Pharmacology-GenPrinciples-Absorption
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- Pharmacokinetics
- refers to the absorption, distribution, biotransformation and excretion of drugs in the intact organism.
- fundamental hypothesis of pharmacokinetics
- relationship exists between the pharmacological or toxic response of a drug and the plasma drug concentration
- In most cases, the plasma concentration of drug will be related to the concentration of drug at ________
- its sites of action
- The ultimate drug concentration at the site of action depends on _________(6)
- the dose administered, the extent and rate of its absorption, distribution, binding in tissues, biotransformation, and excretion
- Permeation
- Passage of drugs across cell membranes
- Most common mode of drug transfer
- Passive transfer:
- Passive diffusion
- Movement of a drug molecule down its concentration gradient by virtues of its solubility in the lipid membrane
- Passive diffusion is directly proportional to ___________ (2)
- 1)concentration gradient across the membrane 2) the lipid: water partition coefficient of the drug.
- Bulk flow
- Movement of drug molecules through membrane channels or pores, e.g., capillary endothelial membranes
- Active transport
- requires energy(ATP) and can move drug molecule across membranes against its concentration gradient.
- Facilitated diffusion
- requires no energy.
- Endocytosis and exocytosis
- e.g., VITAMIN B12, IRON
- Factors affecting the diffusion of drugs across lipid membrane barriers:
- e.g. lipid solubility; charge; size; etc.
- Lipid: water partition coefficient
-
It is defined as the ratio of the concentration of the drug in water and a nonpolar organic solvent (e.g. oil, ether,chloroform, etc.)
-Lipophilic vs. hydrophilic. - Drugs with large lipid: water partition coefficients tend to readily undergo ________ diffusion
- passive
- Degree of ionization: inversely affects ________
- lipid solubility
- Most drugs are either _________
- weak acids or bases
- Ionized molecules have low lipid solubility. Such drugs are often dispensed as _____
- salts
- ______ of drug's aqueous enviornment determines ratio of charged to uncharges species.
- pH
- Henderson Hasselbach equasion
- pH = pKa + log A-/HA
-
Acid pH (e.g. stomach)
favors absorption of ______ - weak acids
- Basic pH (e.g. intestine)favors absorption of _______
- weak bases
- Drugs administered in ______ solution are more rapidly absorbed than drugs administered in ______ solution.
- aqueous / oily
- For drugs given in solid form, the __________ may be the limiting factor in absorption.
- rate of dissolution
- Factors that affect rate of absorption:
-
1)Solubility
2)Concentration (C1-C2)
3)Area of the absorbing surface (A)
4) Thickness of membrane (T)
5) Blood circulation to the absorptive site
6)Route of administration - Enteral
- Oral route
- Most drugs taken orally are absorbed by passive diffusion through GI mucosa -- absorption is favored when the drug is in the __________.
- ionized and lipophilic form
- In orally taken drugs the _______ is usually the major site of absorption, NOT the ________
- upper small intestine/ stomach
- Any factor that decreases gastric emptying time tends to _______ the rate of absorption, while any factor that increases gastric emptying time tends to ______ rate of absorption
- increase/ decrease
- Factors affecting rate of GI absorption
-
1) ionized vs. nonionized form
2)Gastric emptying time (GET)
3) Intestinal transit time (ITT)
4)Food decreases drug absorption by forming complexes with drugs - First-Pass Effect⬝
- orally administered drugs are unusually susceptible to destruction by enzymes in the liver
-
Oral cavity: sublingual; buccal
Advantages & Disadvantages -
1) Advantages: avoids the first-pass effect and gastric acid.
(2) Disadvantages: taste; irritation; only small amounts can be administered. -
Rectal administration: suppositories; retention enema.
Advantages & Disadvantages -
(1) Advantages: useful during vomiting or unconsciousness; voids first-pass effect and gastric acid.
(2) Disadvantages: irritation to mucosa, absorption is irregular and incomplete -
Intravenous
Advantages/Disadvantages -
(1) Advantages:
⬢ rapid and predictable absorption
⬢ dosing is more accurate
⬢ avoid destruction by low gastric pH
⬢ useful if unconscious, uncooperative, vomiting and in emergencies
(2) Disadvantages:
⬢ asepsis must be maintained
⬢ less safe than oral
⬢ painful
⬢ self-medication more difficult
⬢ expensive -
Subcutaneous
Advantages/Disadvantages -
Advantages:
-- ease of administration
-- relatively rapid absorption from aqueous solutions
-- rate of absorption can be altered e.g. vasoconstrictors
⬢ Disadvantages:
- only suitable for small volumes of non-irritating solutions
- pain, tissue necrosis, bacterial infections - Intramuscular
-
-Similar to subcutaneous route, but for irritating solutions
-Relatively rapid absorption but can be altered--e.g. “depot preparations†in oil will provide slow, even absorption - intra-arterial
- mostly used for administration of diagnostic agents
- intrathecal
- used in CNS infections, spinal anesthesia
- Drugs are inhaled as gases (e.g. volatile anesthetics), aerosols of solution or powder
- Very rapid onset of action, but of limited use: e.g. anesthesia treatment of asthma, and other respiratory diseases; substance abuse; etc.
- Topical application:
-
(1) Mucous membranes: conjunctiva,nasopharynx,vagina
(2) Skin (drug must be highly lipid soluable) - Transdermal therapeutic systems (TTS):
- A 4-layer delivery system applied toskin--slow release of potent lipid-soluble drugs for prolonged systemic effects
- Factors affect the rate and extent of drug distribution into tissues:
-
1) Regional blood flow to the tissue
2) Permeability of membrane barriers to the drug
3)Extent of plasma protein and tissue binding.
4) Regional difference in PH.
5) Presence of transport mechanisms - Capillary endothelium is a _________ barrier to a drug
- freely permeable
- Cell membrane as drug barrier
- lipid soluble drugs pass freely.
- Blood-brain barrier as drug barrier
- Entry of polar drugs into the CNS is greatly restricted; highly lipid soluble drugs enter readily.
- Blood-brain barrier consists of __________
- Tight junctions between capillary endothelial cells; capillaries are also covered by glial cells.
- Placenta as barrier for drugs
-
Drugs cross the placenta, primarily by simple diffusion
⬢ Lipid-soluble, non-ionized drugs readily enter the fetal blood from the maternal circulation and expose the fetus to drugs. - Drug reservoirs
-
1)Plasma proteins
2) Cellular reservoirs: Tissues e.g., skeletal muscle, heart; liver.
3)Fat: Important reservoir for lipid soluble drugs, e.g. thiopental.
4) Bones: tetracycline and heavy metals,e.g.,lead. - Many drugs are bound to plasma protein, especially plasma albumin for_____ drugs and a 1- acid glycoprotein for ______drugs.
- acid/ basic
- plasma protien binding is __________
- Reversible, non-covalent binding
- Plasma protein binding alters drug concentration in tissues and at its site of action. It also limits _____________of drug. It does NOT affect ________ or biotransformation.
- glomerular filtration /renal tubular secretion
- Volume of distribution (Vd)
- Total amount of drug in body/ Concentration of drug in plasma.
- Vd is
- the apparent volume of fluid required to contain all of the drug in the body at the same concentration as in plasma
- The total volume of fluid compartment of the body is approximately _____ . These compartments include plasma water ____, interstitial fluid _____, and the intracellular fluid _____.
- 40L/5L/10–15L/20L
- Vd is _____when the drug is highly concentrated in tissues (e.g. high lipid-solubility; tissue binding).
- large
- Vd is ______when the drug is highly concentrated in plasma (e.g. bound to plasma protein).
- small