Pharmacodynamics
Insulin Tyrosin kinase
Efficacy—capacity of drug to (combine with the receptor and) produce pharmacological effect. Clinically it is more important than potency and every drug has its maximum efficacy.
D + R DR Response
Mechanism of Action of drug—
According to specificity—
Specific—Receptors, Enzymes, Ion channels, Carrier molecules.
Non specific—
Physical mechanisms—
o Kaolin produces a protective layer on the mucus
o Heparin is endogenous and highly negatively charged particle
Chemical mechanisms—
o Antacid has acid neutralizing activity
o MgSO4 in the gut dissociates into Mg and SO4 and causes irritation of the mucosa and ↑ peristalsis
Chelating mechanisms—
o Dimecaprol in arsenic poisoning
o Deferoxamine in iron poisoning
Non specific drug action—
o Ether, Barbiturates etc
According to the site of action—
1. Drugs acting on the cell membrane—
a. By specific receptors—adrenoceptors and cholinoceptors.
b. Interference of selective passage of ions across the cell membrane—Na+, Ca++ channel blockers (nifedipine)
c. Inhibition of the membrane bound enzymes and pump—Cardiac glycosides—Na+-K+-ATPase pump
Tricyclic anti depressant drugs—reuptake-I
d. Physio-chemical interaction—general and local anaesthetics and alcohol.
2. Drugs acting within the cell—
Ø Acting within cytoplasm—
a. Enzyme inhibition—Phenelzine (MAO-mono amine oxidase), Neostigmine (cholinesterase)
Allopurinol (xanthine oxidase)
b. Inhibition of the transport process that carry substances across the cell—Probenecid blocks renal tubular secretion.
c. Incorporation into large molecules—5 fluro-uracil is an anti-Ca drug incorporated into mRNA instead of uracil.
d. Altering the metabolic processes of microbes—anti-microbial agents (Penicillin, Sulphonamide, Trimethoprim)
Ø Some drugs may also act on the receptors present on the nucleus.
3. Drugs acting outside the cell—
- Direct chemical interaction—chelating agents (Deferoxamine), neutralizing agents (antacid)
- Osmosis—purgatives (MgSO4), diuretics (mannitol)
Receptors—it is a component of the cell, mostly macro-molecular protein in nature and when combines with the drug initiates chain of biochemical events to produce pharmacological effects.
o It usually determines drug concentration and dose and its pharmacological effects.
o Responsible for selectivity of drug action.
o It is also responsible for action of antagonists.
Types of receptors—
1. Silent receptors—this receptor can combine with the drug and but produce no action. Ex—plasma protein.
2. Spare receptors—this receptor is usually inactive, when the number of the active receptors is less or the drug concentration is more, the receptors are activated.
3. Active receptors—this receptor is active and works with the drug. It is only 1-2%.
*** If the spare receptors become active, toxicity may develop.
Regulation of receptors—
1. Down regulation—in bronchial asthma there is down regulation of the β2 receptors. In obesity there is down regulation of the insulin receptors.
2. Up regulation—during starvation there is up regulation of the insulin receptors.
Electrostatic forces—Forces by which drug combines with the receptors. The forces are—
1. hydrogen bonding (weak)
2. ionic bonding (bond by exchange)
3. co-valent bonding (bond by sharing) (strong)
4. vander-wals force (weak)
Association—when the drug combines with the receptor.
Dissociation—when the drug leaves the receptor
Drug-receptor association and dissociation depends upon—
1. Affinity between the drug and the receptor
2. Type of chemical bond formation
3. Concentration of the drug
4. Number of receptors
How drug receptor complex works?—
1. Receptor operated ion channels—
o Drugs combine with the receptor to open / close ion channels.
o For fast neurotransmitters.
