Pharmacology: Dynamics & Kinetics

General Pharmacology

• Pharmacodynamics refers to the effects of drugs on the body
• Pharmacokinetics refers to the effects of the body on drugs

Pharmacodynamics: Qualitative Aspects

• Qualitative aspects include receptors, enzymes, and selectivity.
• Quantitative aspects include dose response, potency, therapeutic efficacy, and tolerance.

Pharmacokinetics: Core Concepts

• Pharmacokinetics involves the time course of drug concentration, including drug passage across cell membranes.
• It considers the order of reaction, plasma half-life, steady-state concentration, and therapeutic drug monitoring.
• Individual processes in pharmacokinetics are absorption, distribution, metabolism, and elimination.
• Drug dosage involves dosing schedules.
• Chronic pharmacology refers to consequences of prolonged drug administration and drug discontinuation syndromes.

Qualitative Aspects of Pharmacodynamics: Receptor Mechanisms

• Ligand-gated ion channels involve neurotransmitters acting on receptors in the postsynaptic membrane of nerve or muscle cells, resulting in a response within milliseconds.
• G-protein-coupled receptor systems have receptors bound to the cell membrane and coupled to intracellular effector systems by a G-protein; catecholamines activate b-adrenoceptors through these systems.
• These systems are the first messenger which increases the activity of intracellular adenylyl cyclase, increasing the rate of formation of cyclic AMP (the second messenger), a modulator of the activity of several enzyme systems that cause the cell to act, and the process takes seconds
• Protein kinase receptors incorporate a protein kinase and are targets for peptide hormones involved in cell growth, differentiation, and inflammatory mediator release, which takes hours.
• Cytosolic or nuclear receptors, within the cell, regulate DNA transcription and protein synthesis, such as by steroid and thyroid hormones, and this process takes hours or days.

Additional Drug Action Mechanisms

• Enzyme inhibition involves drugs like aspirin, pyridostigmine, and allopurinol.
• Transporter processes can be inhibited or induced, influencing the movement of substances into, across, and out of cells; an example is probenecid blocking anion transport in renal tubule cells to protect against nephrotoxic effects of cidofovir.
• Drugs can incorporate into larger molecules; 5-fluorouracil, an anticancer drug, is incorporated into messenger RNA in place of uracil molecules.
• In successful antimicrobial agents, metabolic processes unique to microorganisms are altered; penicillin interferes with bacterial cell wall formation
• Drugs can also affect a process common to both humans and microbes but in different ways; trimethoprim inhibits folic acid synthesis.

Extracellular Drug Actions

• Direct chemical interaction, such as chelating agents and antacids, is one form of drug action
• Osmosis, as with purgatives and diuretics like magnesium sulfate and mannitol, can also affect the way drugs act

Pharmacodynamics: Receptor Interactions

• Drugs can interact with receptors as agonists, antagonists, partial agonists, or inverse agonists.

Agonists: Mimicking Natural Substances

• Agonists activate receptors because they resemble natural transmitters or hormones.
• Their clinical advantage lies in their ability to resist degradation, which allows them to act longer than natural substances; bronchodilation salbutamol lasts longer than that induced by adrenaline/epinephrine, for this reason

Partial Agonists: Mixed Effects

• Partial agonists block access of the natural agonist but also have a low degree of activation, exhibiting both antagonist and agonist actions; These show partial agonist activity (PAA)
• The β-adrenoceptor antagonists pindolol and oxprenolol have partial agonist activity, often called intrinsic sympathomimetic activity (ISA), while propranolol is devoid of agonist activity, i.e. it is a pure antagonist
• Those taking propranolol may be as extensively 'B-blocked' as by pindolol, i.e. with eradication of exercise tachycardia, but the resting heart rate is lower; such differences can have clinical importance.

Inverse Agonists: Opposite Effects

• Inverse agonists produce effects specifically opposed to those of agonists.
• Benzodiazepines in the central nervous system produce sedation, anxiolysis, muscle relaxation, and control convulsions; B-carbolines, which also bind to the receptor, cause stimulation, anxiety, increased muscle tone and convulsions – they are inverse agonists.
• Both types of drug modulate the effects of the neurotransmitter y-aminobutyric acid (GABA).

