Pharmacokinetics:
Absorption and transport of drugs—
o Biological membranes are lipid bi-layer structure.
o The ability of a drug to diffuse across the cell membrane depends upon the lipid : H2O proportion co-efficient.
o There are pores or channels in the membranes which impose less restriction and permits low molecular weight drugs to pass through.
o It is the pK of the drug and pH of the surroundings which determines the relative proportion of ionized and unionized portion of drugs.
o Drugs whether acidic or basic are absorbed or transported across membrane in unionized form. Drugs favourably excreted in the ionized form.
o Acidic drugs are better absorbed in the acidic media and basic drugs are better absorbed in the basic media.
o Acidic drugs are better excreted in the basic media and basic drugs are better excreted in the acidic media.
Dose—it is an amount of drug which is given to produce a certain amount of response.
Different doses of drugs—
o Therapeutic dose | o Lethal dose |
o Minimal dose | o Fatal dose |
o Maximal dose | o Toxic dose |
Therapeutic dose—this is the minimum amount of drug which brings desired effect in the subject.
Toxic dose—dose that produce excess pharmacological effect.
Lethal dose—it is that dose which will kill at least 1% but not 100% of the subjects.
Fatal dose—it is that dose which will kill 100% of the subjects.
ED50 (median effective dose)—amount of drug which have desired pharmacological effect on 50% of the experimental animal.
LD50 (median lethal dose)—it is the minimal amount of drug which kills 50% of the experimental animal.
Therapeutic index—it is the ratio of lethal dose (LD50) to effective dose (ED50) which indicates the safety margin of use. It means the higher the index is safer the dose. TI = ED50 / LD50
Drugs with higher therapeutic index—Benzodiazepine
Drugs with lower therapeutic index—Warfarin (anti-coagulant), Digoxin (cardiac glycosides).
Different formulations of drug—
o Tablets
o Capsules
o Aerosol—pressurized metered form
o Solutions / Mixtures—there are one or more active ingredients present in water used for internal or external use
o Emulsions
o Cream / Ointment—these and emulsions are preparations which contains one or more ingredients present in hydrophilic or hydrophobic phase.
Factor determining the rational prescribing of drugs—
1. Specific diagnosis
2. Pathophysiology of the disease/condition
3. Selection of therapeutic object
4. Selection of appropriate drug
5. Determination of the dosing schedule
6. Consideration of any other pathology within the host
Different method of drug transport—
1. Passive/simple diffusion
2. Active transport
3. Facilitated diffusion
4. Filtration
5. Bulk flow
6. Endocytosis
7. Ion pair exchange
Criteria for passive diffusion—
1. Drug diffuse from higher to lower concentration
2. Diffusion depends upon the lipid-water proportion co-efficient
3. No carrier molecule is needed
4. No energy id required
Criteria for active transport—
1. Drugs diffuse against concentration gradient
2. Such drugs must resemble endogenous substances
3. Carrier protein molecule are needed
4. Carrier molecule exhibit selectivity and saturability
5. Energy is required
Criteria for facilitated diffusion—
1. Diffusion depends upon the concentration gradient
2. Requires protein carrier molecule
3. Energy is not needed
4. Carrier molecules show selectivity and saturability
Bioavailability—it may be defined as the fraction of unchanged drug that reaches the systemic circulation in the intact form irrespective of the route of administration. It is 100% in case of IV route and next is IM route (90%).
*** higher the bioavailability of drug, longer will be the duration of action.
Factors affecting bioavailability—
1. Solubility of the drug
2. Chemical formulation and stability
3. First pass metabolism after oral dosing
4. Routes of administration
5. Blood flow at the site of administration
6. Concentration of the drug
7. pH of the surrounding area
Routes of administration—
Oral route—
Advantages | Disadvantages |
o It is the safe and easy route o It ensures better patient compliance o It may be cost effective o Longer duration of action o May be used for diagnostic purpose | o It cannot be used in unconscious patients o Cannot be used in emergency situation and vomiting o Some drugs may be destroyed by the gastric juice. (adrenalin and insulin is broken down by pepsin and penicillin-G is broken down by HCl) o Bitter and large volume of drug cannot be given. |
Intravenous route—
Advantages | Disadvantages |
o Rapid onset of action o 100% bioavailability o Avoids first pass metabolism o Can be used in unconscious patients | o Sterility is essential o May cause thrombo-phlebitis o May cause air-embolism o Risk of toxicity |
Subcutaneous route—(insulin is given in case of diabetes)
Advantages | Disadvantages |
o It is a reliable route o Self medication is possible o Can be used in daily basis o Good patient compliance o Acts as a drug reservoir | o Sterility is essential o Pain due to irritation o Poor absorption in the peripheral circulatory failure o Less therapeutic index o Costly route |
Sublingual route—(nitroglycerine tablets in anginal pain)
Advantages | Disadvantages |
o Rapid onset of action o Avoid first pass metabolism o Self medication is possible o The drug can be discarded after its effect. | o Excess salivation o Irritation to oral mucosa o Cannot be used in unconscious patients |
