The word Pharmacokinetics is derived from Greek words Pharmacon (drug) and kinein (to move). Thus Pharmacokinetics is the quantitative study of drug movement through and out of the body. To obtain the right effect with minimum risk of toxicity, the dose and mode of administration of the drug is determined by its pharmacokinetics. Its help is also taken to study latency of onset, time of peak action and frequency of administration a drug.
All pharmacokinetics processes involve transport of the drug across biological membrane (bimolecular lipid layer). It is composed of phospholipids, cholesterol and small quantity of carbohydrates. It also contains pores and intercellular gaps (between certain interepithelial cells). Drugs are transported across the biological membranes by:
- Passive diffusion.
- Specialized transport.
Passive diffusion: Diffusion is a passive process in pharmacokinetics. The biological membrane plays no active role in the process. Thus the mechanism is non-specific and non-energy dependent. The drug diffuses across the membrane in the direction of its concentration gradient. It is dependent upon the solubility of the drug in the lipid layer. It is proportional to lipid: water partition coefficient of the drug.
So a more lipid soluble drug can be absorbed by this process quickly in pharmacokinetics. Further the diffusion of the drug is faster if the difference in the concentration of the drug on two sides of the membrane is greater. Influence of pH is equally important in passive diffusion of drugs. This is because most drugs are weak electrolytes, i.e. their ionization is pH dependent.
As a general principle in pharmacokinetics, basic drugs are more ionized and less diffusible in a relatively acidic medium while they are more lipid soluble and more diffusible in a relatively alkaline medium. Similarly acidic drugs are more ionized and less diffusible in a relatively alkaline medium while they are more lipid soluble and more diffusible in a relative acidic medium.
Thus the non-ionized (non-polar) lipid soluble molecules can diffuse across the lipid membrane while the ionized (polar) water soluble molecules are unable to penetrate it. Weakly acidic drugs form salts with cations, e.g. sodium sulfadiazine, sodium phenobarbitone, potassium penicillin V, etc. They are largely unionized at acid gastric pH.
Hence they are absorbed from the stomach. In pharmacokinetics, Weekly basic drugs form salts with anions, e.g. atropine sulfate, ephedrine hydrochloride, chloroquin phosphate, etc. They are largely ionized in gastric pH. So they are poorly absorbed from stomach In intestinal alkaline pH, they remain unionized and are mainly absorbed from that site.
Acidic drugs are ionized more in alkaline urine. They do not back diffuse in the kidney tubules and are excreted faster. On the other hand, basic drugs are excreted faster if urine is acidified. There are a few exceptions to the basic principles in pharmacokinetics mentioned above as under:
- Both ionized and non-ionjze forms of some drugs are highly water soluble (e.g. penicillin). They are, therefore, excreted rapidly irrespective of the urine pH.
- Some drugs are permanently ionized at all values of body pH, e.g. heparin (acidic) or tubocurarine, suxametho nium, ipratopium (basic). These are non-diffusible polar drugs. They are neither absorbed from the gut nor diffuse into the fissues.
- On the other hand, some drugs are incapable of becoming ionized at any environmental pH (digoxin, and chioramphefficol) These are non-polar drugs that diffuse readily across the membrane
Filtration in pharmacokinetics: It is transportation of drugs with very low molecular weight (100—1 50), e.g. lithium and methanol, through aqueous pores in the biological membrane. Filtration of water soluble drugs can also take place through interepithelial gaps. Since capillary gaps are larger, they allow the filtration of drugs/cherni5 with molecular weight up to 20,000—30,000 into extracellular spaces if not bound to plasma proteins.
These gaps are still bigger in glomerular capillaries. So they allow filtration of drugs with molecular weight up to 69,000. No drug is filtered into the brain or placenta (blood brain/CSF and bloodplacental barrier) because inter-capillary gaps are missing at these sites.