Antagonists: Blocking Action

• Antagonists (blockers) of receptors are similar to the natural agonist but do not activate a response, preventing the natural agonist from exerting its effect.
• Drugs with no activating effect on the receptor are termed pure antagonists.
• A receptor occupied by a low-efficacy agonist is inaccessible to a subsequent dose of a high-efficacy agonist; a low-efficacy agonist acts as an antagonist and can happen with opioids.

Physiological Antagonism: Indirect Effects

• One drug may oppose the effect of another through different mechanisms not on the same receptor.
• Extreme bradycardia following overdose of a b-adrenoceptor blocker can be relieved by atropine, which accelerates the heart by blockade of the parasympathetic branch of the autonomic nervous system, the cholinergic tone of which (vagal tone)operates continuously to slow it.
• Adrenaline/epinephrine and theophylline counteract bronchoconstriction produced by histamine released from mast cells in anaphylactic shock by relaxing bronchial smooth muscle (b2-adrenoceptor effect).
• A second drug overcomes the pharmacological effect by a different physiological mechanism, i.e., there is physiological or functional antagonism.

Enzymes: Drug Interactions

• Interaction between a drug and an enzyme is similar to the interaction between a drug and a receptor.
• Drugs may alter enzyme activity by resembling a natural substrate and competing with it for the enzyme.

Enzyme Examples

• Enalapril is effective in hypertension because it resembles angiotensin I and is attacked by angiotensin-converting enzyme (ACE).
• Enalapril prevents the formation of the pressor angiotensin II by occupying the active site of the enzyme and inhibiting its action.
• Carbidopa competes with levodopa for dopa decarboxylase; in Parkinsonism disease, this combination reduces metabolism of levodopa to dopamine in the blood but not in the brain because carbidopa does not cross the blood-brain barrier.
• Ethanol prevents metabolism of methanol to its toxic metabolite, formic acid, by competing for occupancy of the enzyme alcohol dehydrogenase; this is the rationale for using ethanol in methanol poisoning.
• Irreversible inhibition occurs with organophosphorus insecticides.
• Aspirin covalently binds to cyclo-oxygenase (COX), inhibiting the enzyme in platelets for their entire lifespan because platelets have no system for synthesising new protein.

Selectivity in Drug Action

• The desire that a new drug has a selective action so that unwanted effects do not complicate patient management is shared by both doctor and drug manufacturer
• Approaches to achieveing selectivity include modification of the drug structure, selective delivery or drug targeting, and stereoselectivity

Quantitative Aspects: Dose-Response

• Dose-response relationships and curves for wanted and unwanted effects can show selective vs. non-selective drug action

Dose-Response Curves and Drug Selectivity

• The dose that provides maximum desired effect is less than the lowest dose that produces the unwanted effect; This ratio (ED50 unwanted/ED50 wanted) suggests a drug has a large therapeutic index and is highly selective in its desired effect.
• Drug B causes unwanted effects at doses well below those producing its maximum benefit; This ratio (ED50 unwanted/ED50 wanted) indicates that Drug B has a small therapeutic index and is therefore non-selective.

Potency vs. Efficacy

• Potency refers to the amount (weight) of drug in relation to its effect; if weight-for-weight, drug A has a greater effect than drug B, then drug A is more potent than drug B, although maximum therapeutic effect obtainable may be similar with both drugs.
• Therapeutic efficacy or effectiveness is the capacity of a drug to produce a maximum effect.

Tolerance: Reduced Sensitivity

• Continuous or repeated administration of a drug often leads to decreased effect, requiring increased dose to achieve the same response. This is known as reduced sensitivity.

Tachyphylaxis: Rapid Tolerance

• Tachyphylaxis describes the rapid lessening of effect (refractoriness) in response to frequently administered doses.

Tolerance Example: Nitrates

• Tolerance is acquired rapidly with nitrates, possibly by the generation of oxygen free radicals from nitric oxide.
• It can be avoided by removing transdermal nitrate patches for 4-8 hours, allowing the plasma concentration to fall.

Pharmacokinetics: Drug Concentrations

• It is affected by drug passage across cell membranes.
• It involves the order of reaction or process such as zero or first order
• Drug concentrations are also affected by: plasma half-life and steady-state concentration therapeutic monitoring

Drug Solubility Factors

• Lipid solubility is promoted by benzene rings, hydrocarbon chains, steroid nuclei, or halogen groups (-Br, -Cl, -F).
• Water solubility is promoted by alcoholic (-OH), amide (-CONH2), or carboxylic (-COOH) groups, or the formation of glucuronide and sulfate conjugates.

