Pharmacodynamics (PD) is the study of thebiochemical andphysiologic effects ofdrugs (especiallypharmaceutical drugs). The effects can include those manifested withinanimals (including humans),microorganisms, or combinations oforganisms (for example,infection).
Pharmacodynamics andpharmacokinetics are the main branches ofpharmacology, being itself a topic ofbiology interested in the study of the interactions of both endogenous and exogenous chemical substances with living organisms.
In particular, pharmacodynamics is the study of how a drug affects an organism, whereas pharmacokinetics is the study of how the organism affects the drug. Both together influencedosing, benefit, andadverse effects. Pharmacodynamics is sometimes abbreviated as PD andpharmacokinetics as PK, especially in combined reference (for example, when speaking ofPK/PD models).
Pharmacodynamics places particular emphasis ondose–response relationships, that is, the relationships between drugconcentration and effect.[1] One dominant example is drug-receptor interactions as modeled by
whereL,R, andLR represent ligand (drug), receptor, and ligand-receptor complex concentrations, respectively. This equation represents a simplified model ofreaction dynamics that can be studied mathematically through tools such asfree energy maps.
Pharmacodynamics: Study of pharmacological actions on living systems, including the reactions with and binding to cell constituents, and the biochemical and physiological consequences of these actions.[2]
There are four principal protein targets with which drugs can interact:
| LGIC | TRK | Steroid | GPCR | |
|---|---|---|---|---|
| Location | Membrane | Membrane | Intracellular | Membrane |
| Main action | Ion flux | Phosphorylation | Gene transcription | 2nd messengers |
| Example/drug | Nicotinic/NMBD | Insulin/insulin | Steroid/thyroxine | Opioid/morphine |
| NMDA/ketamine | Growth factor/EGF | Steroid/oestrogen | Adrenoceptor/isoprenaline |
NMBD = neuromuscular blocking drugs; NMDA = N-methyl-d-aspartate; EGF = epidermal growth factor.[3]
The majority of drugs either
There are 7 main drug actions:[4]
The desired activity of a drug is mainly due to successful targeting of one of the following:
General anesthetics were once thought to work by disordering the neural membranes, thereby altering the Na+ influx.Antacids andchelating agents combine chemically in the body. Enzyme-substrate binding is a way to alter the production or metabolism of keyendogenous chemicals, for exampleaspirin irreversibly inhibits the enzymeprostaglandin synthetase (cyclooxygenase) thereby preventinginflammatory response.Colchicine, a drug for gout, interferes with the function of the structural proteintubulin, whiledigitalis, a drug still used in heart failure, inhibits the activity of the carrier molecule,Na-K-ATPase pump. The widest class of drugs act as ligands that bind to receptors that determine cellular effects. Upon drug binding, receptors can elicit their normal action (agonist), blocked action (antagonist), or even action opposite to normal (inverse agonist).
In principle, a pharmacologist would aim for a targetplasma concentration of the drug for a desired level of response. In reality, there are many factors affecting this goal. Pharmacokinetic factors determine peak concentrations, and concentrations cannot be maintained with absolute consistency because of metabolic breakdown and excretory clearance.Genetic factors may exist which would alter metabolism or drug action itself, and a patient's immediate status may also affect indicated dosage.
Undesirable effects of a drug include:
The therapeutic window is the amount of amedication between the amount that gives an effect (effective dose) and the amount that gives moreadverse effects than desired effects. For instance, medication with a small pharmaceutical window must be administered with care and control, e.g. by frequently measuring blood concentration of the drug, since it easily loses effects or gives adverse effects.
Theduration of action of a drug is the length of time that particular drug is effective.[5] Duration of action is a function of several parameters includingplasma half-life, the time to equilibrate between plasma and target compartments, and the off rate of the drug from itsbiological target.[6]
In recreational psychoactive drug spaces, duration refers to the length of time over which thesubjective effects of apsychoactive substance manifest themselves. Duration can be broken down into 6 parts: (1) total duration (2) onset (3) come up (4) peak (5) offset and (6) after effects. Depending upon the substance consumed, each of these occurs in a separate and continuous fashion.
The total duration of a substance can be defined as the amount of time it takes for the effects of a substance to completely wear off intosobriety, starting from the moment the substance is firstadministered.
The onset phase can be defined as the period until the very first changes in perception (i.e. "first alerts") are able to be detected.
The "come up" phase can be defined as the period between the first noticeable changes in perception and the point of highest subjective intensity. This is colloquially known as "coming up."
The peak phase can be defined as period of time in which the intensity of the substance's effects are at its height.
