slide1 n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Definitions PowerPoint Presentation
Download Presentation
Definitions

Loading in 2 Seconds...

play fullscreen
1 / 64

Definitions - PowerPoint PPT Presentation


  • 174 Views
  • Uploaded on

Definitions. Physiology- science which treats the functions of the living organism & its parts Pharmacology- science of the effect of drugs in all aspects a- A/D/M/E b- effects & mechanism of action c- toxicity & drug interactions Pharmacognacy - (neutraceuticals/herbs)

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Definitions' - vail


Download Now An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

Definitions

Physiology- science which treats the functions of the living

organism & its parts

Pharmacology- science of the effect of drugs in all aspects

a- A/D/M/E

b- effects & mechanism of action

c- toxicity & drug interactions

Pharmacognacy - (neutraceuticals/herbs)

Pharmacy- science of preparation, compounding & dispensing

of drugs

Therapeutics- application of pharmacology to the therapy of

disease

slide2

agonist (A) ↔ (A) (receptor) ↔ response

Agonist: stimulus (ex. specific ligand for receptor mediated response)

experimental value:

reveals potential for response.

however, endogenous agonist may not exist.

Antagonist: (ex. specific inhibitor of receptor mediated response)

experimental value:

response indicates blockade of endogenous

functional agonist

Placebo:

inert medication

essential component of experimental analysis

30% response to placebo in some situations

slide5

“tissue Space” Vracko: Am J Pathology 77;313,1974

think:

GIliverbloodGU(prostateprostate fluidbacteria)

slide6

Absorption:

- generally viewed as absorption from site

of administration into blood

slide7

Absorption:

think: Specificity

slide8

routes of drug administration: key factors in absorption into vascular system

- perfusion of site

- chemistry of drug preparation

- disintegration/dissolution for solid

- dissolution for suspension

- solutions

- diffusion:

- lipid/water partition

- size/molecular weight

- transport systems

“enteral vs. parenteral”

“via intestine vs. other”

oral route of administration
Oral route of administration

Advantages:

- convenient, human acceptance

(other species?)

- relatively safe

Issues:

- bioavailability(fraction of dose appearing in blood)*

- inert with respect to GI acid, enzymes & food

- lipid/water partition & size

- resistance to hepatic metabolism

(i.e. minimal “first pass effect”)

- super-infection in GI tract with antibiotics

oral route of administration1
Oral route of administration

Advantages:

- convenient, human acceptance

(other species?)

- relatively safe

Issues:

- bioavailability (fraction of dose appearing in blood)

- inert with respect to GI acid, enzymes & food

- lipid/water partition & size*

- resistance to hepatic metabolism

(i.e. minimal “first pass effect”)

- super-infection in GI tract with antibiotics

slide12

drug penetration through cell membranes:

- aqueous channels <100 mw

- most important process:

passive diffusion due to

lipid/water partition & size

- methodology for partition coefficient

oral route of administration2
Oral route of administration

Advantages:

- convenient, human acceptance

(other species?)

- relatively safe

Issues:

- bioavailability (fraction of dose appearing in blood)

- inert with respect to GI acid, enzymes & food

- lipid/water partition & size

- resistance to hepatic metabolism

(i.e. minimal “first pass effect”)*

- super-infection in GI tract with antibiotics

oral route of administration3
Oral route of administration

Advantages:

- convenient, human acceptance

(other species?)

- relatively safe

Issues:

- bioavailability (fraction of dose appearing in blood)

- inert with respect to GI acid, enzymes & food

- lipid/water partition & size

- resistance to hepatic metabolism

(i.e. minimal “first pass effect”)

- super-infection in GI tract with antibiotics*

slide19

Distribution:

think: Specificity

drug distribution
Drug Distribution

Generally implies initial distribution from blood to

tissue space (fluids & cells) & epithelium

- protein binding in plasma

- organ perfusion

- specialized capillary barriers

- lipid/water partition & size for diffusion

- transport systems

- ion trapping in cellular/extracellular fluid*

- protein binding in cells (host or bacteria)*

slide21

drug distribution

ideal ? total body water? (think specificity)

slide22

“tissue Space” Vracko: Am J Pathology 77;313,1974

think:

GIliverbloodGU(prostateprostate fluidbacteria)

slide24

Metabolism & Excretion

think: Specificity

slide25

Understanding constant

half-life with first order

kinetics:

slide26

- oral dosing @ half-life intervals

- steady state (peak/trough) @ 4-5 half-lives

- note: rate of decline should be slower at lower blood levels

ideal?

slide27

ideal plasma kinetics?

first order:

- constant half-life

- predictable dosing regimens

(therapeutic vs. toxic range)

t1/2 = practicality (? hours)

slide28

- oral dosing @ half-life intervals

- steady state (peak/trough) @ 4-5 half-lives

- note: rate of decline should be slower at lower blood levels

Consider a Loading Dose

slide30

- hepatic portal vein from intestine

- portal venous & arterial blood perfuse into

capillary spaces (sinusoids) between

cells (hepatocytes)

- hepatocytes form bile & water soluble

metabolites primarily for

renal excretion

- selective active secretion into bile;

little diffusion

- central vein to vena cava

slide31
Hepatic metabolism* to increase water solubility & enhance excretion by kidney/urine & liver/bile/intestine

Phase I (oxidation/reduction) in smooth ER

- oxidation via cytochrome P450 enzymes

- other

Phase II (conjugation) in cytosol with:

- sulfate

- glucose

- acetate

- glutathione

- amino acids

* primarily in liver (smooth ER & cytosol)

slide32

Cytochrome P450:

- hydroxylations

- hydrophilic

- isozymes

slide33

Hepatic endoplasmic reticulum:

- smooth ER

- site for P450 oxidation

- surface area & enzymatic activity may

double in 2-3 days in response to drug substrate

slide38

hepatic metabolism & biliary excretion:

ideal? (inert as a substrate)

avoid issues of :

- bioavailability (first-pass effect)

- plasma t1/2 variations (genetics, age, other drugs)

- toxic metabolites

- secretion of antibiotic into intestine

slide39

Renal Excretion:

ideal?

- GFR

slide40

Theoretical mechanisms for selective concentration at site of action:

ion trapping; bio-activation; receptor binding

slide41

Pharmacokinetics:

- tissue fate (effect of target on agonist/antagonist)

- ion trapping

- bioactivation

- receptor specificity (tissue & chemical)

ion trapping
Ion trapping

plasma pH = 7.4

infected prostate fluid pH = 8.2

weak acid antibiotic

- equal plasma-prostate fluid concentrations of

non-ionized drug

- greater ionization of drug in basic fluid than plasma

- greater total drug in basic fluid then plasma

slide43

ion trapping & differential total drug concentration based on pH difference

relevant if ionized & non-ionized are each biologically active

weak acid drug concentrated in basic (pH 8.2) fluid of infected prostate relative to

plasma (pH 7.4)

- due to greater ionization (A-) at basic pH

- ionized form (A-) “trapped”

slide44

pH = pKa + log [A-]/[HA]

calculating total drug concentrations:

- know pH, pKa & total plasma concentration

- calculate [A-]/[HA] at plasma pH

- calculate [HA] at plasma pH, assume same at prostate fluid pH

- calculate [A-]/[HA] at prostate fluid pH

- use [HA] to determine [A-] at prostate fluid pH & sum

specificity concept of bioactivation
specificity & concept of bioactivation
  • theoretical application to specificity of antibacterial action ?

- site of bioactivation

- pharmacodynamic action of substrate vs. product

- kinetics of product

note: precedent for testosterone action

slide47

E. Jensen et al.: Fate of s.c. 3H-estadiol in the female rat

- significance of the organ-specific estrogen receptor

(accumulation/retention in estrogen-dependent organs)