*** other routes are Intramuscular (IM), Rectal and Inhalation.
Factors affecting drug transport—
Drug factors | Host factors |
o Physiochemical nature o Solubility o Polarity o pKa of drug o Formulation o Routes of administration o Dose o Dissolution time o Disintegration time | o Blood flow o Local pH o Surface area o First pass metabolism (oral drugs) o GIT motility (oral drugs) o Presence of food (oral drugs) o Any other pathology |
*** pK—such a condition where the drug is half ionized and half un-ionized.
Distribution of drugs—
Volume of distribution—it is the imaginary volume of fluid expressed in liter which will accommodate the entire quantity of the drug in the body, if the concentration throughout the imaginary volume were same as there in plasma. It is denoted by symbol VD.
o Drug is distributed in combination with the plasma protein binding.
o Drugs mainly bind with albumin.
o Drugs with higher plasma protein binding have lower tissue volume of distribution.
o The extent and strength of protein binding with drug will effect the time drug spends inside the body and its overall duration of action.
Ex—Aspirin (11L), Ampicillin (18L), Warfarin (8L), Basilin (500L), Chloroquine (13000L).
Factors affecting drug distribution—
1. Regional blood flow and capillary permeability.
2. Physiochemical properties of drug.
3. Binding with plasma proteins.
4. Drug concentration.
5. Transport mechanism.
6. Permeability characteristics.
7. Blood flow tissue mass ratio.
Role of plasma protein binding are—
1. Transport drug molecules
2. Affects half life of drug
3. Affects tissue volume of distribution
4. Affects duration of action
5. Acts as a drug reservoir
Selective distribution—this refers to the situation in which some drugs attain higher concentration in certain tissue compared to the other drugs depending upon—
a. the affinity of the drug for the tissue
b. selectivity of the drug binding
such distribution may prolong the activity of a drug or may encourage adverse effects due to persistence of the drug in the body. Ex—
o Chloroquine (anti-malarial drug) accumulates in the retina and causes retinopathy
o Amioderon (anti-arrhythmatic drug) accumulates in the thyroid and may cause thyroid disorder
o Calcium accumulates in the bone
o Iodine accumulates in the thyroid.
Half life—it may be defined as the time taken by a drug in which the drug concentration in the plasma becomes half of its initial or previous drug concentration.
After 5 or 5½ half lives there is no drug in the plasma. Half life of ampicillin is 6hrs and amoxicillin is 8hrs.
First pass metabolism—it is the metabolism that occurs after absorption during the first passage of drug (in the liver) before it reaches the systemic circulation.
It depends on—
o Lipid solubility of drug—highly lipid soluble drugs are more absorbed and more first pass metabolism, on the other hand less bioavailability and less duration of action as they are metabolized very early and also widely distributed. In case of water soluble drugs it is vise versa.
*** if any drug highly binds with the protein then there is less volume of distribution and will not leave the circulation very early. So has long duration of action, less metabolism and less excretion.
***routes which avoid first pass metabolism are IV, sublingual, per-rectal (if the drug is absorbed from lower rectum)
Drugs undergoing significant first pass metabolism—
o β-blocker (Propranolol)
o Anti-depressants (nor-tryptylline)
o Analgesics (Morphine)
o Calcium channel blocker (Nifedipine)
o Anti-psychotic (chlorpromazine)
How pH influences drug absorption—
Acidic drug in acid medium do not disintegrate and remains in the un-ionized form. Un-ionized drugs are lipid soluble and so are more absorbed. In alkaline medium it is ionized and less absorbed. Vise versa in case of alkaline drugs.
Biological half life—it is the time in which the biological effect of drug declines by 50%.
*** with drugs such as competitive agonist or antagonist of a receptor we use this term.
Importance of biological half life—
1. To predict the time taken by the drug to reach steady state concentration in the plasma.
2. To determine dosing schedule.
3. To estimate the time taken by a drug to be eliminated.
4. Half life affects the duration of action of drugs in the presence of other pathology.
Metabolism / Biotransformation—
These are chemical reactions occurring within the body which reduces the lipid solubility and biological activity of drugs, thereby making them progressively more water soluble and favours for elimination. (through kidney)
Biotransformation occurs in the endoplasmic reticulum of the hepatocytes in the microsomes. Microsome is the fragmented smallest part which maintains the characteristics of ER.
