- University of Toledo Health Science Campus
- Pharmacy Practice
- Pharmacy Practice 1000a
- pharmacology 1
Last Modified: 2011-07-19
First pass - The liver is by-passed thus there is no loss of drug by first pass effect for buccal administration. Bioavailability is higher.
Rapid absorption - Because of the good blood supply to the area absorption is usually quite rapid.
Drug stability - pH in mouth relatively neutral (cf. stomach - acidic). Thus a drug may be more stable.
Holding the dose in the mouth is inconvenient. If any is swallowed that portion must be treated as an oral dose and subject to first pass metabolism.
Small doses only can be accommodated easily
By-pass liver - Some of the veins draining the rectum lead directly to the general circulation, thus by-passing the liver. Reduced first-pass effect.
Useful - This route may be most useful for patients unable to take drugs orally or with younger children.
- Filtration = unbound drug is passively filtered by the glomerulus.
- Secretion = drug is actively secreted.
- Reabsorption = drug is passively reabsorbed back into the blood.
Effects on respiration, cardiovascular system
Evaluated in vitro
Cell based systems for genotoxicity
Assessed in animals in Acute and chronic studies
they have reverse ralationship.
if the amount of drug in blood decrease the valume distribution of drug will increase.
- Drugs with high plasma protein binding
- patient’s age
- body composition
- disease state
V = amount of drug in body / C
C= concentration of duge in blood
- Include protein binding
- Fluid volume filtered in the glomerulus
- Disease states may also impact renal clearance
- the science of drugs including their origin, composition, pharmacokinetics, therapeutic use, and toxicology
- the properties and reactions of drugs especially with relation to their therapeutic value
-The study of the interaction between chemicals and living systems
Biomolecules (e.g., DNA, enzymes, receptors)
-Organelles (e.g., mitochondria, nucleus, ribosomes)
-Cells (e.g., b cells, neurons, hepatocytes)
-Tissue (e.g., smooth muscle, renal tissue)
-Organs (e.g., kidney, liver, heart, brain)-
-Organ systems (e.g., cardiovascular and nervous systems)
-Organism (e.g., man, parasite)
-Society Most complex
Drugs have a significant impact on society
- Medicine and health
- Pharmaceutical industry
- Social interactions
ADME and Pharmacokinetics
- Binding and activity at therapeutic target
Physicochemical properties of the drug
o Molecular size and shape
o Degree of ionization
o Lipid solubility
o Most drugs must cross the lipid bilayer of cell membranes to reach the site of
action nProtein binding
o Serum and tissues
state of ionization
Charged forms do not cross readily
Uncharged forms penetrate membranes
- pKa of drug
- pH at which half of drug is in ionized form
- pH on either side of membrane
When the pH is lower than the pKa, the protonated form will predominate
When the pH is higher than the pKa, the unprotonated form will predominate
Fractional extent to which a dose of drug reaches the systemic circulation Depends on: Rute of administration ,Absorption (impact of pH and pKa),Metabolism and/or excretion oFor some routes
Calculated as F= [(AUC)PO . dose IV] / [(AUC)IV.dosePO]
Oral ingestion, Sublingual
Absorption: variable, must cross intestinal mucosa
Easiest route of administration and usually safe
Subject to metabolism andPatient compliance
In oral absoption, Designed for slow, uniform absorption of drug for 8 hours or longer, Reduce frequency of administration ,Potentially improving compliance, More uniform blood levels, Eliminating peaks à decreased side effects oEliminating troughs à maintain therapeutic response
- Interpatient variability in systemic drug concentrations
- Dosage form may fail
- Dose dumping with increased toxicity due to large amount of drug released
- May occur with increased stomach acidity or administration with high-fat meal
- it is for drug which have short half life less than 4 hr
Absorption from oral mucosa
Venous drainage through superior vena cava
Protects drugs from rapid hepatic first-pass metabolism
Useful with more lipid soluble drugs (e.g., nitroglycerin)
- Route of administration
- Absorption (impact of pH and pKa)
- Metabolism and/or excretion
- Subject to metabolism
- Patient compliance
Weak acids absorbed from stomach (pH 1 to 2) rather than from upper intestine (pH 3 to 6)
Absorption of weak acids does occur in the small intestine due to high surface area
- Uniform absorption of drug for 8 hours or longer
- Reduce frequency of administration
- Potentially improving compliance
- More uniform blood levels
- Eliminating peaks à decreased side effects
- Eliminating troughs à maintain therapeutic response
Direct application to skin
Hydration can improve permeability