- significance of competitive antagonism by an anti-estrogen (PD)

predict much greater accumulation/retention of PD vs. estradiol

think: potential analogy to bacteria & antibiotic

slide48

Estrogen(E) + Receptor(R)  ER  response

anti-estrogen

receptors: general concepts

- tissue specificity

- chemical specificity & high affinity

- requisite interaction with ligand for response

think: antibiotic interaction with bacterial receptor

(blocks interaction of endogenous bacterial ligand with its receptor)

slide49

administration of 3 different drugs acting on same receptor

- potency @ ED50

- intrinsic activity @ maximum

- drug “c” is a partial agonist

slide50

Affinity vs. Efficacy

Complex 

Drug + Receptor

Response

affinity

efficacy

slide51

Affinity vs. Efficacy

Complex 

Drug + Receptor

Response

affinity

efficacy

Insulin resistance in Type II diabetes:

- reduced receptor concentration with obesity

Consider the changes in the dose response curve with these abnormalities

slide53

Affinity vs. Efficacy

Drug + Receptor

Complex

Response

affinity

efficacy

Agonist-

Antagonist (ideal?) -

slide54

Competitive antagonism:

effect of agonist (a) alone & in the presence

of increasing doses (b-d) of an antagonist

slide55

antagonism:

a) doses of agonist alone

b-d) agonist dose response the presence of increasing concentrations of

irreversible, competitive antagonist (note same ED50)

advantages of irreversible antagonist: (t1/2 &  maximum @ saturation)

slide56

plasma concentrations with oral dosing @ plasma half-life

- consider fate in bacteria from ion trapping of antibiotic

in prostate fluid & longer t1/2 in bacteria due to receptor binding

ideal? bacterial receptor saturation due to selective accumulation

slide57

Vascular Pathology (angiopathy) in Diabetes

macroangiopathy: not diabetic-specific, but accelerated rate and greater incidence

- atherosclerosis of coronary & peripheral arteries

- occlusive lesion due to abnormal smooth muscle proliferation

& migration toward lumen; fatty deposits & calcification

microangiopathy: specific to uncontrolled diabetes (hyperglycemia)

- impairment of microcirculation (arterioles & capillaries)

- notable in skin (ulcers), retina (blindness), glomerulus of kidney (renal failure)

and peripheral nerves (sensory systems & organs innervated by voluntary/motor

& involuntary/autonomic neurons)

- initially non-occlusive, subsequently occlusive → ↓ perfusion

- ↑ intra-capillary pressure (endothelial damage, ↓NO, inability to

dilate/autoregulate on efferent side of capillarybeds)*

- ↑ permeability/leakage of plasma proteins/growth factors

- ↑ capillary basement membrane thickening

* supportive evidence: less pathology in capillaries distal to

an arterial stenosis (reduced perfusion pressure to downstream capillaries)

slide58

Consider the impact of atherosclerosis & capillary basement

  • membrane thickening of diabetes on:
  • Dosing regimen (?)
          • Fick’s Law of Diffusion:
          • (concentration gradient) (permeability) (surface area)
          • rate = __________________________________________
          • (molecular weight) (thickness)
  • Choice of a cell-cycle specific or cell-cycle-independent
  • antagonist (?)
slide59

Antagonist (antibiotic):

cell-cycle specific: constant drug (antagonist) exposure to

maximize chance for interaction during susceptible

phase

cell-cycle independent: potential for maximal lethal effect

with short-term occupancy

Ideal? Cell-cycle specific of independent?

Ideal plasma kinetics for cell-cycle dependent?

Method of administration?

Loading dose?

slide60

pharmacodynamics:

- effect of agonist/antagonist on target tissue

- think: specificity for desired effect & safety

i.e. bacterial cell wall perturbation via

interaction with bacteria-specific receptor-

mediated process

slide61

Therapeutic Index

toxic or lethal dose 50 / therapeutic or effective dose 50

LD50 / ED50

slide63

theoretical dose-response curves for ideal drug?

ED50 vs TD50 or LD50

Consider the theoretical adjustments required in the dose-response curve with diabetic-induced impaired perfusion/drug diffusion.

advantages of 24 hour constant release transdermal patch route relative to oral 4 doses day
Advantages of 24 hour constant release transdermal (patch) route relative to oral (4 doses/day)
  • Bioavailability ?
  • Superinfection ?
  • Need to increase dose with impaired perfusion?
  • Cell-cycle dependent action?