Pharmakokinetics PDF

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Summary

PharmakoKINETICS: 1. DRUG: A chemical substance of known structure. Other than a nutrient or an essential dietary ingredient, when administered to a living organism, produces a BIOLOGICAL EFFECT. MEDICINE: Dosage forms (capsules, tablets, mixtures and elixirs). May contain MORE THAN 1 drug INACTIVE ...

Description

PharmakoKINETICS:

1. DRUG: A chemical substance of known structure. Other than a nutrient or an essential dietary ingredient, when administered to a living organism, produces a BIOLOGICAL EFFECT.

MEDICINE: Dosage forms (capsules, tablets, mixtures and elixirs). May contain MORE THAN 1 drug + INACTIVE SUBSTANCES necessary for manufacture.

2. LABEL OF THE MEDICINE:           

Trade name Generic name Active ingredients Quantities Registration Lot number Scheduling Forms of dosage Expiry date Storage instructions Preservatives

3. PACKAGE INSERT:             

(11)

(12)

Trade name Generic name Scheduling status Composition of medicine Pharmacological classification Action Indications CIs Warnings Dosage Directions for use SEs Special precautions

4. SCHEDULING:

0   

Sold to any person Still subject to registration Aspirin, nicotine gum, decongestant eye drops, paracetamol

  

Only sold in pharmacies To any person older than 14 Formulations (topical use) (skin, vagina), antimicrobials, NSAIDs, nasal decongestant, anthelmintic, nicotine patches

   

Only sold by PHARMACISTS To any person older than 14 With or without a prescription Antihistamine combinations, bronchodilators, heartburn relief, appetite suppressants, vaccines

  

Only supplied on PRESCIPTION CHRONIC DISORDERS Angina, diabetes, epilepsy, hormonal contraception, inhaled corticosteroids

 

Only supplied on PRESCIPTION Antimicrobials, antimalarial, anticoagulants, anti-Parkinson’s, corticosteroids, cytostatic, statins, warfarin

 

Only supplied on PRESCIPTION Anesthetics, hypnotics, antidepressants, anxiolytics, barbiturates, anabolic steroids

   

Only supplied on PRESCIPTION STRICT national and international control Records of supply demanded by law Narcotic analgesics, morphine, Flunitrazepam (“Rohypnol”)

1

2

3

4

5

6

7&8

  

BANNED substances May NOT be KEPT or MANUFACTURED without a permit issued by the Director-General of Health Cannabis, methaquolone, heroin, LSD, amphetamine, dex-amphetamine

5. ABSORPTION:  The uptake of substances into or across tissues



The movement of a drug into the bloodstream

6. PROPERTIES NB FOR ABSORPTION:

7.

8.

 LIPID SOLUBILITY  UNIONISED  pK of the drug  pH of the environment  Formulation  Stability to acid and enzymes  Gut motility  Food in stomach  Degree of first pass metabolism  PROPERTIES NB FOR RENAL EXCRETION:  WATER-SOLUBLE  URINE pH  IONISED  LESS ACTIVE METABOLITES  Concentrated in the bile and excreted into the intestine DIFFERENCE BETWEEN PD AND PK: PD

PK  Drugs on the body  Study of the biochemical and physiological processes underlying drug action  MoA  Drug-R interaction  Efficacy  Potency (safety profile)

9.

 Science of the rate of movement of drugs within biological systems affected by  Absorption  Distribution  Metabolism  Excretion

DIFFERENCES IN PLASMA HALF-LIFE

1ST ORDER

ZERO-ORDER

     

CONSTANT fraction of a drug eliminated INDEPENDENT of dose Plasma [D] declines exponentially Elimination mechanism adjust their activity to the prevailing [D] Proportion eliminated is INDEPENDENT of the starting [D] Doubling dose  doubling of plasma [] ↑ Dose/frequency of administration  PREDICTABLE ↑ in plasma [D]



THE PLASMA []     

10.

