Pharmacokinetics

Oral Drug administration

Absorption mainly vial lipid diffusion. All drugs given by oral route are absorbed mainly from the *small intestine* Absorption is generally low. Advantages: *safest, cheapest, most appreciated by patient* a) hastened- in aqueous solution b) delayed- controlled release preparation

Calculating Bioavailability

Bioavailability is determined by administering a dose of drug intravenously (IV) and that of the same dose by the other route of interest. *Bioavailabilty is given by: F = AUC other/ AUC iv Oral bioavailability: F = AUC oral / AUC iv* *Drugs administered via IV, the bioavailability, F = 1 (100%), for all others it is F<1*

Pharmacokinetic models Multicompartment models

Body is considered to have a series of compartments of different sizes that communicate reversibly with each other. Drug is distributed uniformly within each compartment, but the amount of drug can vary widely from one compartment to the other.

Pharmacokinetic models One compartment model

*A single compartment in which the drug is uniformly and instantaneously distributed.* Moved dynamically in and out of the compartment. Drug can also be eliminated so it is called the one compartment open model. *This is the model we are most concerned with*

Special Parenteral Routes

*Intraarterial*- Used to localize the effect of a drug in a particular tissue or organ by delaying their systemic distribution (diagnostic agents, anticancer drugs, e.t.c) *Intrathecal*- used with drugs that cross the blood-brain barrier (certain antibiotics, certain anticancer drugs, local anaesthetics) *Intracardiac*- Sometimes used in cardiac emergencies (adrenaline, lidocaine) *Intrapleural*, Intraperitoneal, intraarticular, intravitreal- Used to localize the effect of a drug at a specific site by reducing their systemic absorption (chemotherapeutic drugs, corticosteroids, etc)

Peak concentration (Cmax)

*Maximum drug concentration reached in plasma* after administration of a given dose. Max is related to the dose and to extent of absorption, distribution and elimination of the drug.

Time-Drug concentration curve

Curve is determined by administering a dose of a drug and then measuring the drug plasma concentration at different times. *For drugs administered via IV* For drugs following first order kinetics, *a constant fraction* of the drug is eliminated. Therefore the curve describing the time course of drug disappearance from the site of administration is *exponential.*

Drug bioavailability

Defined as the *fraction of drug dose reaching unchanged in the systemic circulation when administered by any route.* Bioavailability is influenced by: a. route of administration b. all factors acting on absorption *Bioavailability of a drug is constant, i.e. is not dependent on the administered dose.

First Pass Elimination

Drugs given orally must pass the membranes of gastrointestinal tract, and then through the liver before reaching general circulation. - If drug is metabolized in the gut wall or in the liver, a fraction of the active drug will be eliminated, thus first pass before reaching general circulation. *Low systemic bioavailability often indicated a high first pass effect.*

Order Kinetics

First order kinetics: *Constant ***fraction*** of what must be processed, is processed per unit time.* *Most drugs follow first order kinetics.* Zero order kinetics: Constant **amount** of what must be processed, is processed per unit time. *Also called saturation kinetics, also concerned with rate limiting or a saturable process. Very few drugs follow this.

Pulmonary Drug Administration *For drugs inhaled as aerosol*

Goal is to *achieve local effects* *Local drug effect is directly proportional to the amount of the drug reaching the alveoli*, which *depends on the drug concentration in the inhaled air, on pulmonary ventilation and on particle size.* Absorption occurs mainly via *lipid diffusion* through alveoli membrane Absorption is slow and very limited Adv: Drug concentration is locally high - Systemic absorption is delayed and limited, adverse effects minimized Disadv: Specific equipment needed - Control of dosage is limited, depends on patients co-ordination.

Pulmonary Drug Administration *Drugs inhaled as a gas*

Goal is to *achieve systemic effects, if administered as a GAS.* Absorption via lipid diffusion Absorption is *most rapid* (less than a minute), and directly proportional to partial pressure of the the gas in the alveoli. Adv: Consciousness is not required; dosage is tightly controlled Disadv: Drug must be gas or volatile fluid, sophisticated equipment are usually needed.