Specialized transport in pharmacokinetics: It may be: Carrier-mediated transport and Pinocytosis.
i. Carrier_mediated transport in pharmacokinetics: In this case, the drug combines with a carrier (a specialized protein molecule) present in the membrane. The complex thus formed translocates from one face of the membrane to the other. Generally, such transport requires expenditure of energy. So it is called active transport. The transport is against concentration gradient. Metabolic poison inhibits this process. It is a specific, saturable process. It is competitively inhibited by analogues which utilize same carrier. Sometimes non-diffusible substances are translocated along their concentration gradient (e.g. vitamin 812). It is called facilitated diffusion. It is not dependent on energy.
ii. Pinocytosis in pharmacokinetics: In this case, the substance is transported across the cell in particulate form by formation of Carrier-mediated transport
Important features are:
- Active process.
- Occurs against concentration gradient.
- Energy dependent.
- Competitive inhibitive by analogues.
Carrier-mediated Transport in pharmacokinetics: In this case, the drug combines with a carrier (a specialised protien muscle) present in the membrane. The complex thus formed translocates from one face of the membrane to the other. Generally, such transport requires expenditure of energy. So it is called active transport. The transport is against concentration gradient. Metabolic poison inhibits this process.
It is a specific, saturable process. It is competitively inhibited by analogues which utilize same carrier. Sometimes non-diffusible substances are translocated along their concentration gradient (e.g vitamin B12). It is called facilitated diffusion. It is not dependent on energy.
Pinocytosis: In this case, the substance is transported across the cell in particulate form by formation of vesicles. Proteins and other big molecules are transported by this process. This is rarely applicable to drugs.
ABSORPTION AND BIOAVAILABILITY OF A DRUG
- Absorption means the movement of drug from its site of administration into the bloodstream. Clinical efficacy of drug depends on:
- The route of administration that determines the latent period between administration and onset of action.
- The fraction of the administered dose absorbed.
- Rate of absorption; its significance is given in the box.
- Significance of information regarding the rate of absorption
- To decide the frequency of administration of a drug.
- To determine the duration of effectiveness of a drug.
- To forecast the onset of desired or undesired effects of a drug.
The drug has to cross biological membranes except when given i.v. So its absorption is governed by the above described principles. Other factors affecting absorption are:
1. Physical properties:
- Concentrated solution of drug is absorbed faster than from diluted solution because passive transport depends on concentration gradient.
- Drugs are absorbed in aqueous phase. So liquids are better absorbed than solids and crystalloids are better absorbed than colloids.
- Drug is removed from the site of absorption by blood circulation. ft is also responsible for the maintenance of concentration gradient across the membrane. So increased blood flow hastens drug absorption.
2. Dosage form:
- Smaller the particles of the drug in a tablet better is the absorption. So by reducing the particle size, the dosage of the active drug can be reduced without lowering efficacy, e.g. corti coids chloramphenicol, griseofulvin, tolbutamide and spironolactone. On the other hand, in order to reduce absorption of anthelmintic (bephenium hydroxy-naphthoate), the particle size should be large.
- To formulate powders or tablets, lactose, sucrose, starch and calcium phosphate or lactate is used as inert diluents. However, such substances may not be totally inert. They may influence the absorption as well as stability of the medicament. For example, calcium phosphate used as a diluent for calciferol may cause calcium toxicity, when given in large doses.
- “Disintegration time” (rate of break up of the tablet or the capsule into the drug granules) and the dissolution rate (rate at which drug goes to solution) are important factors in determining the absorption of a drug.
3. Larger the area of absorbing surface faster is the absorption.
4. Each route of administration has its own peculiarities. It, therefore, affects drug absorption as under.
- Epithelial lining of the gastrointestinal tract is lipoidal. So it acts as effective barrier to orally administered drugs. The rate of absorption of non-ionized lipid soluble drugs (e.g. ethanol) from stomach as well as intestine is proportional to their lipid: water partition coefficient.
- Acidic drugs (e.g. salicylates, barbiturates, etc.) are absorbed from the stomach because they remain unionized in the gastric juice while basic drugs (e.g. morphine, quinine) are poorly absorbed as they remain ionized in the gastric juice. They are absorbed only on reaching the duodenum (alkaline pH). However, even absorption of acidic drugs from stomach is slower because of the following reasons: Thick mucosa, Mucous on mucosa and Small surface area.