Drug Classification: Physicochemical Properties

• Drugs can be classified based on varying ionization per environmental pH, such electrolytes which are lipid or water soluble.
• They can also be classified as incapable of becoming ionized, non-Roman substances, which are lipid soluble
• Some may be permanently ionized polar substances, which are water soluble

Influence of pH on Drug Action

• Acidic groups become less ionized in an acidic environment, while basic groups become less ionized in a basic (alkaline) environment and vice versa.
• This influences diffusibility, as un-ionized drugs are lipid-soluble and diffusible, whereas ionized drugs are lipid-insoluble and non-diffusible.

Reaction Orders

• The order of reaction is an important influence.
• Molecules reach action sites & crossing membranes
• undergo metabolism. Influenced by the order of reaction or the process

First-Order vs Zero-Order Processes

• First-order processes involve a constant fraction of drug being transported/metabolized per unit time.
• Zero-order processes involve a constant amount of drug being transported/metabolized per unit time.

First-Order Kinetics: Concentration Dependent

• In most cases, absorption, distribution, metabolism, and excretion rates are directly proportional to the drug's concentration in the body.
• The transfer of a drug acoss a cell membrane or metabolite formation is high at high concentrations and lower when concentrations are lower; an exponential relationship

Zero-Order Kinetics: Saturation

• As the quantity of a drug rises in the body, metabolic reactions will occur, as will processes that have the limited capacity to become saturated.
• The rate of the process will plateau at the maximum amount at which it can stay constant, such as due to the enzyme activity. Any further increase is impossible if the enzyme already has limited activity, and no greater dose is possible.
• Rate of reaction is no longer proportional to dose, and exhibits rate-limited or dose-dependent processes.

Drug Concentrations

• Plasma half-life and steady-state concentration are core to this.
• The t½ drug's pharmokinetic value can be a very useful piece of information to be aware of.
• You should know when a drug becomes steady state, after constant rate; ensures a constant amount of drug without decline of effect or toxicity

Steady State

• When give at a constant rate, time to reach the steady state depends only on t1/2.
• Purposes, in 5 t1/2 periods the amount of drug in the body is constant; Plasma concentration is at the plateau

Steady State Percentages

• Taking ultimate steady state at 100%:
• in 1 t½ the concentration will be (100/2) 50%
• in 2 t½ (50 + 50/2) 75%
• in 3 t½ (75 + 25/2) 87.5%
• in 4 t½ (87.5 + 2.5/2) 93.75%
• in 5 t½ (93.75 + 6.25/2) 96.875%
  • of the ultimate steady state.

Pharmacokinetic Equations: Calculations

• Amount of Drug in Body is Xb = Vd · C
  • Xb: amount of drug in the body (units, e.g. mg)
  • Vd: apparent volume of distribution (units, e.g. mL)
  • C: plasma drug concentration (units, e.g. mg/mL) Volume of Distribution Calculation is Vd = Div / Co
  • Vd: apparent volume of distribution (units, e.g. ml/kg)
  • Div: i.v dose (units, e.g. mg/kg)
  • Co: plasma drug concentration (units, e.g. mg/ml)
• Loading dose=CpxVd/F
• Maintenance dose= CpxCL /F x Time Interval
• Elimination Rate Constant kel = km + kex - where kel = drug elimination rate constant km = elimination rate constant due to metabolism - kex = elimination rate constant due to excretion
• Half-Life
  • t1/2 = ln 2 /kel = 0.693/kel
  • where t1/2 is the elimination half-life (units=time)
• Clearance
  • CL = rate of elimination/C
• rate of elimination = CL· C
  • CL = Vd x kel where Vd = volume of distribution and kel is the elimination rate constant
  • CL = Vd · (0.693/t1/2) where 0.693 = ln 2 and t1/2 is the drug elimination half-life
  • note that plasma clearance CLp include renal (CLr) and metabolic (CLm) components
• Renal Clearance - CLr = (U · Cur) / Cp ; where U is urine flow (ml/min); Cur is urinary drug concentration and Cp is plasma drug concentration.
• Steady-State Drug Plasma Concentration (Css)
  • The calculation required to determine being steady-state drug plasma concentration illustrates the sensitivity of the plasma concentration to number of factors, in this case for a drug taken orally. Equations: equation 1 is Css= 1/(keVd) * (FD)/T Css = F · (D/t)/(kel * Vd )

Drug Routes of Administration

• Absorption of drugs can occur via enteral routes (by mouth, sublingual, buccal absorption, rectum).
• Parenteral routes: intravenous injection/infusion, intramuscular, subcutaneous, inhalation, topical (local or systemic/transdermal)
• Additional routes: intrathecal, intradermal, intranasal, intrapleural

Distribution Volume

• If small, a drug remains mostly in the plasma
• If a drug is present mainly in other tissues, the distribution volume will be large.

