The drug system contains the physiologically based pharmacokinetic (PBPK) model and the pharmacodynamic (PD) model. More...

#include <Drugs.h>

Inheritance diagram for biogears::Drugs:

[legend]

Public Member Functions
virtual	~Drugs () override

const char *	classname () const override

size_t	hash_code () const override

void	Clear () override

void	Initialize () override
	Initializes system properties to valid homeostatic values. More...

virtual bool	Load (const CDM::BioGearsDrugSystemData &in)

virtual CDM::BioGearsDrugSystemData *	Unload () const override

void	AtSteadyState () override
	Determines if the engine is stable. More...

void	PreProcess () override
	Substance Preprocess function. More...

void	Process () override
	Substances process function. More...

void	PostProcess () override

Public Member Functions inherited from biogears::SEDrugSystem
	SEDrugSystem (Logger *logger)

	~SEDrugSystem () override

const SEScalar *	GetScalar (const char *name) override

const SEScalar *	GetScalar (const std::string &name) override

bool	Load (const CDM::DrugSystemData &in)

Tree< const char * >	GetPhysiologyRequestGraph () const override

bool	HasAntibioticActivity () const

SEScalar &	GetAntibioticActivity ()

double	GetAntibioticActivity () const

bool	HasBronchodilationLevel () const

SEScalarFraction &	GetBronchodilationLevel ()

double	GetBronchodilationLevel () const

bool	HasFeverChange () const

SEScalarTemperature &	GetFeverChange ()

double	GetFeverChange (const TemperatureUnit &unit) const

bool	HasHeartRateChange () const

SEScalarFrequency &	GetHeartRateChange ()

double	GetHeartRateChange (const FrequencyUnit &unit) const

bool	HasHemorrhageChange () const

SEScalarFraction &	GetHemorrhageChange ()

double	GetHemorrhageChange () const

bool	HasMeanBloodPressureChange () const

SEScalarPressure &	GetMeanBloodPressureChange ()

double	GetMeanBloodPressureChange (const PressureUnit &unit) const

bool	HasNeuromuscularBlockLevel () const

SEScalarFraction &	GetNeuromuscularBlockLevel ()

double	GetNeuromuscularBlockLevel () const

bool	HasPainToleranceChange () const

SEScalarFraction &	GetPainToleranceChange ()

double	GetPainToleranceChange () const

bool	HasPulsePressureChange () const

SEScalarPressure &	GetPulsePressureChange ()

double	GetPulsePressureChange (const PressureUnit &unit) const

bool	HasRespirationRateChange () const

SEScalarFrequency &	GetRespirationRateChange ()

double	GetRespirationRateChange (const FrequencyUnit &unit) const

bool	HasSedationLevel () const

SEScalarFraction &	GetSedationLevel ()

double	GetSedationLevel () const

bool	HasTidalVolumeChange () const

SEScalarVolume &	GetTidalVolumeChange ()

double	GetTidalVolumeChange (const VolumeUnit &unit) const

bool	HasTubularPermeabilityChange () const

SEScalarFraction &	GetTubularPermeabilityChange ()

double	GetTubularPermeabilityChange () const

bool	HasCentralNervousResponse () const

SEScalarFraction &	GetCentralNervousResponse ()

double	GetCentralNervousResponse () const

Public Member Functions inherited from biogears::SESystem
	SESystem (Logger *logger)

virtual	~SESystem ()

bool	Load (const CDM::SystemData &in)

Public Member Functions inherited from biogears::Loggable
	Loggable ()

	Loggable (Logger *log)

virtual	~Loggable ()

virtual Logger *	GetLogger () const

Static Public Member Functions
static size_t	TypeHash ()

static constexpr char const *const	TypeTag ()
	Hopefully this returns a unique ID for every type. More...

