Pharm- Pharmacokinetics Flashcards
Liberation
-Traditional (IR- immediate release)
Special
- Enteric coated (release in intestines)- delayed release
- Abuse resistant
- ER, XR, SR, CR (released thru day)
- Delayed release- needs certain conditions for release
Absorption
- drug moves from site of admin to site of measurement in body ex: mouth-stomach-intestine-liver-blood
- must be dissolved to penetrate membranes (rate limiting step: crossing membranes)
- IV admin has zero absorption rate- fastest
Absorption factors
- physical state (smaller better)
- absorption surface -concentration (more better)
- solubility/ binding
- membrane permeability
- vascularity/ blood flow
- GI motility
Types of absorption
Passive diffusion -gradient driven/ rate dependent on gradient
Active transport -pumps -transport protein (subject to inhibition/induction)
facilitated diffusion -conformational changes of membrane proteins
Endocytosis -large molecule “swallowed” into cell
Distribution
- transfer of drug to and from body compartments
- mvmnt of free drug (molecules not bound to proteins)
Volume of distribution
(amount of drug outside of blood in high cncntrn.)
Factors that affect:
- plasma prot. binding
- metabolism
active transport by target organs
- intracellular binding
- pH
- fat (lipophilicity)
- membrane permeability
- storage
* lipophilic drugs “sit” in fat- leak out slowly back into system*
Distribution
Efflux pumps/ transport system
- P-glycoprotein: liver, intestines, kidney, BBB/BTB
- pump drug out of cells
- tumor cells produce
Paracellular transport via capillary membrane
- tissue pentration without crossing lipid bilayer
- dependnt on blood flow
Distribution / BBB
- brain needs protected environment (BBB)
- protect/ maintain homeostasis
- brain capillaries- tightly joined- fatty barrier (glial sheath)
- drug leaving brain capills. has to cross capill wall and astrocyte membrn
- high ionized drugs penetrate poor
- fat soluble drugs penetrate rapidly
- drugs that target CNS must be lipid soluble to reach brain target site
Metabolism
What is it?
-transformation of one chemical to another
Why is it occur?
-so body can get rid of drug
Where does it occur?
-mostly in liver-metabolism happens in every tissue
Drug metabolism
Outcomes:
- Drug to interactive molecule
- Drove to active molecule
- Drove to multiple molecules (Active/inactive)
- No metabolism (Eliminated unchanged)
Phase 1 reactions
-Introduces Polar functional group (-OH/-NH2)
Oxidation: Involve cytochrome P450 Enzymes
- 75% of drug metabolism
- CYP450 Enzymes involved in many biologic functions (Steroid hormone synthesis)
Effects on pharmacologic activity:
- Decrease (typical metabolism)
- Increase (some drugs- prodrugs need metabolism to become active
*One drug can have multiple metabolites (active/ inactive/ toxic)
Cytochrome P 450 (CYP450)
Enzyme system composed of heme-containing isozymes
- 3A4
- 2D6
- 2C9
- 2C19
- 2E1
- 1A2
Drug me to the substrate of more than one isozyme
Polymorphisms affect metabolism
- Ultra rapid (low serum concentration)
- Poor (hgh serum)
- Extensive (normal- expected serum concentration)
Phase 2 reactions
Conjugation reaction make more hydrophilic/ generally larger molecular weight
- aids elimination via kidneys
- Results in non-toxic inactive metabolite
- glucuronidation- Most common (adds Glucose-like molecule)
CYP Terminology
- Substrate: Drug/molecule that gets metabolized
- Inducer: Drug/molecule that increases synthesis of CYP isozymes
- Autoinducer: Drug increases synthesis of isozymes for which it is a substrate
- Inhibitor: Reduces activity or competes for isozyme
(cause enzymes to be less active)
CYP450 metabolism
- Metabolism-Chemical reaction
- Enzyme facilitates chemical conversion of substrate (drug) to metabolite product
- Chemical reaction favors substrate or metabolite depending on induction/inhibition of enzyme
CYP450 Enzyme Induction
- When enzyme inducer present activity of enzyme increased- pushes reaction to the right
- Increased serum metabolite concentration/decreased the drug concentration
CYP450 enzyme inhibition
- Activity of enzyme is decreased pushes reaction to the left
- Increased serum drug concentration/slows drug becoming metabolites
Example
- Drug A substrate of CYP3A4
- Drug B is inducer of 3A4
- If drug B added to drug regimen what happens to serum concentration of drug A?
- Serum Concentration of A would decrease
- Metabolite A would increase
Elimination
Organs involved in elimination:
- KIDNEY, liver, bile
- Renal issues affect the drugs we can give to patients
Renal Elimination:
- Glomerular filtration (Protein do not get passed, Passive free drug only, move from capillary to glomerular space)
- Proximal tubular secretion (active transport)
- Distal tubular reabsorption (drug may diffuse back into systemic circulation)
Pediatrics: absorption
Oral route
-neonates: decreased gastric acid/ gastric emptying
rectal route
-useful, similar to adults
Topical/skin
- infants have larger skin surface area
- absorption significantly increased
- inflammation, occlusion, heat increases absorption
Parenteral
- IM (given lateral thigh due to low muscle mass in delt/ glute)
- neonates: IV preferable to IM
Pediatrics: metabolism
Highly variable and depends on:
- Drugs mother was on during pregnancy
- Agent patient
- Some enzymes produced earlier than others
- During first few weeks/months metabolic rate lower will need lower doses
- During toddler/early childhood metabolic rate higher- dose may need to be higher
Pediatrics: Drug sensitivity
Organ immaturity (Greater risk of toxicities)
-CNS develop slowly ( increased permeability of BBB)
Temperature regulation unstable
-toxic doses of tylenol/ asprin raise body temp
Skin more sensitive (allergic, ^ SA, ^ permeability, temp regulation)
- Immediate onset ( urticaria, angioedema, anaphylaxis)
- Delayed onset( erythema multiforme, fixed drug eruption)
Half- life (t1/2)
-Time to change amount of drug in body by 1/2
steady state concentration (Css)
What is Css?
-Concentration in the blood of the drug from in to out
What determines the Css?
-Amount of drug given
What determines how long to CSss?
-t1/2
How long does it take to reach Css?
-4-5 half-lifes
General concepts
Dosing options
- continous infusion (IV)
- effect continuosly/ stop whenever
- infection risk/ vasculitis/ inflamm response
Interval (scheduled dosing)
Dosing Intervals
Loading dose
When need to obtain rapid plasma level
-Initial doses of antibiotics/ Drugs that have relatively long half-life
Followed by maintenance doses to maintain steady-state
Dose Adjustment