Drug Distribution

• The distribution volume of a drug is the volume in which it appears to distribute if the concentration throughout the body were equal to that in plasma, assuming the body were a single compartment.

Selective Distribution

• It occurs due to special affinity between particular drugs and particular body constituents.
• Proteins in the plasma: phenothiazines and chloroquine bind to melanin-containing tissues, including the retina, which may explain the occurrence of retinopathy
• Drugs selectively concentrate due to transport mechanisms, e.g. iodine in the thyroid

Metabolism Processes

• Metabolism is a general term for processes of chemical transformations occurring in the body.
• Its processes change drugs in two major ways by reducing lipid solubility and/or altering the biological activity of the compounds.

Phase I and II Metabolism

• Phase I metabolism modifies drug molecules by oxidation, reduction, or hydrolysis and usually introduces or exposes a chemically active site on it and often has reduced biological activity and different pharmacokinetic properties, e.g. a shorter t½..
• The principal group of reactions is the oxidations, in particular those undertaken by the (microsomal) mixedfunction oxidases which, as the name indicates, are capable of metabolising a wide variety of compounds; The most important of these is a large 'superfamily' of haem proteins, the cytochrome P450 enzymes, which metabolise chemicals from the environment, the diet and drugs.
• By a complex process, the drug molecule incorporates one atom of molecular oxygen (O2) to form a (chemically active) hydroxyl group and the other oxygen atom
• Phase II creates water-soluble molecules by Phase 1 metabolism that can be easily removed by the kidney

CYP2E1

• It is an isoenzyme that catalyzes a reaction involved in the metabolism of alcohol, paracetamol, estradiol and ethinylestradiol molecules

Phase I and II Continued

• Phase I oxidation of some drugs results in the formation of epoxides, which are short-lived and highly reactive metabolites that bind irreversibly through covalent bonds to cell constituents and are toxic to body tissues.
• Glutathione is a tripeptide that combines with epoxides, rendering them inactive, and its presence in the liver is part of an important defence mechanism against hepatic damage by halothane and paracetamol.
• Phase II metabolism involves combination of the drugWith one of several polar (water-soluble) endogenous molecules (products of intermediary metabolism), often at the active site (hydroxyl, amino, thiol) created by Phasel metabolism. The kidney readily eliminates the resultingwater-soluble conjugate, or the bile if the molecular weightexceeds 300. Morphine, paracetamol and salicylates formconjugates with glucuronic acid (derived from glucose);oral contraceptive steroids form sulphates; isoniazid,phenelzine and dapsone are acetylated.
• Conjugation with a more polar molecule is also an elimination mechanismfor natural substances, e.g. bilirubin as glucuronide,oestrogens as sulphates.
• Phase Il processes almost invariably terminates biological activity.

Enzyme Inhibition and Induction

• Enzyme induction and enzyme inhibition are important concepts

Clinical Significance of Enzyme Induction

• Enzyme induction is relevant to drug therapy because: - Clinically important drug–drug (and drug–herb18)interactions may result, for example, in failure of oral contraceptives, loss of anticoagulant control, failure of cytotoxic chemotherapy. - Disease may result. Antiepilepsy drugs accelerate the breakdown of dietary and endogenously formed vitamin D, producing an inactive metabolite – in effect a vitamin D deficiency state, which can result in osteomalacia. The accompanying hypocalcaemia can increase the tendency to fits and a convulsion may lead to fracture of the demineralised bones. - Tolerance to drug therapy may result in and provide an explanation for suboptimal treatmente.g. with an antiepilepsy drug. - Variability in response to drugs is increased. Enzyme induction caused by heavy alcohol drinking or heavy smoking may be an unrecognized cause for failure of an individual to achieve the expected response to a normal dose of a drug, e.g. warfarin, theophylline.

