Pharmacology I Unit-II: Pharmacodynamics, Drug Interactions & Pharmacovigilance
Welcome to Pharmshala’s comprehensive B.Pharm Sem IV Pharmacology I Unit-II notes. This unit focuses on Pharmacodynamics, receptor mechanisms, signal transduction pathways, adverse drug reactions (ADRs), drug interactions, drug discovery and development, clinical trials, and pharmacovigilance. These exam-oriented notes are designed to help pharmacy students understand core pharmacological concepts with simplified explanations, classifications, mechanisms, flowcharts, and important university examination points.
BP 404 T. Pharmacology-I (Theory): Unit-II syllabus
B.Pharm Pharmacology I, BP404T
UNIT-II: 1. General Pharmacology
Pharmacodynamics – Principles and mechanisms of drug action. Receptor theories and classification of receptors, regulation of receptors. Drug receptors interactions, signal transduction mechanisms, G-protein–coupled receptors, ion channel receptor, transmembrane enzyme linked receptors, transmembrane JAK-STAT binding receptor and receptors that regulate transcription factors, dose response relationship, therapeutic index, combined effects of drugs and factors modifying drug action.
Adverse drug reactions.
Drug interactions (pharmacokinetic and pharmacodynamic).
Drug discovery and clinical evaluation of new drugs – Drug discovery phase, preclinical evaluation phase, clinical trial phase, phases of clinical trials and pharmacovigilance.
The PDF also holds introductory notes on the autonomic nervous system and cholinergic drugs. They sit outside the Unit II syllabus above, so they are kept at the end as Part E.
Pharmacodynamics
Principles and mechanisms of drug action, receptors and signal transduction, dose–response, and drug antagonism.
Pharmacology and its branches
Pharmacology is the study of drugs. A particular drug is useful for a particular function but may be harmful to other parts of the body: these unwanted effects are its side effects. A drug produces a response, is metabolised, and is then excreted.
- Pharmacokinetics
- Pharmacodynamics
- Toxicology
- Clinical pharmacology
- Pharmacotherapeutics
- Pharmacogenomics
- Pharmacovigilance
Pharmacokinetics and pharmacodynamics (boxed in the class notes) are the two core branches.
Key terms used throughout this unit:
- Agonist
- Antagonist
- Receptors
- Ligands
- Affinity
- Intrinsic activity
Pharmacokinetics and pharmacodynamics
Pharmacokinetics (PK)
What the body does to the drug: the movement of the drug in the body.
ADME: absorption, distribution, metabolism, excretion.
Pharmacodynamics (PD)
What the drug does to the body: the mechanism of action of drugs, that is, the effect of drugs on the body.
A medicine taken shows a response (effect); action is how and where that response is produced.
Site and mechanism of drug action
Site of drug action
- Extracellular: e.g. antacids
- Cellular: e.g. acetylcholine, noradrenaline
- Intracellular: e.g. antibiotics
Mechanism of drug action
- Non-receptor mechanism: e.g. sulfonamides and other antimicrobials that inhibit folic acid synthesis (enzyme inhibition).
- Receptor mechanism (most drugs): the drug acts as an agonist, partial agonist, antagonist or inverse agonist (see A5).
The notes name four receptor families: ion-channel linked, G-protein coupled, kinase linked, and enzyme as receptor. The full classification is in A8.
Receptors and ligands
- Receptor
- A binding site, protein in nature, present on the cell membrane and in the nucleus as well. It has a mechanism to attach to ligands.
- Ligand
- A chemical with the potential to bind to a binding site. It may produce either a positive or a negative response, and it binds owing to structural resemblance.
- Affinity
- The tendency to combine or attach.
- Intrinsic activity
- The ability to produce an effect (efficacy, written E).
Agonists and antagonists
A drug (D) combines with its receptor (R) to form the drug–receptor complex (DR). Agonists, antagonists, partial agonists and inverse agonists all have affinity for the receptor; what separates them is their intrinsic activity (E), which decides whether a response follows.
| Type | Intrinsic activity (E) | What happens | Examples |
|---|---|---|---|
| Agonist | 1 | Binds and produces a response. | Opioids, histamine, dopamine, acetylcholine, noradrenaline |
| Antagonist (blocker) | 0 | Binds but produces no response. It has to be removed to let the agonist work. | Atropine, propranolol, chlorpromazine |
| Partial agonist | Between 0 and 1 | Produces a response smaller than a full agonist, even when all receptors are occupied. | Pentazocine |
| Inverse agonist | Below 0 | Produces a response opposite to that of an agonist. | β-carbolines |
At the GABA receptor, benzodiazepines (agonists) reduce anxiety and nervousness, whereas β-carbolines (inverse agonists) increase anxiety and nervousness.
