Presented by Dr. Sannithi Nagarjuna
Coordinator for RIPER-GPAT Cell, Hyderabad Academy & Online GPAT Academy 7899107907
9885784793 [email protected] It is a branch of pharmacology deals with the study of mechanism of action, pharmacological actions and uses of drugs.
(What the drug does to the body)
(OR)
It is defined as the response of the body to the drug. It refers to the relationship between drug concentration at the site of action and resulting effect.
(OR)
It is the study of biochemical, physiological and molecular effects of drugs on the body. Most of the drugs produce their mechanism of action by binding to the receptors. DEFINITIONS
1. RECEPTORS → defined as specific binding sites for drug
molecules/ ligands and chemically they are protein in nature.
All receptors are proteins but all proteins are not receptors.
2. LIGAND → defined as a substance that selectively attaches to
the receptors, activates the receptors and produces maximum
pharmacological action.
Both receptors and ligand are highly specific. Receptors Ligand
Muscarinic and Nicotinic Acetylcholine receptors (Cholinergic)
Adrenergic receptors Noradrenaline
Histamine receptors Histamine
Dopamine receptors Dopamine
5-HT receptors 5-HT (Serotonin)
GABA receptors GABA 3. AFFINITY → ability of an agent to bind with the receptors
4. INTRINSIC ACTIVITY ( EFFICACY)→ ability of an agent to activate the receptors and produces pharmacological action 5. AGONIST : Affinity + Maximum Intrinsic activity (IA= + 1)
Agonist and ligand both are same, the only difference is agonist is exogenous and ligand is endogenous. Agonist produces actions similar to ligand or Agonist increases the actions of ligand
6. ANTAGONIST: Affinity + No Intrinsic activity (IA= 0)
Antagonist blocks or stops the actions of ligand hence it is otherwise called as blocker. Source : Google Source : Google Ligand Agonist Antagonist
Acetylcholine Carbachol, Atropine
Bethanechol
Noradrenaline Dobutamine Propranolol
Histamine 2-methyl histamine Diphenhydramine TYPES OF RECEPTORS
❖ Receptors will not exist as alone and they are always present in attached manner
(Coupled manner)
❖ Based upon the coupled substance receptors are classified into 4 types 1. G-Protein Coupled Receptors ( Receptors coupled to G-Protein )
2. Ionotropic receptors ( Receptors coupled to Ion channels )
3. Enzyme linked receptors ( Receptors coupled to Enzymes)
4. Nuclear receptors ( Receptors coupled to nucleus) G-Protein Coupled Receptors ( Receptors coupled to G-Protein )
❖ Receptors located across/on/within the cell
membrane
❖ Hence called as transcellular receptors
❖ Here there are two parts one is G-protein and
another one is Receptor Receptor consist of
7 transcellular helical structures
3 loops
-NH2 group present on extracellular side
-COOH group present on intracellular side
G-protein is trimeric in nature consist of 3 subunits called as α, β, and γ and these three subunits attached to GDP. binding of ligand with the receptors
GDP replaces with GTP
G-Protein dissociated into 2 complexes
GTP α β γ
Interacts with the pathways
Release of substances called as secondary messengers
Produces pharmacological actions Source : Google Source : Google PATHWAYS
1. ADENYL CYCLASE PATHWAY
ATP ------→ cAMP ------→ Inactive
❖ cAMP acts as a second messenger
❖ Enzyme Phosphodiesterase involved in the inactivation of cAMP Source : Google ACTIONS OF CAMP In cardiac muscle/Heart -- Increases force of contraction, Increases cardiac output, Increases blood pressure, Increases heart rate.
In smooth muscles (GIT, Bronchi, Uterus) – Smooth muscle relaxation
In Liver – Glycogenolysis
In adipose tissue Lipolysis
In Platelets Decreases platelet aggregation 2. PHOSPHOLIPASE PATHWAY
Stimulation of this pathway results in the breakdown of cell membrane phospholipids.
Cell membrane phospholipids upon breakdown will release Inositol-1,4,5- triphosphate (IP3)and Diacylglycerol (DAG) which act as second messengers.
