pharmacology/introduction

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II. major routes of drug administration: enteral
parental
other
II. A. enteral routes of drug administration: oral (most common, most variable, some drugs are absorbed from stomach, most common site is duodenom, portal circulation befor general circulation eg nitro - 90% is cleared during a single passage through liver, acid can destroy - penicillin can't be taken orally; enteric coating protects, release of a drug may be prolonged)
sublingual(placement under the tongue allows the drug to diffuse into the capillary network and therefore enter the systemic circulation directly, advantage: bypasses the intestine and liver and is not inactivated by metabolism)
rectal (50% of the drainage of rectal region bypasses the liver, prevent the destruction by intestinal enzymes, good for antiemetics)
II. B. use of parenteral drug administration: for drugs that are
- poorly absorbed from GI tract
- agents (insulin) that are unstable in the GI tract
- for unconscious patients
- undercircumstances that require rapid onset of action
II. B. parenteral routes of drug administration: intravascular (intervenous (IV)injection = most common, first-pass metabolism by liver avoided, rapid effect, maximal degree of control over circulation levels, can't be recalled, can introduce bacteria thorugh contamination, can induce hemolysis or other adverse reactions by too rapid/too high concentrations; similiar concerns for intra-arterially (IA) drugs)
Intramuscular ((IM) aqueous solutions or specialized depot preparations (e.g ethylene glycol or peanut oil, slow sustained release (e.g haloperidol decanoate)
subcutaneous (SC)requires absoprtion, is somewhat slower than IV route, minimizes risks (note minute amounts of epinephrine are sometimes combined with a drug to restrict its area of action. works as local vasoconstrictor and decreases the removal of a drug from the site of administration)other examples includes solids such as silastic capsules containing the contraceptive levenorgestrel that are implanted for long-term activity or insulin pumps
II. C. other routes of drug administration: Inhalation (provides rapid delivery of a drug across a large surface and pulmonary epithelium - effect almost as fast as IV, used for drugs that are gases eg some anesthetics or those that can be dipsersed in an aerosol, effective and convenient for patients with respiratory complaints)
Intranasal ( desmopressin is admisitered intranaslly in the tx of diabetes insipidus; slamon calcitonin in the tx of osteoporosis is available as nasal spray)
Intrathecal/Intraventricular (directly into the CSF such as methtrexate in acute lymphatic leukemia)
Topical (used when local effect is desired eg cotrimoxazolfor dermatophystosis and atropine in eye for dilatation of pupil)
Transdermal (=pplication of drugs to the skin via a transderma patch, used for the sustained delivery of drugs such as the antianginal drug nitroglycerin)
III. Absorption of drugs: is the transfer of a drug from its site of admini-stration to the bloodstream, rate and efficiency depend on route of absoprtion; for IV delivery absorption is complete = total dose of drug reaches the systemic circulation; drug delivery by other sources may result in only partial absorption and thus lower bioavailibilty
III. A. Transport of drug from the GI tract: Depending on their chemical properties, drugs may be absorbed from the GI tract either by (1.) passive diffusion or (2.) active transport:
III. A. (1.) Passive diffusion: driving force for passive absorption of a durg is the concentration gradient across a membrane separating two body compartments; a drug moves from a region of high concentration to one of lower concentration.
-does not involve a carrier
-is not saturable
-shows a low structural specificity
-vast majority of drugs by this mechanism
-lipid-soluble drugs readily move across most biological membranes
-water-soluble drugspenetrate the cell membrane through acqueous channels
III. A. (2.) Active transport: -involves specific carrier proteins that span the membrane.
-few drugs that closely resmble the structure of naturally occurring metabolites are actively transported aacross cell membranes using these specific carrier proteins
-active transport is energy dependent and driven by the hydrolysis of adenosine triphosphate (ATP)
- it is capable of moving drugs against a concentration gradient
-the process shows saturation kinetics for the carrier 9much in th esame way that enzyme-catalyzed reaction shows a maximal velocity at high substrate levels when binding to the enzyme is maximal)
