Pharmacodynamics of Drugs PDF

PHARMACODYNAMICS OF DRUGS Dr. Nazmun Nahar Alam AIMST MBBS B-30 10/15/2024 Dr. Nazmun, Aimst University 2 Specific Learning outcomes: At the end of the lecture, student should be able to: Define pharmacodynamics, and exp...

PHARMACODYNAMICS OF DRUGS Dr. Nazmun Nahar Alam AIMST MBBS B-30 10/15/2024 Dr. Nazmun, Aimst University 2 Specific Learning outcomes: At the end of the lecture, student should be able to: Define pharmacodynamics, and explain the site of action and type of action of drugs, therapeutic effects and toxic effects of drugs. Explain the different mechanisms (physical, chemical, enzymes and receptors) by which drugs act, with examples. Define receptor, ligand, agonist, antagonist and partial agonist with examples. State the receptor types / super families, with examples. State the role of second messengers in drug action. 10/15/2024 Dr. Nazmun, Aimst University 3 Pharmacodynamics: It is a branch of pharmacology that deals with the mechanism of action and pharmacological effects of a drug. It deals with what the drug does to the body. Whereas pharmacokinetics deals with what the body does the drug. 10/15/2024 Dr. Nazmun, Aimst University 4 Pharmacological effects Pharmacological effects are two types desirable and undesirable. The desirable effects of drugs are therapeutic effects. e.g. antihistamine is used in allergic condition. The undesirable effects of drug within the therapeutic dose is adverse effects or side effects. e.g. Dry mouth, blurred vision occurred by anticholinergic drug. The undesirable effect produced at toxic dose or over dosage is toxic effects.e.g. – hepatotoxicity by paracetamol. 10/15/2024 Dr. Nazmun, Aimst University 5 Molecular target of drug action Receptor Ion channel Enzymes Carrier proteins Structural proteins Plasma protein 10/15/2024 Dr. Nazmun, Aimst University 6 Ligand- Any molecule that binds selectively to a specific receptor is called ligand. Affinity- It is the ability of the molecule to bind to a receptor. Efficacy- It is the ability of the molecule to elicit a response after binding with the receptor. 10/15/2024 Dr. Nazmun, Aimst University 7 Receptor Receptors are macromolecular structure, protein in nature, to which a drug binds to produce an effect. 10/15/2024 Dr. Nazmun, Aimst University 8 Types of receptor According to location Membrane receptor- cholinergic receptors Cytoplasmic receptor- steroid receptors Nuclear receptor- thyroid receptors According to activity  Active receptor- adrenergic receptors (1-2%)  Silent receptor - plasma protein  Spare receptor- (98%) 10/15/2024 Dr. Nazmun, Aimst University 9 Types of receptor According to receptor mechanism of drug action: Type I: ligand gated ion channel receptor. e.g. Nicotinic receptor, GABA receptor. Type II: G- protein coupled receptor. e.g. muscarinic receptor, adrenergic receptor, opioid receptor. Type III: receptor kinases or enzyme linked receptor. e.g. insulin receptor. Type IV: Intracellular receptor. e.g. steroid receptor 10/15/2024 Dr. Nazmun, Aimst University 10 Fig: 10/15/2024 Dr. Nazmun, Aimst University 11 Mechanism of drug action Drugs act by two ways- Specific mechanism - Receptor mechanism - Non receptor mechanism Non specific mechanism- By altering physio- chemical properties of cell. e.g. anaesthetic drugs. By direct chemical interaction. e.g. Antacids By physical means. e.g. purgatives, osmotic diuretics 10/15/2024 Dr. Nazmun, Aimst University 12 Receptor Mechanism of action Act via specialized receptors found in cell membrane and inside the cell.  Ligand gated ion channel  G protein coupled receptor system  kinase receptors  nuclear receptors 10/15/2024 Dr. Nazmun, Aimst University 13 Mechanism of drug action by ligand gated ion channel The extracellular portion of ligand-gated ion channels contains the drug-binding site. This site regulates the opening of the pore through which ions can flow across cell membranes. The channel is usually closed until the receptor is activated by an agonist. Depending on the ion conducted through these channels, these receptors mediate diverse functions, including neurotransmission and muscle contraction. 10/15/2024 Dr. Nazmun, Aimst University 14 Mechanism of drug action by ligand gated ion channel For example, Benzodiazepine bind with drug binding site in GABA receptor then Chloride channel open, increases chloride influx and hyperpolarization occurs, produces inhibitory effect Stimulation of the nicotinic receptor by acetylcholine opens a channel that allows sodium influx and potassium out flux across the cell membranes of neurons or muscle cells. This change in ionic concentrations across the membrane results depolarization , produces excitatory effect 10/15/2024 Dr. Nazmun, Aimst University 15 Ligand gated ion channel mechanism 10/15/2024 Dr. Nazmun, Aimst University 16 Mechanism of drug action by G protein coupled receptor The extracellular portion of this receptor contains the ligand binding site , and the intracellular portion interacts (when activated) with G protein. There are many kinds of G proteins (for example, Gs, Gi, and Gq), but all types are composed of three protein subunits. The α subunit binds guanosine triphosphate (GTP), and the β and γ subunits anchor the G protein in the cell membrane. 