Agonist and antagonist pairs
| Natural agonist | Antagonist (blocker) |
|---|---|
| Acetylcholine | Atropine |
| Noradrenaline | Propranolol |
| Histamine (H1, H2, H3 receptors) | H-receptor blockers (antihistamines) |
| Dopamine | Chlorpromazine |
Theories of receptor occupancy
As drug concentration rises, the response rises until a ceiling point: the maximum achieved (peak pharmacological) response, reached when all receptors are occupied.
Rate theory Paton, 1961
Agonist activity depends on the rate of agonist–receptor association and dissociation, and this decides the magnitude of the drug effect.
An antagonist forms a stable complex with the receptor that does not break easily, so no response is produced even when a large amount of agonist is added.
Occupation theory Ariëns, 1954
The magnitude of the response depends on the proportion (%) of receptors occupied by the drug. The maximum effect is seen when all receptors are occupied. Also known as “capturing of receptors”.
Regulation of receptors
Down-regulation (desensitisation)
Long exposure of receptors to an agonist lowers receptor number and sensitivity, so the full response is no longer produced.
- β2-agonists (isoprenaline, salbutamol) in bronchial asthma: the effect on bronchial smooth muscle falls with continued use.
- Levodopa: dopamine receptors in the basal ganglia lose sensitivity, so the benefit in Parkinsonism fades with time.
Up-regulation (super-sensitivity)
Chronic exposure of receptors to an antagonist does the reverse: receptor number and sensitivity increase.
- Propranolol (β1 receptors in the heart): sudden withdrawal can bring a sudden anginal attack and a rise in BP (hypertension).
- Clonidine (α2-agonist acting in the CNS): sudden withdrawal produces a hypertensive crisis.
Drugs such as propranolol and clonidine should be stopped slowly, never abruptly.
Types of receptors
Receptors fall into four types. Types I, II and III are membrane proteins; Type IV receptors are soluble intracellular proteins.
Type I
Ion-channel linked (ionotropic)- Agonist binds the receptor (R)
- Ion channel opens and ions flow
- Hyperpolarisation or depolarisation
- Cellular effect
Membrane receptors directly linked to ion channels, hence the name. Fast-acting neurotransmitters act on the channel and give fast responses.
Examples
Nicotinic ACh receptors
(fast acting), GABA receptors (inhibitory neurotransmitter), glutamate
(excitatory neurotransmitter), 5-HT receptors.
Time scale: milliseconds
Type II
G-protein coupled (metabotropic)- Agonist binds R
- G-protein is activated
- Effector (enzyme or ion channel); change in excitability
- Second messengers: Ca2+ release, protein phosphorylation, others
- Cellular effect
Membrane receptors coupled to an intracellular effector system through G-proteins.
Examples
Muscarinic receptors for acetylcholine, adrenergic, dopaminergic, histaminic and opioid receptors.
Time scale: seconds
Type III
Kinase linked- Agonist binds R/E (receptor with an enzyme part)
- Protein phosphorylation
- Cellular effect
Membrane receptors coupled to an intracellular protein kinase.
Examples
Receptors for insulin, cytokines and growth factors.
Time scale: minutes
Type IV
Nuclear- Ligand binds the receptor inside the cell
- Signal reaches the nucleus
- mRNA synthesis
- Protein synthesis
- Cellular effect
Receptors that regulate gene transcription, located in the cytosol of the nuclear compartment.
Examples
Receptors for steroids (estrogen) and for thyroid hormone.
Time scale: hours
Acetylcholine acts on muscarinic receptors (G-protein coupled) and on nicotinic receptors (ion channel, fast acting). Insulin acts on a kinase-linked receptor; estrogen and thyroid hormone act on nuclear receptors.
G-protein–coupled receptors and signal transduction
- G-proteins interact with the guanine nucleotides GTP and GDP.
- The nucleotide binds the α-subunit, which has enzymatic activity: it catalyses the conversion of GTP to GDP.
- The β and γ subunits stay together as a βγ complex.