Parenteral administration Subcutaneous or Intramuscular

Goal is to *achieve systemic* or (rarely) local effects Absorption occurs *mainly over bulk flow* through the intercellular pores of the endothelium of blood capillaries or through lymphatic vessels. The main *rate-limiting factors* in absorption from the injection site are the *local blood flow* and the drug solubility into the interstitial fluid - Absorption from IM is generally rapid (10-30 minutes) - Absorption from SC is generally slower than IM administration Can be hastened: a) by warming or rubbing the injection area. b) delayed (by cooling the injected area, by coinjecting vasoconstrictors, by administering slowly dissolving form of the drug). Adv: Most drugs well absorbed, fast pass effect avoided, dosage is rightly controlled Disadv: Injection of irritation drug may be painful, patient compliance can be poor

Cutaneous Drug Administration

Goal is to achieve *local effects* Absorption via lipid diffusion, and systemic effects are minimized. However, systemic effects can occur *if skin is damaged* (cutaneous absorption is greatly enhanced through the damaged skin.)

Parenteral Administration *Intravenous*

Goal is to achieve *systemic effects* Drug is *injected directly into the general circulation, so problems of absorption are circumvented.* Adv: Dosage, intensity and duration of drug response is tightly and completely controlled. - Highly irritating drugs and large volume of fluid (IV infusion) can be administered Diadv: Too rapid injection rate may evoke catastrophic effects in the cardiovascular, respiratory and CNS. - Risk of anaphylactic reaction is increased. - In case of overdose, the drug cannot be removed.

Transdermal administration

Goal is to achieve systemic effects Absorption occurs mainly via lipid diffusion, uniform and usually slow Adv: first pass effect avoided, consciousness not required. Disadv: Few drugs can be effectively absorbed through the skin

Oral administration time-concentration curve

Since the beginning *absorption processes are greater than distribution elimination processes*, the plasma concentration of the drug will increase in time. A *peak level is reached when absorption = elimination*. then elimination processes prevails and the plasma concentration will decrease in time.

Rectal Drug Administration

The achieve *systemic* or sometimes local effects Absorption occurs mainly via lipid diffusion *Absorption is usually slow.* Adv: Partially avoid the first pass effect, consciousness is not required. Disadv: irritation of the rectal mucosa, absorption is irregular being heavily influenced by the degree of fullness of the ampulla recitalis.

Pharmacokinetic models Two-compartment models

The body is considered to have two compartments, a central and peripheral compartment. *Drug administration and elimination occur only from the central compartment.* It is assumed that the two communicate reversibly, drug can distribute from the central to peripheral and back again. Since the drug can be eliminated from the central compartment, the model is named two compartment open model.

The time to peak concentration (Tmax)

Time of maximum drug concentration in plasma (unit: time, i.e. min). T maxis roughly inversely proportional to the rate of drug absorption.

Drug Administration on mucus membrane

To achieve local or systemic effects Prep includes: eyedrops and ophthalmic ointments, nose drops and sprays, ear drops Absorption via lipid diffusion Absorption usually rapid Adv: Systemic adverse effects are minimized Disadv: Drugs applied on mucous membrane can often be absorbed quickly enough to cause systemic actions.

Sublingual and Buccal Drug Administration

To achieve systemic or (very rarely) local effects Occurs mainly via lipid diffusion *Absorption is usually rapid.* Adv. - First Pass effect is avoided, and drugs not exposed to digestive juices Remaining drug can be removed, easily once the effect has been reached. Disadv: have a disgusting taste or smell, may be irritating to the mucosa.

Area under curve (AUC

Total area subtended to the curve (unit: concentration by time, i.e. (mcg/ml) min. AUC indicates the *total amount of drug that reaches the systemic circulation over time* and reflects absorption, distribution and elimination factors of drugs.

Dosage Formulations

the dosage formulation of a drug can influence its *oral bioavailability*.