introduction

INTRODUCTIONlecture 3

* Kinetics of drug elimination
Drug elimination is the sum total of metabolic inactivation and excretion 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 CL = rate of elimination/concentration of drug in biologic fluid CLsystemic = CLrenal + CLliver +CLpulmonary + Clother where CLliver + CLrenal are typically the most important.

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.

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* Kinetics of Elimination drugs can be described in simple kinetic terms: zero order, first order, or (a combination of the two). 1- 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. First order kinetics is a constant fractional rate per unit of time eg 10% per min . The absorption, distribution, and elimination of compounds commonly exhibit this type of kinetics first-order processes are essentially complete (94%) after four half-lives.


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* 2-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).

* 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.


* 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.

* Excretion continued

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.


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* 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 . 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).

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* methods utilized for prolonging drug action
1-by prolonging absorption from site of administration 2-by increase plasma protein binding. 3-by retarding rate of metabolism 4- by retarding renal excretion

Pharmacodynamic

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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
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* Principles of drug action

1-stimulation: selective enhancement of the level of activity of specialized cells.eg Adrenaline stimulates heart . 2- depression : selective diminution 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

* 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.


* 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 as 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 = complex effect


Receptor: macromolecule or the component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects.Receptors are determine the dose or concentration of drug required to form a significant of drug-receptor complexes. Types and location of receptors:1-type I :on external surface of cell like catecholamine.2-type II: in cytoplasm of cell like steroid hormones3-typeIII: in nucleus like thyroid hormones


General Type of Drugs Interactions
1-AGONIST 2- Antagonists 1-Pharmacological A- Competitive. B-Non-Competitive 2- Physiologic ANTAGONIST (functional antagonist ) 3- Chemical ANTAGONIST 3- PARTIAL AGONIST 4- Inverse agonists

General Type of Drugs Interactions

1-AGONISTA drug is binds to a receptor and causes a response or effect. Eg phenylephrine is an agonist at α1 adrenoceptor. It has intrinsic activity = 1 + + +
+ + -
- - -
+ - -
- - -
+ + +
Depolarization

2-Antagonists

A drug is binds to a receptor and prevents (blocks or inhibits) a natural compound or a drug to have no effect on the receptor. i:e Antagonist : prevent the action of agonist on receptor but dose not have any effect on its ownAn antagonist has NO activity. Eg Prazocin (antihypertensive ) competes with the endogenous ligand norepinephrine at α1 – adrenoceptor. Its intrinsic activity is = 0

3- PARTIAL AGONIST A drug is said to be a partial agonist when it binds to a receptor and causes a partial response. i:e Partial agonist: activate a receptor to produce a submaximal effect but antagonizes the action of a full agonist It has intrinsic activity < 1. i:e agonist that act on the same receptor as a full agonist but do not produce the same maximum response in large concentration or dose , because it has a high affinity with very low intrinsic activity

4- Inverse agonists Typically, unbound receptors are inactive and require interaction with an agonist to activation. However, some receptors show a spontaneous conversion from Ri to Ra in the absence of agonist (that is, they can be active without the presence of agonist). inverse agonists reverse the constitutive activity of receptors and exert the opposite pharmacological effect of receptor agonists. Inverse agonists, unlike full agonists, stabilize the inactive R form.

Full agonists can increase the ratio of active to inactive receptors (Ra /Ri ) above that which causes the ceiling effect . partial agonists also increase the ratio, but to a lesser maximal degree. Antagonists bind without disturbing the existing Ra/Ri ratio. inverse agonists exert an opposite effect by reducing the Ra/Ri ratio and inhibiting a normally active pathway. In this example, all the drugs are assumed to have the same receptor affinity.



inverse agonist Such agents (e.g. β-carboline) have been described for the benzodiazepine receptor. these experimental drugs cause anxiety and CNS arousal. In contrast to sedative benzodiazepines such as diazepam, Flumazenil, a competitive antagonist of the benzodiazepine receptor, reverses the effects of agonists and inverse agonists.

inverse agonist Such agents (e.g. β-carboline) have been described for the benzodiazepine receptor. these experimental drugs cause anxiety and CNS arousal. Note : benzodiazepine receptor is inhibitory receptor . In contrast to sedative benzodiazepines such as diazepam, Flumazenil, a competitive antagonist of the benzodiazepine receptor, reverses the effects of agonists and inverse agonists.