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1 Module II The Basics of the Brain, the Body and Drug Actions Segment B General Principles of Drug Actions – The Foundation of Drug Actions in the CNS.

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Presentation on theme: "1 Module II The Basics of the Brain, the Body and Drug Actions Segment B General Principles of Drug Actions – The Foundation of Drug Actions in the CNS."— Presentation transcript:

1 1 Module II The Basics of the Brain, the Body and Drug Actions Segment B General Principles of Drug Actions – The Foundation of Drug Actions in the CNS Kim Edward Light, Ph.D. Professor, College of Pharmacy University of Arkansas for Medical Sciences

2 2 Objectives 1.Identify the various perspectives for understanding drug actions. 2.Describe the pharmaceutical and pharmacokinetic phases of drug actions. 3.Describe the pharmacodynamic, therapeutic, and toxic phases of drug actions. 4.Identify ADME and the important aspects of each. 5.List the major routes of drug administration and elimination. 6.Identify the role of distribution and biotransformation in drug actions. 7.What is the importance of dose-response relationships in drug action?

3 3 Objectives 8.Identify the difference between quantal and graded dose-responses. 9.Differentiate between potency and efficacy in regards to drug actions? 10.Define agonists, antagonists, partial agonists and how their presence in combination impacts the resulting drug effects. 11.Identify the difference between competitive and non- competitive antagonist drug actions. 12.Identify the importance of signal transduction and how the type of receptor determines the transduction process.

4 4 Pharmaceutical Pharmacokinetic Pharmacodynamic Therapeutic Toxic Aspects of Drug Actions

5 5 Pharmaceutical aspects Drug absorption. Routes of administration »Oral »Injection (iv, im, ia) »Topical »Inhalation »Rectal

6 6 Pharmacokinetic Aspects


8 8 Distribution Delivery of the drug to tissues Blood flow Most drugs like fat (lipophilic) Plasma protein binding Apparent barriers Blood-Brain Barrier Synovial barrier Placental Barrier Breast milk

9 9 Metabolism Biotransformation To render the drug more water-soluble Liver, GI tract, lungs, kidneys, brain Cytochrome P450 (CYP) / mixed function oxidases Split molecular O 2 to oxidize drug X + O 2 + X-O + H 2 O CYP + 2NADPHCYP + 2NADP +

10 10 Metabolism Biotransformation Specialized forms of CYP enzymes CYP3A4 >50% of drugs CYP2D6 many CNS and cardiovascular drugs Other enzyme systems: alcohol dehydrogenase plasma esterase enzymes

11 11 Elimination or Excretion Filtration by the kidneys Eliminated in urine Some passed into the bile After liver metabolism Other important routes: breath, sweat, saliva, milk, hair, finger/toe nails

12 12 Time Course of Drug Actions Plasma Concentration

13 13 Pharmacokinetic Terminology Clearance the total time to completely eliminate the drug from the body Half-life (T ½ ) the amount of time for the concentration to decrease by half

14 14 For example, for a drug with an T ½ of 6 0 hours = 100 mg/ml in the 6 hours = hours = 25 mg/ml »Note: each T ½ decreases the previous concentration by half This type of elimination is called FIRST-ORDER since the amount of drug eliminated per unit time is dependent on one variable – concentration Half-Lives One half-life Two half-lives Three half-lives Four half-lives Five half-lives

15 15 Dose-Response Relationships Drug actions are related to dose More drug = more actions Two perspectives response of a population of subjects to a given drug (i.e. how many respond) The response magnitude (or graded response) Pharmacodynamics

16 16 Dose Responses in Populations Relates the number (or %) of subjects that respond in a specific manner (i.e. sleep). Large numbers of individuals increases accuracy. Clinical trials in new drug testing If tested population is too small or not diverse then the results will not be translatable to all individuals.

17 17 Graded Dose Responses Dose that produces 50% of Maximal Response

18 18 Receptor Drug Interactions Affinity How well the receptor and drug are attracted to each other Efficacy How much response is produced by drug-receptor interaction Potency Comparative measure of how much drug is required to produce a certain magnitude of response

19 19 Graded Dose Responses Types of drug actions Agonist = bind and produce a response »Affinity and efficacy (Drug A or B) Antagonist = bind but dont produce response (block agonist, however) »Affinity but no efficacy (Drug D) Partial Agonist = bind and produce weak response »Affinity and weak efficacy (Drug C)

20 20 Understanding Drug Actions A fundamental principle of pharmacology is that drugs do not produce effects that are new or novel to the physiological system. Drugs act within the physiological system to alter responses How drug actions are produced is essentially a question of how physiological systems are designed.

21 21 Drug Mechanisms Agonist direct = a drug that binds to and activates specific receptors »affinity and efficacy indirect = a drug that results in an increase in the presence and ability of the endogenous transmitters binding to the receptor

22 22 Drug Mechanisms Antagonist direct = a drug that binds to but does not activate specific receptors »Affinity no efficacy indirect = a drug that results in a decrease in the presence or ability of the transmitter to bind with the receptor

23 23 Partial Agonist Affinity and weak efficacy Therefore, it may sometimes act as an agonist or antagonist. If no agonist is present, then partial agonist produces some response. If agonist and partial agonist are present then less agonist can bind so total response is less – like antagonist Drug Mechanisms

24 24 Pharmacodynamic Principles Tolerance Tolerance the ability of the body to adapt to the presence of a drug that alters physiological functioning. subsequent exposure will require higher doses to produce the same magnitude of response

25 25 Pharmacodynamic Principles Withdrawal Withdrawal adverse physiological symptoms produced by the absence of a drug physiological alterations to oppose drug actions removal of the drug results in the expression of the physiological alterations

26 26 Pharmacodynamic Principles Dependence Dependence physiological state characterized by the presence of adverse signs and symptoms that occur when the drug or treatment is withdrawn.

27 27 Pharmacodynamic Principles Drug effects to alter the system System responds to oppose drug effects (tolerance) Absence of drug results in expression of the systems adaptations (withdrawal) Drug presence is necessary to balance the systems adaptations (dependence) Homeostasis (balance) adaptation drug adaptation withdrawal dependence

28 28 Summary Perspectives of drug actions Pharmaceutics, kinetics, dynamics, etc. ADME Dose-response relationships Drug Actions agonists, partial agonists, antagonists Pharmacodynamic principles (affinity, efficacy, tolerance, dependance, etc.)

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