity of action:
example – Catecholamines (isopropyl substitution on ethylamine side chain of
sympathetic drugs – cardiac and bronchial)

2. Competitive Antagonism: Between agonists and antagonists (Atropine - M

type receptors) – by Langley

3. Acetylcholine - 1/6000th of cardiac cell surface –maximal effect – by Clark

 Drug – Receptor occupation theory –
Clark`s equation (1937)
• Drugs are small molecular ligands (pace of cellular function can be altered)

• Drug (D) and receptor (R) interaction governed by “law of mass action”

• Effect (E) Is the direct function of the Drug-Receptor complex

• DR complex may not be sufficient to elicit E (response)

• D must be able to bring a conformational change in R to get E

 Drug – Receptor occupation theory –
Clark`s equation (1937)

• Affinity: Ability to bind with a Receptor

• Intrinsic activity (IA): Capacity to induce functional change in the receptor

• Competitive antagonists have Affinity but no IA

• Therefore, a theoretical quantity (S) – denoting strength of stimulus imparted to the cell
was interposed
Definitions redefined

If explained in terms of “affinity and IA”:

• Agonist: Affinity + IA (1)

• Antagonist: Affinity + IA (0)

• Partial agonist: Affinity + IA (0-1)

• Inverse agonist: Affinity + IA (0 to -1)

Nature of Receptor

• Physiological receptors - which mediate responses to transmitters, hormones, autacoids and

other endogenous signal molecules; examples are cholinergic, adrenergic, histaminergic,
steroid, leukotriene, insulin etc.

• Drug receptors - for which there are no known physiological ligands, e.g. benzodiazepine
receptor, sulfonylurea receptor.

• Orphan receptors - Receptors for which no endogenous mediator or ligand is known

• Silent receptors - These are sites which bind specific drugs but no pharmacological
response is elicited. They are better called drug acceptors or sites of loss, e.g. plasma
proteins which have binding sites for many drugs.
Receptor subtypes

• Play an important role in development of a number of targeted and more selective drugs

• Actions of acetylcholine could be grouped into ‘muscarinic’ and ‘nicotinic’ depending upon
whether they were mimicked by then known alkaloids muscarine or nicotine.

• Ahlquist (1948) divided adrenergic receptors into ‘α’ and ‘β’ on the basis of two distinct
rank order of potencies of adrenergic agonists.

• These receptors have now been further subdivided (M1, M2 ….M5), (NM, NN) (α1, α2)
(β1, β2, β3).
Criteria of receptor classification

Receptor classification is now decided on a continuing basis by an expert group of the

International Union of Pharmacological Sciences (IUPHAR).
1.Pharmacological criteria
2.Tissue distribution
3.Ligand binding
4.Transducer pathway
5.Molecular cloning
Action-effect sequence

• Drug action - It is the initial combination of the drug with its receptor resulting in a
conformational change in the latter (in case of agonists), or prevention of conformational
change through exclusion of the agonist (in case of antagonists).

• Drug effect - It is the ultimate change in biologicalfunction brought about as a

consequence of drug action, through a series of intermediate steps (transducer).
Receptor’s Functions

• Recognition - of the specific ligand molecule and Transduction of the signal into a
response.
• Accordingly, the receptor molecule has a ligand binding domain (spatially and
energetically suitable for binding the specific ligand) and an effector domain

https://www.youtube.com/watch?v=tobx537kFaI&t=538s
Signal transduction

1. Enzyme linked
(multiple actions)
2. Ion channel linked
(speedy)
3. G protein linked
(amplifier)
4. Nuclear (gene) linked
(long lasting)
G protein-linked/coupled receptors (GPCR)
Structure:
•Single polypeptide chain threaded
back and forth resulting in 7
transmembrane å helices
•There’s a G protein attached to the
cytoplasmic side of the membrane
(functions as a switch).

https://www.youtube.com/watch?v=Glu_T6DQuLU

https://www.youtube.com/watch?v=ZBSo_GFN3qI
https://www.youtube.com/watch?v=cn6mMlKedwU
Second Messengers
•Small, nonprotein, water-soluble molecules or ions
•Readily spread throughout the cell by diffusion
•Two most widely used second messengers are:
1. Cycle AMP
2. Calcium ions Ca2+

Two benefits of a signal-transduction pathway

1. Signal amplification
2. Signal specificity
Calcium Ions (Ca2+) and Inositol Trisphosphate
• Calcium more widely used than cAMP
• used in neurotransmitters, growth factors, some hormones
• Increases in Ca2+ causes many possible responses:
•Muscle cell contraction
•Secretion of certain substance
•Cell division
 Ion channel receptors
Structure: Protein pores in the
plasma membrane
Tyrosine-kinase receptors
Structure:
•Receptors exist as individual polypeptides
•Each has an extracellular signal-binding site
•An intracellular tail with a number of tyrosines and a single alpha helix spanning the
membrane
Intracellular receptors (Nuclear Receptor)

 Not all signal receptors are located on the plasma membrane.

 Some are proteins located in the cytoplasm or nucleus of target cells.

 • The signal molecule must be able to pass through plasma membrane.

Examples:

~Nitric oxide (NO)

~Steroid (e.g., estradiol, progesterone, testosterone) and thyroid hormones of animals

Open for Questions