- Presence of food retards/aids the absorption of drug by altering the gastric emptying time. It is observed that food retards the absorption of aspirin, ampicillin, captopril, digoxin, isoniazid, levodopa, penicillin G, rifampicin and tetracycline while it aids the absorption of carbamazepine, chioroquin, griseofulvin, lithium carbonate, nitrofurantoin, riboflavin, and spironolactone. However, rapid absorption occurs if most drugs are given on empty stomach.
- Certain drugs are ineffective orally because of the following reasons:
a. Insulin and adrenocorticotrophic hormone (ACTH) are polypeptides. They undergo enzymatic degradation within the lumen of gastrointestinal tract.
b. Poor absorption from the gastrointestinal tract, e.g. aminoglycoside antibiotics.
c. Sex hormones and aldosterone are readily absorbed from the gut. However, they are inactivated in the gut wall as well as during the passage through liver before reaching to their site of action.
- Concurrentiy administered drugs may alter the absorption of a drug due to:
a. Luminal effect: Insoluble complexes are formed, e.g. tetracycline with iron and antacids, phenytoin with sucralfate, cholesterol with liquid paraffin.
b. Gut wall effects: Number of thugs may alter motility of gut and thus alter the absorption of a drug, e.g. opioids, tn- cyclic antidepressants, metaclopramide, anticholinergics, etc. Further, absorption of a drug may be altered if mucosa of the gut wall is damaged by concurrent administration of a drug such as methotrexate, neomycin, and vinblastin.
Limitations of Oral Administrations in pharmacokinetics
- Onset of effect of the drug is delayed.
- Peak effect occurs after a lapse of 30—60 minutes.
- Peak plasma concentration is low because of slow rate of absorption and continuous elimination of the drug.
- Drugs administered orally may give rise to esophageal and gastric irritation or ulceration, nausea, vomiting and diarrhea.
Subcutaneous and intramuscular
- Many drugs are not absorbed on oral administration.
- However, they are absorbed on subcutaneous or intramuscular administration because they are deposited directly in the vicinity of capillaries on parenteral administration. Capillaries are highly porous. So they do not obstruct absorption of even large lipid insoluble molecules.
- Drug absorption is accelerated by application of heat and exercise by increasing blood flow.
- Vasoconstrictors, e.g. adrenaline retard absorption when injected along with the drug.
- Hyaluronidase facilitates drug absorption from subcutaneous site by promoting spread.
- Many depot preparations, e.g. benzathine penicillin, protamine zinc insulin, depot progestins can be given by these routes.
- Pellets and implants can be inserted subcutaneously for prolonged action.
Topical Sites (Skin, Cornea, Mucous Membranes)
On topical application, systemic absorption depends primarily on lipid solubility of the drugs. Mucous membranes of cornea, mouth, rectum and vagina absorb lipophylic drugs.
Lipid soluble unionized drugs are absorbed but lipid soluble ionized drugs are not absorbed. Abraded surfaces readily absorb drugs.
Few drugs such as corticosteroids, hyoscine, nitroglycerin, organophosphorous insecticides, etc. can be absorbed through intact skin. Absorption can be promoted by rubbing the drug incorporated in an oleaginous base or by use of occlusive dressing.
Drugs or their metabolites are eliminated through channels of excretion from the body. Important channels of excretion in pharmacokinetics are:
I. Kidney: Most of the drugs are excreted through kidney. So this is the most important route of drug elimination. Following processes contribute to the excretion of a drug in the urine.
i. Passive glomerular filtration: All non protein bound drugs presented to the glomerulus are filtered. The rate of elimination of drug is dependent upon the glomerular filtration rate, molecular size of the drug and concentration of free drug in the plasma.
ii. Active tubular secretion: This occurs at proximal tubules. This is the active transfer of organic acids and bases by organic acid transport and organic base transport respectively (non-selective saturable carrier systems). This transport is against electrochemical gradient. Further, this carrier system transports both free and protein bound drugs. Hence this is the most important mechanism of drug elimination by the kidney. There can be competitive inhibition if two drugs utilize the same carrier system for tubular secretion, e.g. simultaneous use of probenecid and penicillin prolongs the plasma t½ life of the later.
iii. Passive diffusion across the tubules: This depends on lipid solubility and ionization of the drug at existing urinary pH. Since 99% of the gbmerular filtrate is reabsorbed and only 1% is excreted in the urine, there is a concentration gradient of solutes between tubular fluid and plasma, which allows passive diffusion of weak acids and weak bases. Weak acids (e.g. barbiturates, aspirin) are reabsorbed in acidic urine but eliminated in alkaline urine. On the other hand, weak bases (e.g. amphetamine, pethidine) are reabsorbed in alkaline urine but excreted in acidic urine. Strong acids and strong bases are not reabsorbed because they remain ionized in the urine at all pH ranges. Similarly highly water soluble drugs (e.g. mannitol, quaternary ammonium compounds, penicillin, aminoglycosides) irrespective of urinary pH are not reabsorbed.