Objective—to make lipid soluble, un-ionized and less polar drugs more water soluble, ionized and polar.
Biotransformation involves—
- Conversion of inactive drug into active drug—
Levodopa (anti-parkinsonism drug) → Dopamine (active drug)
- Conversion of active drug / agent into active metabolites—
Diazepam (sedative) → Oxazepam
- Conversion of active drug or active metabolite into inactive metabolite—
Propranolol (β-blocker) → Hydropropranolol
Phases of metabolism—
Phase-1 (non synthetic reaction)—it is the phase which usually converts the parent drug to a more polar form by introducing or unmasking a functional group (OH, NH2, SH). Phase-1 involves three important reactions—oxidation, reduction and hydrolysis. The metabolites formed may retain biological activity. Among the three oxidation is the single most important reaction. The oxidative enzymes are located in the cellular microsomal components.
The drug metabolizing enzymes are known as cytochrome P450 or cyt-P450.
Phase-1 reactions—
Oxidation—
Aromatic hydroxylation— | Propranolol, Phenytoil, Phenobarbitone |
Aliphatic hydroxylation— | Amobarbital, Ibuprohpen, Chlorpropamide |
Deamination— | Amphetamine, Diazepam |
Desulfuration— | Thiopental Sodium |
Reduction—
Nitro-reduction— | Chloramphenicol |
Hydrolysis—
Esters— | Aspirin, procaine |
Amide— | Lidocaine, Procainamide |
*** if phase-1 metabolites are sufficiently polar, they may be readily excreted. However many phase-1 products are not eliminated rapidly and undergo subsequent phase-2 changes.
*** phase-2 reactions might precede phase-1.
*** Isoniazide can produce an acetyl conjugate type of metabolites in phase-2 and then metabolites are hydrolyzed in phase-1.
Phase-2 (conjugation reaction)—it is the phase which involves the union of a drug molecule or an active metabolite with one or more endogenous substances that are products of intermediary metabolism in order to produce a highly polar conjugate. This phase terminates the biological activity of a drug. Phase-2 involves reactions such as Glucoronidation, Acetylation, Methylation
Phase-2 reactions—
Reaction | Endogenous substances | Drug |
Glucoronidation | UDP, Glucoronic acid | Morphine, Diazepam, Digitoxin, Paracetamol. |
Acetylation | Acetyl co-A | Isoniazide, Dapsone |
Sulphation | Phospho-sulphate | Methyldopa |
Methylation | S-adenosyl Methionine | Epinephrine, Dopamine |
The phase-2 reactions or conjugation reaction involves high energy intermediates and specific transfer enzyme. The enzymes are located in the microsomes or cytosol. These enzymes catalyzes coupling of an activated endogenous substance with a drug or an activated drug with and endogenous substance.
o Most metabolic reactions or biotransformation occur at some point between absorption of the drug into the general circulation and its elimination.
o Metabolic products are pharmacologically less active than the parent drug.
o 2 phases of biotransformation leads to termination of activity of drug.
Prodrug—it may be defined as the drugs which are inactive when administered which upon entering the body is converted by the body fluid or tissues enzymes into active form.
First order kinetics—the kinetic processes for which the rates of the reactions are proportional to the concentration of the drug, is called first order kinetics. In the majority of cases the drugs commonly taken follow the 1st order kinetics. When a drug follows first order kinetics half life will be constant.
Saturation or zero order kinetics—the kinetic processes for which the rates of the reactions are disproportionate to the concentration of the drug. Many drug may exhibit saturation kinetics if given at high enough doses. The distinction between 1st order and zero order kinetics become the clinically important issue when the change from one to the other occurs in the therapeutic range. In saturation kinetics half life is not constant.
Factors affecting drug metabolism—
1. Genetic factors
2. Diet and environmental factors
3. Age
4. Sex
5. Diseases
6. Drug—drug interaction
7. Interaction between endogenous substances and drug
8. Physiological status of pregnancy
9. Pharmacokinetic properties of the drug
10. Physiochemical properties of the drugs
Enzyme Induction—it is the ability of a drug or an agent upon repeated administration to induce cyt-P450 enzyme either by enhancing the rate of synthesis or decreasing the rate of degradation of the enzyme. Induction thus accelerate drug metabolism and decrease pharmacological action of a drug.
Enzyme inducers are—Rifampicin, Phenobarbital, Phenytoin, and Carbamazepine.
