INTRODUCTION TO DRUGS AND THEIR PROPERTIES

Drugs

…. chemicals that alter physiological or biochemical processes in the body in a manner that makes them useful in the treatment, prevention, or cure of diseases

By extension they must also possess the ability to do harm– Too little no effect – can be dangerous– Too much adverse effects- can also be dangerous

Optimize Route, Dose and Dosing Interval

RouteDoseDose Frequency

INPUT OUTPUTResponse

Drug Daily Dose (mg) Dose Frequency Administration Route

Calcium Carbonate 3000 2 hours OralIbuprofen 1600 6 hours OralVancomycin (for MRSA) 2000 12 hours IVAmoxicillin 750 8 hours OralVancomycin (for P. Colitis) 1000 6 hours OralAtenolol 100 24 hours OralFluoxetine 10 24 hour OralRamipril 5 12 hours OralDigoxin 0.250 24 hours Oral

BODY

EXAMPLES

Steps in Drug ResponseSteps in Drug Response

Absorption

Distribution

CpCp

Elimination

D

D

D

DSite of action

Response

PK Phase: Dose Cp PD Phase CSA Response

D

Adherence

DOSE of Drug (D) D

D

D D

D

D

Toxicity

Site oftoxicity

D D

Plasma

Two Phases of Drug Action

Pharmaco – “drug”Dynamics – “ variation of intensity”: Kinetics – “moving”PD- study of the magnitude of drug effect – specifically – the onset, intensity and duration of drug response. PD is interested in relating these to the “thing” driving it: concentration at SOA.PK study of drug movement into, around and out of the body: drug Absorption, Distribution, and elimination (Metabolism and Excretion) (ADME).

TabletOr site of action

1. Pharmacodynamics -PD

Pharmacodynamics is the study of the drug response (onset, intensity and

duration), and how these are related to the concentration of drug at its site of

action.

How does the drug bring about its effect?

Drug-Receptor Interaction

• Drug response - initiated by a chemical interaction between a drug and a special binding site on a macromolecule in a tissue. This macromolecule is known as a drug receptor.

• Interaction → alters the receptor in some way, which produces a signal or stimulus, which ultimately leads to a biochemical or physiological response

AG

SIGNAL

RESPONSE

Drug Action at Site

• Over 95% of receptors are proteins, others include DNA• Most drug-receptor interactions are reversible

AG is drug (agonist)

Receptor

Receptors

• Exist for natural “drugs” or ligands• For example acetylcholine, norepinephrine,

serotonin, dopamine, e.t.c.• Drugs that mimic the action of the natural

ligand are referred to as agonists• Drugs that block the action of the natural

ligands are called antagonists

Agonists, Antagonists

Antagonists block the action of an agonist but produce no response themselves

AG

Receptor

ATG

Examples of Agonists and Antgonists

• Albuterol ( a β-agonist) mimics the action of norepinephrine in the bronchial tube- dilates bronchi

• Propranolol (β-blocker:antagonist) blocks NE’s action on blood vessels – shouldn’t be used in asthmatics

• Curare is a poison that blocks the action of Ach on muscle and causes paralysis. A related compound succinylcholine -used to relax muscles during surgery

• Many of the antipsychotic drugs are dopamine antagonists - risperidone

Characteristics of Drug-Receptor Interaction

Chemical Interaction• Highly dependent on chemical structure of drug and

receptor• Small changes in either can alter or abolish activity• Often can distinguish R and S isomers of drugs with

chiral centers- S-omeprazole, S-warfarin, R-methadone (Prilosec vs Nexium)

• Magnitude of response depends on concentration of drug and receptors

• A maximum response observed when all the receptors occupied or some post-receptor event is saturated

Concentration-Response

Drug action is an example of a capacity limited process:Response increases with concentration up to a maximum value.It has a hyperbolic shape and a sigmpoidal shape on linear and semi-log plots respectively

Therapeutic Range

Clinically, a drug’s therapeutic range is often used to simplify a drug’s PD properties:

Therapeutic RangeTherapeutic Range

MTC

MEC

Cp

Cp after an Oral Dose

Onset of Action ? Duration of Action ?

Toxicity

Response

No response

Range of Cps associated with therapeutic, optimum response (no toxicity) in a large fraction of the population. Range boundaries: Minimum Effective Concentration (MEC) and Maximum Tolerated Concentration. (MTC)

time

Example of TR of some drugsDrug Therapeutic Range Cyclosporine 100-400* mcg/L Whole blood trough HPLC analysis Digoxin 0.5 – 2* mcg/L Lithium 0.6 – 1.5 mEq/L trough Phenytoin 10 -20 mg/L Tacrolimus 5- 20* mcg/L whole blood trough Theophylline 5-15 mg/L

NOTE: The TR represents the optimum concentrations for most, but not all people

Related Parameter Therapeutic Index• Therapeutic index (TI) or therapeutic ratio:

• TD toxic dose that kills 50% of lab animals• ED effective dose. Dose that produces desired

therapeutic effect in 50% of lab animalsCompare two drugs A and B:

TIA = 100 (large margin of error)

TIB = 3 (small margin of error)

50

50

TDTI

ED

2. Pharmacokinetics

• Study of time course of drug concentrations• Concentration at site (Csite) that drives response –

main interest but can’t be measured• Plasma Concentration Cp is main focus in PK:

– Blood can be easily, and frequently sampled– Central fluid where absorption ends and distribution and

elimination start– Often, though not always in equilibrium with Csite

Notes on CpWhy and why not blood:

a) Complex physical system: suspension of cells (red blood cells, white blood cells platelets in plasma water)

1. Plasma (from non-clotted blood) or serum (clotted)

2. In blood almost all drugs bind in a reversible way to proteins in plasma (protein binding)

Note many drugs bind to proteins suspended in the plasma

water. The term plasma concentration (Cp) represents the TOTAL drug (free plus bound) concentration

Factors Affecting Cp

Study of Absorption (A), Distribution (D) Metabolism (M) and Elimination (E)

Any drug that is absorbed through the GI tract must pass the liver before it gets into the systemic circulations: see: http://www.icp.org.nz/icp_t6.html

1. Drug Absorption (A)Drug absorption is the process that enables an administered

drug to reach the blood or systemic circulation• Drug contained in a tablet that is swallowed must enter

the body through the gastrointestinal membrane and eventually reach the circulation

• Drug from other routes ( transdermal, subcutaneous, e.t.c) must pass through the membranes at their respective sites to enter the circulation

• Intravascular routes (intravenous, intraarterial) by pass absorption, and drug is administered directly into the blood

2. Distribution (D)

• Distribution refers to the process by which drug within the systemic circulation travels beyond this volume to other areas of the body.

• Each drug has its own distribution pattern that is dependent on the drug’s physiochemical properties and the extent to which it binds to macromolecules in the plasma and tissues in the body

2. Drug Elimination (E)Drug elimination encompasses all the processes through

which drug is removed from the body• Drug EXCRETION, renal excretion. In this process the

parent drug is itself directly removed from the body. The renal excretion of the parent drug into the urine is the most important type of excretion

• Drug METABOLISM, biotransformation, hepatic elimination. In this process enzymes in the body (mainly the liver) chemically alter the drug so that the products can be more easily eliminated in the kidney. When a drug is metabolized, it has been eliminated

Review and Simulation Exercisehttp://forio.com/simulate/sarar/introduction-to-pk-and-

pd• Review the definitions of PK and PD• Navigate to “Try Dosing” page. Use trial and error to

try to appropriately dose the drug• Try dosing with intravenous administration• Try dosing with oral administration• Why do these two routes have different optimum

dosing regimens?