Receptors are macromolecules involved in chemic signaling betwixt and inside cells; they may be located on the prison cell surface membrane or within the cytoplasm (run into table Some Types of Physiologic and Drug-Receptor Proteins
Effect of Aging on Drug Response
). Activated receptors directly or indirectly regulate cellular biochemical processes (eg, ion conductance, protein phosphorylation, DNA transcription, enzymatic activity).
A drug’s power to bear upon a given receptor is related to the drug’s affinity (probability of the drug occupying a receptor at any given instant) and intrinsic efficacy (intrinsic action—degree to which a ligand activates receptors and leads to cellular response). A drug’south analogousness and action are determined by its chemical construction.
The pharmacologic effect is as well determined past the duration of time that the drug-receptor complex persists (residence time). The lifetime of the drug-receptor complex is affected by dynamic processes (conformation changes) that command the rate of drug clan and dissociation from the target. A longer residence fourth dimension explains a prolonged pharmacologic effect. Drugs with long residence times include
darunavir. A longer residence time can be a potential disadvantage when it prolongs a drug’s toxicity. For some receptors, transient drug occupancy produces the desired pharmacologic event, whereas prolonged occupancy causes toxicity.
Physiologic functions (eg, wrinkle, secretion) are commonly regulated by multiple receptor-mediated mechanisms, and several steps (eg, receptor-coupling, multiple intracellular 2nd messenger substances) may be interposed between the initial molecular drug–receptor interaction and ultimate tissue or organ response. Thus, several dissimilar drug molecules tin often exist used to produce the same desired response.
Ability to bind to a receptor is influenced by external factors likewise as by intracellular regulatory mechanisms. Baseline receptor density and the efficiency of stimulus-response mechanisms vary from tissue to tissue. Drugs, crumbling, genetic mutations, and disorders tin increment (upregulate) or decrease (downregulate) the number and binding affinity of receptors. For case,
downregulates alpha ii receptors; thus, rapid withdrawal of
can crusade hypertensive crisis
A hypertensive emergency is severe hypertension with signs of damage to target organs (primarily the encephalon, cardiovascular system, and kidneys). Diagnosis is past blood pressure (BP) measurement…
read more than
. Chronic therapy with beta-blockers upregulates beta-receptor density; thus, severe hypertension or tachycardia tin can result from abrupt withdrawal. Receptor upregulation and downregulation impact adaptation to drugs (eg, desensitization, tachyphylaxis, tolerance, caused resistance, postwithdrawal supersensitivity).
Ligands demark to precise molecular regions, called recognition sites, on receptor macromolecules. The binding site for a drug may be the same as or different from that of an endogenous agonist (hormone or neurotransmitter). Agonists that bind to an side by side site or a different site on a receptor are sometimes called allosteric agonists. Nonspecific drug bounden also occurs—ie, at molecular sites not designated equally receptors (eg, plasma proteins). Drug bounden to such nonspecific sites, such as bounden to serum proteins, prohibits the drug from binding to the receptor and thus inactivates the drug. Unbound drug is available to bind to receptors and thus have an issue.
Agonists activate receptors to produce the desired response. Conventional agonists increment the proportion of activated receptors. Inverse agonists stabilize the receptor in its inactive conformation and act similarly to competitive antagonists. Many hormones, neurotransmitters (eg, acetylcholine, histamine,
norepinephrine), and drugs (eg,
isoproterenol, benzodiazepines, barbiturates) act equally agonists.
Antagonists preclude receptor activation. Preventing activation has many effects. Antagonists increase cellular role if they block the action of a substance that normally decreases cellular function. Antagonists decrease cellular office if they cake the action of a substance that commonly increases cellular function.
Receptor antagonists tin be classified every bit reversible or irreversible. Reversible antagonists readily dissociate from their receptor; irreversible antagonists form a stable, permanent or nearly permanent chemic bond with their receptor (eg, by alkylation). Pseudo-irreversible antagonists slowly dissociate from their receptor.
binding of the adversary to the receptor prevents binding of the agonist to the receptor.
agonist and adversary tin can be bound simultaneously, simply antagonist bounden reduces or prevents the activeness of the agonist.
reversible competitive antagonism,
agonist and adversary form short-lasting bonds with the receptor, and a steady state amidst agonist, antagonist, and receptor is reached. Such antagonism tin be overcome past increasing the concentration of the agonist. For instance,
(an opioid receptor antagonist that is structurally like to
morphine), when given shortly before or later
morphine’south effects. Withal, competitive animosity past
tin be overcome by giving more
Structural analogs of agonist molecules frequently take agonist and antagonist properties; such drugs are called partial (depression-efficacy) agonists, or agonist-antagonists. For case,
activates opioid receptors simply blocks their activation by other opioids. Thus,
provides opioid effects simply blunts the effects of another opioid if the opioid is given while
is still bound. A drug that acts as a partial agonist in one tissue may deed every bit a total agonist in some other.
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Agonists Bind to ________ and Antagonists Bind to ________