Static Public Member Functions inherited from biogears::SEDrugSystem
static size_t	TypeHash ()

static constexpr char const *const	TypeTag ()

Static Public Member Functions inherited from biogears::SESystem
static const SEScalar *	GetScalar (const char name, std::vector< SESystem > *systems)

static const SEScalar *	GetScalar (const std::string &name, std::vector< SESystem * > *systems)

Protected Member Functions
	Drugs (BioGears &bg)

virtual void	Unload (CDM::BioGearsDrugSystemData &data) const

void	SetUp () override
	Initializes parameters for the Drugs Class. More...

void	AdministerSubstanceBolus ()
	Increments the mass of a substance to represent drug injection. More...

void	AdministerSubstanceInfusion ()
	Increments the mass of a substance to represent drug infusion. More...

void	AdministerSubstanceCompoundInfusion ()
	Increases the substance masses for compounds. More...

void	AdministerSubstanceNasal ()
	Administer drugs via nasal route. More...

void	AdministerSubstanceOral ()
	Administer drugs via transmucosal and gastrointestinal routes. More...

void	CalculatePartitionCoefficients ()
	Calculate partition coefficients for the PK Model. More...

void	CalculateSubstanceClearance ()
	Calculates the substance mass cleared. More...

void	CalculatePlasmaSubstanceConcentration ()
	Calculates the concentration of a substance in the plasma. More...

void	CalculateDrugEffects ()
	Calculates the drug effects on other system parameters. More...

void	SarinKinetics ()
	Calculates the inhibition of erythrocyte bound acetylcholinesterase by the nerve agent Sarin using reaction kinetics. More...

double	OralTransmucosalModel (const SESubstance sub, SETransmucosalState ot)
	Calculates the transport of drugs across the transmucosal lining into circulation Returns the total drug mass remaining in the mouth. More...

Protected Member Functions inherited from biogears::SEDrugSystem
void	Unload (CDM::DrugSystemData &data) const

Protected Member Functions inherited from biogears::SESystem
void	Unload (CDM::SystemData &data) const

Protected Member Functions inherited from biogears::Loggable
virtual void	Debug (const char msg, const char origin="") const

virtual void	Debug (const std::string &msg, const std::string &origin=empty) const

virtual void	Debug (std::ostream &msg, const std::string &origin=empty) const

virtual void	Info (const char msg, const char origin="") const

virtual void	Info (const std::string &msg, const std::string &origin=empty) const

virtual void	Info (std::ostream &msg, const std::string &origin=empty) const

virtual void	Warning (const char msg, const char origin="") const

virtual void	Warning (const std::string &msg, const std::string &origin=empty) const

virtual void	Warning (std::ostream &msg, const std::string &origin=empty) const

virtual void	Error (const char msg, const char origin="") const

virtual void	Error (const std::string msg, const std::string origin=empty) const

virtual void	Error (std::ostream &msg, const std::string &origin=empty) const

virtual void	Fatal (const char msg, const char origin="") const

virtual void	Fatal (const std::string &msg, const std::string &origin=empty) const

virtual void	Fatal (std::ostream &msg, const std::string &origin=empty) const

Protected Member Functions inherited from biogears::BioGearsSystem
virtual void	LoadState ()

Static Protected Member Functions
static auto	make_unique (BioGears &bg) -> std::unique_ptr< Drugs >

Protected Attributes
BioGears &	m_data

std::map< const SESubstance , SESubstanceBolusState >	m_BolusAdministrations

std::map< const SESubstance , SENasalState >	m_NasalStates

std::map< const SESubstance , SETransmucosalState >	m_TransmucosalStates

double	m_SarinRbcAcetylcholinesteraseComplex_nM

double	m_AgedRbcAcetylcholinesterase_nM

double	m_dt_s

double	m_totalAdministered_uL

double	m_RbcAcetylcholinesteraseFractionInhibited

SELiquidCompartment *	m_aortaVascular

SELiquidCompartment *	m_venaCavaVascular

SELiquidCompartment *	m_muscleIntracellular

SELiquidCompartment *	m_liverVascular

SETissueCompartment *	m_liverTissue

SEFluidCircuitPath *	m_IVToVenaCava

SETissueCompartment *	m_fatTissue

SESubstance *	m_Sarin

SESubstance *	m_Pralidoxime

Protected Attributes inherited from biogears::SEDrugSystem
SEScalar *	m_AntibioticActivity