The offset phase can be defined as the amount of time in between the conclusion of the peak and shifting into a sober state. This is colloquially referred to as "coming down."
The after effects can be defined as any residual effects which may remain after the experience has reached its conclusion. After effects depend on the substance and usage. This is colloquially known as a "hangover" for negative after effects of substances, such asalcohol,cocaine, andMDMA or an "afterglow" for describing a typically positive, pleasant effect, typically found in substances such ascannabis,LSD in low to high doses, andketamine.
The binding of ligands (drug) to receptors is governed by thelaw of mass action which relates the large-scale status to the rate of numerous molecular processes. The rates of formation and un-formation can be used to determine the equilibrium concentration of bound receptors. Theequilibrium dissociation constant is defined by:
whereL=ligand,R=receptor, square brackets [] denote concentration. The fraction of bound receptors is
Where is the fraction of receptor bound by the ligand.
This expression is one way to consider the effect of a drug, in which the response is related to the fraction of bound receptors (see:Hill equation). The fraction of bound receptors is known as occupancy. The relationship between occupancy and pharmacological response is usually non-linear. This explains the so-calledreceptor reserve phenomenon i.e. the concentration producing 50% occupancy is typically higher than the concentration producing 50% of maximum response. More precisely, receptor reserve refers to a phenomenon whereby stimulation of only a fraction of the whole receptor population apparently elicits the maximal effect achievable in a particular tissue.
The simplest interpretation of receptor reserve is that it is a model that states there are excess receptors on the cell surface than what is necessary for full effect. Taking a more sophisticated approach, receptor reserve is an integrative measure of the response-inducing capacity of anagonist (in some receptor models it is termed intrinsic efficacy orintrinsic activity) and of the signal amplification capacity of the corresponding receptor (and its downstream signaling pathways). Thus, the existence (and magnitude) of receptor reserve depends on the agonist (efficacy), tissue (signal amplification ability) and measured effect (pathways activated to cause signal amplification). As receptor reserve is very sensitive to agonist's intrinsic efficacy, it is usually defined only for full (high-efficacy) agonists.[7][8][9]
Often the response is determined as a function of log[L] to consider many orders of magnitude of concentration. However, there is no biological or physical theory that relates effects to the log of concentration. It is just convenient for graphing purposes. It is useful to note that 50% of the receptors are bound when [L]=Kd .
The graph shown represents the conc-response for two hypothetical receptor agonists, plotted in a semi-log fashion. The curve toward the left represents a higher potency (potency arrow does not indicate direction of increase) since lower concentrations are needed for a given response. The effect increases as a function of concentration.
The concept of pharmacodynamics has been expanded to includeMulticellular Pharmacodynamics (MCPD). MCPD is the study of the static and dynamic properties and relationships between a set of drugs and a dynamic and diverse multicellular four-dimensional organization. It is the study of the workings of a drug on a minimal multicellular system (mMCS), bothin vivo andin silico.Networked Multicellular Pharmacodynamics (Net-MCPD) further extends the concept of MCPD to model regulatory genomic networks together with signal transduction pathways, as part of a complex of interacting components in the cell.[10]
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Toxicodynamics (TD) and pharmacodynamics (PD) link a therapeutic agent or toxicant, or toxin (xenobiotic)'s dosage to the features, amount, and time course of its biological action.[11] The mechanism of action is a crucial factor in determining effect and toxicity of the drug, taking in consideration the pharmacokinetic (PK) factors.[12] The sort and extent of altered cellular physiology will depend on the combination of the drug's presence (as established by pharmacokinetic (PK) studies) and/or its mechanism and duration of action (PD). Types of xenobiotic-target interaction can be described either by reversible, irreversible, noncompetitive, and allosteric interaction or agonist, partial agonist, antagonist, and inverse interactions.In vitro, ex vivo, orin vivo studies can be used to assess PD and TD from the molecule to the level of the entire organism.
The mechanism of drug action and adverse drug reaction is either physiochemical property based and biochemical based. Adverse drugs reactions can be classified as either idiosyncratic (type B) or intrinsic (type A). Idiosyncratic toxicity is not dosage dependent and defy the mass-action relationship. Immune-mediated processes are frequently cited as the source of type B reactions.[13] These cannot be accurately described in preclinical research or clinical trials due to their low incidence frequency. Type A reactions are dosage (concentration) dependent. Usually, this kind of side effect is an extension of an ongoing treatment.
Pharmacokinetics and pharmacodynamics are termedtoxicokinetics andtoxicodynamics in the field ofecotoxicology. Here, the focus is on toxic effects on a wide range of organisms. The corresponding models are called toxicokinetic-toxicodynamic models.[14]
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