Factors Affecting Receptor Occupancy by Drugs

Factors affecting receptor occupancy by drugs • • • Pharmacological response is usually directly proportional to receptor occupancy – number/fraction of receptors to which drug molecules have adhered to Receptor occupancy depends on: o Drug concentration (depends on dose) o Drug affinity Drug with high affinity will achieve a large degree of receptor saturation at low concentrations Drug-receptor binding • Most drugs produce effect by non-covalent binding to target molecules – almost always reversible and occurs via: o Electrostatic forces such as ionic bonds (opposite charges) and hydrogen bonds o Weak electrostatic van der Waals force • Strength and duration of bonding depends on number of such bonds – depends on how complementary in shape and drug and target are • Rarely is the bond irreversible via strong covalent bonds Dissociation constant (Kd) for drug-receptor interactions • • • Kd is the ratio of the backward and forward reaction constants Kd is equal to the concentration of drug required to occupy 50% of the receptor sites Lower Kd reflects higher receptor affinity – less drug is required to bind the same percentage of receptors to receptors and activate signalling Dose-response curve • X-axis = drug concentration, y-axis = effect → hyperbola • Drug effect reaches a plateau (max) because there is a finite number of receptors • Log of the drug concentration is plotted versus the effect – sigmoid curve • Affinity: drug’s ability to bind to its biological target (receptor, transport system) o Readout: EC (50) – measured in mol/l • Potency: relative amount or concentration of drug that has to be present to produce a desired physiological effect o Readout: EC (50) – measured mol/l • Efficacy: max ability to activate receptors after binding and elicit a desired physiological effect Readout: effect measured in % of maximum Parameters of benefit and risk • EC50/ED50 = median effective concentration/dose – refers to the dose required to produce a related drug effect in 50% of subjects • TD50 (median toxic dose): dose required to produce a toxic effect in 50% of subjects • LD50: dose required to produce death in 50% of animal subjects • Therapeutic index: TI=LD50/ED50 Limitations of TI as an indicator for drug safety • LD50 is determined in animals – does not reflect toxicity in human therapeutic setting (needs mathematical models) • ED50 is often not definable e.g. in psychiatric disease • Some toxicities are idiosyncratic (occur rarely and unpredictably amongst population) e.g. for a special genetic condition • In some cases toxicity depends on clinical state of patients e.g. renal failure Transporters • Active transport – movement against concentration gradient, requires chemical energy e.g. ATP • Ions and other larger molecules require active carrier (pumps) to move across cell membrane against their concentration gradient → drugs interfere and inhibit these systems • Examples: antidepressants inhibit reuptake of noradrenaline or serotonin into the nerve terminals after synaptic transmission →  their effect on postsynaptic receptors Drugs that work by simple chemical action (act on simple chemical processes) • Drugs are often basic inorganic compounds or non-complex organic compounds • E.g. magnesium hydroxide (antacid) in the treatment of peptic ulcer → Mg(OH)2+2HCl  MgCl2+2H2O Drugs that work by physical action • Act by a purely physical mechanism e.g. drugs that act on osmosis → osmotic laxatives, osmotic diuretics • Down-regulation: molecular mechanism is often a decrease in receptor expression Loss of drug efficacy over time – tachyphylaxis and tolerance • • • • Desensitisation/tachyphylaxis: gradual decrease in responsiveness to a drug (e.g. opiate, benzodiazepine or other drug) so that larger and larger doses are required to achieve the same effect Often develops in the course of a few minutes Tolerance: conventionally used to describe a more gradual decrease in responsiveness to a drug, taking days or weeks to develop Caused by: o Changes in the receptor (e.g. conformational – phosphorylation) o Loss of receptors o Exhaustion of mediators o Increased metabolic degradation of drug o Physiological adaptation o Active extrusion of drug from cells