Enzyme Inhibition

• Consequences of inhibiting drug metabolism can be more profound and more selective than enzyme induction.
• Consequentially, enzyme inhibitors offer more scope for therapy

Substances Causing Enzyme Induction in Humans

• It can be a barbecued meat product, particular drugs like nevirapine, particular drugs like the generic barbiturates, phenobarbital.
• Brussel sprouts, genetic class phenytoin

Further Enzyme Inducers

• These include carbamazepine and primidone-based medications, pesticides, rifampicin and ethanol use (chronic).
• Others are St John's wort, and smoking tobacco and other types.

Plasma Protein Binding: Core Idea

• Many natural substances circulate around the body partly free in plasma water and partly bound to plasma proteins; these include cortisol, thyroxine, iron, copper and, in hepatic or renal failure, by-products of physiological intermediary metabolism.
• Free and bound fractions are in equilibrium, and free drug removed from the plasma by metabolism, renal function or dialysis is replaced by drug released from the bound fraction

Primary Protein in Blood

• Albumin is the main binding protein for many natural substances and drugs; Its complex structure has a net negative charge at blood pH and a high capacity but low (weak) affinity for many basic drugs, i.e. a lot is bound, but it is readily released.
• Two particular sites on the albumin molecule bind acidic drugs with high affinity (strongly), but these sites have low capacity. Saturation of binding sites on plasma proteins in general is unlikely in the doses in which most drugs are used.
• Other binding proteins in the blood include lipoprotein and α1-acid glycoprotein, both of which carry basic drugs such as quinidine, chlorpromazine and imipramine.
• Thyroxine and sex hormones are bound in the plasma to specific globulins.

Influence of Disease on Protein Binding

• In chronic renal failure, hypoalbuminaemia and retention of products of metabolism that compete for binding sites on protein are both responsible for the decrease in protein binding of drugs.
• Most affected are acidic drugs that are highly protein bound, e.g. phenytoin, and initiating or modifying the dose of such drugs for patients with renal failure requires special attention.

Conditions That Can Affect Protein Binding

• Chronic liver disease results in greater hypoalbuminaemia and increase of endogenous substances such as bilirubin that may compete for binding sites on protein
• Drugs that are normally extremely commonly bound to blood protein should be handled carefully, for example, diazepam and tolbutamide drug types.

Drugs that Inhibit Enzymes

• Acetazolamide and Allopurinol
• Benserazide, Disulfiram, Enalapril
• Moclobemide, Non-steroidal anti-inflammatory drugs and Selegiline

Routes of Elimination

• These usually include renal or feacal elimination
• Sometimes biliary or pulmonary excretion

Drug Clearance from Body

• Clearance values show biological fate useful, and the methods for calculating represent hepatic functions
• The renal clearance of a drug eliminated only by filtration by the kidney obviously cannot exceed the glomerular filtration rate (adult male 124 mL/min, female 109 mL/min). If a drug has a renal clearance in excess of this, then the kidney tubules must actively secrete it, e.g.benzylpenicillin (renal clearance 480 mL/min).

Five Dosage Types

• Fixed and Variable dose type
• Variable with finer adjustments
• Maximum tolerated dose
• A minimum tolerated dose

Fixed-Dose Regimens

• Fixed Doses often provide desired effects and are below toxicity
• Individual variation due to enough drug may be clinically irrelevant (such as mydriatics, or analgesics, oral contraceptives, antibiotics)

Variable Dosing

• Dosing requires comparative insignificance, and therapeutic endpoint hard to measure if the disorder is depression
• Disorders may change only slowly (such as thyrotoxicosis),
• They may also fluctuate do the patient's physiological factors (for example analgesics, adrenalcorticosteroids suppress disease)

Variable Dose Regimens cont.

