1. INTRODUCTION
Lecture 2

2. III. Drug metabolism Metabolism of drug may lead to:
Drug metabolism (Drug biotransformation):
mean chemical alteration of the drug in the body .
Liver is the major site for drug metabolism but specific drugs may undergo biotransformation in other tissue such as the kidney , intestines, lungs and plasma.
Metabolism of drug may lead to:
1-inactivation of active drugs or drug metabolites
e.g. lignocaine , paracetamol
2-active metabolite from an active drug
e.g. diazepam oxazepam
codeine morphine
3- activation of inactive drug :
few drugs are inactive and need conversion in the body to one or more active metabolites ,such a drug is called a prodrug , it is more stable and having better bioavailability.
Eg: Levodopa Dopamine

3. Cytochrome P450 enzyme inductions (Enzyme induction )
some drugs Stimulation the hepatic drug metabolism and increase the metabolism of other drugs . drugs increase the synthesis of microsomal enzyme protein , especially cytochrome p 450 as a result rate of metabolism of inducing drug itself and /or other drugs is increased.
- Enzyme inducers stimulate their own metabolism and also accelerate metabolism of other drugs.
Many Example of drug inducers:
phenobarbital, rifampin, phenytoin, carbamazepine, griseofulvin, cigarette smoking

4. 2- increase intensity of drug that activated by metabolism .
(Enzyme induction ) lead to :
1- decrease intensity and/or duration of action of drug that is inactivated by metabolism
2- increase intensity of drug that activated by metabolism .
3- lead to tolerance :
tolerance which is characterized by the need to increase the dose continually to achieve the desired effect

5. Cytochrome P450 enzyme inhibition
Some drugs may decrease the activity of hepatic drug-metabolizing enzymes
lead to increase levels of active drug in the body that lead to serious adverse effect .
Ex of inhibitors:
alcohol,, erythromycin,,
oral contraceptives, cimetidine

6. Reaction of drug metabolism
the kidney cannot efficiently eliminate lipophilic drugs and reabsorbed in the distal tubules, therefore ,
lipid soluble drug must be first metabolize in the liver using two general sets of reaction called:
Phase I and Phase II

7. Reaction of drug metabolism the kidney cannot efficiently eliminate lipophilic drugs and reabsorbed in the distal tubules, therefore , lipid soluble drug must be first metabolize in the liver using two general sets of reaction called: Phase I and Phase II
Drug
Phase I
(Oxidation
Reduction
Hydrolysis)
Activation/Inactivation
Phase II
Glucuronidation
Conjugation Products

8. Phase I reaction Phase II reaction
Phase I reaction – (oxidation, reduction, hydrolysis)
Generally, the parent drug is oxidized or reduced to a more polar metabolite by introducing a functional group (-OH, -NH2, -SH).
The more polar the drug, the more likely excretion will occur.
This reaction takes place in the liver cells (hepatocytes).
Phase II reaction
This involves coupling the drug metabolite with an endogenous substrate (glucuronic acid, sulfate, glycine, or amino acids)
results in polar , usually more water soluble compounds that are most often therapeutically inactive .

9. First-pass effect metabolism
some drugs go straight from the GI tract to the portal system where they undergo extensive metabolism in the liver (ex: morphine, nitroglycerin) before entering the systemic circulation.
Other drugs may be destroyed before absorption eg: penicillin G

10. Example of First Pass Effect

11. Enterohepatic Cycle
After an orally ingested drug has been absorbed from the gut, it is transported via the portal blood to the liver, where it can be conjugated to glucuronic acid or sulfuric acid or to other organic acids.
At the pH of body fluids, these acids are ionized; and, hence, low membrane penetrability.
The conjugated products may pass from hepatocyte into biliary fluid and from there back into the intestine. O-glucuronides (conjugated products) can be cleaved by bacterial.
The enterohepatic cycle acts to trap drugs in the body.
Drugs that are subject to enterohepatic cycling are, therefore, excreted slowly. Eg contraceptive pills

13. IV. Excretion Pharmacokinetics
Elimination of unchanged drug or metabolite from the body and terminating its activity. Drugs may be eliminated by several different routes: 1- urine 2- Feces 3- exhaled air 4- sweat 5- saliva 6- Tears 7- Milk Urine is the principle route of excretion

14. MAJOR organ of drug excretion
1- KIDNEY:
2- LIVER:
3- GIT and lung
Minor organ of drug excretion
1-Milk gland
2- Salivary gland
3- sweat

15. renal excretion: Three mechanisms for renal execration
1. Glomerular filtration – passive diffusion
Small molecules water soluble, free drugs pass more readily.
Note: Drugs bound to plasma proteins do not pass through the glomerular filtration
2.Tubular secretion - drugs which specifically bind to carriers are transported (ex: penicillin)
Tubular reabsorption –
Small nonionic ( lipid soluble) drugs may diffuse
out of the nephric lumen back into the systemic
circulation (ex: diuretics).

