Eliminated from the body It is the process by which a drug or metabolite is 1Prof.DR.AL SAYED...

eliminated from the body

It is the process by which

a drug or metabolite is

1Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA

o Passive glomerular filtration

o Active tubular secretion in proximal tubules

o Passive tubular reabsorption.


Factors affecting renal excretion:

1-Glomerular filtration rate:

D

• Free • Water soluble • Low molecular weight

Filtered


Acidification of urine• vitamin C • NH4Cl

weak basebase drugs

2-Change in urinary pH

B+

B+

B+B+

B+

B+B+

Ionized

e.g. amphetamine

In AcidicAcidic medium

Excretion


Alkalinization of urine

weak AcidicAcidic drugs

2-Change in urinary pH

Ionized

In AlkalineAlkaline medium

Excretion

e.g. aspirin

A-A-A-A-

A-A-A-

NaHCO3


oIodides

oRifampicin

oSalicylates

Morphin

e

Tetracycline

Streptomycin


Portal v.

Bile

Ampicillin

Rifampicin

Biliary infection

Morphine

Enterohepatic circulation


3-Sweat: e.g., rifampicin (red color), vitamin B1.

4-Lungs: e.g., gases and volatile anesthetics.

5-Milk: Morphine Amphetamine Chloramphenicol Oral anticoagulants


What the drug does to body


It is the study of the:

Their mechanisms of action

Biological & therapeutic effects of drugs


Physical action :

kaolin adsorbs toxins in diarrhea.


Chemical action :

Hcl

+ NaHCO3

12

Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA

RIntracellular

5. Cytotoxic action

Cell membrane

Nucleus

ion

2. selective passage of ions

XY → X +Y

E

Z

4. Metabolic pathway

1. Specific receptors

3. Enzyme

13


E

Rev

Action on enzyme

Irrev

Stimulation Inhibition

Reversible

• short lasting

• e.g: Neostigmine

Cholinesterase

Irreversible

long-lasting (new enzyme synthesis )

e.g:

Organophsphrous compounds

E

E 14


R

Intracellular

Cell membrane

Nucleus

Action on Specific receptors

RR

Bind specifically with a ligand:

• Neurotransmitter

• Drug

• Hormone

Biological response

ligand

15Prof.DR.AL SAYED ZAKI-BMC-

SAUDIA ARABIA

R

Nucleus

Biological response

ligand

Affinity =tendency to bind receptors

Efficacy =

Potency = how much drug is required to elicit a response.


SAUDIA ARABIA

Agonists

R

ligand

• Affinity

• Efficacy

• Rapid dissociation rate

initiate changes

Antagonists • Affinity

R

ligand

• No efficacy

without initiating change

• slow dissociation rate

• Prevent action of agonist

ligand

17


Competitive antagonism

R

antag

Ag

Ag

Ag

R

antag

Ag

Ag

Ag

Non-Competitive antagonism

Displaced by an

excess agonist Not displaced by an

excess agonist 18Prof.DR.AL SAYED ZAKI-BMC-

SAUDIA ARABIA

Partial agonists

Stimulate and block receptors

Affinity

Efficacy (less than full agonist)

Moderate dissociation rate


Inverse agonists •Produce effects opposite to that of agonist

•Benzodiazepines

•Agonists of Bz receptors

• Sedation, • Muscle relaxation • Anxiolytic action

•Inverse agonists of the Bz receptors

•Carbolines

• Convulsions • Anxiety.



1 (Age:Newborn infants especially premature are

more susceptible to drugs due to:

Underdevelopment of microsomal enzymes

Low plasma protein and low binding capacity

Reduced excretory function

Immaturity of blood brain barrier 22Prof.DR.AL SAYED ZAKI-BMC-

SAUDIA ARABIA

In infants use:

Clark's formula = adult dose x weight in kg

70

1 (Age:


•Children require small dose than adults

• In children use

Young's formula = adult dose x Age in years

Age +12

•They may metabolize some drugs more rapid

&so may need high dose of digitalis

1 (Age:


between 60-70 years

Elderly:

3/4 of adult dose

above 70 years ½the dose.

This is due to :

• Ageing of liver microsomal enzymes

• Underweight

•Reduced renal function

1 (Age:


2 (Body weight and surface area :

• The bigger the body weight the larger the dose

The increase in weight due to :

Oedema

Or Fat

Is not taken into consideration


In obese patients :

Dose of fat soluble drugs

Dose of water soluble drugs .

Surface area is more accurate parameter for dose calculation


2 (Sex:

need smaller dose than

This is due toThis is due to : :

Fat content

Enzyme inhibiting effect of female sex hormones

Enzyme inducing effect of male sex hormone 28Prof.DR.AL SAYED ZAKI-BMC-

SAUDIA ARABIA

During menstruation avoid : salicylates and castor oil.

During pregnancy avoid :

teratogenic drugs,

cathartics and uterine stimulants

During lactation avoid: chloramphenicol,

oral anticoagulantsphenolphthalein

2 (Sex:


3 (Route of administration:

I.V sublingual & inhalation

S.C I.M. oral >>> >Affect the dose:

I.V dose less than oral.


Magnesium sulphate:

• Orally is purgative

• Rectally is dehydrating agent

• I.V. it is anticonvulsions &

antagonizes Ca++

Affect the Action:

3 (Route of administration:


4) Drugs intolerance = supersensitivity

= hypersusceptibility:

Exaggerated action to normal dose of a drug

it may be due to:

• Decrease clearance of drug

or

• Upregulation of receptors.

dose


5(Tolerance:

Failure of response to the usual dose of a drug.