{Rifampicin + Oral contraceptives, Phenobarbital + Propranolol}
Clinical relevance of drug metabolism induction—
1. Variability in drug response
2. Risk of toxicity
3. Development of tolerance
4. New disease
(Phenytoin is an anti-epileptic drug that may cause Osteomalacia by interfering with vit-D / Calcium metabolism)
Auto-induction—an enzyme inducing drug that not only increases the metabolism of another drug but also that of its own metabolism. This is called auto-induction. The drug is called enzyme auto-inducer. Ex—Carbamazepine.
Enzyme inhibition—certain drugs may inhibit cyt-P450 enzyme thus decreasing the metabolism of other drugs and increases their pharmacological effect. Drug may irreversibly inhibit the enzyme. Ex—Cimetidine, INH (Isoniazide), Metronidazole, Quinolones.
Bio-assay—it is the process by which the activity of a substance (identified or un-identified) is measured on living material. It is used only when physical and chemical methods are not applicable.
Biological standardization—it is a specialized form of bio-assay. It involves matching of materials of inknown potency with an international or national standard with the objective of providing preparations for use in therapeutics and research. It is expressed in the units of the substances.
Drug elimination / Excretion—
It is the pharmacokinetics process by which drugs after being partly or wholly converted to water soluble metabolites and in some cases in unchanged form are removed from the body.
Different routes of drug elimination—
Renal—nearly all drugs except those bound to plasma protein
Pulmonary—volatile anaesthetics like Ethanol, Halothane, Alcohol, Nitrous oxide
Hepatic/Biliary—Digoxin, Morphine, Chloramphenicol, Diltiazem, Propranolol, Rifampicin
Faecal—Tetracycline, Erythromycin
Breast milk—Tetracycline, Anti-asthmatics, Anti-epileptics, Anticancer drugs
Saliva—Nicotine, Quinine, Metronidazole, Theophylline
Sweat—Drugs of low concentration, NaCl
Hair and nails—Arsenic, Lead
Factors affecting the renal excretion of drug—
Renal perfusion and glomerular filtration | o Plasma protein binding affects filtration o Filtration rate depends upon plasma drug concentration and molecular weight of drug o Renal perfusion influences GFR |
Tubular reabsorption | o Most drug reabsorption takes place in distal tubules and collecting ducts o Extent of reabsorption depends upon pK and pH o Active reabsorption is important for endogenous substances |
Tubular secretion | o Secretory mechanism for acidic and basic drugs are located in the renal tubules o These secretory processes may become saturated at high drug concentration o Drugs of similar changes compete for same secretory mechanism |
pH of the tubular fluid | o Tubular pH effects the ionization of drugs o Acidic drugs are excreted if tubular fluid is alkaline o Basic drugs are excreted if tubular fluid is acidic o Modification of the tubular fluid pH helps in drug poisoning |
*** to make the urine alkaline we give NaHCO3
*** to make the urine acidic we give Citric acid
Pulmonary elimination—
This kind of elimination is useful for drugs like anaesthetics. The drug elimination through the lung will depend upon respiratory rate, pulmonary blood flow, solubility of the drug in the pulmonary blood flow. So the elimination of the poorly soluble drugs depends upon CO, highly soluble drugs are readily eliminated.
Biliary excretion—this process of drug excretion through the bile is important for heavy metals and also for some un-ionized drugs (cardiac glycosides). Passage of most foreign compounds from the liver into the bile is not restricted. Conjugation of a drug or its metabolites is important for biliary excretion of a drug. If the drug is in small molecular size it can be easily reabsorbed into the bile canaliculi.
Faecal excretion—if a drug is given orally for systemic purpose a proportion of a drug may remain inside the gut, this portion will be excreted in the stool. There are some drugs which are given to produce the local effect on the GIT. Neomycin is an antibiotic which can be used for gut sterilization. Actively secreted drugs generally do not undergo recycling because they are not substrate for intestinal bile transport system.
Breast milk excretion—milk is generally acidic in nature than the plasma, therefore basic drugs can easily concentrate in the breast milk. Weakly acidic organic drugs attain lower concentration in the breast milk than the plasma. Highly lipid soluble drugs (Morphine) tend to accumulate in the breast milk fat. Examples of drugs which are excreted through the breast milk are aspirin, morphine, barbiturates, ethanol, caffeine etc.
Drugs like opioid analgesics (Morphine) in the suckling baby can produce respiratory depression. β-blockers given to the mother may produce hypoglycemia in the children. Barbiturates given to the mother can cause somnolence in the child.
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