Drug- Receptor Interaction

Drug-Receptor interaction I- Ka and Kd II- Dose response relationship III- Potency Understand Efficacy Agonist Antagonist

1 Kd = Ka Drug (D) + Receptor (R) (D) (R) complex Effect versely Rate of D binding affinity Ka = k1/k2 which is association constant K1 to R Drug (D) + Receptor (R) Effect (D) (R) complex Rate of DR complex to dissociation K2 Kd = k2/k1 or 1/Ka which is equilibrium dissociation constant or affinity constant 1 Kd = Ka versely •Kd value reflects affinity of a drug to bind to that receptor. •Kd is the concentration of that drug that will occupy 50% of a receptor Kd value and affinity are in related

when a drug has a low Kd. The binding of the ligand to the receptor is …S..t,rong and the affinity is …..High Affinity describes the strength of the binding between a ligand & its receptor. The  the affinity, the  the drug conc. required to occupy a receptors. Affinity is directly related to the potency of the drug (because it determine drug concentration) 1 Kd = Ka K2 The low Kd value, the the The higher the Kd value, the weaker the interaction and the lower the affinity Or higher interaction, K1 higher the affinity & the more potent drug K1 So if a drug has a high affinity for a receptor….., DR complex will be …… & value of Kd will be …S…mall

DRUG RESPONSE The magnitude of the response will be function of fractional occupancy of recep. & the total number of recep. occupied

DOSE-RESPONSE RELATIONSHIP This is the connection between the amount of a drug & the magnitude of the effect produced Characteristics of curve: Is the maximal effect of a drug Steep dose- response curve indicates that small change in dose produces a large change in drug effect X axis represent Dose Y axis represent response

DOSE-RESPONSE CURVE Hyperbolic curve Sigmoid curve permits display of a wide range of doses on a single graph Hyperbolic curve

1- GRADED DOSE-RESPO NSE CURVE sponse to  drug conc. or dose (the relationshi ation & the magnitude of the response). simple occupancy theory, but after time it was mo ug not linearly proportional to the percent of recepto cts could be produced by an agonist occupying o ay have varying capacities to initiate a response. esulted in the concepts of drug efficacy and p effects that can be determined from graded d NSE CURVE A graph of  re receptor occup At first there was a Response of dr Maximum effe receptors. Different drugs m These findings r properties for drug p between drug dose, dified due to: rs occupied. nly a small proportion of otency (two important ose response curve).

POTENCY Refers to the conc. (EC50) or dose (ED50) of a drug necessary to produce 50% of that drug's maximal response. Potency can be determined from either graded or quantal dose-response curves. The potency of a drug depends on: (1)Receptor affinity for binding the drug (Kd value) (2)The efficiency with which drug-receptor interaction is coupled to response

EFFICACY (E MAX, MAXIMAL EFFICACY) Refers to the maximal effect (magnitude of response) that can be achieved with a drug, regardless of dose. Efficacy can be measured with a graded dose-response curve but not with a quantal dose response curve. Efficacy depends on: The number of DR complexes formed The intrinsic activity of the drug The clinical effectiveness of a drug depends on its maximal efficacy (E max) not on its potency (EC50)

INTRINSIC ACTIVITY (INTRINSIC EFFICACY) Describes the ability of the bound drug to  conformational changes in the receptor (i.e effect of drugs on receptor). Although affinity is a prerequisite for drug binding to a receptor, a drug may bind with high affinity but have low intrinsic activity. A drug with zero intrinsic activity is an antagonist.

AGONIST Inverse Agonist Full Agonist Partial Agonist S + R S + R Large Drugs that interact with and activate receptors Inverse Agonist Full Agonist Partial Agonist n S + R S + R conformational changes in R to be active unable to produce a maximal response eve when it occupies all of the receptors Large effect effect •Drug has higher affinity for the inactive receptor form (R) than R* & also allow conversion of R* to R. has affinity but low intrinsic efficacy (<1) high affinity & high intrinsic efficacy (=1) e.g: buspirone, buprenorphine, pindolol and salbutamol Act by reverses the basal e.g: phenylephrine is an agonist at α1- adrenoceptors gives effect like NE. response of the system when it is due to spontaneous receptor activation (constitutive activity)

AGONIST

ANTAGONISTS Antagonists: drugs that  the actions of another drug or endogenous ligand. Antagonists bind to a receptor with high affinity & zero intrinsic activity There are 5 types

1-COMPETITIVE ANTAGONISTS: • Are drugs that bind to, reversible way without ac 1-COMPETITIVE ANTAGONISTS: or very close to, the agonist receptor site in a tivating the receptor. Note: If agonist is given in  conc., this fully activate the receptors & log do shifted to the right Example: atenolol is β1-adrenocep will displace competitive antagonist se response curve for an agonist will b tors antagonist & e