May be irregular and incomplete but it is Useful when oral ingestion is precluded and good for Patient unconscious or vomiting
50% of the drugs will bypass the liver and (some elimination via lung)
a disadvantage is Irritation of rectal mucosa
Allow for absorption by simple diffusion from drug depot to plasma
- Circumvented by direct injection of drug
- Immediate effects
- Useful in emergencies
- Titration or adjustment of doses possible
- Not subject to first pass metabolism in the liver oLimitations
- Adverse effects – once injected, no going back
- Slow injections usually required
Which route of administration is useful in emergencies
Prompt from aqueous solution
Slow from depot formulations
Useful for poorly soluble suspensions and depot formulations
Not subject to first pass metabolism in the liver oLimitations
Not suitable for large volumes
Potential pain or necrosis at injection site
Extent to which drugs reach potential target sites in the body
Depends on cardiac output, blood flow, capillary permeability, tissue volume, First phase – well-perfused organs (rain, lungs, liver, kidney), Second phase (Muscle, viscera, fat)
Determined by partitioning of drug between bloodstream and tissues
Lipid solubility and pH gradients important for weak acids and weak bases
pH gradient usually has small small effecto because tissue pH is almost the same with blood pH
Protein binding in plasma and tissue (has most effective one for distribution)
limit their availability to pass through glomures for filtration
limit drug availability to to cross the membrain. only unbounded drug can pass through memberain.
Some drugs accumulate in tissues by active transport or binding to tissue proteins and Act as reservoir of bound drug that prolongs activity in the tissue and May also produce local toxicity .
Lipid soluble drugs may be stored in body fat and because Fat has relatively low blood flow and drugs such as thiopental can remain in body fat for several hours
prolongs activity in the tissue
produce local toxicity
synthetic analog of pyrophosphate
its a med for osteoporosis that can stay in bone by binding to bone and slow release can treat the patients.
lipid solubile drug
small size drugs
there are some drugs with charge go into the brain because of active transport
key amino acid can pass by active transport
free drugs go through rapid equilibration in renal tubular secretion
biotransformation of free drugs occur faster.
- tight junction in endothelial cells
- astrocytes outside the endothelial cells
- microglia also they are outside the endothelial cells of brain
they all help to limit drugs access into brain
A similar barrier exists at the choroid plexus with epithelial cells separating blood from the CSF
- Tight junctions
- Efflux transporters
Drugs also leave CNS via the arachnoid villi
Drugs can cross the placenta causing potential problems for the developing fetus - Lipid solubility
- plasma binding
- ionization important determinants of drug transfer across placenta
Fetal plasma pH slightly lower (7.0 to 7.2) than mother’s plasma (pH 7.4)
unchanged (water soluble)
following metabolism(lipid soluble generally require metabolism)
Active tubular secretion
Passive tubular reabsorption
glomerular filtration rate
extent of plasma binding of the drug, because only unbounded drug is filtered by glomerular
active secretion of proximal and active reabsobtion of distal tubular
in active secretion of proximal there are to transporter exist, one of them which is p-gp and MRP2 which secrete anion to the tubular.
the other transporter is ABC which secrete organic cation to the tubular.
passive reabsoption proximal and distal tubular
in passive reabsoption of proximal and distal tubular the water reabsobed to the blood, also the unionized weak acid and base reabsorb to the blood depend to pH
Drugs can be given orally to bind substances excreted from bile to limit reabsorption.
example: Ezetimibe reduces intestinal reabsorption of cholesterol
unabsorbed drugs and/or metabolites
Lungs Primarily for volatile anesthetics (gases)
Significant route Breast milk – minor route for mother, important route for neonate
Chemical modification of drug molecule and increase water solubility of lipophilic drugs and prevents reabsorption and improve elimination. it may be active or inactive.
Liver microsomal enzymes
- Cytochrome P450
- to increase water solubility of lipophilic drugs
- prevents reabsorption
- improves elimination
Phase I and phase 2
phase 1: functionalization reactions which is Introduce or expose functional groups (e.g., hydrolysis) whichResult in both active and inactive compounds
may convert prodrugs into pharmacologically active compounds
Example, ACE inhibitors
Enalapril à Enalaprilat through esterases
Net result is water-soluble compounds that can be easily excreted into urine
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