17. Tubular reabsorption
This depend on lipid solubility and ionization of drug at the existing urinary PH
Lipid soluble drugs filtered at the glomerulus back diffuse passively in the tubule
Non lipid soluble and highly ionized drugs are not tubular reabsorption of drug , so change in urinary PH affect on the tubular reabsorption of drugs that are partially ionized so :
Weak bases ionize more and less reabsorbed in acidic urine
(acidification can done by NH4CL)
Weak acids ionize more and are less reabsorbed in alkaline urine (alkalization can be done by bicarbonate) e.g. barbiturate Toxicity , salicylate Toxicity

18. Kinetics of drug elimination
Drug elimination is the sum total of metabolic inactivation and excretion.
CLliver + CLrenal are typically the most important.
Clearance of drug by other routes: includes: intestines, bile, lungs, and milk in nursing mothers.
The rate of elimination is directly proportionate to drug concentration
Clearance
Half-life (t1/2)
The time required for the plasma concentration of a drug to be reduced by 50% (half of drug is eliminated).
Or the Time required to metabolize 1/2 of the original dose of the drug
Use of this terms helps in determining how long a drug will remain in the body.

20. Kinetics of Elimination
Most biologic events involving the fate of drugs can be described in simple kinetic terms:
zero order, first order, or (a combination of the two).

21. First order kinetics
The rate of elimination is directly proportional to drug concentration.
or a constant fraction of drug present in the body is eliminated in unit time.
is a constant fractional rate per unit of time eg 10% per min .
first-order processes are essentially complete (94%) after four half-lives.

23. Zero order kinetics
With a few drugs such as aspirin ,ethanol , the intake doses very large, therefore the concentration of free drug in the body is much grater than elimination.
Zero-order kinetics define processes that occur at a constant rate per unit of time.
The rate of elimination remain constant irrespective of drug concentration.
Or a constant amount of the drug is eliminated in unit time eg ethyl alcohol.
(e.g., 5 mg/ min).

24. Cont. Kinetics changes from first to zero order at high doses
and when the dose of drug is very large the enzyme is saturated by high free drug concentration and the rate of metabolism remains constant over time eg phenytoin , warfarin.

25. Excretion continued
Steady state-Occurs when the rate of drug’s administration equals its rate of excretion (occurs within about 4 half-lives).
When a drug is given repeatedly at regular intervals, the plasma concentration increases until a steady state is reached. 25

26. some drug from the first dose remains in the body at the time that the second dose is administered, some from the second dose remains at the time that the third dose is given, and so forth.
Therefore, the drug accumulates until, within the dosing interval, the rate of drug loss exactly balances the rate of drug administration, that is, until a steady state is achieved.
Whenever a drug is administered more than once every four elimination half-lives, accumulation of the compound occurs within the body.
a plateau concentration is reached in approximately four elimination half-lives. 26

30. Excretion continued
Loading doses-(drug can be injected as a single dose to achieve the desired plasma level rapidly).
utilized when a therapeutic level is desired quickly and an initial larger dose is administered followed by smaller maintenance doses.
Loading doses can be given as a single dose or a series of doses.
Loading doses are given if :
the time required to achieve half-life is relatively long.
and the therapeutic benefit of the drug is required immediately (for example, lidocaine for arrhythmias).
Disadvantages (may increase risk of toxicity and adverse effects). 30

32. Pharmacodynamic

33. Pharmacodynamic
Describes the biochemical and physiological action, and effects of drugs in the body.
This phase occurs when the medication reaches: the target (cell, tissue, organ) and a therapeutic effect occurs.
Model of Drug/Receptor Binding

34. Principles of drug action
1-stimulation: selective enhancement of the level of activity of specialized cells.eg Adrenaline stimulates heart .
2- depression : selective diminution of activity of specialized cells.eg Barbiturate depress CNS.
3-Irritation : noxious effect applied to less specialized cells and can result in diminution or loss of function. Irritation result in inflammation and necrosis .
4-replacement state : use of drug in deficiency state e.g. insulin in diabetes , iron in anemia .
5-cytotoxic action: selective action for parasites or cancer cells without affecting host cells

35. Mechanisms of drug action
1-enzymes: are target of drug action ,drugs can either increase or decrease rate of enzymatically mediated reactions
2-ion channels : drugs can affect ion channels either through specific receptors or by direct binding to the channels and affecting ion movement through it ,
in addition ,certain drugs modulate opening and closing of the channel.

36. 3- Carriers :many drugs produce their action by direct interaction with carrier protein to inhibit the physiological transport of metabolite\ion eg probenecid inhibits transport of organic acid (uric acid , penicillin) in renal tubules.
4-receptors :are a specialized target macromolecules present on the cell surface or intracellular that binds a drug and mediate its action.
The amount of response is proportional to the no. of drug-receptor complex
Drug + Receptor = (DR)complex effect

37. Thank you