III. B. Effect of pH on drug absorption: most drugs are either wek acids or weak bases.
-acidic Drugs (HA) release a H+ causing a charged anion (A-) to form: HA <=> H+ + A-
-weak bases (BH+) can also release a H+; however, the protonated form of basic drugs is usually charged and loss of a proton produces the uncharged base (B): BH+ <=> B + H+
III. B. (1.) Passage of an uncharged drug through a membrane: A drug passes through membranes more readily if it is uncharged:
- HA can permeate, A- cannot
- B can permeate, BH+ does not
therefore the effecive concentration of the permeable form of each drug at its absorption point is determined by the relative concentrations of the charged and uncharged forms; the ratio between the two forms is, in turn, determined by
-the pH at the site of absorption and
-the strength of the weak acid or base (represented by the pKa)
-distribution euqilibrium is achieved when the permeable formof drug achieves an equal concentraion in all body water spaces
-highly lipid-soluble drugs rapidly cross membranesand often enter tissues at a rate determined by blood flow
pKa: is the measure of strength of the interaction of a compound with a proton:
-the lower th pKa of a drug, the stronger the acid
-the higher the pKa the stronger the base
III. B. (2.) Determination of how much drug will be found on either side of a membrane: the relationship of pKa and the ratio of acid-base concentrations to pH is expressed by the Henderson-Hasselbalch equation:
pH=PKa + log (Nonprotonated species/protonated species)
-for acids:pH=pKa+log(A-/HA)--for bases:pH=pKa+log(B/BH+)
equation is useful for determining how much drug will be found on eiotgher side of a membrane that separates two compartments that differ in pH (eg stomach pH 1.0-1.5 and blood plasma pH 7.4)
Note: the liipd solubility of the nonionized drug directly determines its rate of equilibration)
III. C. Physical factors influencing absorption (1 & 2): 1.Blood flow to the absorption site (b.f. to the intestine is much greater than the flow to the stomach, therefore absorption from the intestine is favored over that from the stomach
2.Total surface area available for absorption: intestine (microvilli) surface area 1,000 times that of stomach ->absorption of the drug across the intestine is more efficient
III. C. Physical factors influencing absorption (3): 3. Contact time at the absorption surface: If a drug moves through the GI tratc very quickly (severe diarrhea) it is not well absorbed); anything that delays the transport of the drug form the stomach to the intestine delays the rate of absorption of the drug (Parasympathetic input increases the rate of gastric emptying, whereas sympathetic input (stress...) prolongs gastric emptying. Presence of food dilutes the drug and slows the gastric emptying = drug taken with meal is absorbed mores slowly
IV. Bioavailability: - is the fraction of administered drug that reaches the systemic circulation.
- is expressed as fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form (e.g. if 100 mg of a drug is administered orally and 70 mg of the drug is absorbed unchanged, bioavailability is 70 %)
IV. Bioavailability A.Determination of bioavailability: - by comparing plasma lervels of a drug after a particular route of administration (e.g.oral)with plasma levels achived by IV injection (when drug is adninistered orally only part of the dose appears in the plasma. By plotting plasma concentration of the drug versus time, one can measure the area under the curve (AUC). The curve reflects the extent of absorption of the drug. Bioavailability of a durg adminitered orally is the ratio of the area calculated for oral administration compared with the area calculated for IV injection.
IV. Bioavailability B. Factors that influence bioavailability 1. First-pass hepatic metabolism: When a drug is absorbed across the GI tract,it enters the portal circulation before entering the systemic circulation.If the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased. Many drugs , such as propanolol or lidocaine , undergo significant biotransformation during a single paassage through the liver.
IV. Bioavailability B. Factors that influence bioavailability 2.Solubility of drug: Very hydrophilic drugs are poorly absorbed because their inability to cross the lipid-rich cell membranes.Paradoxicaly, drugs that asre extremely hydrophobic are alos poorly absorbed, because they are totally insoluble in the aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed it must be largely hydrophobic yet have some solubility in aqueous solutions.
IV. Bioavailability B. Factors that influence bioavailability 3. Chemical instability: Some drugs, such as penicillin G areunstable in the pH of the gastric contents. Others, such as insulin, may be destroyed in the GI tract by degradative enzymes.
IV. Bioavailability B. Factors that influence bioavailability 4. Nature of the drug formation: Drug absorption may e altered by factors unrelated to the chemistry of the drug. E.g. particle size, salt form, crystal polymorphism, and the presence of excipients (such as binders and dipersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption.
IV. Bioavailability C. Bioequivalence: 2 related drugs are therapeutically equivalent if they have comparable efficacy and safety.(Note: clinical effectiveness often depends both on maximum serum drug concentrations and the time after administration required to reach peak concentration. Therefore, two drugs that are bioequivalent may not be therapeutically equivalent).
V. Drug Distribution: - is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. The delivery of a drug from the plasma to the interstitium depends on blood flow, capillary peermeability, the degree of binding of the drug to plasma and tissue proteins, and the relative hydrophobicity of the drug.
V. Drug Distribution A. Blood flow: The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distirbution of caridac output to the various organs. Blood flow to the brai, liver, and kidneys is greater than that to the skeletal muscles, whereas adipose tissue has still a lower rate of blood flow.
V. Drug Distribution B. Capillary permeability: is determined
-by capillary structure and
-by the chemical nature of the drug
V. Drug Distribution B. Capillary permeability 1. Capillary structure: Capillary structure varies widely in terms of the fraction of the basement, membrane that is exposed by slit junctions.In the brain, the capillary structure is continuous, and there are no slit junctions. In contrasts with the liver and the spleen, where a large part of the basement membrane is exposed due to large dicontinuous capillaries, through which large proteins can pass.
