Pharmacology-1 PHL 351 Abdelkader Ashour, Ph.D.

Therapeutic Index (T.I.) A measure of drug safety The ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals Therapeutic Index = TD50/ED50 where TD50is the dose that produces a toxic effect in 50% of the population, and ED50 is the dose that produces therapeutic response in 50% of the population In general, a larger T.I. indicates a clinically safer drug TD50

Therapeutic Index, contd. Why don’t we use a drug with a T.I. <1? ED50 > TD50 = Very Bad!

Drug-Receptor Bonds 1. Covalent Bond -very strong 2. Ionic bond -not reversible under biologic conditions  unusual in therapeutic drugs Example 1: phenoxybenzamine at a adrenergic receptors Example 2: DNA-alkylating agents (e.g., cyclophosphamide) used in cancer chemotherapy to disrupt cell division in the neoplastic tissue. The rest of pharmacology is concerned with weak, reversible, electrostatic attractions: 2. Ionic bond -Weak, electrostatic attraction between +ve and -ve forces. Easily made and destroyed. 3. Dipole - dipole interaction -A stronger form of dispersion forces formed by the instantaneous dipole formed as a result of electrons being biased towards a particular atom in a molecule (an electronegative atom). E.g. Hydrogen bonds.

Drug-Receptor Bonds, contd. 4. Hydrophobic interactions -The tendency of hydrocarbons (or of lipophilic hydrocarbon-like groups in solutes) to form intermolecular aggregates in an aqueous medium, and analogous intramolecular interactions. -usually quite weak important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor "pockets.“ 5. Dispersion (Van der Waal) forces -Attractive forces that arise between particles as a result of momentary imbalances in the distribution of electrons in the particles. -These imbalances produce fluctuating dipoles that can induce similar dipoles in nearby particles, generating a net attractive force.

Drug-Receptor Bonds and Selectivity Drugs which bind through weak bonds to their receptors are generally more selective than drugs which bind through very strong bonds. This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur. Only a few receptor types are likely to provide such a precise fit for a particular drug structure. To design a highly selective short acting drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose molecules that form weaker bonds.

Selectivity More Examples of Selectivity: Preferential binding to a certain receptor subtype leads to a greater effect at that subtype than others e.g. salbutamol binds at β2 receptors (lungs) rather than β1 receptors (heart) Lack of selectivity can lead to unwanted drug effects e.g. salbutamol (b2-selective agonist ) vs isoprenaline (non-specific b-agonist) for patients with asthma. Isoprenaline  more cardiac side effects (e.g., tachycardia) More Examples of Selectivity: Histamine H1 receptors are expressed throughout the body. H1 antagonists are used to treat allergies like allergic rhinitis and allergic conjunctivitis, urticaria and pruritus e.g. chlorpheniramine, loratadine Histamine H2 receptors are expressed in gastric parietal cells, vascular smooth muscle, neutrophils, central nervous system, heart, uterus. H2 antagonists are used for inhibition of gastric acid secretion e.g. ranitidine, famotidine In addition to H3 and H4 histamine receptors Is selectivity absolute??

Law of Mass Action k1 [D] + [R] [DR] (1) The rate of any given chemical reaction is proportional to the product of the activities (or concentrations) of the reactants. When a drug (D) combines with a receptor (R), it does so at a rate which is dependent on the concentration of the drug and the concentration of the receptor. k1 [D] + [R] [DR] (1) k2 D = drug R = receptor, DR = drug-receptor complex k1 = rate for association k2 = rate for dissociation.  

Law of Mass Action association rate = dissociation rate At equilibrium, the rate at which the ligand binds to the receptor is equal to the rate at which it dissociates:   association rate = dissociation rate k1 [D][R] = k2 [DR] (2) k2 = [D][R] k1 [DR] (3) k2 = KD = [D][R] k1 [DR] (4) Where KD is the equilibrium dissociation constant. The units for the KD are concentration units (e.g. nM).

Law of Mass Action Another constant related to the KD is the affinity (KA) which is essentially equivalent to the reciprocal of the KD. The units for the KA are inverse concentration units (e.g. nM-1).   1 = KA = k1 = [DR] KD k2 [D] [R] (5) The relationship between the binding of a drug to a receptor at equilibrium and the free concentration of the drug provides the basis for characterizing the affinity of the drug for the receptor. The mathematical derivation of this relationship is given below: KD = [D][R] [DR] (6) KD [DR] = [D][R] (7)

Spare Receptors In some systems, full agonists are capable of eliciting 50% response with less than 50% of the receptors bound (receptor occupancy). Maximal effect does not require occupation of all receptors by agonist. Low concentrations of competitive irreversible antagonists may bind to receptors and a maximal response can still be achieved. Pool of available receptors exceeds the number required for a full response Common for receptors that bind hormones and neurotransmitters if [R] is increased, the same [DR] can be achieved with a smaller [D] a similar physiological response is achieved with a smaller [D] If Economy of hormone or neurotransmitter secretion is achieved at the expense of providing more receptors