View source for Pharmacodynamics

{{Short description|Branch of pharmacology}}
[[File:Pharmacodynamics.svg|thumb|Topics of pharmacodynamics]]
'''Pharmacodynamics''' ('''PD''') is the study of the [[biochemistry|biochemical]] and [[physiology|physiologic]] effects of [[drug]]s (especially [[pharmaceutical drug]]s). The effects can include those manifested within [[animal]]s (including humans), [[microorganism]]s, or combinations of [[organism]]s (for example, [[infection]]).

Pharmacodynamics and [[pharmacokinetics]] are the main branches of [[pharmacology]],  being itself a topic of [[biology]] 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 influence [[dosing]], benefit, and [[adverse effect]]s. Pharmacodynamics is sometimes abbreviated as PD and [[pharmacokinetics]] as PK, especially in combined reference (for example, when speaking of [[PK/PD models]]).

Pharmacodynamics places particular emphasis on [[dose–response relationship]]s, that is, the relationships between drug [[concentration]] and effect.<ref>{{cite journal |vauthors=Lees P, Cunningham FM, Elliott J |title=Principles of pharmacodynamics and their applications in veterinary pharmacology |journal=J. Vet. Pharmacol. Ther. |volume=27 |issue=6 |pages=397–414 |year=2004 |pmid=15601436 |doi=10.1111/j.1365-2885.2004.00620.x|url=http://researchonline.rvc.ac.uk/id/eprint/912/ }}</ref>  One dominant example is drug-receptor interactions as modeled by

:<chem>L + R <=> LR </chem>

where ''L'', ''R'', and ''LR'' represent ligand (drug), receptor, and ligand-receptor complex concentrations, respectively. This equation represents a simplified model of [[reaction dynamics]] that can be studied mathematically through tools such as [[thermodynamic free energy|free energy]] maps.

{{Quote box
| title = [[International Union of Pure and Applied Chemistry|IUPAC]] definition
| quote = '''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.<ref>{{cite book |author=<!--Not stated--> |date=2019 |title=IUPAC Compendium of Chemical Terminology|doi=10.1351/goldbook.P04526|publisher=International Union of Pure and Applied Chemistry|edition=3.0.1}}</ref>
| align = right
| width = 30%
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==Basics==
There are four principal protein targets with which drugs can interact:

* [[Enzyme modulator|Enzymes]]{{snd}} (e.g. [[neostigmine]] and [[Acetylcholinesterase|acetyl cholinesterase]])
** [[Enzyme inhibitor|Inhibitors]]
** [[Enzyme inducer|Inducers]] 
** [[Enzyme activator|Activators]] 
* [[:Category:Membrane transport modulators|Membrane carriers]]{{snd}} [<nowiki/>[[Reuptake]] vs [[Reverse transport|Efflux]]] (e.g. [[tricyclic antidepressant]]s and [[catecholamine]] uptake-1)
** [[Reuptake enhancer|Enhancer]] (RE)
** [[Reuptake inhibitor|Inhibitor]] (RI)
** [[Releasing agent|Releaser]] (RA)
* [[Channel modulator|Ion channels]]{{snd}} (e.g. [[nimodipine]] and [[Voltage-gated calcium channel|voltage-gated Ca<sup>2+</sup> channels]])
** [[Channel blocker|Blocker]]
** [[Channel opener|Opener]]
* [[Receptor modulator|Receptor]]{{snd}} (e.g. Listed in table below)
** [[Agonist]]s can be full, [[Partial agonist|partial]] or [[Inverse agonist|inverse]].
** [[Receptor antagonist|Antagonists]] can be competitive, non-competitive, or uncompetive.
** [[Allosteric modulator]] can have 3 effects within a receptor. One is its capability or incapability to activate a receptor (2 possibilities). The other two are agonist [[Affinity (pharmacology)|affinity]] and [[Efficacy (pharmacology)|efficacy]]. They may be increased, decreased or unaffected (3 and 3 possibilities).