V. Drug Distribution B. Capillary permeability 1. Capillary structure a. Blood-brain barrier: In order to enter the brain, drugs must pass through the endothelial cells of capillaries of the CNS or be actively transported. E.g. the large neutral amino acid carriers transports levodopa into the brain. Lipid-soluble drugs readily penetrate into the CNS because they can dissolve in membrane of the endothelial cells of the CNS, which have no slit junctions. These tighly juxtaposed cells form tight junctions that constitute the so-called blodd-brain barrier.
V. Drug Distribution B. Capillary permeability 2. Drug structure: The chemical nature of the drug strongly influences its ability to cross cell membranes. Hydrophobic drugs, which have a uniform distribution of electrons and no net charge, readily move acrooss most biological membranes. These drugs can dissolve in the lipid membranes and therefore permeate the entire cells's surface. The major factor influencing the hydrophobioc drug's distribution is the blood flow to the area. By contrast, hydrophilic drugs, which have either a nonuniform distribution of electrons or a positive or negative charge, do not rapdily penetrate cell membranes and must go through the slit junctions.
V. Drug Distribution C. Binding of drugs to proteins: Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows their transfer out of the vascular compartment. Binding is relatively non-selective as to chemical structure and takes place at sites on the protein to which endogenous compounds such as bilirubin, normally attach. Plasma albumin is the major drug-binding protein and may act as a drug reservoir, e.g., as the concentraion of the free drug decreases due to a elimination by metabolism or excretion, the bound drug dissociates form the protein of the total drug in the plasma.
VI. Volume of Distribution: is a hypothetical volume of fluid into which the drug is disseminated. Although Vd has no physiological or physical basis, it is sometimes useful to compare the distribution of a drug with the volumes of the water compartments in the body.
VI. Volume of Distribution A. Water compartments in the body: Once a drug enters the body, from whatever rout e of administration, it has the potential to distribute to any one of the 3 functionally distinct compartments of body water, or to become sequestered in some cellular site.
VI. Volume of Distribution A. Water compartments in the body 1. Plasma compartment: If a drug has a very large molecular weight or binds extensively to plasma proteins, it is too large to move out through the endothelial slit junctions of the capillaries and thus is effectively trapped within the plasma (vascular) compartment. As a consequence, the drug distributes in a volume (the plasma ) that is about 6% of the body weight or, in a 70-kg individual, about 4 L of body fluid. Aminoglycoside antibiotics show this type of distribution.
VI. Volume of Distribution A. Water compartments in the body 2. Extracellular fluid: If the drug has low molecular weight but is hydrophilic, it can move through the endothelial slit junctions of the capillaries into the interstitial fluid. However, hydrophilic drugs, cannot move across the membranes of the cells to enter the water phase inside the cell. Therefore, these drugs distribute into a volume that is the sum of the plasma water and the interstitial fluid, which together constitute the extracellular fluid.
- about 20% of the body weight ( about 14 L in a 70-kg individual)
VI. Volume of Distribution A. Water compartments in the body 3. Total body water: If the drug has a low molecular weight and is hydrophobic, it can not only move into the interstitium through the slit junctions, but can als move through the cell membranes into the intracellular fluid. The drug therefore distributes into a volume of about 60% of body weight, or about 4L in 70-kg individual.
VI. Volume of Distribution A. Water compartments in the body 4. Other sites: In pregnancy, the fetus may take up drugs and thus increase the Vd. Drugs as thiopental, which are stored in fat, may also have unusually high volumes of distribution.
VI. Volume of Distribution B. The apparent volume distribution: A drug rarely associates exclusively with only one of the water compartments of the body. instead, the vast majority of drugs distribute into several compartments, often avidly bionding cellular components, e.g., lipids (abundant in adipocytes and cell membranes), proteins (abundant in plasma and within cells), or nucleic acids (abundant in the nuclei of cells). Therefore, the volume into which drugs distribute is called the apparent volume of distribution of Vd.
VI. Volume of Distribution B. The apparent volume distribution 1. Determination of Vd a. Distribution of drug in the absence of elimination: Vd is determined by injection of a standard drug which is initally contained entirely in the vascular system. The agent then may move from the plasma into the interstitium and into cells, causing the plasma concentration to decrease with time. Assume for simplicity that the drug is not eliminated from the body; the drug then achieves a uniform concentraion that is sustained with time. The concentration within the vascular compartment is the total amount of drug administered divided by the volume into which it distributes, Vd: C = D/Vd or Vd = C/D (C= Plasma concentration of drug
d + Total amount of drug in the body)
e.g., if 25 mg of a drug (D= 25 mg is administered and the plasma concentration is 1.o mg/L, then the Vd = 25 mg/1.0 mg/L = 25 L

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