Constant fraction of drug is eliminated DEPENDENT on dose REGARDLESS OF [D] in plasma declines LINEARLY SATURATION kinetics (elimination becomes saturated) Repetitive administration is thus COMPLICATED PREDICTION of [D] over time PROBLEMATIC ↑ dose/frequency of administration  UNPREDICTABLE ↑ in plasma [D]

HALF-LIFE:    

Time required to excrete 50% of the absorbed dose of the D. Time required to lower the plasma [] of the drug by 50% [D] ↓ half its original Determined when injected IV

CLINICAL APPLICATION:        11.

WHEN IS SS REACHED:  

12.

4-5 HALF-LIVES Rate of drug ENTERING the systemic circulation (dosage rate) = rate of elimination

LOADING DOSE:    

13.

4 = 90% ELIMINATED ATLEAST 5 = COMPLETE ELIMINATION INDEX of time course of drug accumulation 4-5 = STEADY-STATE Determine DOSAGE INTERVAL INDEPENDENT of dosage Drug must follow 1ST ORDER kinetics

When time to reach SS is appreciable LONG half-lives Raises the [] of drug in the plasma  the target [] Rate of administration of LD need not be computed

BIOAVAILABILITY:

    14.

FRACTION of UNCHANGED drug reaching the SC following any route of administration 1st order = AUC F IV = 1

VOLUME OF DISTRIBUTION:    

Relates the AMOUNT of drug in the body to the [] in the blood or plasma Apparent volume May exceed any physical volume in the body Volume APPARENTLY necessary to CONTAIN the amount of drug HOMOGENOUSLY at the [] found in the blood, plasma or water

CLINICAL APPLICATION:  

LD can be calculated to obtain a specific blood level Calculate the TOTAL AMOUNT OF DRUG in the body at any given time

*DEDUCT EQUATION* 15.

CLEARANCE:        

16.

Volume of plasma cleared of drug per unit time A CONSTANT relating to the rate of elimination (CLxCp) to the [D] in the plasma (Cp) INDEX of how well a drug is removed IRREVERSIBLY from circulation Determines the DOSE RATE (dose/unit time) required to MAINTAIN a Cp Drug must follow 1ST ORDER kinetics A CONSTANT relating the RoE to the Cp, and the volume of plasma cleared of drug per unit time UNIT: L/h NB to calculate MAINTENANCE DOSE in individual patients

1ST PASS EFFECT:

Drugs secreted into the bile

Gall bladder

Periodically emptied into the small intestine

May be absorbed back into the body

A fraction secreted into the bile again (may re-enter the body)

Prolongs the length of time that the drug is in the body

IF THE CYCLE IS INTERRUPTED (Oral administration that binds the drug and prevents its absorption from the intestine (e.g. activated charcoal))

↓ Half-life 17.

ROUTES OF ADMINISTRATION:         

Oral Sublingual IM IV SC Rectal Inhalation Intranasal Topical

18.

2 GENERAL TYPES OF REACTION:

PHASE 1 reactions 

BIOTRANSFORMATION of drugs to a MORE POLAR metabolite

PHASE 2 reactions 

Drugs are made more HYDROPHILIC

     

Introducing/unmasking a functional group (-OH, -NH2, -SH) Oxidation = most common Catalyzed by MIXED FUNCTION OXIDASES (Cytochrome P450) VERY LOW substrate specificity Many different drugs can be oxidized Reductions and hydrolysis are other reactions

CYTOCHROME P-450DEPENDENT OXIDATIONS AROMATIC HYDROXYLATION Phenobarbital, propranolol, phenytoin, amphetamine, warfarin OXIDATIVE N-DEALKYLATION Morphine P-450-INDEPENDENT OXIDATION Amineoxidase, adrenaline (epinephrine)



CONJUGATION with endogenous compounds in the LIVER

TYPES OF CONJUGATION  Glucoronide  Acetyl  Glutathione  Glycine  Sulphate  methyl