It may be:

1 .Congenital:

a) Racial:

b) Species:

c) Individual variation

2 .Acquired:


2 .Acquired Tolerance:

e.g:.

• Morphine,

Reversible

It may develop to some actions only & not to all actions

•Ethyl alcohol

• Nitrates, •Ephedrine


Special types of tolerance:

1) Tachyphylaxis e.g:

ephedrine on B.P.

2) Cross tolerance

(tolerance between related drugs)

e.g:

between ethyl alcohol & general anaesthesia.


Variation in drug response may be due to:

3. Number or

function of receptors

R

D

Variation in:

1 .Drug concentration

DD

D2 .Concentration of

endogenous transmitters

RR


SAUDIA ARABIA

6 (Hypersensitivity (allergic) reaction:

D

Hapten

Immune response

D Does not occur on first exposure

Not dependent on dose


7) Idiosyncrasy = pharmacogenetics:

Abnormal reaction to drug due to: genetic

or enzyme defect:

o Succinylcholine apnea cholinesterase enzyme

o Malignant hyperthermia with

succinylcholine or halothane


7) Idiosyncrasy = pharmacogenetics:

o Anaemia & methemoglobinemia

G-6-PD

slow isoniazid acetylatoro Peripheral neuritis with


8 (Drug dependence:

Habituation :

Emotional or psychological

dependence on the drug

when stopped

Emotional distress


Addiction

Psychic craving for and physical

dependence on the drug

when stopped

severe withdrawal reaction

8 (Drug dependence:


9 (Pathological State:

Aspirin lowers fever temperature to normal,

but no effect on normal one.


10 (Cummulation:

Rate of drug administration > elimination

e,g, digitalis and guanethidine


11 (Emotional State (Placebo effect):

•Placebo are inert dosage forms which produce

their effect psychologically.

•They are used in testing new drugs


12 (Drug Combinations:

a. Addition or summation:

b. Synergism :

c. Potentiation:

d. Antagonism:

1 (Physiological

2 (Chemical

3 (Pharmacological


Toxicity of Drugs

Adverse (unwanted) drug effects

A) Unpredictable

1- Allergy (hypersensitivity reaction)

2- Idiosyncrasy.

B) Predictable


B) Predictable:

1- Overdose toxicity.

2- Teratogenic effects

3- Iatrogenic drugs

4- Long-acting sulphonamides can produce

jaundice in premature babies.


5- Blood dyscrasias by chloramphenicol,

6- Carcinogenic effect, e.g. smoking and radiation.

7- Hepatic toxicity, e.g., halothane.

8- Nephrotoxicity by: sulphonamides, aminoglycosides, phenacetin.

9- Nerve damage, e.g.: streptomycin can produce 8th cranial nerve damage


10 -Secondary effects, e.g:.

prolonged use of broad spectrum antibiotic

• superinfection &

• Vit. B & K deficiency.


11-Intolerance.

12-Drug dependence and addiction.

13-Drug interactions.



Therapeutic dose:

the average adult dose required

to produce a therapeutic effect.


Lethal dose:

dose that produces death

Maximal tolerated dose:

largest safe dose that can be taken.


Loading dose :

the dose given at the onset of therapy to

achieve rapid increase in

plasma drug concentration to reach Css

within therapeutic range.


Maintenance dose :

It is the dose needed to keep

the plasma drug concentration constant

at the steady state

i.e. to compensate for drug loss

in between doses.55Prof.DR.AL SAYED ZAKI-BMC-

SAUDIA ARABIA

Therapeutic index :

LD50/ED50

LD50 (median lethal dose): minimum dose that produces death

in 50% of experimental animals.

ED50 (median effective dose):

dose that produces

a certain pharmacological effect

in 50% of experimental animals.

it is measure for safety of drugs

56



SAUDIA ARABIA

Plasma half life of a drug (t ½):

24

6

12

18

Drug concentration in Plasma

Time

Decline by

one half

=4 hours ?


SAUDIA ARABIA

Plasma half life of a drug (t ½):

• It depends on drug clearance

• Half-life (t1/2) is important to indicate

the time required to attain steady state

• It is a measure for drug elimination


Types of drug elimination kinetics

First order kinetics:

a constant proportion of drug is

absorbed, metabolized or eliminated

depending on the drug

concentration


Types of drug elimination kinetics

Zero order kinetics:

where a constant number of

moles are absorbed or eliminated

irrespective of the total amount present.


First order kinetics

Rate of the process

≠α the amount of drug

t ½ is constant

Linear disappearance curve if log dose is used

Zero order kinetics

Rate of the process

the amount of drug

t ½ increases with dose

Non-linear disappearance curve if log dose is used


Methods to prolong duration of action of drugs

11--Delay absorptionDelay absorption

a) add vasoconstriction e.g adrenaline to local anaesthetics.

b) Add oil e.g. vasopressin.


e) Use of sustained release (SR) or controlled release (CR)

or timed release (TR)

c) Use of suspensions e.g. protamine zinc insulin.

d) S.C pellet implantation e.g. contraceptives

long acting preparations


3-Decrease metabolism

4-Delay renal excretion:

probenecid to decrease penicillin excretion.

2-Increase protein binding:

e.g. sulfonamides.

e.g. enzyme inhibitors


Prof.DR.AL

66

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Eliminated from the body It is the process by which a drug or metabolite is 1Prof.DR.AL SAYED...

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