Pharmacodynamics

Pharmacodynamics

Definition

Pharmacodynamics are what a drug does to the body.

Drug: -Target Site (Therapeutic Effect) -Other Sites (Adverse Effects)

 They are the studies of the therapeutic effects, the adverse effects and the mechanism of action of each effect.

MECHANISM OF ACTION OF DRUGS: -

·        Receptor-mediated mechanisms

·        Non-receptor-mediated mechanisms

Ø Receptor-mediated mechanisms

Receptors:

•         Are protein macromolecules that combine chemically with small molecules (ligands) and produce physiological regulatory functions. They may be extracellular or intracellular.

·         Ligand is any chemical substance that combines with the receptors and produce an effect.

·         Ligands that activate the receptors are called agonists, ligands that combine the same site without causing activation are called antagonists.

·         The receptor site or recognition site for a drug has a high and selective affinity for the drug molecule. Thus receptors are selective, sensitive and specific.

·         The interaction of a drug with its receptor is the event that initiates the action of the drug.

      Drug + Receptor à Drug-receptor complex à Biologic effect

·         The interaction with the receptor is termed “binding”, while eliciting the effect is through a “signaling system”.

Types of Ligands

·         Agonist:

     Drugs which alter the physiology of a cell by binding to plasma membrane or intracellular receptors. Drug binds with the receptor →activates the receptor → complete effect (e.g.,morphine & opoid receptors).

·         Antagonist (Blocker): Drug binds with the receptor →but does not activate the receptor → no effect (e.g., atropine & muscarinic receptors).

·         Partial agonist (agonist-antagonist): A drug which does not produce maximal effect even when all of the receptors are occupied.  Drug binds with the receptor → partially activates the receptor → lower effect than the agonist (e.g., butorphanol & opoid receptors).

Ø  Types of Antagonists

Competitive antagonists:

  Drug binds to the active site of the receptor by a weak bond & competes with agonists for the same recognition site of the receptor. High doses of an agonist can generally overcome antagonist. It is usually reversible. (e.g., naloxone & opioid receptors).

Non-competitive antagonists:

 Drug binds to the active site of the receptor by a strong bond & prevents binding of the agonist or prevent activation of the receptor by the agonist.

   Induces a conformation change in the receptor such that the agonist no longer “recognizes” the agonist binding site and therefore High doses of an agonist do not overcome the antagonist in this situation.

 It is either reversible (Nicotine LD) or irreversible. (e.g., phenoxybenzamine & α-receptors).

Chemical or neutralization antagonists:

 They chemically interact with the agonist away from the receptor site (e.g., heparin and its antidote protamine sulphate).

Physiological or Functional antagonists:

   One drug antagonizes the effect of another by acting on a different receptor (e.g. bronchodilator effect of epinephrine on β2 receptors antagonizes bronchconstrictor effect of histamine on H1 receptors).

Cellular Receptors & Signaling System

 Two functional domains should exist within the receptor:

•         Ligand-binding domain to which the agonist is bound generating a signal.

•         Effector domain linked to an effector system which amplifies the signal and generates the response.

Types of Effector Domain

1. Ligand- Gated ion channels:

Binding of the agonist to the receptors results in opening of the channel leading to alteration in membrane potential or change in intracellular ion concentration → change in cell activity. e.g., Nicotinic receptors (Na ion channels).

2. Receptors as Enzymes:

e.g. Insulin receptors. Binding of insulin causes activation of tyrosine kinase enzyme

3-G-protein coupled Receptors:

where receptors are linked to G proteins. G proteins are either stimulatory or inhibitory.

ü   Stimulatory G proteins causes activation of Adenyle cyclase which forms 2^nd messenger cAMP which alters cell activity by activating cAMP- dependent protein kinases

ü  Inhibitory G proteins result in decreased cAMP.

4.Receptors regulating transcription:

when agonist binds with receptors will cause activation or inhibition of transcription of the nearby gene thus modifying protein production. As in steroid hormone and thyroid hormone receptors.

Non-Receptor-Mediated Mechanisms

1. Drugs acting on Enzymes: 

Drugs may activate or inhibit enzyme systems e.g. MAOIs inhibit MAO(Monoamine oxidases ) enzyme.

2. Drugs acting on subcellular structures

Mitochondria: as, salicylates uncouples oxidative phosphorylation.