{| class="wikitable"
|+Receptors can be subdivided into four main classes: ligand-gated ion channels(LGIC), tyrosine kinase-coupled(TRK), intracellular steroid, G-protein-coupled (GPCR).
!
![[Ligand-gated ion channel|LGIC]]
![[Receptor tyrosine kinase|TRK]]
![[Steroid hormone receptor|Steroid]]
![[G protein-coupled receptor|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.''<ref>{{Cite journal |title=Drugs and receptors |last=Lambert |first=DG |journal=Continuing Education in Anaesthesia Critical Care & Pain |issn=2058-5357 |volume=4 |issue=6 |pages=181–184 |date=2004-12-01 |url=https://academic.oup.com/bjaed/article/4/6/181/314691 |access-date=2023-01-15}}</ref>

== Effects on the body ==
The majority of drugs either {{ordered list|list_style_type=lower-alpha
|induce(mimic) or inhibit(prevent) normal physiological/biochemical processes and pathological processes in animals or
|inhibit vital processes of endo- or ectoparasites and microbial organisms.}}
There are 7 main drug actions:<ref>{{cite web |title=Introduction to Pharmacology |url=https://www.psychdb.com/meds/pharmacology/home#pharmacodynamics |website=PsychDB|date=25 March 2018 }}</ref>
*[[Stimulation|stimulating action]] through direct [[Agonist|receptor agonism]] and downstream effects
*[[Depression (physiology)|depressing action]] through direct [[Agonist|receptor agonism]] and downstream effects (ex.: [[inverse agonist]])
*blocking/antagonizing action (as with [[Receptor antagonist|silent antagonists]]), the drug binds the receptor but does not activate it
*stabilizing action, the drug seems to act neither as a stimulant or as a depressant (ex.: some drugs possess receptor activity that allows them to stabilize general receptor activation, like [[buprenorphine]] in opioid dependent individuals or [[aripiprazole]] in schizophrenia, all depending on the dose and the recipient)
*exchanging/replacing substances or accumulating them to form a reserve (ex.: [[glycogen]] storage)
*direct beneficial chemical reaction as in [[Antioxidant#Oxidative challenge in biology|free radical scavenging]]
*direct harmful chemical reaction which might result in damage or destruction of the cells, through induced toxic or lethal damage ([[cytotoxicity]] or [[irritation]])

[[File:Molecular mechanisms.svg|thumb|Some molecular mechanisms of pharmacological agents]]

===Desired activity===
The desired activity of a drug is mainly due to successful targeting of one of the following:
*[[Cellular membrane]] disruption
*[[Chemical reaction]] with downstream effects
*Interaction with [[enzyme]] proteins
*Interaction with [[structural]] proteins
*Interaction with [[Carrier-protein|carrier]] proteins
*Interaction with [[ion channel]]s
*[[Ligand binding]] to [[Receptor (biochemistry)|receptors]]:
**[[Hormone]] receptors
**[[Neuromodulator]] receptors
**[[Neurotransmitter]] receptors

[[General anesthetic]]s were once thought to work by disordering the neural membranes, thereby altering the Na<sup>+</sup> influx. [[Antacid]]s and [[chelating agent]]s combine chemically in the body. Enzyme-substrate binding is a way to alter the production or metabolism of key [[endogenous]] chemicals, for example [[aspirin]] irreversibly inhibits the enzyme [[cyclooxygenase|prostaglandin synthetase (cyclooxygenase)]] thereby preventing [[Inflammation|inflammatory]] response. [[Colchicine]], a drug for gout, interferes with the function of the structural protein [[tubulin]], while [[digitalis]], 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 target [[blood plasma|plasma]] 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. [[Genetics|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=== 
Undesirable effects of a drug include:
*Increased probability of cell [[Mutagen|mutation]] ([[carcinogen]]ic activity)
*A multitude of simultaneous assorted actions which may be deleterious
*Interaction (additive, multiplicative, or metabolic)
*Induced physiological damage, or abnormal chronic conditions

===Therapeutic window===
{{Main|Therapeutic window}}
The therapeutic window is the amount of a [[medication]] between the amount that gives an effect ([[effective dose (pharmacology)|effective dose]]) and the amount that gives more [[adverse 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.

