Principle of Pharmacology Pharmacokinetics Dr. Guangyu Wu Department of Pharmacology
General pharmacology ( Pharmacokinetics; drug and administration and absorption)
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Transcript of General pharmacology ( Pharmacokinetics; drug and administration and absorption)
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.