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2nd semester pharm week 1


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Parenteral-overall positives 3
1 relatively rapid response

2 accurate dose

3 circumvents GI tract
Parenteral-overall negatives 4
1 potentially more toxicity

2 requires sterile drug/access

3 can be painful

4 often more expensive
Intravenous (iv) positives 4

emergency use


accurate dose
Intravenous (iv) negatives 3
potentially more toxicity

req. IV access

req. water soluble form
Intramuscular (im) positives 3
aqueous drugs-usually rapid

emergency use

vs, depot suspensions

less dependent on solubility or MW
intramuscular (im) negatives
local irritation/myonecrosis

variable absorption
Subcutaneous (sc/sq) positives
slow and constant absorption

o/w similar to IM
Subcutaneous (sc/sq) negatives
absorption blood flow-limited

o/w similar to IM
Intraperitoneal (ip) positives
moderately fast

popular for animals
Intraperitoneal (ip) negatives
metabolized in liver

variable absorption
Oral (po) positives

slower and safer

Oral (po) negatives
GI tract irritation

variable absorption rate

proteins inactivated

intestine/liver sees drug first
Sublingual (sl) positives

rapid (e.g. nitroglycerin)

bypass liver
Sublingual (sl) negatives
irritation or bad taste

potential for toxicity

req. potent, lipid-soluble drug
Rectal (pr) positives
circumvent oral route

can remove easily
Rectal (pr) negatives

variable absorption
Topical (Skin or eye) positives, 4
local activity

bypass liver for systemic drugs

can remove easily

continuous-release forms
Topical (Skin or eye) negatives
irritation, excess absorption

success has been limited
Inhalation positives
rapid if lipid soluble

local effect on lung

emergency use
Inhalation negatives
limited by particle size

limited by volatility
Spinal Intrathecal, Epidural positives
direct access to CNS

direct access to nerves
spinal negatives
technically challenging
Ficks Law
dQ/dt = -D ⬢ A dC/dx

D is constant that increases with temperature and decreases with MW of drug
Henderson Hasselboach for acid and base
pH=pKa+log[A-]/[HA], [A-]/[HA]=10(pH-pKa)

pH=pKb-log [BH+]/[B], [BH+]/[B]=10(pKb-pH)
bioequivalence vs pharmaceutical equivalence
bioequivalent if the rates and extents of bioavailability same in vivo.

pharmaceutical equivalence if same active ingredients and are identical in strength or concentration, dosage form, and route of administration
define: prodrug
administered in an inactive form and require metabolism to be activated (bioactivation)
the three cytochrome P450's
CYP 2E1--ethanol, acetone and isoniazid

CYP 3A4--anticonvulsants, St. John’s Wort, rifampin, steroids

CYP 1A--aromatic hydrocarbons
cellular locations of Phase I vs Phase II metabolisation
Phase I mostly endoplasmic reticulum

Phase II mostly cytosol
--glucuronidation actually in ER
non endoplasmic reticulum oxidation, 3 enzymes
alcohol dehydrogenase--cytosol

xanthine oxidase, monoamine oxidase
phase II reaction in ER

highly polar sugar conjugates

rapidly excreted in urine and bile
tripeptide substrate for glutathione-S-transferases that detoxify electrophilic metabolic intermediates using the sulfhydryl group of cysteine
how to cause better excretion of weak acids by altering urine pH
excretion can be increased by alkalinizing urine relative to plasma
how to cause better excretion of weak bases by altering urine pH
excretion can be increased by acidifying urine relative to plasma
Solving for kel
kel = ln (C0 /Ct)/t
relationsip of T1/2 and kel
T1/2 = 0.693 / kel
Relating T1/2 to Vd and Cls
T1/2 = 0.693 ⬢ Vd / Cls

Cls = systemic clearance
calculation of total Systemic Clearance based on

(Clsystemic) = kel ⬢ Vd
Steady state concentration calculation
Css ≈ 1.5 •( T1/2 /T) • C0; T=dosing interval
Determining Drug Dose and Interval, 3 factors
· Peak level must not give toxicity

· Trough level must not be sub-therapeutic

· Dosing interval must be conducive to patient compliance.
relationship b/t

[DR], [Rt], [D], Kd
[DR] = ([Rt][D])/([D] + Kd)
dose ratio
the ratio of the agonist concentrations (or doses) required to elicit equal responses in the presence and absence of antagonist
reflected by its EC50 in eliciting a response.