IP3 & DAG always produce stimulation. ACTIONS OF IP3 AND DAG
Location Action
Cardiac muscles Contraction
Smooth muscles Contraction
Skeletal muscles Contraction
Glands Increase in secretions
CNS CNS Stimulation GS → Increased levels of cAMP
Gi → Decreased levels of cAMP
Gq → Increased levels of IP3 and DAG EXAMPLES: 1.Muscarinic receptors (M1- M5)
2. Adrenergic receptors (α1- α2 & β1- β3)
3.Histamine receptors (H1-H3)
4.Dopamine receptors (D1-D5)
5.5-HT receptors (5-HT1 to 5-HT 7 except 5-HT 3)
6.Opiod receptors
7.GABAB receptors MUSCARINIC RECEPTORS(M1 - M5)
Gq Gi
M1 M2
M3 M4
M5 Type of Second Location Pharmacological actions receptor Messenger
M1 Gq ❖ Gastric Parietal Cells
❖ Ciliary Muscles of Iris
M3 Gq ❖ Smooth muscles like Bronchi, Uterus, GIT
❖ Glands like sweat glands, salivary glands & lacrimal glands
M5 Gq CNS Type of Second Location Pharmacological actions receptor Messenger
M1 Gq ❖ Gastric Parietal Cells ❖ Increase in acid secretion
❖ Ciliary Muscles of Iris ❖ Contraction of Ciliary Muscles of Iris (Miosis)
M3 Gq ❖ Smooth muscles like ❖ Smooth muscle contraction like Bronchi, Uterus, GIT Bronchoconstriction, Uterus constriction, Contraction of GIT, Increase in motility of GIT
❖ Glands like sweat ❖ Increase in secretions glands, salivary glands like sweating, salivation and & lacrimal glands lacrimation
M5 Gq CNS ❖ CNS stimulation Type of Second Location Pharmacological receptor Messenger actions
M2 Gi Heart
M4 Gi CNS Type of receptor Second Location Pharmacological Messenger actions
Decrease in M2 Gi Heart force of contraction, Decrease in cardiac output, Decrease in blood pressure, Decrease in heart rate
No action M4 Gi CNS Source: Google PHARMACOLOGICAL ACTIONS OF ACETYLCHOLINE
Location Pharmacological actions Heart Decrease in force of contraction, Decrease in cardiac output, Decrease in blood pressure, Decrease in heart rate Smooth muscles like Smooth muscle contraction like Bronchoconstriction, Bronchi, Uterus, GIT Uterus constriction, Contraction of GIT, Increase in motility of GIT Gastric Parietal Cells Increase in acid secretion
Ciliary Muscles of Iris Contraction of Ciliary Muscles of Iris (Miosis)
Glands like sweat glands, salivary Increase in secretions like sweating, glands & lacrimal glands salivation and lacrimation
CNS CNS stimulation ADRENERGIC RECEPTORS {α1 – α2 & β1- β3}
Gq Gi GS
α1 α2 β1
β2
β3 Type of Second Location Pharmacological actions receptor Messenger
α1 Gq ❖ Blood vessels
α2 Gi ❖ CNS Type of Second Location Pharmacological actions receptor Messenger
Vasoconstriction, α1 Gq ❖ Blood vessels increase in blood pressure
No Action α2 Gi ❖ CNS Type of Second Location Pharmacological actions receptor Messenger
β1 GS ❖ Heart
β2 GS ❖ Smooth muscles ❖ Bronchi ❖ Liver
β3 GS ❖ Adipose tissue Type of Second Location Pharmacological actions receptor Messenger
Increase in force of β1 GS ❖ Heart contraction, Increase in cardiac output, Increase in blood pressure, Increase in heart rate
❖ Smooth muscle β2 GS ❖ Smooth muscles relaxation ❖ Bronchi ❖ Bronchodilation ❖ Liver ❖ Glycogenolysis
β3 GS ❖ Adipose tissue ❖ Lipolysis PHARMACOLOGICAL ACTIONS OF NORADRENALINE
Location Pharmacological actions Heart Increase in force of contraction, Increase in cardiac output, Increase in blood pressure, Increase in heart rate
Smooth muscles Smooth muscle relaxation
Bronchi Bronchodilation
Blood vessels Vasoconstriction, increase in blood pressure
Metabolic effects Glycogenolysis & Lipolysis IONOTROPIC RECEPTORS (RECEPTORS COUPLED TO ION CHANNELS )
❖ Receptors coupled to ion channels
❖ Receptors located across/on/within the cell membrane
❖ These are also transcellular receptors
❖ Also called as ligand gated ion channels Ligand binds to the receptors
Opening of ion channelsO will take place p
Result in either influx or efflux of ions depending upon concentration gradient
Result in pharmacological actions which may be stimulation or inhibition Source : Google Sodium, Calcium & Chloride ions present extracellularly so when these ion channels get opened that result in influx of ions.