o Coupled directly to ion channels
o Ex—Nicotinic, GABA, Glutamate receptors
2. Receptors with G-protein linked (2nd messenger system)—
They produce their action through—
o C-AMP system
o C-GMP system
o IP3DAG / Phospholipase-C system
G-protein is a coupling unit and Adenyl Cyclase is a catalytic unit. G protein is of 2 types (stimulatory and inhibitory)
Receptor + drug → stimulation of the G-protein → adenylate cyclase stimulation / inhibition → ATP → C-AMP →Protein kinase A (active)
G-protein → Phospholipase A2 → PiP2 (phosphatidyl-inositol-di-phosphate)
Intracellular Ca++ ← IP3 DAG → protein kinase C→ protein phosphorylation → effect
3. Receptors that are enzymes—
Dihydrofolate reductase—receptor for Methotrexate (anti-cancer drug)
4. Receptors that are directly linked with tyrosin kinase—
Directly linked
Insulin Tyrosin kinase5. DNA linked receptors—corticosteroids, thyroid hormone, sex hormone, vit-D
6. Structural protein can act as receptors—Tubulin (cytoskeleton), acts as a receptor for Colchicine.
Affinity—tendency of a drug to combine with a receptor, to produce drug receptor complex and maintain it. There is always affinity constant for specific receptors.
Affinity may vary—it ↑ when the receptor is vacant and ↓ when the receptor is occupied.
K1
D + R DR effect
K2
Here, D=Drug, R= Receptor, K1=Association constant, K2=Dissociation constant .
Ex—Prazosin blocks both α1 and α2 receptors but affinity for α1 is 1000 times more. Propranolol has equal affinity for both β1 and β2 is equal.Efficacy—capacity of drug to (combine with the receptor and) produce pharmacological effect. Clinically it is more important than potency and every drug has its maximum efficacy.
Potency—it is a comparative measures refers to the different doses of two drugs that are needed to produce some effect. So it is the amount of drug (weight) in relation to its effect.
Effects of drug receptor interaction—
1. Agonist—agonism
2. Partial agonist—partial agonism
3. Antagonist—antagonism
Agonist—it is a drug which when combines with the receptor produces pharmacological effect or cellular response. Drugs which have full affinity with full efficacy. Ex—adrenoceptor agonist—adrenalin.
Agonism—it is a phenomena where the drug interacts with the receptor and produces response.
K1 K3
D + R DR Response K2
Partial agonist—drugs which when combines with the receptors, produces less effect than maximum. These drugs have full affinity but less efficacy. Ex—Nalorphine.
Partial Agonism—it is a phenomena when a drug interact with receptor but produce sub-maximal effect.
Antagonist—the drugs which when combines with the receptors and produces no action. Having full affinity but no efficacy. Ex—Naloxone.
Antagonism—it is a phenomena when a drug interact with receptor but produce no action.
Antagonism
Physiological Pharmacological Chemical
Competitive Non-competitive
Reversible Irreversible
Physiological antagonism—it occurs when two drugs combine with different receptors and antagonize each others action.
Ex—Adrenalin works on the Adrenoceptors, Histamine acts on the Histamine receptor—they antagonizes each others action.
Chemical antagonism—the drugs that don’t combine with the receptors but works in another mechanism. They antagonizes each others action by non-receptor mechanism.
Ex—antacid (acts by neutralization), chelation (Deferoxamine, Tetracycline)
Pharmacological antagonism—when two drugs act on the same receptor and antagonizes each others action.
Ex—adrenalin (agonist) and prazosin (antagonist)
Competitive antagonism—when a drug competitively combines with a receptor and antagonizes the action of the agonist.
Reversible antagonist—when a drug competitively and reversibly combines with a receptor and antagonizes the action of the agonist.
Features—
1. When a drug combines with the receptor with any bond other than the covalent bond.
2. Agonist and antagonist combine with the same receptor and able to displace each others actions.
3. Key feature is submountibility, when large doses of agonist is given with antagonists, the effect of the antagonist is less or abolished.
*** when a log dose concentration is plotted in a curve, the curve will be sigmoid shape. When antagonist is given with the agonist the shape of the curve will be the same but the curve will parallelly shift to the right.
Irreversible antagonism—when drug binds with the receptor by covalent bond and cannot reverse each others action.
Ex—OPC + cholinesterase, Adrenalin + Phenoxybenzamine.
Non-competitive antagonism—this antagonism occurs when the antagonist binds with the receptor near the site of agonist binding, or it may bind with the receptor-effector linkage. Ex—Calcium channel blocker.