The potency of a drug is related primarily to its affinity at the receptor (KD)
capacity to elicit effect

characterized by maximal response
avidity for the receptor
EC50 and ED50 in a quantal concentration-response curve
EC50 refers to the concentration that produces a specified response in 50% of the subjects

ED50 expresses drug dose
therapeutic index
Toxic dose 1/Therapeutic dose99
dosing approach for wide therapeutic window
a maximal efficacy (dose) strategy can be used
dosing approach when drug effect is easily measured
rial and error approach should be used (< 50% change in dose every 3 to 4 half-lives)
dosing approach when drug effects are difficult to measure, or toxicity is seerious
target-level strategy should be used.
Clearance, CL significance for dosing
Defines dosing rate, D(ose)/t (time)
Half-life significance for dosing
Defines dosing interval, t (time)
Bioavailability (F) significance for dosing
Defines dosage rate adjustment depending on route of administration (fraction)
Volume of distribution (V) significance for dosing
Defines the size of loading dose
Target Cpss, clearance, and rate of dose relationship
Target CPss= dosing rate/Clearance = Rate of infusion/Clearance
Cpss, bioavailability (F), dosing interval (t), and clearance, and dose
Cpss = (F*D/t)/Cl
Estimate Volume of Distribution (Jusko Equation)
Vd = 226 + [(298 x CrCl) / (29.1 + CrCl)] x (BSA / 1.73)
where CrCl = normalized creatinine clearance(ml/min)
BSA = Body surface area (square meters)
Calculate Loading Dose based on

Vd = Volume of distribution (liters)
Cp = target serum level (mcg/l)
F = bioavailability factor
LD = Vd x Cp/F

where Vd = Volume of distribution (liters)

Cp = target serum level (mcg/l)
F = bioavailability factor

IV push = 1
Calculate Maintenance Dose
based on

Cl = Clearance (liters/hour)
Cp = target serum level (mcg/l)
tau = dosing interval (hours)
F = bioavailability factor
MD = (Cl x Cp x tau) / F

where Cl = Clearance (liters/hour)

Cp = target serum level (mcg/l)
tau = dosing interval (hours)
F = bioavailability factor
Estimate steady-state trough level based on

MD = Maintenance dose (mcg)

F = bioavailability factor
Cl = Clearance (liters/hour)
tau = dosing interval (hours)
Cpss = (MD x F) / (Cl x tau)

where MD = Maintenance dose (mcg)

F = bioavailability factor
Cl = Clearance (liters/hour)
tau = dosing interval (hours)
Calculate clearance based on

MD = Maintenance dose
F = Bioavailability factor
Cp = Steady-state serum digoxin concentration (mcg/l)
tau = Dosing interval (hours)
Cl = [(MD x F) / Cp] / tau

where MD = Maintenance dose (mcg)

F = Bioavailability factor
Cp = Steady-state serum digoxin concentration (mcg/l)
tau = Dosing interval (hours)
Estimate ration between peak and trough levels at steady state based on

half life
dosing interval

when x=t1/2, Cpmx/Cpmn=2
Determining loading dose based on

MD= maintainance dose
t1/2= half life
x= dosing interval
Loading dose = (1.44*MD*t1/2)/x
Dose adjustment with 1st order kinetics based on

Desired plasma drug level
Current plasma drug level
Old dose
D1= (Cd/Cc)*D0
cause of non linear pharmacokinetics important for dose adjustment
Dose-response curves may show an unusually large increase in pharmacologic effect with increasing dose, starting at the dose level where “saturation” effects become evident.
Principle: Steady-state concentration is directly proportional to ____
the drug dosing rate

*except with non-linear pharmacokinetics
The time required to reach a steady-state is determined solely by ____
drug's elimination half-lif

**completely independent of dosing rate

**essentially complete in 3-5 half lives
Principle: Drug accumulation is a function of ____
the size of the dose and frequency of administration.

**It is not an intrinsic property of the drug.
Principle: During intermittent dosing at a rate calculated to provide a desired steady state, the magnitude of the fluctuation between peak and trough levels is determined by ____
the ratio between the dosage interval and the drug's elimination half-life
Principle: Unpredictable variability in the pharmacokinetic parameter values
__, __, and __ between individuals is usually quite marked.
(F, CL, V)

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