Introduction To Pharmacodynamics Notes

Pharmacodynamics

Pharmacodynamics (Gr. Pharmacon: drug; dynamic: power): In short, it covers all the aspects relating to ‘what the drug does to the body’. It is the study of drugs— their mechanism of action, pharmacological actions and adverse effects.

Types Of Drug Action

1. Stimulation: Some drugs act by increasing the activity of specific organs/systems, for example, adrenaline stimulates the heart resulting in an increase in heart rate and force of contraction.
2. Depression: Some drugs act by decreasing the activity of specific organs/systems,
   example alcohol, barbiturates, general anaesthetics, etc. depress the central nervous system.
3. Irritation: Certain agents on topical application can cause irritation of the skin and adjacent tissues. When an agent on application to the skin relieves deep-seated pain, it is known as a counterirritant (for example eucalyptus oil, methyl salicylate, etc.). They are useful in sprain, joint pain and myalgia. They exert their action by:
   • Reflexly increasing local circulation in deeper structures.
   • Blocking impulse conduction in the spinal cord.
4. Cytotoxic: Drugs are selectively toxic for the infecting organism/cancer cells, for example, antibiotics/anticancer drugs.
5. Replacement: When there is a deficiency of endogenous substances, they can be replaced by drugs, for example, insulin in diabetes mellitus, thyroxine in cretinism and myxoedema.

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Mechanism Of Drug Action

1. Nonreceptor-mediated mechanisms of action of drugs
   • By physical action:
     • Osmosis: Some drugs act by exerting an osmotic effect, for example, 20% mannitol in cerebral oedema and acute congestive glaucoma.
     • Adsorption: Activated charcoal adsorbs toxins; hence it is used in the treatment of drug poisoning.
     • Demulcent: Cough syrup produces a soothing effect in pharyngitis by coating the inflamed mucosa.
     • Radioactivity: Radioactive isotopes emit rays and destroy the tissues, for example ¹³¹I in hyperthyroidism.
   • By chemical action:
     • Antacids are weak bases— they neutralize gastric acid and are useful in peptic ulcers.
     • Metals like iron, copper and mercury are eliminated from the body with the help of chelating agents. They trap metals and form water-soluble complexes, which are rapidly excreted from the body. For example, dimercaprol (BAL) in arsenic poisoning, desferrioxamine in iron poisoning and d-penicillamine in copper poisoning.
   • Through enzymes: Some drugs act by inhibiting enzyme activity.
     • Angiotensin-converting-enzyme (ACE) inhibitors such as captopril, enalapril and ramipril act by inhibiting ACE and are used in the treatment of hypertension, CCF, etc.
     • Xanthine and hypoxanthine are oxidized to uric acid by the enzyme xanthine oxidase, which is inhibited by allopurinol. Allopurinol is used in the treatment of chronic gout to reduce the synthesis of uric acid.
   • Through ion channels: Some drugs directly bind to ion channels and alter the flow of ions, for example local anaesthetics block sodium channels in the neuronal membrane to produce local anaesthesia.
   • Through antibody production: Vaccines produce their effect by stimulating the formation of antibodies, for example vaccines against tuberculosis (BCG), oral polio vaccine, etc.
   • Transporters: Some drugs produce their effect by binding to transporters. Selective serotonin reuptake inhibitors (SSRIs) → bind to 5-HT transporter → block 5-HT reuptake into neurons → antidepressant effect.
   • Others: Anticancer drugs like cyclophosphamide produce their effect by binding to nucleic acids.
2. Receptor-mediated mechanisms Receptors are macromolecules present either on the cell surface, cytoplasm or in the nucleus with which the drug binds and interacts to produce cellular changes.
   • Drug (D) + Receptor (R) ⇌ Drug–receptor complex → Response

For example, adrenergic receptors (α and β), cholinergic receptors (muscarinic and nicotinic), opioid receptors, etc.

1. Affinity: The ability of the drug to get bound to the receptor is known as affinity.
2. Intrinsic activity: The ability of the drug to produce pharmacological action after combining with the receptor is known as the intrinsic activity of the drug.
3. Agonist: A drug that is capable of producing pharmacological action after binding to the receptor is called an agonist.
   • Agonist has high affinity + high intrinsic activity (for example morphine, and adrenaline).
4. Antagonist: A drug that prevents the binding of agonists to its receptor or blocks its effect is called an antagonist. The competitive antagonist has high affinity without intrinsic activity (for example naloxone, atropine). It produces receptor blockade.
5. Partial agonist: A drug that binds to the receptor but produces an effect less than that of an agonist is called a partial agonist.
   • Partial agonist has affinity + less intrinsic activity (for example pindolol, buprenorphine).
6. Inverse agonist: It has a full affinity towards the receptor but produces an effect opposite to that of an agonist. For example, benzodiazepines produce antianxiety and anticonvulsant effects by interacting with its receptors; but β- carbolines act as inverse agonists at benzodiazepine receptors, and produce anxiety and convulsions. Inverse agonist has an affinity and intrinsic activity between 0 and −1 (for example carbolines).

• Receptor families

1. 1. 1. Ligand-gated ion channels (inotropic receptors).
      2. G-protein-coupled receptors (GPCRs; metabotropic receptors).
      3. Enzymatic receptors.
      4. Receptor regulating gene expression (transcription factors) or the nuclear receptor.

• Characteristics of Various Receptor Families
• Ligand-gated ion channels (inotropic receptors)

Examples are nicotinic (N_M) acetylcholine receptors of the neuromuscular junction, GABA (gamma-aminobutyric acid) and glutamate receptors in the central nervous system (CNS).

The onset of action of a drug is fastest through this receptor.

