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L2 Absorption / Distribution (PK Parameters (Bioavailability…
L2 Absorption / Distribution
(2.2) Absorption
Lipid Soluble
Easily absorbed
Difficult to excrete
Anatomical
Stomach: Partial Dissolution
Small Intestine: Main absorption site
Mainly
passive diffusion
LNAA (large neutral amino acid)
or PEPT1 (oligopeptide)
Drug Characteristic
Mostly weak acids or weak bases
Distribution depends on pKa of drug and pH gradient across membrane
ICF (7.0pH)
ECF (7.4pH)
Graph
Concentration (y)
TCR
(Therapeutic Concentration Range)
MEC
(Minimum Effective Concentration)
PDC
(Plasma Drug Concentration)
Cmax
(Maximum Concentration)
Intensity
(Range)
Between Cmax and MEC
Time (x)
Duration
Period in Therapeutic Concentration Range)
Onset
Period before Therapeutic Concentration Range)
PK Parameters
Bioavailability
Bioavailability Factors
Dosage forms (Solid / Liquid)
Rate of disintegration
Rate of dissolution
Lipid solubility
Excipients (For the purpose of LT stabilization)
Gastric emptying
Gastric motility
pH in GI fluids
Changes in first-pass
Changes in blood flow
GI disease
Food
Usually decreases absorption, except propanolol)
Chelation of tetracycline with antacid / milk (form insoluble complex)
Drugs affecting GE rate and GI motility
Bioavailability
(F)
Absolute Bioavailability F
: AUC of Dose A / AUC of I.V Ref Std
Oral Dose Vs Intravenous
Relative Biolavailability F
: AUC of Dose A / AUC of Dose X
Amount of drug
absorbed into systemic circulation (%)
Affects frequency of taking drugs
Cmax
AUC
Apparent Volume of Distribution (Vd)
Vd
is a
Constant
No physiological meaning
No anatomical meaning
Vd
= Amount in body / Plasma Conc.
Higher
= More distribution
Lower
= Less distribution
Amount of drug
distributed out of plasma
Calculate total amount in body once Plasma Conc is determined (?)
Vd Factors
Binding to tissue (muscles & fat)
Highly bounded to tissue
Weak basic drugs
(eg. Nortiptyline)
ICF more acidic (7.0pH)
Predominant Reason
Binding to plasma protein
Highly bounded to plasma protein
Weak acidic drugs
(eg. Wafarin)
Acidic drugs bind to HCO3- in blood
Blood more basic (7.4pH)
Loading Dose
= Dose x Bioavailability (If Oral)
= Dose
(1) Administration
Types
Oral
Tablet
Liquid
Suspension
Advantages
Safest
Most convenient
Most economical
Disadvantages
Absorption (first pass)
Emesis/Vomitting (Irritation to GI mucosa)
Unconscious / dysphagic (Esophagus obstruction)
Patient compliance
Only small molecules (no peptides/biologicals)
Why only small molecules? (Slide 9)
Injections
Intravenous
Intramuscular
Subcutaneous
Intradermal
Considerations
Areas
Skin (Topical)
Ear (Intra-Aural)
Respiratory (Inhaled)
Brain (Penetrate BBB)
Urgency
Dosage
Patient compliance
(2.3) First Pass
Mechanism
Metabolic elimination in liver
Biliary excretion
Efflux at intestinal enterocytes
Cyclosporine
P-glycoprotein
MDR1
ABCB1
Drugs with high First Pass Metabolism
Morphine
Salbutamol
Ways to avoid
Intravenous (IV)
Intranasal (IN)
Sub-lingual (SL)
Per-rectum (PR)
Subcutaneous (SC)
Intra-muscular (IM)
(2.1) G.I Loss
(2.4) Target Organ/Distribution
Factors
Physico-chemical properties of drug
Blood flow through organs
Permeability through membranes
Affinity to proteins (binding of albumin)
pH difference of biological fluids
Distribution depends on pKa of drug and pH gradient across membrane
ICF (7.0pH)
ECF (7.4pH)
(2.5) Acculumation in tissues (No Action)
(2.6) Drug at site of action
Pharmacokinetics
: Relationship between
Drug Concentration (y)
vs
Time (x)
Pharmacodynamics
: Relationship between drug
Effect (y)
& drug
Concentration (x)
Aim to
maximize drug concentration
at
site of disease
MDR
: Multiple Drug Resistance
ABC
: ATP-binding cassette transporter
What is rate of absorption as per the graph
Affect frequency of taking drugs
Value for money?
Bioequivalence
= 80 - 125%