• Variable with fine adjustments are required if one of the person's vital functions (blood pressure, blood sugar levels) must be measured, such that accurate dose adjustments can be measured
  • An example is adrenocortical replacement therapy

Maximum-Tolerated Dose

• Occurs when the wanted therapeutic effect is achieved, even though unwanted, undesired effects often appear (due to anti-cancer, anti-microbial compounds)

Minimum Dose Tolerated

• The concept is rare than what occurs above, however it is applicable for the long-term to minimize effects to an inflammatory or immunological condition
• Examples include arthritis, where relief in a symptomatic manner may cause inevitable adverse effects, so the process cannot continue indefinitely

Priming Dose

• The dosing schedules specify attaining the desired effort without toxicity. Achieved effectively quickly by using: To specify an initial dose that attains the desired effect rapidly without causing toxicity
• The effect may be achieved earlier by giving an initial dose that is larger than the maintenance dose

Initial Dose Characteristics

• The effect is usually given earlier. The dose is often larger than a maintained dose
• Called “priming dose”. It means achieving positive therapuetic effects, whose body doesn’t consist enough of the effect

Maintenance Dosing

• In regards frequency:
• The drug “might be half as initial/priming dose every plasma (such as 𝑡1/2); to mean an achieve the wanted therapeutic effect. But it declines in half”
• Depending very much of 𝑡1/2: whether or not, it is satisfactory and practicable to depend on this

Maintenace Dose Type 1

• A hald-life must be for example, “6-12 hs”
• Replace half, at intervals for a dose/interval so a regular one is maintained (every 6-12 is okay)

Maintenance Dose Type 2

• A half-life must be 24 hours! Comply with giving dose each priming (more enters than exits.
• Solution is for amount that gets removed each interval, from each dose
  • Note: dose, starting dose and 𝑡½

Maintenance Dose Rules

• What if a half-life is below 3 h?
  • The dosing must be frequent and regular
• If long, bolus IV may be too complicated

Prolonging Actions of Drugs

• Vasoconstriction reduces local blood flow and retards drug distribution from the injection site; combination with adrenaline prolongs local anaesthetic action.
• Epinephrine prolongs actions locally
• Slowing of metabolism may usefully extend drug action, such as carbidopa combinating with levodopa

Drug Actions Can Be Prolonged

• Delayed excretion is seldom practicable, the only important example being the use of probenecid to block renal tubular excretion of penicillin for single dose treatment of gonorrhoea.
• Altered molecular structure can prolong effect, particularly the benzodiazepines
• Pharmaceutical formulation with modified-release can be done, to ensure drug effect

Chronic Pharmacology Concepts

• Chronic pharmacology should be taken in considerations; feedback systems; regulation of receptors; Down-regulation; Up-regulation; rebound, withdrawal etc.

Feedback System Characteristics

• The endocrine system serves fluctuating body needs; Glands can increase/decrease output using feedback usually negatives.
• An administered hormone/analogue activates system for hormone analogue so high and doses will reduce hormones production, where the control mechanism takes months and sensitivity, if withdrawal

Regulation: Up and Down Regulation

• Down-regulation, and the accompanying receptor changes, may explain the ‘on–off’ phenomenon in Parkinson’s disease and the action of luteinising hormone releasing hormone (LHRH) super- agonists in reducing follicle stimulating hormone (FSH) concentrations for treating endocrine-sensitive prostate cancer.
• regulation; The occasional exacerbation of ischaemic cardiac disease on sudden withdrawal of a β-adrenoceptor blocker may be explained by up- regulation during its administration, so that, on withdrawal, an above-normal number of receptors suddenly become accessible to the normal transmitter, i.e. noradrenaline/norepinephrine.

Rebound Phenomenon

• The use of a B blocker that contains less B -reciproitor properties is plainly safe;
• The beta adrenocorpiod blockers can prevent generation up receptors
• There is thus less, when having with pindolol and B adrenocorpeitor is done in this scenario

Abrupt Withdrawals

• There may be important issues regarding this that may occur; interrupting therapy to undergo surgery, these examples occur with:

• --Cardiovascular (B blockers are an example); and anti-hypertensives (example clonidine)

• Nervous systems (depressants (hypnotics, sedatives, alcohol/opiates); Anti-epilepsy Anti-Parkinson agents, and Tricyclic Anti-Depressants Endocrine System, Adrenal Corticosteroids Immune Inflammation; Using Adrenal Corticosteroids

Other Aspects of Chronic Drug Use

• Metabolic can occur over longer duration, as well as enhancing their own drug's metabolism and of drugs too
• Cell injury or cell function is more complicated

More Chronic Drug Use Insights

• Take periods of time off from the med! In particular long-term (may also occur) in periods of time to reduce toxicity or restore sensitive periods
• Plainly, this needs to stop
• These must be balanced, and are notable! anti-coagulants, corticosteroids