General pharmacologyGeneral pharmacology((Pharmacokinetics; drug and Pharmacokinetics; drug and

administration and absorptionadministration and absorption ) )

Prof. Hanan HagarProf. Hanan HagarDr.Ishfaq BukhariDr.Ishfaq Bukhari

Pharmacology DepartmentPharmacology Department

The student should be able to Discuss the different routes of drug administration Identify the advantages and disadvantages of various routes

of drug administration Know the various mechanisms of drug absorption List different factors affecting drug absorption Define bioavailability

Pharmacokinetics (Drug absorption)

Recommended books

Lippincott’s illustrated reviews (Pharmacology( by Howland and Mycek

Basic and Clinical Pharmacology by by Katzung

PHARMACOKINETICS:

Pharmacokinetics:It is the study of what the body does to the drug i.e ADME

ABSORPTION DISTRIBUTION METABOLISM EXCRETION

of the drug

Note: Pharmacodynamic is what the drug does to our body

Enteral via gastrointestinal tract (GIT(( Oral and Rectal (

Sublingual Parenteral administration = injections. Topical application Inhalation

Advantages Disadvantages

- Easy- Self use-Safe- convenient

- cheap

- No need for sterilization

- Slow effect-No complete absorption- Destruction by pH and enzymes- GIT irritation- Food - Drug interactions-Drug-Drug interactions- First pass effect- (low bioavailability).Not suitable for vomiting & unconscious patient emergency & bad taste drugs

Factors affecting absorption from GIT GIT motility changed by drug / diseases Presence of food Blood flow/surface area GIT juices pH of GIT fluids Chemical/drug interactions dosage form of a drug

Most of the drug is absorbed with in 1-3 hours,mostly it occurs in small intestine ,rate of absorption depends on lipid solubility ,ionization and pH.

Factors affecting absorption from GIT Drugs administered in aqueous solution are

absorbed faster & completely than tablet or suspension forms.

Drugs such as the tetracyclines, which are highly ionized, can complex with Ca++ ions in membranes, food, or milk, leading to a reduction in their rate of absorption.

Factors that accelerate gastric emptying time, permitting drugs to reach the large absorptive surface of the small intestine sooner, will increase drug absorption unless the drug is slow to dissolve.

First pass Metabolism

Metabolism of drug in the gut wall or portal circulation before reaching systemic circulation

So the amount reaching system circulation is less than the amount absorbed

Where ? Liver Gut wall Gut Lumen

Results ?

Low bioavailability.

Short duration of action of drugs (t ½).

First pass Metabolism

First pass effect

Stomach pH

The low pH of the gastric contents (pH 1–2) may influence absorption of drugs because it can affect the degree of drug ionization. e.g, the weak base diazepam (pKa 3.3) will be highly Ioninized in the gastric juice, and absorption will be slow.

weak acid drug, acetaminophen (pKa 9.5) will exist mainly in its unionized form and can more readily diffuse from the stomach into the systemic circulation.

Small intestine

The small intestine, with its large surface area and high blood perfusion rate, has a greater capacity for absorption than does the stomach.

Conditions that shorten intestinal transit time (e.g., diarrhea) decrease intestinal drug absorption, while increases in transit time will enhance absorption by permitting drugs to remain in contact with the intestinal mucosa longer.

Oral Dosage Forms (oral formulations(

Tablets (enteric coated tablets) Capsules (hard and soft gelatin capsules) Syrup Suspension Emulsion

TabletsTablets

Hard- gelatin Hard- gelatin capsulecapsule

SpansuleSpansule

Soft- gelatin Soft- gelatin capsulecapsule

Advantages Disadvantages

Rapid effect (Emergency) No first pass metabolism. High bioavailability No GIT destruction No food drug

interaction

Dosage form: friable tablet

Not for

- irritant drugs

- Frequent use

Advantages Disadvantages Suitable for children Vomiting or unconscious

patients Irritant & Bad taste drugs. less first pass metabolism

(50%)

Dosage form:

suppository or enema

Irregular absorption & bioavailability.

Irritation of rectal mucosa.

Intradermal (I.D.) (into skin)

Subcutaneous (S.C.) (under skin)

Intramuscular (I.M.) (into muscles)

Intravenous (I.V.) (into veins)

Intra-arterial (I.A.) (into arteries)

Intrathecal (I.T.) (cerebrospinal fluids )

Intraperitoneal (I.P.) (peritoneal cavity)

Intra - articular (Synovial fluids)

Advantages Disadvantages Rapid action (emergency) High bioavailability No food-drug interaction No first pass metabolism No gastric irritation

Suitable forVomiting &unconsciousness Irritant & Bad taste drugs.

Dosage form:

Vial or ampoule

Infection Sterilization. Pain Needs skill Anaphylaxis Expensive.