Clinical importance of drug antagonism—
1. For specific antidote in acute poisoning. Morphine→ Naloxone, Heparin→ Prothrombin Sulphate.
2. To correct the adverse effect of drug. Histamine→ Anti-histamine.
3. Treatment of disease. Peptic ulcer→ antacid.
4. To prolong the drug action. Penicillin + Probenecid.
5. In anaphylactic shock. Histamine, adrenalin.
Dose response relationship—it is the relationship between the concentration of the drug and its cellular response.
Types—
1. Graded dose response
2. Quantal dose response
Graded dose response—when the concentration of the drug increases, response increases upto a certain limit. When the response will be plotted, the curve will be sigmoid shaped.
Importance—
1. Potency of the drug can be compared
2. Indicates efficacy (ED50 and maximal efficacy)
3. A wide range of drug easily plotted on a graph
4. Competitive antagonism can be measured
5. Provides information about selectivity of drug
Quantal dose response—when amount of response in groups or quantum of response are plotted against dose.
Quantal response—is all or none response to a drug and relates to the frequency with which a specific dose of a drug produce a specific response in a population (ex—death % among the mice in the preclinical study or 20% decrease in the BP among the patients in a clinical trial).
The quantal dose response is often characterized by stating the—
ED50—median effective dose
TD50—median toxic dose
LD50—median lethal dose
Margin of safety of drug is,
LD50
TI = (here TI is therapeutic index)
(here TI is therapeutic index) ED50
Effects of drug combination—
A. Enhancement of the drug effect—
i. Additive drug effect—two drugs with the same effect if given together produce an effect that is equal in magnitude to the sum of the effects when the drugs are given individually.
ΣAB = ΣA + ΣB. Ex—Penicillin + Cephalosporin, Aspirin + Paracetamol.
ii. Synergism—ΣAB > ΣA + ΣB. Ex—Co-trimoxazole = (Sulfamethoxazole + Trimethoprim)
iii.Potentiation—one drug increases the activity of other drug. ΣAB > 0A + ΣB.
Ex—in asthma salbutamol + aminophylline
B. Reduction of the drug effect—
i. Antagonism—ΣAB < ΣA + ΣB. Ex—Histamine + Anti-Histamine, Penicillin + Tetracycline.
How can you prolong the drug action?—
i. Use of large doses of non-toxic drug with increased frequency.
ii. Pharmaceutical factor. Ex—Depot formation (Penicillin), slowing metabolism (MAO inhibitors)
iii. Addition of vaso-constrictors. Ex—Adrenalin to prolong the action of anaesthetics
iv. By delaying the excretion. Ex—Penicillin + Probenecid.
v. By changing the molecular structure. Ex—Benzodiazepine group.
Factors influencing drug action—
i. Patient compliance
ii. Dose of the drug
iii. Age of the patient, sex, race
iv. Lactation
v. Routes of administration
vi. Time and environment
vii. Genetic factor
viii. Glucose-6-PO4 deficiency
Rational use of drug—(principles of all anti-microbial therapy)
1. Proper diagnosis (clinical diagnosis and laboratory investigation)
2. Proper decision (whether chemotherapy is needed or not)
3. Proper selection of drug—
a. specificity
b. proper combination (bactericidal and bacteriostatic drugs should not be used together)
c. right route of administration
d. easily available
e. essential drug (needed in the vast majority of the community)
f. cost effectiveness
g. high efficacy
4. Right dose
5. Right duration (antibiotics→5-7 days and should not be withdrawn in less than 3 days to prevent resistance formation)
6. Right time schedule (amoxicillin 8 hourly, ampicillin 6 hourly)
7. Status of the patient (age, sex, pregnancy, lactation, liver disease, kidney disease, immune status, allergy)
Antibiotic failure / therapeutic failure of drugs—
1. Wrong diagnosis | |||
2. Wrong indication of drug | |||
3. Drug factor— | a. wrong selection | b. wrong combination | |
c. wrong dose | d. low efficacious drug | ||
e. wrong duration | f. unsafe drug | ||
g. poor penetration of the drug at the site of infection | |||
4. Host factor— | a. poor host defense | b. undrained pus | |
Adverse effects of drugs—harmful or seriously unpleasant effect occurring at doses intended for therapeutic effects.
