Pharmacodynamics

Pharmacodynamics

·         Pharmacodynamics is derived from the Greek word i.e. “Pharmacon” means Drugs and “Dynamics” means Action.

·         It is the study of biochemical and physiological effects of drug and their mechanism of action at organ level and cellular level.

·         “What the drugs does to the body when they administered”.

Site of drugs action

·         Extracellular

·         Cellular

·         Intracellular

Principle/types of drugs action

1.     Stimulation

·         The enhancement of the activity of specialized cells.

·         Example: Adrenaline stimulates heart, pilocarpine stimulates salivary glands.

·         Excessive stimulation is often followed by depression of that function.

·         Example: high dose of picrotoxin (CNS stimulant) produces convulsions followed by coma and respiratory depression.

2.     Depression

·         The specialized cells selectively diminished.

·         Barbiturates depress CNS, quinidine depresses heart, and omeprazole etc. depresses gastric acid secretion.

3.     Replacement

·         The use of natural metabolites, hormones or their congeners in deficiency states.

·         Example: Levodopa in Parkinsonism, insulin in diabetes mellitus, iron in anaemia.

4.     Irritation

·         Produce noxious effect particularly less specialized cells (epithelium, connective tissue).

·         Strong irritation results in inflammation, corrosion, necrosis and morphological damage.

5.     Cytotoxic

·         Produce Selective cytotoxic action on invading the pathogens or cancerous cells.

·         Example: penicillin, chloroquine, zidovudine, cyclophosphamide, etc.

Mechanism action of drugs

·         Only few drugs work by their simple physical or chemical properties; examples are.

     o   Bulk laxatives (ispaghula)—physical mass

o   Para amino benzoic acid—absorption of UV rays

o   Activated charcoal—adsorptive property

o   Mannitol, mag. sulfate—osmotic activity

o   131 I and other radioisotopes—radioactivity

o   Antacids—neutralization of gastric HCl

o   Pot. permanganate—oxidizing property

o   Chelating agents (EDTA, dimercaprol)—chelation of heavy metals.

·         Most drugs produce effects by interacting with a different target biomolecule, which usually is a protein.

·         Functional proteins that are targets of drug action can be grouped into four major categories i.e.

1.      Enzymes

2.      Ion channels

3.      Transporters

4.      Receptors.

1. Enzyme

·         Almost all biological reactions are carried out under catalytic influence of enzymes;

·         Drugs can either increase or decrease the rate of enzymatically mediated reactions.

Enzyme inhibition

·         Some chemicals (heavy metal salts, strong acids and alkalies, formaldehyde, phenol, etc.) denature proteins and inhibit all enzymes non-selectively.

·         The selective inhibition of a particular enzyme is a common mode of drug action.

·         Such inhibition is either competitive or noncompetitive.

Competitive

Equilibrium type

·         The drug is structurally similar, competing with the normal substrate for the enzyme catalytic binding site, which does not create a product or create a non-functional product.

Non-equilibrium type

·         The drugs bind with same catalytic site of the enzyme.

·         Either formation of covalent bond or have such high affinity for the enzyme that the normal substrate is not able to displace the inhibitor

·         Example: Organophosphates react covalently with the esteretic site of the enzyme cholinesterase

Non-competitive

·         The inhibitor bind to the enzyme adjacent from the active site and loses the catalytic properties.

2. Ion channels

·         Ion channels are integral membrane proteins that form a pore to allow the passage of specific ions by passive diffusion.

·         Some channels are operated by signal molecules either directly or through G-Protein.

·         Directly: Ligand gated channels (e.g. nicotinic receptor)

·         G-protein: G-protein regulated channels (e.g. cardiac β1 adrenergic receptor activated Ca2+ channel).

·         Drugs can also act on voltage operated and stretch sensitive channels by directly binding to the channel and affecting ion movement through it, e.g. local anaesthetics which obstruct voltage sensitive Na+ channels.

·         Certain drugs modulate opening and closing of the channels, e.g.:

o   Nifedipine blocks L-type of voltage sensitive Ca2+ channel.

o   Ethosuximide inhibits T-type of Ca2+ channels in thalamic neurons.

3. Transporter

·         Several subtracts are transported across the membrane by carrier, which facilitate diffusion in the direction of the concentration gradient or pump the metabolite/ion against the concentration gradient using metabolic energy.