SEScalarFraction *	m_BronchodilationLevel

SEScalarTemperature *	m_FeverChange

SEScalarFrequency *	m_HeartRateChange

SEScalarFraction *	m_HemorrhageChange

SEScalarPressure *	m_MeanBloodPressureChange

SEScalarFraction *	m_NeuromuscularBlockLevel

SEScalarFraction *	m_PainToleranceChange

SEScalarPressure *	m_PulsePressureChange

SEScalarFrequency *	m_RespirationRateChange

SEScalarFraction *	m_SedationLevel

SEScalarVolume *	m_TidalVolumeChange

SEScalarFraction *	m_TubularPermeabilityChange

SEScalarFraction *	m_CentralNervousResponse

Protected Attributes inherited from biogears::SESystem
std::stringstream	m_ss

Protected Attributes inherited from biogears::Loggable
Logger *	m_Logger

Friends
class	BioGears

class	BioGearsEngineTest

Additional Inherited Members
Static Public Attributes inherited from biogears::Loggable
static const std::string	empty

static const char *	empty_cStr

Detailed Description

The drug system contains the physiologically based pharmacokinetic (PBPK) model and the pharmacodynamic (PD) model.

Drug transvascular transport is modeled with a physiologically-based pharmacokinetic (PBPK) model, and the physiologic effects on the body are modeled with a low-fidelity pharmacodynamic (PD) model.

Constructor & Destructor Documentation

biogears::Drugs::Drugs ( BioGears & bg )

protected

biogears::Drugs::~Drugs ( )

overridevirtual

Member Function Documentation

void biogears::Drugs::AdministerSubstanceBolus ( )

protected

Increments the mass of a substance to represent drug injection.

The mass of a substance is increased based on the administration of a substance. For a bolus administration, the user specifies a dose (amount), a concentration, and a substance. The calculated mass is then incrementally added to the vena cava over two seconds.

Error:: Error: Unavailable Administration Route

Todo:: Add fluid amount to fluid system

void biogears::Drugs::AdministerSubstanceCompoundInfusion ( )

protected

Increases the substance masses for compounds.

The masses of all substances associated with the compound substance are increased. The mass of each substance is incremented in the vena cava based on the rate specified by the user and a concentration specified in the compound substance file.

: Re. Sepsis - How does rate compare to that cited in literature? ///@cite malbrain2014fluid, [397]

void biogears::Drugs::AdministerSubstanceInfusion ( )

protected

Increments the mass of a substance to represent drug infusion.

The mass of a substance is increased based on the administration of a substance. For an infusion, the user specifies a concentration and a rate. The calculated mass is then added to the vena cava every time step until the infusion is stopped.

Todo:: sub needs to be const

void biogears::Drugs::AdministerSubstanceNasal ( )

protected

Administer drugs via nasal route.

This function administers drug into the nose as substance that can interact with three different sections: anterior, posterior, and gastrointestinal. Drug is initially deposited in the anterior and posterior sections and goes through rate constant-determined translocation into either uptake or excretion through the GI section. This administration path is generalized and assumes that the drug has a carrier, however, adjustment of drug release constants allows for administration with non-carrier drugs

void biogears::Drugs::AdministerSubstanceOral ( )

protected

Administer drugs via transmucosal and gastrointestinal routes.

This function adminsters drug as lozenges which dissolve in the mouth (transmucosal) or as pills that are swallowed and dissolve in the stomarch (gastrointestinal). The transmucosal route takes into account dissolved drug that is swallowed and enters circulation through the GI and thus intitiates a GI drug state. This function intiates the transmucosal and oral states–other functions (Drugs::ProcessOralTransmucosalModel, Gastrointestinal::ProcessCATModel) handle the actual substance transport and absorption.

void biogears::Drugs::AtSteadyState ( )

overridevirtual

Determines if the engine is stable.

