Course Coordinator Rebaz Fayaq Hamarawf Department of Pharmacy, Kurdistan Technical institute Lecture-5 May 03, 2021 As mentioned before, the term Distribution means the process by which the drug reaches the site of action (active site on the receptor). Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 2 As we mentioned before, the term "drug" means any Substance used in the diagnosis, cure, mitigation, treatment, or prevention of disease in human, animals or plants… When A drug inhaled, injected, smoked, consumed, absorbed via one of the drug administration routs causes a physiological change in the body (pharmacological response). Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 3 For a drug (ligand) to have an action, it should interact(bind) with one of the receptor molecules in a specific positon to form drugreceptor complex. The ligand binds to the ligand-binding site on the receptor protein causes activation or inhibition of the receptor. A ligand may be any molecule (drug) , from organic and inorganic minerals to organism-created proteins, hormones, and neurotransmitters. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 4 A receptor is a protein which binds to a specific molecule. The molecule it binds is known as the ligand. Most of the receptors are found on the macromolecules. Macromolecules such as: 1. Proteins (mainly enzymes, receptors and transport proteins) 2. Lipids 3. Carbohydrates 4. Nucleic acids (DNA and RNA) are the main molecular targets for drugs. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 5 The area of the macromolecule where the interaction takes place is called the binding site; which is a pocket or canyon at the surface of the macromolecule. Many drug receptors are the same as those used by endogenously produced ligands. Such as Cholinergic agents interact with the same receptors as the neurotransmitter acetylcholine and most metalloenzymes. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 6 Lock and Key Hypothesis “ The drug molecule must fit into the receptor AND produce its action like a key fits into the lock AND opens it also” This is known as Intrinsic Activity Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 7 Intrinsic activity is a measure of the ability of a drug that is bound to the receptor to generate an activating stimulus and produce a change in cellular activity. Both agonists and antagonists can bind to a receptor. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 8 Receptor: a binding site located on the surface/inside the effector macromolecule cell that serves to recognize the signal molecule/drug (Ligand) and initiate the response to it, but has no other function itself. Efficacy: potential maximum therapeutic response that a drug can produce. Potency: amount of drug needed to produce an effect. Ligand: a molecule which binds selectively to a receptor or site. Affinity: the ability to bind with the receptor. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 9 Agonist: activates a receptor to produce an effect similar to that of the physiological signal molecule. Partial Agonist: activates a receptor to produce a submaximal effect - but antagonizes the action of a full agonist. Inverse Agonist: activates a receptor to produce an effect in the opposite direction to that of the agonist. Antagonist: prevents the action of an agonist on a receptor or the subsequent response but does not have an effect of its own. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 10 Active site The active site is the three-dimensional clefts region (crevices or pockets) occupying small region in big enzyme or protein molecules The active site consists of amino acid and non-amino acids residues that form temporary bonds with the substrate as a ligand (binding site). Enzymes are flexible structures, while the active site change the shape to fit with substrate. Active site Site of reaction catalysis. Only substrates of specific size, shape, solubility, and charge can bind. Basis of enzyme specificity Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 11 Drug-target interactions can be grouped into two types: 1- Permanent (Irreversible): covalent bonding (strength of 200-400 KJ/mol). 2- Reversible: by different types of interactions. A drug combine with a receptor and may initiate a sequence of effects The ability of drug to combine with the receptor to form the drug-receptor complex is defined as affinity. The ability of drug to initiate the effect is termed as intrinsic activity. Agonist is the drug possess both affinity as well as intrinsic activity. Antagonist is the drug possess affinity but not intrinsic activity. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 12 A biological response is produced by the interaction of a drug with a functional or organized group of molecules on a macromolecule like protein, known as active site of the receptor. This interaction would be expected to take place by using the same bonding forces as are involved when simple molecules interact. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 13 Simply an antagonist is a drug that binds to the receptor without activating the receptor Antagonists block the action of agonists simply by getting in the way of the agonist, preventing the agonist from binding to the receptor and producing the drug effect. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 14 Competitive antagonism (Reversible/irreversible) is present when increasing concentrations of the antagonist progressively inhibit the response to the agonist. Noncompetitive antagonism (Irreversible) is present when, after administration of an antagonist, even high concentrations of agonist cannot completely overcome the antagonism Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 15 A drug is said to be an antagonist when it binds to a receptor and prevents (blocks or inhibits) a natural compound or a drug to have an effect on the receptor. An antagonist has no activity. Types of Antagonism: 1. 2. 3. 4. Chemical antagonism Physiological/Functional antagonism Pharmacokinetic antagonism Pharmacological antagonism Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 16 Antagonist effectively reduces the concentration of the active drug at its site of action (at the receptor). Either by increased metabolic degradation, decreased absorption or increased excretion. ACalcium & tetracycline, Cholestyramine & warfarin/digoxin DPhenylbutazone & warfarin M- ↑ Phenobarbital/rifampicin & warfarin, rifampicin & OCP ↓ciprofloxacin/chloramphenicol/erythromycin & theophylline. E- ↓ Probencid/aspirin/sulfonamides/thiazides/indomethacin & penicillin/zidovudine, NSAIDS & methotrexate/ furosemide Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 17 Receptors: come in many types, but they can be divided into two categories: intracellular receptors, which are found inside of the cell (in the cytoplasm or nucleus), and cell surface receptors, which are found in the plasma membrane. Ion Channels: are located within the membrane of all excitable cells, and of many intracellular organelles. Is narrow, water-filled tunnels that allow only ions of a certain size and/or charge to pass through. Enzymes: are biological molecules (typically proteins) that significantly speed up the rate of virtually all of the chemical reactions that take place within cells. Transporters: are membrane proteins involved in the uptake or efflux of drugs by several tissues such as the intestine, liver, kidney and brain. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 18 The distribution of Sodium and potassium ions across the cell membrane is unequal: Na is extracellular cation, while K is intercellular cation. Sodium is very soluble and easily absorbed from the stomach and small intestine. reabsorb or eliminate it in order to maintain stable blood sodium levels. Absorption of potassium from the diet is passive and does not require any specific mechanism. Aldosterone, a hormone made and secreted by the adrenal cortex, acts on the kidneys to regulate sodium metabolism and tends to promote potassium excretion. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 19 The Sodium-Potassium Pump The process of moving sodium and potassium ions across the cell membrane is an active transport process involving the hydrolysis of ATP to ADP provide the necessary energy. It involves an enzyme referred to as Na+/K+-ATPase. This process is responsible for maintaining the large excess of Na+ outside the cell and the large excess of K+ ions Mg2+ on the inside. 3Na+ic + 2K+ec + ATP4- + H2O 3Na+ec + 2K+ic + ADP3- + HPO42- + H+ It accomplishes the transport of three Na+ to the outside of the cell and the transport of two K+ ions to the inside. The sodium-potassium pump moves toward an equilibrium state with the relative concentrations of Na+ and K+ shown at left. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 20 Mechanisms for Membrane Transport Passive Transport: moves ions down the concentration gradient, requiring no energy source. ◦ Ionophores and Ion Channels are Passive Active Transport: moves ions against the concentration gradient, requiring energy from ATP hydrolysis ◦ Ion Pumps are Active Choice of Transport Mechanism ◦ Charge ◦ Size ◦ Ligand Preference Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 21 Mechanisms for Membrane Transport Ionophores: special carrier molecules that wrap around metal ions so they can pass through the membrane by diffusion. Ion Channels: large, membrane-spanning molecule that form a hydrophilic path for diffusion. Ion Pumps: molecules using energy to transport ions in one direction through a membrane. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 22 The Sodium-Potassium Pump Examples of Ionophores Nonactin and tetranactin: is a macrotetrolide that forms complexes with alkali cations, such as potassium and sodium. Nonactin Tetranactin Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 23 Lithium Salts Ions Channels and Lithium Carbonate Lithium carbonate is used in the treatment of manic depression (bipolar disorder or mania), is a serious change from the way a person normally thinks or behaves, to carry out day to day tasks. Lithium carbonate tablets are taken usually 1 to 2 g per day to maintain a plasma lithium concentration of 0.5 -1.0 mmol/dm3. Toxicity are observed at about 2.0 mmol/dm3. leading to course tremor of the hand, polyurea, vomiting and diarrhea. The mechanism of action of lithium salts in bipolar disease is unknown: The following hypotheses are proposed: A- Li+ enhances the effect of the neurotransmitter serotonin. B- Li+ target second messenger systems. C- Interferes with transport of Na+ and K+ ions. Pharmaceutical Chemistry Rebaz F. Hamarawf Lecture 4 / KTI 24 End of Lecture Five I really appreciate your comprehension If you need any further information, please do not hesitate to contact me via email