2. Gastrointestinal tract: Orally administer unabsorbed drugs and drugs excrete in the bile are eliminated in the feces.
3. Lungs: Gases and volatile liquids (general anesthetics, paraldehyde, alcohol) are eliminated by lungs irrespective of their solubility.
4. Bile: Unchanged drugs and their metabolize products may be excreted in bile. In gut, some of the metabolites specially glucuronides are deconjugated by intestinal bacteria and the released lipid- soluble drug is reabsorbed into circulation (enterohepatic circulation). Due to this, duration of action of the drug is prolonged. Examples of such drugs are rifampicin, benzodiazepines, stilbestrol and morphine. However, some amount of the drug or its metabolite is eliminated in the feces.
5. Breast milk: Excretion of drugs in milk is important for the suckling infant who inadvertently receive the drugs. Most of the drugs are detectable in breast milk, but usually their concentration is low. However, relatively significant concentrations of lipid soluble drugs enter into breast milk. So a few drugs, such as sulfonamides, tetracyclines, sedative hypnotics, etc. should be avoided or breast-feeding should be suspended.
6. Skin and saliva: Metalloids like arsenic and heavy metals like mercury are excreted in small quantity through skin. Certain drugs like iodides and metallic salts are excreted in the saliva.
To produce a certain degree of response in a patient an appropriate amount of drug is required. This amount is called “dose”. Dose of a drug varies in terms of chosen response and is called as prophylactic dose, therapeutic dose or a toxic dose. Further, a clinician has to keep following points in mind while deciding dosage regimen of a drug for a particular patient.
- Duration of treatment
- Frequency of administration of a drug
- Route of administration
- Amount of a single dose
In fact the decision of the physician will be based on the following pharmacokinetics considerations to individualize drug dosage.
i. Standard dose: It is one which is sufficient to produce desired therapeutic effect in most patients. This is possible with those drugs which have minor individual variation or wide safety margin, e.g. amantadine, chioroquin, mebendazole, penicillin, oral contraceptives.
In certain clinical situations, a drug may have to be given in a single dose as and when required or at long intervals, e.g. analgesics, laxatives and hypnotics. There will be no accumulation of the drug and constant therapeutic plasma concentration is not essential. if patient does not respond, the dose of the drug is doubled.
ii. Regulated dose: Most of the drugs are administered in multiple doses. To avoid wide fluctuations in plasma, the clinician has to fix up the dose and frequency of its administration. It is better to give smaller doses at shorter intervals, rather than higher doses at longer intervals.
A finely regulated body function can be easily measured. When drug is to be employed to modify such a function, its dose can be regulated by repeated measurement of this body function. It is possible with the use of anti hypertensives, anticoagulants, diuretics, general anesthetics, hypoglycaemics, etc.
iii. Titrated dose: With few drugs, the dose required to achieve maximal therapeutic effect, cannot be given due to intolerable adverse effects. In such cases, dose of the drug is titrated to have therapeutic effect with an acceptable level of adverse effect. It can be practiced in two ways:
a. In most non-critical situations, give low initial dose and titrate upwards.
b. In critical situations, give high dose initially and titrate downwards.
Examples are anticancer drugs, corticosteriods, and levodopa.
iv. Target level dose: In some cases, response is not easily measurable. Further, response occurs at a certain range of drug concentration in plasma. To achieve this plasma concentration initially, a loading dose is given.
v. Loading dose: It is a single dose or a few quickly repeated doses given in the beginning to attain target concentration rapidly. It is approximately equivalent to the anticipated total amount of the drug in the body at the time of desired therapeutic plasma concentration. This is seen with drugs which have the following characteristics:
- Long t½
- High volume of distribution
- Slow rate of clearance
- Cumulative in nature
- Take several days for a steady state level to be reached.
