Mechanisms Of Action

Mechanisms of Action Dr. Melinda C. Tagle RPh, RN, M.D. Dept Chairman – Pharmacology, DMSF

Specific and Nonspecific Structure – Activity Relationships  To determine whether a drug effect is due to a specific structural component of the drug molecule or from non-specific drug action.

Nonspecific Drugs  Do not specifically bind with a particular biological structure;  Are active only in relatively high doses;  Have similar activity but vastly different chemical structures ; and  Show largely similar activity after chemical modification.

Specific Drugs  Interact with specific receptors ( stimulatio or blockade)  Open or block ion channels  Modify transport systems ( carriermediated and active transport)  Inhibit or activate enzymes, or  Interfere with particular aspects of biosynthesis in microorganisms.

Nonspecific

Vs.

 Activity is often related to lipophilicity  Activity differences explained by differences in partition coefficients  Interacts with lipophilic cell components to alter membrane function  Ex. Inhalation anesthetics and some disinfectants

Specific

 Specific drugs are more potent than non-specific drugs  Effects are seen with lower concentration  Activity is highly dependent on the structure  Small structural changes result in drastic changes in pharmacological activity

 Drugs which act at the same site frequently have significant chemical similarities.  The active site is the Pharmacophore, or the molecular component responsible for the activity.  Table A 3-1. Mechanisms of Drug Action

Mechanisms of Drug Action 1. 2. 3. 4.

Receptor Interactions Altering Cellular Transport Processes Changing Enzyme Functions Altering Microorganism Biosynthesis

Receptor Interactions 

Stimulating Receptors a. Activating adrenergic receptors with sympathomimetics (B.1.13.3) b. Activating Muscarinic Receptors with cholinergic agonists ( B.1.14.1) 2. Blocking Receptors a. Inhibiting adrenergic receptors with alpha or beta blockers ( B.1.13.) b. Inhibiting Histamine Receptors with H1 or H2 antihistamines ( B.2.9.1.1.2 and B5.5)

Altering Cellular Transport Processes 1. Blocking Ion Channels a. Inhibiting Ion channels with local anesthetics b. Blocking calcium channels with calcium channel blockers 2. Altering Carrier Mediated Transport a. Inhibitng Na+ /K+/ 2Cl_ carrier with loop diuretics like furosemide b. Inhibiting Na+ /Cl- cotransport with thiazides 3. Interfering with active transport a. inhibiting Na+/K+/ATPase with cardiac glycosides b. Inhibitng reuptake of monoamines with antidepressants

Changing Enzyme Functions 1. Enzyme Inhibition a. Inhibitng Prostaglandin synthesis with non-opioid analgesics b. Inhibiting acetylcholinesterase with indirect cholinergic stimulators c. Inhibiting Angiotensin converting enzyme with ACE inhibitors 2. Enzyme Activation a. activating enzymes with metal ions like magnesium, calcium, zinc, copper or manganese ions

Altering Micoorganism Biosynthesis 1. Inhibiting Bacterial Cell Wall Synthesis a. Bacteriocidal activity of B-lactams 2. Obstructing normal protein synthesis in bacteria a. Bacteriostatic activity of Tetracyclines 3. Obstructing Folic Acid Synthesis a. Bacteriostatic Activity of Sulfonamides

Receptor Mediated Drug Effects 1. Pharmacological Receptors are: a. intracellular or membrane bound proteins; b. produce a pharmacological effect after binding with a specific ligand. 6. L + R ( LR) E where: L= ligand R= Receptor E= Effect

Dual Function of Pharmacological Receptor 1. Detects a ligand signal by forming a ligand-receptor complex and 2. Conduct and translate the signal leading to the pharmacological effect

Physiological Sensory Receptors VS. Pharmacological Receptors  Physiological Sensory Receptors are specialized cells or cellular components which are able to detect physical or chemical stimuli from the outside environment or the internal milieu, and trigger an action potential ( taste receptors, baroreceptors, pressure receptors).  Receptor in Physiology is more often used to denote proteins which bind hormones and numerous other substances.

 The number of pharmacological receptors is limited just as are other endogenous functional molecules in the body, HENCE Ligand binding to receptors is saturable. Binding is also Stereoselective.  In contrast, Substrate Binding, to a pharmacological receptor is reversible and does not chemically change the ligand.  Drugs can replace endogenous physiological ligands to interact with receptors.  Drug-Receptor Complex  Affinity ( agonist, Antagonist)  Intrinsic Activity

Major Phases in Formation of a Drug Receptor Complex +

+

+ +

Orientation Hydrophobic Bond

+

Attraction

+ Fixation Ionic Bond

Occupation Theory assumes that the activity of an Agonist is proportional to the number of occupied receptors and that the agonist has the same affinity for all receptors.

Induced Fit Theory Agonists are compounds which causes conformational change of the receptor while antagonists bind to the receptor but do not change its conformation.