REDUCTION Methadone, naloxone

HYDROLYSIS Procaine, aspirin, lidocaine 19. DRUG PLASMA-PROTEIN BINDING:  If a drug is displaced from PPs = ↑ [unbound drug] and ↑ drug effect, toxicity  NOT like above in the body  5% ↑ in the amount of unbound drug  5% ↑in pharmacologically active drug at SoA  ↑ amount of unbound drug in the plasma  ↑ rate of elimination (if unbound clearance is unchanged)  After 4 half-lives = the unbound [] returns to its previous SS  Displacing drug is an INHIBITOR of clearance  Change in clearance of the unbound drug is the relevant mechanism explaining the interaction 20. THERAPEUTIC INDEX:  A measurement relating the dose of a drug required to produce a desired effect to that which produces an undesired effect  Ratio of the TD50 to the ED50  Narrow = TI 1 then the solution is 99-100% ionized or 99-100% unionized*

22. Renal excretion o o o o o o o

GFR Tubular secretion Tubular reabsorption Alkaline urine = ↑ excretion of acidic drugs Aspirin = weak acid Administer Sodium bicarbonate to alkalinize urine TRAP aspirin in the tubule

23. BBB  P-glycoprotein = large family of ATP-transporters  Efflux transporter = transports drugs out of the cell to the extracellular space  LIPOPHILIC DRUGS crosses the BBB 24. HALF-LIFE, CLEARANCE AND VoD  ↓ VoD = no change in clearance = shorter half-life = faster to eliminate the drug from deep within the tissues  ↑ clearance = no change in VoD = ↓ half-life 25. TYPES OF KINETICS 1ST ORDER  CONSTANT fraction of drug eliminated/unit time  [plasma] ↓ = EXPONENTIALLY  Elimination mechanisms adjust their activity to the prevailing [D]  Proportion of the drug eliminated = INDEPENDENT of the starting [D]  Double dose = double [plasma]

0 ORDER  CONSTANT fraction of drug eliminated/unit time REGARDLESS of plasma [D] [D] plasma ↓ = LINEAR  SATURATION kinetics  

Eliminations becomes SATURABLE Prediction of [D] = PROBLEMATIC

 

Time to eliminate the drug is INDEPENDENT of dose ↑ dose/frequency of administration = PREDICTABLE ↑ in plasma [D]

  

Time to eliminate the drug is DEPENDENT on dose Repetitive administration = COMPLICATED ↑ dose/frequency of administration = UNPREDICTABLE ↑ in plasma [D]

EXAMPLES:       

Phenytoin, Phenylbutazone Warfarin Heparin Ethanol Aspirin Theophylline, Tolbutamide Salicylates

26. STEADY STATE    

The drug must be administered at a rate = rate of elimination at that concentration Rate of dose administration (unit dose divided by dosing interval), which affects proportionally the steady state plasma concentration. Bioavailability, which modulates rate of dose administration. Clearance: Reduced clearance will lead to higher steady state concentration, and vice-versa, making clearance inversely related to steady state concentration.

27. PLACENTA           

Semi permeable barrier. Site of metabolism of some D’s Toxic metabolites may form Fetal enzymes are poorly developed D’s are partially metabolized Shunting of D’s can take place Slow redistribution Cell membrane = lipid bilayers Passage of SMALL, LIPID-SOLUBLE molecules = relatively EASY Diet, hormones and pregnancy affect this Unionized drugs cross

28. ENZYME INDUCTION [D]  Drugs can either or ↓ metabolic enzyme activity



Long-term administration of D’s can induce CYP450 activity by rate of synthesis or ↓ rate of degradation of hepatic microsomal enzymes

 

More rapid metabolism of D’s and all D’s metabolised by the same enzymes Plasma levels and biological effects of D’s ↓

ENZYME INHIBITION of [D]   

The metabolism of other drugs ↓ This results in Blood levels of these D’s Clinical effect can be biologic effects or toxicity

29. FIRST ORDER ELIMINATION RATE CONSTANT:  [D] in the plasma falls exponentially during the elimination phase  Remaining [D] at time t: Ct = C0 x e-Kt (e = “Euler’s e’ with value 2.718)

30. CONSTANT STEADY STATE: 

The drug must be administered at a rate = rate of elimination at that concentration

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