Pharmacodynamics

Pharmacodynamics is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms.
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 effects. Pharmacodynamics is sometimes abbreviated as PD and pharmacokinetics as PK, especially in combined reference.
Pharmacodynamics places particular emphasis on dose–response relationships, that is, the relationships between drug concentration and effect. One dominant example is drug-receptor interactions as modeled by
where L, R, and LR represent ligand, 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 free energy maps.

Basics

There are four principal protein targets with which drugs can interact:

Enzymes
* Inhibitors
* Inducers
* Activators
Membrane carriers
* Enhancer
* Inhibitor
* Releaser
Ion channels
* Blocker
* Opener
Receptor
* Agonists can be full, partial or inverse.
* 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. The other two are agonist affinity and efficacy. They may be increased, decreased or unaffected.

	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.''

Effects on the body

The majority of drugs either
There are 7 main drug actions:

stimulating action through direct receptor agonism and downstream effects
depressing action through direct receptor agonism and downstream effects
blocking/antagonizing action, 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
exchanging/replacing substances or accumulating them to form a reserve
direct beneficial chemical reaction as in free radical scavenging
direct harmful chemical reaction which might result in damage or destruction of the cells, through induced toxic or lethal damage
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 proteins
Interaction with ion channels
Ligand binding to receptors:
*Hormone receptors
*Neuromodulator receptors
*Neurotransmitter receptors

General anesthetics were once thought to work by disordering the neural membranes, thereby altering the Na⁺ influx. Antacids and chelating agents 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 prostaglandin synthetase thereby preventing 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, blocked action, or even action opposite to normal.
In principle, a pharmacologist would aim for a target 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. 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 mutation
A multitude of simultaneous assorted actions which may be deleterious
Interaction
Induced physiological damage, or abnormal chronic conditions
Overstimulation or Inhibition of receptors- lead to harmful physiological changes
Development of tolerance - reduce their responsiveness, requiring higher doses of drug.
Induced pathological conditions - long term structural or functional changes
Disturbed homeostasis
Functional selectivity - preferentially activate certain pathways over others, potentially leading to off-target or unanticipated effects.
Therapeutic window

The therapeutic window is the amount of a medication between the amount that gives an effect 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. Duration of action is a function of several parameters including plasma half-life, the time to equilibrate between plasma and target compartments, and the off rate of the drug from its biological target.

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: total duration onset come up peak offset and 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 administered.

Onset

The onset phase can be defined as the period until the very first changes in perception 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, 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 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:
where L=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. 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 and of the signal amplification capacity of the corresponding receptor. Thus, the existence of receptor reserve depends on the agonist, tissue and measured effect. As receptor reserve is very sensitive to agonist's intrinsic efficacy, it is usually defined only for full agonists.
Often the response is determined as a function of log 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 =K_d.
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 since lower concentrations are needed for a given response. The effect increases as a function of concentration.