Toxicity—direct action of the drug. Often at high doses damaging cells.
Ex—Paracetamol (liver damage), Gentamycin (8th cranial nerve damage)
Types of Toxicity—
Type A (augmented)
Type B (bizarre)
Type C (chronic)
Type D (delayed)
Type E (ending of use)
Type A—adverse effects that occurs from the direct extension of the effects of drug. It is dose related, relatively common and usually not fatal. Ex—Insulin (hypoglycemia), β-blocker (hypotension), Anticoagulants (haemorrhage).
Type B—these are unpredictable adverse effects. Not the extension of the pharmacological effect, it is not dose related and high rate of mortality and morbidity. It is not common.
It is of two types—
a. Idiosyncrasy
b. Drug allergy or hypersensitivity
Idiosyncrasy—inherited abnormal response to drug mediated by a single gene. Ex—Porphyria
Drug allergy or hypersensitivity—occurs when there is antigen-antibody reaction.
Types of allergy—
o Type-1—immediate or anaphylaxis. ex—Penicillin, IV anaesthetics, X-ray contrast media.
o Type-2—Hepatic, cholestatic. Clinical features are Jaundice, Haemolytic Anaemia, Thrombocytopenia, Aplastic Anaemia, Collagen, Skin Rashes. Ex—Methyl Dopa, Penicillin, Rifampicin, Quinine, Sulfonamides.
o Type-3—Complement mediated. Clinical features are Serum Sickness, Glomerulonephritis, Vasculitis, Pulmonary disease. Ex—Anti-microbials.
o Type-4—Delayed. Clinical feature is Contact Dermatitis. Ex—Metals.
Type C—Adverse effects occur due to long term use. Ex—Paracetamol (analgesic nephropathy), Cortisol (Cushing syndrome), Chloroquine (corneal opacity)
Type D—Adverse effects occur in the children or treated patients or in patients themselves after long time.
Ex—teratogenecity in children, carcinoma treated with alkylating agents.
Type E—adverse effects occur when a drug is stopped, usually suddenly. Ex—β adrenoceptor blocker in angina, prednisolone in adrenocortical insufficiency.
Essential drugs—these are the most needed drug to satisfy the health care of vast majority of population .They should be available in proper dose form, at all the time, in adequate amounts, in acceptable quality and at a price that people can afford.
o WHO experts published EDL (essential drug list) in 1977and there were 250 drugs.
o In 1995 the EDL was revised and it became 300 drugs.
o EDL may vary country to country. More than 80 countries are practicing EDL.
Criteria for selecting EDL—
SANE—safety, availability, need to the community, efficacy.
Advantage of using EDL—
o Reduction in the number of pharmaceutical products to be manufactured, imported, stored, analyzed and distributed from amongst the thousands.
o Improvement of the quality of drug utilizing management information and monitoring.
o Stimulation of the local pharmaceutical industries.
o Solutions of the primary health care problems by providing high priority on safe and cost effective drugs.
o Facilitating the use of drugs more economically and rationally.
Special features of Bangladesh NEDL—( it is that number of essential drugs that have been recommended to be used by the various levels of the health care personnel)
A. Primary health care complex—
At village level—15 drugs
At thana level—15 + 58 = 73 drugs
B. At secondary level—
District hospital—15 + 58 + 78 = 151 drugs
C. At tertiary level—
Medical colleges and universities—15 + 58 + 78 + 73 = 224 drugs
P-drugs—P denotes for personal / priority / primary. P-drug is selcted on the basis of following criteria—
SANES—safety, availability, need to the community, efficacy, status if the patient.
Or, CASES—cost effective, availability, safety, efficacy, suitability.
P-drug is variable in case of child, old age, pregnancy and lactation.
Poly-pharmacy—two or more drugs when taken concurrently in a disease is called poly-pharmacy. Usually it is not advocated. But in some particular situation it can be used with following advantages—
1. Potentiation—drugs act on different mechanism thus potentates each others action
2. Individual dose becomes reduced
3. Less chance of toxicity
4. In case of anti-microbial agents there is decrease chance of developing resistance
5. Decreases the duration of treatment
Diseases where poly-pharmacy is given—Hypertension, Carcinoma, TB, Leprosy, Epilepsy.
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