10/15/2024 Dr. Nazmun, Aimst University 17 Mechanism of drug action by G protein coupled receptor (cont) Binding of an agonist to the receptor increases GTP binding to the α subunit, causing dissociation of the α-GTP complex from the βγ complex. The α and βγ subunits are then free to interact with specific cellular effectors, usually an enzyme or an ion channel, that cause further actions within the cell. The activated effectors produce “second messenger” molecules that further activate other effectors in the cell, causing a signal cascade effect 10/15/2024 Dr. Nazmun, Aimst University 18 G protein coupled receptor mechanism 10/15/2024 Dr. Nazmun, Aimst University 19 Second messenger- Chemical substances produced when a ligand binds with G-protein coupled receptor, via which cellular effect is produced. e.g. cAMP, cGMP, IP₃, DAG 10/15/2024 Dr. Nazmun, Aimst University 20 Mechanism of drug action by tyrosine kinase coupled receptor This family of receptors undergoes conformational changes when activated by a ligand, resulting in increased intracellular enzyme activity. The most common enzyme linked receptors (for example, growth factors and insulin) possess tyrosine kinase activity. When activated, the receptor phosphorylates tyrosine residues on itself and other specific proteins. Phosphorylation can substantially modify the structure of the target protein and produces drug action. 10/15/2024 Dr. Nazmun, Aimst University 21 10/15/2024 Dr. Nazmun, Aimst University 22 Mechanism of drug action by cytosolic receptor Drug binds with receptor in cytosol, enters nucleus and regulate gene expression for protein synthesis to produce effect of drug. 10/15/2024 Dr. Nazmun, Aimst University 23 Intracellular receptor 10/15/2024 Dr. Nazmun, Aimst University 24 Non- classical receptor mechanism Enzyme as receptor- Acetyl-transferase acts as a receptor for acetylcholine. Transport protein as receptor- H+-K+-ATPase acts as a receptor for omeprazole. Voltage gated ion channel- Na+ channel, Ca2+ channel 10/15/2024 Dr. Nazmun, Aimst University 25 Different types of drug action Stimulation- Adrenaline on heart. Depression- benzodiazepine on CNS Replacement- Insulin in DM Thyroxin in hypothyroidism Cytotoxicity- Anticancer drugs. 10/15/2024 Dr. Nazmun, Aimst University 26 Agonist A drug when combines with the receptor and produces pharmacological effect or cellular response similar to physiological signal. D + R → DR (complex) effects. Drugs which have full affinity + full efficacy.  Eg: salbutamol (β receptor agonist), adrenaline (α and β receptor agonist) 10/15/2024 Dr. Nazmun, Aimst University 27 Partial agonist Drugs which when combines with the receptors, produces less effect than maximum. Even when all the receptors are occupied, partial agonists cannot produce the same effect as a full agonist. They have both antagonist and agonist action. eg., Pindolol, oxprenolol. 10/15/2024 Dr. Nazmun, Aimst University 28 Inverse agonist A drug that has affinity for receptor but produces opposite effect to that of an agonist. e.g. ß carboline (benzodiazepine receptor) 10/15/2024 Dr. Nazmun, Aimst University 29 10/15/2024 Dr. Nazmun, Aimst University 30 Antagonist A drug which binds to its specific receptor without causing activation and thereby prevents a full agonist from acting at the particular receptor. Antagonists have affinity to a receptor but no efficacy e.g: propranolol (β receptor antagonist) 10/15/2024 Dr. Nazmun, Aimst University 31 Competitive antagonist If the antagonist binds to the same site on the receptor as the agonist in a reversible manner, it is “competitive.” A competitive antagonist interferes with an agonist binding to its receptor. For example, the antihypertensive drug terazosin competes with the endogenous ligand norepinephrine at α1-adrenoceptors, thus decreasing vascular smooth muscle tone and reducing blood pressure. However, increasing the concentration of agonist relative to antagonist can overcome this inhibition. Thus, competitive antagonists characteristically shift the agonist dose–response curve to the right (increased EC50) without affecting Emax 10/15/2024 Dr. Nazmun, Aimst University 32 Irreversible antagonist Irreversible antagonists bind covalently to the active site of the receptor, thereby permanently reducing the number of receptors available to the agonist. In contrast to competitive antagonists, addition of more agonist does not overcome the effect of irreversible antagonists. Thus, irreversible antagonists and allosteric antagonists are both considered noncompetitive antagonists. A fundamental difference between competitive and noncompetitive antagonists is that competitive antagonists reduce agonist potency (increase EC50) and noncompetitive antagonists reduce agonist efficacy (decrease Emax). 10/15/2024 Dr. Nazmun, Aimst University 33 Allosteric antagonist An allosteric antagonist binds to a site (allosteric site) other than the agonist-binding site and prevents receptor activation by the agonist. An example of an allosteric agonist is picrotoxin, which binds to the inside of the GABA controlled chloride channel. When picrotoxin binds inside the channel, no chloride can pass through the channel, even when GABA fully occupies the receptor. 10/15/2024 Dr. Nazmun, Aimst University 34 Thank You