      Microtubules: as, colchicine, griseofluvin → disrupts microtubules → inhibition of mitosis.

3. Drugs acting on Plasmatic membranes:

as, antifungal drugs ↑ permeability of fungi membranes.

4. Drugs acting on Storage Vesicles:

Reserpine (inhibit the reuptake of NE in storage vesicles).

5. Drugs acting on Genetic apparatus:

as, Antibiotics, anticancer.

6. Drugs acting by Chemical Action

1. Antacids neutralize HCL in stomach.
2. Protamine antagonize heparin.
3. Chelation:  It is the capacity of organic compounds to form complexes with metals.e.g. desferrioxamine (chelates iron in iron toxicity).

7-Drugs acting by Physical Action: Lubricants: in constipation as liquid parrafin.

DOSE-RESPONSE CURVE

•         Represents the relationship between gradually increasing doses of the drug and the responses elicited by these doses.

Values obtained from The dose-response curve

•         Efficacy:

1.      It is the capacity of the drug to produce maximal effect (E_max).

2.      It is determined along the response axis of the curve.

•         Potency (Effective-dose concentration):

1.      It is the dose required to produce a given effect. It is expressed as (ED₅₀ = dose producing 50% of maximal response).

2.      It is determined along  the dose axis of the curve.

ADVERSE EFFECTS

v  Predictable Adverse effects      

v   Unpredictable adverse effects

Predictable AE:

Type A: (Augmented AE): due to exaggeration of drug action:

1. Side effects: occurs at therapeutic doses. e.g. sedation in antihistaminics

2.   Toxicity: occurs at supra-therapeutic doses. e.g. ototoxicity in aminoglycosides overdose.

Non-predictable AE:

Type B: (Bizarre AE):

1. Hypersensitivity reactions: due to abnormal immune responses.
2. Idiosyncrasy (pharmacogenetics defects): These are genetics defects that are revealed only by the effect of drugs, as, G6PD deficiency with antimalarial.

Type C: (Continuous AE):

      AE that occurs only with long term therapy (chronic use), as analgesic nephropathy with aspirin.

Type D: (Delayed AE):

      AE detected long term after cessationتوقف of therapy:

1. Mutagenicity: as, metronidazole.
2. Teratogenicity: as, tetracyclin→bone deformity.

Type E: (End of dose AE):

AE that occurs on drug withdrawal, as, withdrawal syndrome with addiction of alcohol and opioids.

TOLERANCE (ACQUIRED RESISTANCE)•         It is a gradual decrease in responsiveness to a drug that develop upon repeated administration so that higher doses are needed to obtain the initial response (e.g., insulin). It takes days or weeks to develop

v  Mechanism:

• Enzyme induction (increased rate of metabolism).
•  b- Development of antihormones
•  c- Decreased sensitivity of receptors
•  d- Downregulation of receptors.

CROSS TOLERANCE

•         Development of tolerance to a drug → tolerance to other drugs of the same group. e.g. members of Opioids with each other.

TACHYPHYLAXIS (ACUTE TOLERANCE)

It is a rapidly-developing form of tolerance, in which we cannot get the same response by  increasing the dose of the drug, (e.g., ephedrine tachyphylaxis →due to downregulation of receptors and depletion of catecholamine stores).

THERAPEUTIC INDEX (TI)

•         DEFINITION:

It is the ratio between the dose that produces toxicity (toxic dose) to the dose that produces a clinically desired or effective response (therapeutic dose).

       TI = TOXIC DOSE / THERAPEUTIC DOSE

      It is a measure of the safety of a drug

    The higher the TI, the safer the drug.

•         EXAMPLES:

•         Warfarin → small TI. (unsafe to increase the dose)

•         Penicillin → large TI. (safe to increase the dose)

Pharmacodynamics Interactions

Addition or Summation:

Results in algebraic summation of each drug.

1+1 = 2

So, use ½ dose of each drug if we need the same effect.

Example: Ach + Histamine on intestinal contraction.

Synergism:

Results in more than algebraic summation of each drug.

1+1 = 3

So, use ⅓ dose of each drug if we need the same effect.

Example: curare + Ether = severe paralysis

Potentiation:

One drug has no action but potentiates the effect of the other.

1+0 = 2

Decrease the dose of the active drug if we need the same effect.

Example: Physostigmine + Ach = severe muscle contraction.

links and sources:

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lippincott illustrated reviews pharmacology pdf

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