Once the desired therapeutic plasma concentration of the drug has reached after giving loading dose, thereafter the effect is sustained by giving a maintenance dose. This dose is one that is to be repeated at specific intervals after the attainment of target steady state plasma concentration. Theoretically, it should be equivalent to daily excretion of the drug. Usually it is calculated by actual monitoring of plasma concentration, if facilities exist. If monitoring is not possible observe the effect of these drugs for a long period and make necessary adjustment in the maintenance doses. Examples are antidepressants, antiepileptics, digoxin, lithium and theophylline.
Fixed dose combination preparations:
These are the preparations which contain two or more drugs in a fixed dose ratio. It never means a concomitant drug therapy, where two or more drugs are used separately for treatment of disease. Rational or logical use of fixed dose combination of two or more drugs can be advantageous but illogical combination could be dangerous.
Pharmacokinetics rules for drug combination are:
- If two drugs are to be combined in a single pharmaceutical formulation, they should have approximately equal plasma half-lives (t½).
- The ratio of the doses of two drugs, in such a formulation, will depend upon their apparent volume of distribution (aVd) and peak plasma concentration at steady state.
Examples of drug combination in pharmacokinetics:
- Sulphamethoxazole + trimethoprim (cotrimoxazole)
- Sulphadoxin + pyrimethamine for malaria
- Amoxycillin + clavulanic acid (augmentin)
- Carbidopa + levodopa for parkinsonism
- Ibuprofen + paracetamol as analgesic and anti-inflammatory agent
- Paracetamol + codeine as analgesic
- Beta blockers + diuretic as antihypertensive Drug combination may lead to summation of effects, additive effects or synergistic effects.
- Better patient compliance
- Better effect among drugs combined
- Two drugs may counter the side effects of each other
- All the drugs of combination may not be needed for treatment.
- Additional side effects and expense.
- Adjustment and individualization of doses is not possible.
- Time course of actions of its components may be different.
- Pharmacokinetics of its components may be differently affected under altered hepatic and renal function of the patient.
- The combination cannot be used if one of the components is contraindicated.
- Confusion of therapeutic aims and false sense of superiority of two drugs over one. This is particularly so in case of antimicrobial combinations. Corticosteroids should never be combined with any other drug.
In fact only handful of fixed dose combinations is rational and justified. However, present day situation is that far too many drug combinations are available and promoted. In fact this should be discouraged.
Monitoring of plasma concentration of drugs in pharmacokinetics:
It is useful under the following conditions:
- To check patient compliance
- In case of poisoning
- In case of failure of response without any apparent reason, e.g. antimicrobials
- Drug with low safety margin
- Large individual variation in doses of a drug
- Use of potentially toxic drugs in presence of renal failure
It is not useful under the following situations in pharmacokinetics:
- Drugs activated in the body, e.g. levodopa
- Drugs with irreversible action such as organophosphorus anticholinesterase
- With easily measurable response of drug e.g. antihypertensives, hypoglycaemics, diuretics, oral anticoagulants
- ‘Flit and run’ drugs (whose effect lasts much longer than the drug itself), e.g. reserpine, MAO inhibitors.
Prolongation of drug action in pharmacokinetics: The aims of prolongation of drug actions are:
- To avoid large fluctuations in plasma concentration
- To improve patient compliance
- To maintain drug effect overnight without disturbing sleep
- To reduce frequency of administration
Methods for prolonging drug action in pharmacokinetics are:
1. By retarding drug absorption:
i. Oral: By administering it full stomach or by giving it in sustained release tablets, spansules, capsules, etc.
- Injecting drug in insoluble form or as oily solution subcutaneously and intramuscularly
- Pellet implantation
- Sialistic and biodegradable implants
Transdermal drug delivery system: Drug is impregnated in adhesive patches, strips or as ointment and applied on the skin.
2. By increasing plasma protein binding
3. By decreasing rate of metabolism
4. By diminishing renal excretion.
Pharmacokinetics for Dental professionals.
[Source: Principles of Pharmacology for Dental Students]