When the engine is stable, the CDM makes this call to update the member variable.

Reimplemented from biogears::BioGearsSystem.

void biogears::Drugs::CalculateDrugEffects ( )

protected

Calculates the drug effects on other system parameters.

If the substance is a drug with an EC50 value, the effects on heart rate, blood pressure, respiration rate, tidal volume, neuromuscular block level, sedation level, bronchodilation level, and pupillary state are calculated using the current plasma concentration, the EC50, and the maximum drug response.

Todo:: The drug effect is being applied to the baseline, so if the baseline changes the delta heart rate changes.

\ [Regoes2004Pharmacodynamics]

void biogears::Drugs::CalculatePartitionCoefficients ( )

protected

Calculate partition coefficients for the PK Model.

Parameters

vSubstances Coefficients are calculated for the substances in the vector with IonicState.

The partition coefficients are calculated for each substance in the input vector (active substances). To ensure the diffusion is modeled with PK for the substance, a check is performed for Ionic State. If the property is present the coefficients are calculated. They are calculated for all tissue compartments. coefficients are set on the substance compartment effects for use during the diffusion calculation.

Error:: Fatal: Binding Protein not supported

void biogears::Drugs::CalculatePlasmaSubstanceConcentration ( )

protected

Calculates the concentration of a substance in the plasma.

If the substance has PK properties, the concentration of the substance in the plasma is calculated. PlasmaConcentration = TotalMassInTheBlood / PlasmaVolume. The plasma concentration is then set on the substance. The concentration computation is obviously erroneous. This is a known issue. See pharmacokinetics

void biogears::Drugs::CalculateSubstanceClearance ( )

protected

Calculates the substance mass cleared.

If the substance has PK properties, the substance clearance is calculated. The renal, liver, and systemic clearance terms are applied to each anatomy compartment per substance. The amount of mass is then removed from the tissue node each time step. The tissue node mass and concentration are then updated. Sets the amount of substance cleared as a compartment effect for each substance.

const char* biogears::Drugs::classname ( ) const

inlineoverridevirtual

Reimplemented from biogears::SEDrugSystem.

void biogears::Drugs::Clear ( )

overridevirtual

Reimplemented from biogears::SEDrugSystem.

size_t biogears::Drugs::hash_code ( ) const

inlineoverridevirtual

Reimplemented from biogears::SEDrugSystem.

void biogears::Drugs::Initialize ( )

overridevirtual

Initializes system properties to valid homeostatic values.

Reimplemented from biogears::BioGearsSystem.

bool biogears::Drugs::Load ( const CDM::BioGearsDrugSystemData & in )

virtual

Error:: Error: Unable to find substance for IV bolus administration

auto biogears::Drugs::make_unique ( BioGears & bg ) -> std::unique_ptr<Drugs>

staticprotected

double biogears::Drugs::OralTransmucosalModel	(	const SESubstance *	sub,
		SETransmucosalState *	ot
	)

protected

Calculates the transport of drugs across the transmucosal lining into circulation Returns the total drug mass remaining in the mouth.

This model assumes that drug has been given as a lozenge that dissolves completely in the mouth and enters circulation by diffusing across the mucosal layer. The diffusion model assumes that drug can cross the sublingual and buccal mucosa, which are the most permeable sections of the mouth to drugs. The sublingual and buccal layers are discretized into seven compartments so that the diffusion equation can be estimated across them using finite difference methods. This number of compartments was used in study of Xia The model was designed originally by Xia2015Development. This mode was designed for oral transmucosal fentanyl citrate (OTFC), and thus many paramters are optimized for it. If more drugs utilize this route, the fentanyl specific parameters may need to be changed to substance CDM parameters.

void biogears::Drugs::PostProcess ( )

inlineoverridevirtual

Implements biogears::BioGearsSystem.

void biogears::Drugs::PreProcess ( )

overridevirtual

Substance Preprocess function.