===Duration of action===
The ''duration of action'' of a drug is the length of time that particular drug is effective.<ref name="pmid7352385">{{cite journal | author = Carruthers SG | title = Duration of drug action | journal = Am. Fam. Physician | volume = 21 | issue = 2 | pages = 119–26 |date=February 1980 | pmid = 7352385 }}</ref>  Duration of action is a function of several parameters including [[biological half-life|plasma half-life]], the time to equilibrate between plasma and target compartments, and the off rate of the drug from its [[biological target]].<ref name="pmid20880390">{{cite journal |vauthors=Vauquelin G, Charlton SJ | title = Long-lasting target binding and rebinding as mechanisms to prolong in vivo drug action | journal = Br. J. Pharmacol. | volume = 161 | issue = 3 | pages = 488–508 |date=October 2010 | pmid = 20880390 | pmc = 2990149 | doi = 10.1111/j.1476-5381.2010.00936.x }}</ref>

==== Recreational drug use ====
{{Main|Recreational drug use}}
In recreational psychoactive drug spaces, duration refers to the length of time over which the [[subjective effects]] of a [[psychoactive 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.

====Total====
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 into [[sobriety]], starting from the moment the substance is first [[drug administration|administered]].

====Onset====
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.

====Come up====
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."

====Peak====
The peak phase can be defined as period of time in which the intensity of the substance's effects are at its height.

====Offset====
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."

====After effects====
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 as [[Alcohol (drug)|alcohol]], [[cocaine]], and [[MDMA]] or an "afterglow" for describing a typically positive, pleasant effect, typically found in substances such as [[cannabis]], [[LSD]] in low to high doses, and [[ketamine]].

==Receptor binding and effect==
The binding of ligands (drug) to receptors is governed by the ''[[law 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. The ''equilibrium dissociation constant'' is defined by:
:<chem>L + R <=> LR </chem> &nbsp;&nbsp;&nbsp;  &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;<math>K_d = \frac{[L][R]}{[L R]}</math>
where ''L''=ligand, ''R''=receptor, square brackets [] denote concentration. The fraction of bound receptors is

:<math>{p}_{LR} = \frac{[L R]}{[R]+[L R]} =\frac{1}{1+\frac{K_d}{[L]}}</math>

Where <math>{p}_{LR}</math> 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 (biochemistry)|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-called ''receptor 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 an [[agonist]] (in some receptor models it is termed intrinsic efficacy or [[intrinsic 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.<ref name="pmid7161296">{{cite journal | author = Ruffolo RR Jr | title = Review important concepts of receptor theory | journal = Journal of Autonomic Pharmacology | volume = 2 | issue = 4 | pages = 277–295 |date=December 1982 | pmid = 7161296 | doi = 10.1111/j.1474-8673.1982.tb00520.x }}</ref><ref name="pmid12570756">{{cite journal |vauthors=Dhalla AK, Shryock JC, Shreeniwas R, Belardinelli L | title = Pharmacology and therapeutic applications of A1 adenosine receptor ligands | journal = Curr. Top. Med. Chem. | volume = 3 | issue = 4 | pages = 369–385 |date= 2003 | pmid = 12570756 | doi = 10.2174/1568026033392246 }}</ref><ref name="pmid23456693">{{cite journal |vauthors=Gesztelyi R, Kiss Z, Wachal Z, Juhasz B, Bombicz M, Csepanyi E, Pak K, Zsuga J, Papp C, Galajda Z, Branzaniuc K, Porszasz R, Szentmiklosi AJ, Tosaki A | title = The surmountable effect of FSCPX, an irreversible A(1) adenosine receptor antagonist, on the negative inotropic action of A(1) adenosine receptor full agonists in isolated guinea pig left atria | journal = Arch. Pharm. Res. | volume = 36 | issue = 3 | pages = 293–305 |date= 2013 | pmid = 23456693 | doi = 10.1007/s12272-013-0056-z | s2cid = 13439779 }}</ref>

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'']=''K<sub>d</sub>'' .

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.