Not suitable for oily solutions or poorly soluble substance

Ampoule Vial

Single useSingle use Repeated useRepeated use

Injection Special Utility LimitationsI.D. Minute volume (0.1 ml)

Suitable for vaccinations

& sensitivity test

Not suitable for large volumes

S.C. 0.1 ml – 1 ml

Suitable for some poorly soluble suspensions and for instillation of slow-release implants e.g. insulin zinc preparation

Not suitable for large volumes

I.M. larger volume 3-5 ml Suitable for moderate volumes, oily vehicles, and some irritating substances

Not suitable for irritant drugs

I.V. Suitable for large volumes and for irritating substances

Not suitable for oily solutions or poorly soluble substances

Must inject solutions slowly as a rule

Drugs are mainly applied topically to produce local effects. They are applied to

Skin (percutaneous) e.g. allergy test, topical antibacterial and steroids prep and local anesthesia

Mucous membrane of respiratory tract (Inhalation) e.g. asthma

Eye drops e.g. conjunctivitis Ear drops e.g. otitis externa Intranasal, e.g. decongestant nasal spray

Advantages Disadvantages Mucous membrane of respiratory system Rapid absorption )large surface area) Provide local action Minor systemic effect Less side effects. No first pass effect

Dosage form: volatile gases (anesthetics), aerosol, nebulizer for asthma

Only few drugs can be used

Nebulizer AtomizerNebulizer Atomizer

a medicated adhesive patch applied to skin to provide systemic effect (prolonged drug action)

e.g. the nicotine patches (quit smoking)

Scopolamine

(vestibular depressant)

Is the passage of drug from its site of administration to its site of action through various cell membranes.

Except for intravenous administration, all routes of drug administration require that the drug be transported from the site of administration into the systemic circulation.

Is the passage of drug from its site of administration to its site of action through cell membranes.

Sites of Administration

Sites of action

Cell membrane

Sites of Administration

Absorption & distribution Elimination

The transport of drugs across membranes occurs through one or more of the following processes:

1. Simple diffusion = passive diffusion.

2. Active transport.

3. Facilitated diffusion.

4. Pinocytosis (Endocytosis(.

water soluble drug )ionized or polar) is readily absorbed via diffusion through aqueous channels or pores in cell membrane.

Lipid soluble drug )nonionized or non polar) is readily absorbed via diffusion through lipid cell membrane itself.

Characters common. Occurs along concentration gradient. Non selective Not saturable Requires no energy No carrier is needed Depends on lipid solubility. Depends on pka of drug - pH of medium.

Drugs exist in two forms ionized (water soluble) nonionized forms (lipid soluble) in equilibrium.

Drug ionized form + nonionized form

Only nonionized form is absorbable. Nonionized / ionized fraction is determined

by pH and pKaAs general basic drugs are more ionized and less diffusible in a relatively acidic(less than the pka) medium, on the contrary basic are more lipid soluble and more diffusible in a relatively alkaline medium

PKa of the drug(Dissociation or ionization constant): pH at which half of the substance is ionized & half is unionized.

The lower the pKa value (pKa < 6) of the acidic drug the stronger the acid e.g aspirin (Pka= 3.0 ),

The higher the pKa value (pKa >8) of a basic drug, the stronger the base e.g propranolol ( pKa= 9.4)

PKa of the drug(Dissociation or ionization constant):pH at which half of the substance is ionized & half is unionized.

pH of the medium

Affects ionization of drugs. Weak acids best absorbed in stomach. Weak bases best absorbed in intestine.

Which one of the following drugs will be best absorbed in stomach )pH=3)?

Aspirin pka=3.0

warfarin pka=5.0

Arrange the following drugs in ascending order from least to greatest in rate of absorption in small intestine )pH=7.8)?

Propranolol pka= 9.4

Aspirin pka=3.0

warfarin pka=5.0

Relatively unusual. Occurs against concentration gradient. Requires carrier and energy. Specific Saturable. eg. Sugar, amino acids and Iron absorption. Uptake of levodopa by brain.

Occurs along concentration gradient. Requires carriers Selective. Saturable. No energy is required.

Passive transport Active transport

along concentration gradient

(From high to low)

against concentration gradient

(From low to high)

No carriers Needs carriers

Not saturable saturable

Not selective Selective

No energy energy is required

Active transport Carrier-mediated facilitated diffusion

Against concentration gradient

(From low to high)

along concentration gradient

(From high to low)

Needs carriers Needs carriers

saturable saturable

Selective Selective

Energy is required No energy is required

Endocytosis: uptake of membrane-bound particles. Exocytosis: expulsion of membrane-bound particles.

Phagocytosis occurs for high molecular weightDrugs or highly lipid insoluble drugs.

OUTINOUT IN

Factors modifying drug absorption GENERAL FACTORS lipid solubility Degree of ionization Drug solubility (aqueous sol better than oily,susp,sol) Dosage forms (depending on particle size and disintegration)

Concentration of drugs Circulation at site of absorption Area of absorbing surface (small intestine has large

surface area) Route of administration.

Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action I.V. provides 100% bioavailability. Oral usually has less than I.V.