The AdminsterSubstances, AdministerIVSubstances, and Hemorrhage actions are processed in this step. The masses of the substances associated with these actions are updated as the actions are processed.

Implements biogears::BioGearsSystem.

void biogears::Drugs::Process ( )

overridevirtual

Substances process function.

For any drugs circulating in the system the renal and hepatic clearance factors and metabolic factors are assigned to the appropriate compartments. The drug effects categories and system level drug effects are calculated and the values are set on the common data model for use in other systems. Drug effects are only calculated if the PD is enabled.

Implements biogears::BioGearsSystem.

void biogears::Drugs::SarinKinetics ( )

protected

Calculates the inhibition of erythrocyte bound acetylcholinesterase by the nerve agent Sarin using reaction kinetics.

Unlike other drugs in BioGears, the PD effects of Sarin are not based directly on agent plasma concentration. Instead, we model Sarin binding to red blood cell acetylcholinesterase (Rbc-Ache) and link the inhibition of this enzyme to Sarin pharmacodynamics. This calculation utilizies a kinetic model that incorporates irreversible aging of Rbc-Ache and the salvaging effect of Pralidoxime. As such, this strategy represents a more mechanistic, receptor-target approach to pharmacodynamics

[24] [289]

[125]

[289]

[289] and [24]

void biogears::Drugs::SetUp ( )

overrideprotectedvirtual

Initializes parameters for the Drugs Class.

Initializes member variables and system level values on the common data model.

Implements biogears::BioGearsSystem.

static size_t biogears::Drugs::TypeHash ( )

inlinestatic

static constexpr char const* const biogears::Drugs::TypeTag ( )

inlinestatic

Hopefully this returns a unique ID for every type.

CDM::BioGearsDrugSystemData * biogears::Drugs::Unload ( ) const

overridevirtual

Reimplemented from biogears::SEDrugSystem.

void biogears::Drugs::Unload ( CDM::BioGearsDrugSystemData & data ) const

protectedvirtual

Friends And Related Function Documentation

friend class BioGears

friend

friend class BioGearsEngineTest

friend

Member Data Documentation

double biogears::Drugs::m_AgedRbcAcetylcholinesterase_nM

protected

SELiquidCompartment* biogears::Drugs::m_aortaVascular

protected

std::map<const SESubstance*, SESubstanceBolusState*> biogears::Drugs::m_BolusAdministrations

protected

BioGears& biogears::Drugs::m_data

protected

double biogears::Drugs::m_dt_s

protected

SETissueCompartment* biogears::Drugs::m_fatTissue

protected

SEFluidCircuitPath* biogears::Drugs::m_IVToVenaCava

protected

SETissueCompartment* biogears::Drugs::m_liverTissue

protected

SELiquidCompartment* biogears::Drugs::m_liverVascular

protected

SELiquidCompartment* biogears::Drugs::m_muscleIntracellular

protected

std::map<const SESubstance*, SENasalState*> biogears::Drugs::m_NasalStates

protected

SESubstance* biogears::Drugs::m_Pralidoxime

protected

double biogears::Drugs::m_RbcAcetylcholinesteraseFractionInhibited

protected

SESubstance* biogears::Drugs::m_Sarin

protected

double biogears::Drugs::m_SarinRbcAcetylcholinesteraseComplex_nM

protected

double biogears::Drugs::m_totalAdministered_uL

protected

std::map<const SESubstance*, SETransmucosalState*> biogears::Drugs::m_TransmucosalStates

protected

SELiquidCompartment* biogears::Drugs::m_venaCavaVascular

protected

Public Member Functions

Static Public Member Functions

Protected Member Functions

Static Protected Member Functions

Protected Attributes

Friends

Additional Inherited Members

Detailed Description

Constructor & Destructor Documentation

Member Function Documentation

Friends And Related Function Documentation

Member Data Documentation