1. Principles of pharmacokinetics Passage of drugs across membranes Drug absorption Distribution of drugs A. Kohút

2. What is Pharmacology? Is the study of what drug do in the body, and how the body reacts to them Drug Organism Drug Organism Pharmacokinetics Pharmacodynamics Pharmacokinetics Pharmacodynamics 1. Resorption drug action 1. Resorption drug action 2. Distribution how drugs act 2. Distribution how drugs act 3. Metabolism (mechanism of drug action) 3. Metabolism (mechanism of drug action) 3. Excretion 3. Excretion metabolism + excretion = elimination metabolism + excretion = elimination

3. Drug absorption, distribution, metabolism, and excretion elimination

5. Pharmacokinetics Resorption Distribution Metabolism Excretion

6. TRANSFER OF DRUGS ACROSS CELL MEMBRANES I. Passive proces II. Active proces

7. diffusion – passive channals – passive pumps – active cariers – active TRANSFER OF DRUGS ACROSS membranes

8. 1. Passive transport characteristic  along a concentration gradient,  liposolubility  pH,  ionization,  size of molecules (substances generally do not pass through cell membranes if their molecular masses are greater than 100 to 200 Da

10. Ion channals (passive transport)

11. Pores (passive transprt) Typical for glomerular filtration (water solubility, molecular size, filtration preasure)

12. II. Active processes The characteristics of active transport:  carrier-mediated membrane transport,  a requirement for energy,  movement against an electrochemical gradient.  low selectivity - competitive inhibition,  saturability, Active transport of some drugs occurs across neuronal membranes, the chorioid plexus, renal tubular cells, and hepatocytes

13. Types of active transport uniport symport - (glucose and Na ++ in intestine antiport - (Ca 2+ /Na +

14. Uniport C alcium pumps (ATPase) Membranes of sarcoplasmic reticulum 2 Ca 2+ - 1 molecule of ATP

15. Antiport Na + /K + -ATPase 3 Na ++ / 2 K + 1 molecule of ATP membrane action potential

16. Resorption (how the drug enters the blood)

17. Factors That Modify Absorption. The physicochemical factors that affect transport across membranes, Drug solubility. (the rate of dissolution may be the limiting factor in their absorption). The concentration of a drug (solutions of high concentration are absorbed more rapidly The circulation to the site of absorption (blood flow, vasodilatation, vasoconstriction, shock, other disease factors) The area of the absorbing surface pulmonary alveolar epithelium, the intestinal mucosa, or, in a few cases after extensive application - the skin.

18. ROUTES OF DRUG ADMINISTRATION I. Enteral lI. Parenteral - orally - intravenously (i.v) - sublingually - intramuscularly (i.m) - rectally - subcutaneously (s.c) - III. Other - inhalation - topical - transdermal

19. Absorption after PERORAL ADMINISTRATION OF DRUGS how the drug enters the blood - usually from tablets or capsules in the stomach and intestines. for some drugs, the amount of acid in the stomach, or the amount of food in the stomach, really changes the amount of drug that is absorbed.

20. PERORAL ADMINISTRATION OF DRUGS (is the most common of drug administration ) A. Advantages: safest, most convenient, most economical B. Disadvantages 1.. local iritation 2. emesis as a result of irritation to the gastrointestinal mucosa, 3. destruction of some drugs coating prevents dissolution in the acidic gastric contents. 4. irregularities in absorption or propulsion in the presence of food or other drugs, 5. necessity for cooperation on the part of the patient. 6. first pass effect – metabolism of drugs before entering systemyc circulationin (gastrointestinal tract and in the liver)

21. First pass effect

22. BIOAVAILABILITY The fraction of administered drug reaching the systemic circulation (systemic concentration that becomes available to the site of action )

23. Factors influencing bioavailability 1. first pass effect 2. all factors influencing absorption Drugs undergoig substantial presystemic metabolism : Aspirin, Chlorpromazine, Nitroglycerine, Propranolol Morphine

26. Other routs of application Sublingual Administration -  nitroglycerin protection from first-pass effect Rectal Administration  Is useful when oral ingestion is precluded by vomiting or when the patient is unconscious.  first-pass effect less than that for an oral administration Administration by inhalation  Gaseous and volatile drugs  Access to the circulation is rapid by this route, because the surface area is large general anaesthetics  solutions of drugs can be atomized and the fine droplets in air (aerosol) inhaled.  avoidance of hepatic first-pass loss local application of the drug at the desired site of action (bronchial asthma).  The main disadvantages are poor ability to regulate the dose,

27. Topical Application ( primarily for their local effects) 1. Mucous Membranes: nasopharynx, oropharynx, vagina, colon, urethra, urinary bladder 2. Skin  lipid solubility,  readily through abraded, burned, or denuded skin,  inflammation  Controlled-release topical patches are recent innovations - transdermal estrogen replacement therapy, nitrates 3. Eye

28. Drug distribution The proces by which a drug reaches different organs and tissues Drug in the systemic circulation occures as : 1. Free fraction 2 Protein-bound fraction

29. VOLUME OF DISTRIBUTION ( V d ) Volume of distribution ( V d ) is defined as the volume of water that would contain the total body content of the drug - water compartments in the body - plasma compartment 4 – 5 liters - extracellular fluid 10 -14 liters - intracellular fluid 25 - 28 liters - total body water 42 liters

32. M 1000mg Vd= -------- -------------- =40l C 25

33. Factors influencing drug distribution - ability of the drug to bind to plasma proteins - lipid solubility, - blood flow to those regions - effect of pH - capillary permeability

34.  Heart, liver, kidney, brain (and other well perfused organs) recive most of the drug during the first few ninutes after absorption.  Drugs that are strongly protein-bound stay mainly in the plasma –have limited acces to cellular sites.  Diffusion into the interstitial compartment occurs rapidly (highly permeable capillary endothelial cells).  Lipid-soluble drugs reach all compartmens and fat  For the drug that accumulate outside the plasma compartment (e.g. fat or by being bound to tissues (Vd) is large

35. Binding of drugs to plasma proteins 1. Plasma albumin (binds mainly acidic) - basic drugs may be bound by  -globulins and glycoproteins. 2. Binding depends on the concentration of drug and on, how many of bindig sites is free (binding capacity is limited) 3. The protein-bound fraction of drug is restricted from the reaching its site of action and is inactive 4. The protein - bound drug is not filtered trough renal glomeruli and is protected from metabolism (are eliminated slowly) 5. Competition between drugs for protein binding can lead to significant drug interaction 6. Deficiency of binding proteins (hypoalbuminemia) increses action of drugs

37. Examples of Vd 1. M = 100 mg, c = 20 mg/l Vd = 100:20 = 5 l (drug is in the blood)) 2. M = 100 mg, c = 10 mg/l Vd = 100:10 = 10 l (the extracellular part) 3. M=100 mg, c = 2,5 mg/l Vd = 100:2,5 = 40 litrov (drug is in extracellular and in intracellular water 4. M = 100 mg, c = 1mg/l Vd = 100/1 = 100 litrov (drug is specifically concentrated in some tissue)

38. Factors influencing Vd fysiological factors (age, gravidity, obezity), patological states oedema of different origin (insuficiency of kidney, liver, hearth) Loss of the water - diarrhea

39. Models of drug distribution