== Multicellular pharmacodynamics ==
The concept of pharmacodynamics has been expanded to include '''Multicellular 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), both ''in vivo'' and ''in 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.<ref>{{Cite journal|last1=Zhao|first1=Shan|last2=Iyengar|first2=Ravi|date=2012|title=Systems Pharmacology: Network Analysis to Identify Multiscale Mechanisms of Drug Action|journal=Annual Review of Pharmacology and Toxicology|volume=52|pages=505–521|doi=10.1146/annurev-pharmtox-010611-134520|issn=0362-1642|pmc=3619403|pmid=22235860}}</ref>

== Toxicodynamics ==
{{expand section|date=April 2019}}
{{main|Toxicodynamics}}
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.<ref>{{Cite book |last1=Riviere |first1=Jim Edmond |title=Veterinary pharmacology and therapeutics |last2=Papich |first2=Mark G. |date=2009 |publisher=Wiley-Blackwell |isbn=978-0-8138-2061-3 |edition=9th |location=Ames (Iowa)}}</ref> The mechanism of action is a crucial factor in determining effect and toxicity of the drug, taking in consideration the pharmacokinetic (PK) factors.<ref>{{Citation |last1=Wang |first1=Jin |title=Chapter 5 - Principles of Pharmacodynamics and Toxicodynamics |date=2022-01-01 |work=Haschek and Rousseaux's Handbook of Toxicologic Pathology (Fourth Edition) |pages=101–112 |editor-last=Haschek |editor-first=Wanda M. |url=https://linkinghub.elsevier.com/retrieve/pii/B9780128210444000273 |access-date=2024-11-05 |publisher=Academic Press |doi=10.1016/b978-0-12-821044-4.00027-3 |isbn=978-0-12-821044-4 |last2=Stresser |first2=David M. |editor2-last=Rousseaux |editor2-first=Colin G. |editor3-last=Wallig |editor3-first=Matthew A. |editor4-last=Bolon |editor4-first=Brad}}</ref> 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,'' or ''in 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.<ref>{{Cite journal |last1=Roth |first1=Robert A. |last2=Ganey |first2=Patricia E. |date=March 2010 |title=Intrinsic versus Idiosyncratic Drug-Induced Hepatotoxicity—Two Villains or One? |journal=Journal of Pharmacology and Experimental Therapeutics |language=en |volume=332 |issue=3 |pages=692–697 |doi=10.1124/jpet.109.162651 |issn=0022-3565 |pmc=2835443 |pmid=20019161}}</ref> 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 termed [[toxicokinetics]] and [[toxicodynamics]] in the field of [[ecotoxicology]]. Here, the focus is on toxic effects on a wide range of organisms. The corresponding models are called toxicokinetic-toxicodynamic models.<ref name="pmid20863871">{{cite journal | vauthors = Li Q, Hickman M | title = Toxicokinetic and toxicodynamic (TK/TD) evaluation to determine and predict the neurotoxicity of artemisinins | journal = Toxicology | volume = 279 | issue = 1–3 | pages = 1–9 | year = 2011 | pmid = 20863871 | doi = 10.1016/j.tox.2010.09.005 | bibcode = 2011Toxgy.279....1L | url = https://zenodo.org/record/1259395 }}</ref>

== See also ==
* [[Mechanism of action]]
* [[Dose-response relationship]]
* [[Pharmacokinetics]]
* [[ADME]]
* [[Antimicrobial pharmacodynamics]]
* [[Pharmaceutical company]]
* [[Schild regression]]

==References==
{{reflist}}

==External links==
{{Commons category}}
* Vijay. (2003) [http://www.ingentaconnect.com/content/adis/pdr/2003/00000001/00000003/art00002 Predictive software for drug design and development]. Pharmaceutical Development and Regulation 1 ((3)), 159–168.
* Werner, E., [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14678738&query_hl=3 In silico multicellular systems biology and minimal genomes], DDT vol 8, no 24, pp 1121–1127, Dec 2003. (Introduces the concepts MCPD and Net-MCPD)
*Dr. David W. A. Bourne, OU College of Pharmacy [http://www.boomer.org/pkin/ Pharmacokinetic and Pharmacodynamic Resources].
*[https://www.ashp.org/-/media/store%20files/p2418-sample-chapter-1.pdf Introduction to Pharmacokinetics and Pharmacodynamics] (PDF)

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