• G-protein-coupled receptors (metabotropic receptors)

GPCRs are transmembrane receptors which control cell function via adenylyl cyclase, phospholipase C, ion channels, etc. They are coupled to intracellular effectors through G proteins. G proteins are membrane proteins and have three subunits (α, β, γ) with GDP bound to α subunit The agonist that binds to the receptor is the first messenger. It results in the formation or recruitment of molecules (second messengers) that initiate the signalling mechanism in a cell. Examples of second messengers are cAMP (generated by adenylyl cyclase), cGMP (generated by guanylyl cyclase), Ca²⁺, inositol triphosphate–diacylglycerol (IP₃– DAG) (generated by phospholipase C), nitric oxide, etc.

1. Transmembrane Enzyme-Linked Receptors. Transmembrane enzyme-linked receptors have enzymatic activity in their intracellular portion. The enzyme is mainly tyrosine kinase, e.g. receptor tyrosine kinases for insulin and epidermal growth factor.
2. Nuclear Receptors. These regulate gene expression. Examples: receptors for thyroxine, vitamins A and D, sex steroids and glucocorticoids. Steroids → bind to receptors in cytoplasm → steroid–receptor complex → migrates to nucleus → binds to a specific site on the DNA → regulates protein synthesis → response

• Regulation of receptorsReceptors can be regulated by various mechanisms resulting in either their upregulation or downregulation

• Regulation of Receptors
• Dose-response relationship

The pharmacological effect of a drug depends on its concentration at the site of action, which, in turn, is determined by the dose of the drug administered. Such a relationship is called a ‘dose-response relationship’.

• Graded dose-response curve:

This curve, when plotted on a graph, takes the form of a rectangular hyperbola; whereas the log dose-response curve (DRC) is sigmoid-shaped.

• Therapeutic index

The therapeutic index (TI) is an index of drug safety.

It is the ratio of the median lethal dose to the median effective dose.

1. LD₅₀: It is the dose of a drug, which is lethal for 50% of the population.
2. ED₅₀: It is the dose of the drug, which produces desired effect in 50% of the population.

The higher the value of the therapeutic index, the safer the drug. For example, penicillin has a
high therapeutic index; digitalis, lithium and phenytoin have a narrow therapeutic index.

• Drug potency

The amount of a drug required to produce a desired response is called the potency of the drug. The lower the dose required for a given response, the more potent the drug. For example, the analgesic dose of morphine is 10 mg and that of pethidine is 100 mg. Therefore, morphine is ten times more potent than pethidine as an analgesic. DRC of drug A (morphine) and drug B (pethidine, rightward DRC) as an analgesic are compared.

• Drug efficacy

It is the maximum effect of a drug. For example, morphine is more efficacious than aspirin as an analgesic; the DRC of drug A (morphine) and drug B (aspirin) as an analgesic is compared.

• Therapeutic range

It is the range of concentration of the drug that produces the desired response with minimal toxicity.

The combined effect of drugs

A combination of two or more drugs can result in an increase or a decrease in response.

1. Increased response:
   • Additive effect: The combined effect of two or more drugs is equal to the sum of their individual effect.
     • Effect of drugs A + B = Effect of drug A + Effect of drug B
     • For example, combination of ibuprofen and paracetamol as analgesic.
   • Potentiation (supra-additive): The enhancement of the action of one drug by another drug which is inactive is called potentiation.
     • Effect of drugs A + B > Effect of drug A + Effect of drug B
     • For example, levodopa + carbidopa; acetylcholine + physostigmine. Carbidopa and physostigmine inhibit the breakdown of levodopa and acetylcholine, respectively; thus enhancing their effects.
   • Synergism: When two or more drugs are administered simultaneously, their combined effect is greater than that elicited by either drug alone.
     • For example, sulfamethoxazole + trimethoprim.
2. Decreased response (drug antagonism): In antagonism, the effect of one drug is decreased or abolished in the presence of another drug.
   • Physical antagonism: The opposing action of the two drugs is due to their physical property, for example adsorption of alkaloids by activated charcoal – useful in alkaloid poisoning.
   • Chemical antagonism: The opposing action of two drugs is due to their chemical property, example antacids are weak bases – they neutralize gastric acid and are useful in peptic ulcer; chelating agents form complexes with metals and are useful in heavy metal poisoning (desferrioxamine in iron poisoning).
   • Physiological (functional) antagonism: Here, two drugs act at different receptors or by different mechanisms on the same physiological system and produce opposite effects. For example, insulin and glucagon on blood sugar, adrenaline and histamine on bronchial smooth muscle— histamine produces bronchoconstriction (via histamine receptors), whereas adrenaline produces bronchodilatation by acting through adrenergic) β2 receptors— hence, adrenaline helps to reverse bronchospasm in anaphylactic shock.
   • Receptor antagonism: The antagonist binds to the same receptor as the agonist and inhibits its effects. It can be competitive or noncompetitive.
     • Competitive antagonism (equilibrium type): In competitive antagonism, both the agonist and the antagonist bind reversibly to the same site on the receptor. This type of antagonism can be overcome (reversible) by increasing the concentration of the agonist. The log dose-response curve of the agonist shows a rightward parallel shift in the presence of a competitive antagonist.
       • For example, Acetylcholine → Muscarinic receptors ← Atropine
         Morphine (Agonists) → Opioid receptors ← Naloxone(Antagonists)
     • Noncompetitive antagonism: The antagonist binds to a different site on the receptor and prevents the agonist from interacting with the receptor. In this type, the antagonistic effect cannot be overcome by increasing the concentration of the agonist. There is a flattening of the dose-response curve (DRC) in noncompetitive antagonism, for example, diazepam and bicuculline.