Potassium ions present intracellularly so when these ion channels get opened that result in efflux of ions. Ligand binds to the receptors → Sodium channels → Influx of sodium ions→
Ligand binds to the receptors → Calcium channels → Influx of Calcium ions→
Ligand binds to the receptors → Chloride channels → Influx of chloride ions→
Ligand binds to the receptors → Potassium channels → Efflux of potassium ions → Ligand binds to the receptors →Sodium channels → Influx of sodium ions→ Stimulation
Ligand binds to the receptors → Calcium channels → Influx of Calcium ions→ Stimulation
Ligand binds to the receptors → Chloride channels → Influx of chloride ions→ Inhibition
Ligand binds to the receptors → Potassium channels → Efflux of potassium ions →Inhibition Location Stimulation Inhibition Contraction, Relaxation, Cardiac Increase in force of Decrease in force of contraction, contraction, muscle/Heart Increase in cardiac Decrease in cardiac output, output, Increase in blood Decrease in blood pressure, pressure, Increase in heart rate Decrease in heart rate
Smooth muscles Contraction Relaxation
Skeletal muscles Contraction Relaxation
Glands Increase in secretions Decrease in secretions
CNS CNS Stimulation CNS depression EXAMPLES:
1. Nicotinic receptors (NM & NN receptors)
2. 5-HT3 receptors
3. GABAA receptors
4. NMDA receptors Type of Type of ion Location Pharmacological actions receptor channel attached
NM Sodium ❖ Skeletal muscles
NN Sodium ❖ Autonomic ganglia
5-HT3 Sodium ❖ CTZ
GABAA Chloride ❖ CNS
NMDA Calcium ❖ CNS Type of Type of ion Location Pharmacological actions receptor channel attached Skeletal muscle contraction NM Sodium ❖ Skeletal muscles
Ganglionic stimulation NN Sodium ❖ Autonomic ganglia
Nausea and vomiting 5-HT3 Sodium ❖ CTZ
CNS depression GABAA Chloride ❖ CNS
NMDA Calcium ❖ CNS CNS stimulation Type of Pharmacological Category Therapeutic receptor actions Uses
NM Skeletal muscle Skeletal NM receptor contraction Muscle blockers relaxants
NN Ganglionic stimulation Ganglionic NN receptor blockers blockers
5-HT3 Nausea and vomiting Antiemetics 5-HT3 antagonists
GABAA CNS depression CNS GABAA depressants receptor agonists
NMDA CNS stimulation CNS NMDA depressants receptor blockers ENZYME LINKED RECEPTORS
(RECEPTORS COUPLED TO ENZYMES)
❖ Receptors coupled to enzymes
❖ Receptors located across/on/within the cell
membrane
❖ These are also transcellular receptors Ligand binds to the receptors
Enzymes automatically undergo phosphorylation (Autophosphorylation)
Responsible for mediating the pharmacological actions Most of the enzymatic receptors are coupled to the enzyme
Tyrosine Kinase EXAMPLES:
1. Insulin receptors (Tyrosine Kinase)
2. Epidermal growth factor receptors (Tyrosine Kinase)
3. Natriuretic peptide receptors (Guanyl cyclase) NUCLEAR RECEPTORS ( RECEPTORS COUPLED TO NUCLEUS)
❖ Receptors coupled directly to nucleus
❖ Receptors located inside the cell
❖ These are also called as intracellular receptors
❖ Otherwise called as steroidal receptors Ligand binds to the receptors
Direct change in gene expression
Synthesis of specific mRNA
Synthesis of specific proteins
Responsible for mediating pharmacological actions Source: Google EXAMPLES:
1. Glucocorticoid receptors
2. Mineralocorticoid receptors (Aldosterone receptors)
3. Estrogen receptors
4. Progesterone receptors
5. Androgen receptors (Testosterone receptors)
6. Vitamin A & Vitamin D receptors
7. Thyroid hormone receptors Source: Google Source : Google SIGNAL TRANSDUCTION
Ligand after binding to the receptors a sequence of events/steps taking place in order to produce pharmacological actions. Fastest acting receptors
Most intensifying action observed in case of Fastest acting receptors Ionotropic receptors
Most intensifying action Nuclear receptors observed in case of Transcellular Intracellular receptors receptors
Ligand binding site
Reactions
Examples Transcellular Intracellular receptors receptors
Ligand binding site Extracellular Intracellular
Reactions Intracellular Intracellular
Examples GPCR, Ionotropic Nuclear receptors receptors, Enzyme linked receptors Presented by Dr. Sannithi Nagarjuna
Coordinator for RIPER-GPAT Cell, Hyderabad Academy & Online GPAT Academy 7899107907
9885784793 [email protected]