·         Many drugs are interacting with solute carrier class (SLC) of transporter protein and exert their action by directly.

·         Example:

o   Norepinephrine transporter (NET): blocked by Desipramine and Cocaine

o   Serotonin reuptake transporter (SERT): blocked by Fluoxetine

o   dopamine transporter (DAT): blocked by Amphetamines

o   vesicular mono-amine transporter (VMAT-2): blocked by Reserpine

o   Choline uptake into cholinergic neurons: Hemicholinium.

4. Receptor

·         Receptors are defined as cellular macromolecule or binding site located on the surface or inside the effector cell that serves to recognized the signal molecules or drugs.

·         Drugs + Receptor – drug receptor complex – Response

Drugs receptor interaction

Selectivity

·         Degree of complimentary co relation between drug and receptor

·         Example: Adrenaline Selectivity for α, ß Receptor.

Affinity

·         Ability of drug to get bound to the receptor.

Intrinsic activity (IA) or Efficacy

·         Ability of drug to produce a pharmacological response after making the drug receptor complex.

Agonist

·         An agent which activates a receptor to produce an effect similar to that of the physiological signal molecule.

Partial agonist

·         An agent which activates a receptor to produce submaximal intrinsic activity (IA between 0 and 1).

·         Example: Dichloroisoproterenol (on β adrenergic receptor), pentazocine (on μ opioid receptor).

Inverse agonist

·         An agent which activates a receptor to produce an effect in the opposite direction to that of the agonist.

Antagonist

·         An agent which prevents the action of an agonist on a receptor or the subsequent response, but does not have any effect of its own.

Competitive antagonist

·         The agonist and antagonist binds to the same site of the receptor, they are said to be “Competitive”.

·         The efficacy and repulsion depends on the concentration of the agonist and antagonist.

·         Drug response curve shifted rightward.

·         Example: Acetylcholine = Atropine, Morphine = Naloxone.

Non-competitive antagonist

·         It binds to another side of the receptor.

·         The response depends on the concentration of the antagonist.

·         Drug response curve is flattening.

·         Example: Diazepam = Bicuculline

Ligand

·         Any molecule which attaches selectively to particular receptors or sites.

Transducer mechanism

1. G – Protein couple receptor (GPCRs)

·         The GPCR consist of 7 α – helical membrane spanning hydrophobic amino acid segments which run into 3 extracellular and 3 intracellular loops.

·         The GPCRs composed of α, β, and γ subunits.

·         The G – protein and their domains laying in the cytosol.

·         In the inactive state GDP is bound to the sub-unit at the exposed domain.

·         After activation state GTP is split to GDP.

·         The activated α subunit carrying GTP dissociate form the other subunits and shows either activation and inhibition effects.

·         The β and γ subunits are also shows the operation of K⁺ channels and inhibit voltage gated Ca²⁺ channels.

·         Action of receptor

o   Gs        : Adenylyl cyclase activation, Ca²⁺ channel opening.

o   Gi        : Adenylyl cyclase inhibition, K⁺ channel opening.

o   Go       : Ca²⁺ channel inhibition.

o   Gq       : Phospholipase C activation.

·         There are three major pathways of GPCRs.

1.      Adenylyl cyclase (cAMP pathway)

2.      Phospholipase C (IP₃ DAG pathway)

3.      Channel regulation

1. Adenylyl cyclase (cAMP pathway)

·         After activation of receptor (Adr – binds to β adrenergic receptor) α subunit with GTP activate AC.

·         Activation of AC leads to intracellular accumulation of second messenger cAMP that acts primarily through cAMP – dependent protein kinase (PK_A).

·         The PK_A phosphorylates many functional protein including troponin and phospholamban, and alter the function of several enzyme, ion channels, transporter, transcription factor and structural protein to produce;

o   Increased contractility (impulse generation – cardiac)

o   Glycogenolysis

o   Lipolysis

o   Hormone synthesis

·         Phospholamban and troponin interact with Ca²⁺, respectively resulting faster relaxation and increased force of contraction.

·         The cAMP direct open Ca²⁺ channel (cyclic nucleotide gated channel – CNG) in heart, brain, and kidney.

·         Ach binds to M₂ receptor and produce adenylyl cyclase inhibition through inhibitory G_i – protein.

·         The action of cAMP is terminated by the enzyme phosphodiesterase (PDEs) which hydrolyzed it to 5 – AMP.