Pharmacokinetics 4 Flashcards
Absorption
Movement of drug from site of administration inot the blood.
Excludes intravascular administration
Routes of Administration
- Parenteral
- Intravenous
- Intramuscular
- Subcutaneous
- Intraperitoneal*
- Inhalation
- Transdermal
- Enteral (GI tract)
- Oral*
- Esophagostomy tube*
- Gastrostomy tube*
- Enterotomy tube*
- Rectal*
- Buccal
* subject to first pass hepatic metabolism
Intravenous
Rapid onset
most condidtent plasma concentration
rapid plasma concentrations
virtually all of the drug is available systemically
Best route for emergency treatment
Drug must be in SOLUTION (not suspension)
Requires aseptic technique, skill
Some irritating, hypertonic, or poorly absorbed drugs can be only injected IV
Intramuscular/Subcutaneous
Well perfused tissue (Intermediate flow)
Drug deposited in interstitial fluid
Drug must enter capillaries/lymphatics
Lipid or aqueous diffusion
Potential for tissue binding
Inflammation/irritation/hematoma
Formulation can alter absorption characteristics
Site of administration can affect absorption and tissue residues
Capillary beds / Fluid movement
- Capillaries drain to central venous circulation
- avoids first pass metabolism
- plasma concentrations often more vairiable than IV
- Less skill
- +/- pain
- SQ~IM, but SQ tends to be more vairable
- dehydration, hypotension, hypothermia, obesity can markedly affect SQ absorption
Formulation Effects on IM/SQ absorptin
- Poorly soluble solutions can result in delayed/sustained absortion
- May allows for extended dose intervals
*
- May allows for extended dose intervals
Per Os (PO) Oral
- Primary route of adminstration
- Ruminants? Horses?
- Usually least expensive
- May increase owner compliance
- Less skill
- Diversity of GI tract
- anatomy
- physiology
- Each species is different
Disintegration
Solid -> suspension
Solid dosage form physically disperses
May be modified for sustained/extended release meds
Dissolution
Suspension -> Solution
Drug molecules enter a solution
May be modified to enhance or retard absorption
pH sensitive coverings only dissolve at specific pH
Diffusion
Surface ares, thickness, lipothilicity, pKa/pH
Thicker tissue will decrease diffusion
GIT Anatomy & Physiology:
Stomach
- Stomach (pH ~1.5)
- Cornified epithelium similar to skin (Thick)
- Mucous layer
- Gastric emptying
- Continuous eaters (ruminants/horses)
- Relatively steady rate of gastric emptying
- Periodic eaters (dogs, cats, pigs)
- Gastric Empyting altered in fed vs. fasted state
- Sometimes food/drug retained in stomach
- Variable pH
- Dig (stomach pH: fed~1.3, fasted~4.4)
- Enhances drug dissolution for some drugs
- Continuous eaters (ruminants/horses)
GIT Anatomy & Physiology:
Small Intestine
- pH~5.5
- Villi increase surface area ~600x taht of a plain tube
- Primary site for drug absorption in GIT
- Good blood flow 21ml/(min*kg) to GIT
- Specific carrier mediated transporters present
- Vit. B12, amino acid transporters
- Amino Acid Transporters - gabapentin
- Bile
- emulsifies water insolube or poorly soluble drugs, increase absorption in aqueous environment at the tip of the villi
- Food - may increase or decrease extent of absorption
Species Differences:
Ruminants
- Rumen large (50L in cattle, ~5L in sheep)
- Results in tremendous dulution of PO drugs
- may delay drug movement to intestines
- Stratified squamous epithelium
- thick with little to no absorption
- pH~6
- Primarily absorption of fatty acids, little drug absorption
- Calves - Rumen-reticulo groove
- essentially monogastric
- potential rumen microbial disruption by drugs
- Potential drug degradation by rumen flora
Species differences:
Horses
- Hind gut fermentation
- Microbial disruption by drug
- Colic
- Death
- GIT motility
Pro-Drugs / Drug esters
Drug that is metabolized to an active form
- Increase absorption, decrease degradation in GIT
- metabolized to active drug
- enalapril
- Administration of drug esters to increase absorption
- increased lipiphilicity
- enalapril maleate
*
- metabolized to active drug
First Pass metabolism
Drugs adminsterd orally may be metabolized in the intestines or liver before reaching systemic circulation
First pass metabolism:
Intestinal metabolism
Metabolizing enzymes in intestinal walls
Drug absorbed, but metabolized/inactivated prior to systemic exposure
First Pass Metabolism:
Hepatic Metabolism
Majority of drug metabolism occurs in the liver
Drug absorbed from GIT enters the portal vein which empties directly into the liver
Drug may be metabolized prior to reaching its target
Other Factors Affecting PO absorption
- Drug degraded before absorption
- acid hydrolisis
- Enzymatic hydrolysis
- Microbial degradation
- Drug cannot diffuse across GI membrane
- Fixed charge of poor lipid solubility
- Chelation
- GIT transit time
- Too fast
- Too slow
- Increased Permeability
- Inflammation, neonate
- Leaky GI membrane may increase absorption
Rectal Absorption
Similar to small intestine, smaller surface area
In contrast to humans,
Majority of the drug is subject to first pass metabolism
majority of colonic blood flow drains into portal vein then through liver
Topical Amdinistation:
Local Effect
Otic medications
Ophthalmic preparations
Minimal systemic effects - effects only at site of administration
Topical Administration:
Systemic Effects
Antiparasitic drugs
Requires partitioning; vehicle through skin
Increase lipid solubility, increase absorption
Transdermal Absorption
Factos affecting absorption:
- Drug lipophilicity
- pKa / ionization
- hydration
- blood flow
- Solvents / detergents
- Species specific differences
- hair density, skin thickness, compostion, blood flow
- Location, Location, Location
- scrotum>forehead>axilla=scalp> back=abdomen>palmar=plantar
- Metabolism - metabolizing enzymes are present in skin, but tipically minor in effect
Respiratory Absorption
Lung
- Large surface area (50-100m2)
- Primary absorption site are alveoli
- Thin membrane
- Highly vascularized
- Trache, bronchi, bronchioles, - little absorption
- Aerosols, particles >6mcm do not reach alveoli
- ciliary clearance
- local effects
- No first pass hepatic metabolism
Mucosal Absorption
Absorption related to lipophilicity and pKa/pH
- Mucosa thinner than skin
- Avoids a 1st pass effect
- well hydrated areas
- Nasal
- Oral mucosal
- Swallowed drug - PO absorption and 1st pass metabolism