- The subunits are anchored to the membrane through a fatty-acid chain attached to an amino-acid residue, a reaction known as prenylation.
- G-proteins diffuse freely in the plane of the membrane. At rest they exist as an unattached αβγ trimer with GDP occupying its site on the α-subunit.
- When an agonist occupies the receptor, a conformational change occurs. The αβγ trimer associates with the receptor, the bound GDP dissociates and is replaced by GTP (GDP–GTP exchange). The trimer then dissociates, releasing α-GTP and the βγ subunit.
- These are the active forms. They diffuse in the membrane and associate with enzymes and ion channels, causing activation or inactivation as the case may be.
Three effector pathways
1. Adenylate cyclase / cAMP system
- AC is the membrane-bound enzyme adenylate cyclase; PDE is phosphodiesterase. cAMP is produced continuously and inactivated by hydrolysis to 5′-AMP.
- Many drugs, hormones and neurotransmitters act by raising or lowering adenylate cyclase activity, and so the cAMP concentration in the cell.
- cAMP regulates enzymes of energy metabolism, cell division, cell differentiation, ion transport, ion channels and contractile proteins in smooth muscle.
- Common mechanism: cAMP activates protein kinases, which phosphorylate serine and threonine residues of cellular proteins (ATP is the phosphate source). Phosphorylation can activate or inhibit target enzymes or ion channels.
2. Phospholipase C / inositol phosphate system
- An important intracellular second-messenger system. It forms two messengers from membrane phospholipid: inositol triphosphate (IP3) and diacylglycerol (DAG).
- IP3 raises free cytosolic Ca2+ by releasing it from intracellular compartments. The extra Ca2+ starts contraction, secretion, enzyme activation and membrane hyperpolarisation.
- DAG is highly lipophilic and stays in the membrane. It activates membrane-bound protein kinase C (PKC), which phosphorylates serine and threonine residues of many intracellular proteins. At least 13 PKC types are known.
- IP3 and DAG are made whenever receptor-induced phosphoinositide (PI) hydrolysis occurs.
3. Regulation of ion channels
- G-protein–coupled receptors can control channel function without second messengers such as cAMP or IP3: the G-protein interacts directly with the ion channel.
- Example: in cardiac muscle, muscarinic ACh receptors enhance K+ permeability. This hyperpolarises the cell and inhibits electrical activity.
Dose–response relationship and therapeutic index
The dose–response curve (DRC), also called the concentration–response curve (CRC), plots the height of the response against the concentration (dose) of the drug.
- At first the receptors are free; as the concentration rises they get occupied.
- When all are occupied the response is maximal (Emax).
- After that, adding more agonist has no further effect.
Median effective and lethal doses
- EC50
- Median effective concentration: shows the response, is safe, and gives no side effect.
- LD50
- Median lethal concentration or dose: toxicity occurs (in laboratory animals or tissues).
The wider the therapeutic index, the safer the drug.
Combined effects of drugs: drug antagonism
- Agonism
- The property of a chemical which, when combined with its receptor, binds and generates a response.
- Antagonism
- Drugs combined together (inadvertently) nullify or prevent the response, through chemical neutralisation, structural changes, and so on.
1. Antagonism at the receptor level
Reversible (competitive)
The antagonist competes with the agonist for the receptor. A higher dose of antagonist shifts the agonist curve in parallel to the right.
- Muscarinic receptor: acetylcholine (agonist), atropine (antagonist)
- Adrenaline: propranolol
- Morphine: naloxone
Irreversible (non-competitive)
Shows the non-competitive curve: the maximum response falls.
- Phenoxybenzamine is an irreversible antagonist at adrenergic (α) receptors.
- Organophosphate insecticides (irreversible cholinesterase inhibitors) cause respiratory failure in insects.
2. Antagonism at the enzyme level
Drugs are available that target enzymes such as Na+/K+-ATPase, H+/K+-ATPase, carbonic anhydrase, ACE and xanthine oxidase (XO, which converts purines).
| Enzyme | Drug action |
|---|---|
| H+/K+-ATPase | The proton pump: inhibiting it lowers gastric acid secretion. |
| Xanthine oxidase | Allopurinol inhibits XO, so uric acid is not formed. Used in gout. |
| ACE | Angiotensinogen → angiotensin I → angiotensin II, which raises BP. Drugs inhibit this pathway by targeting the converting enzyme. |
3. Physical and chemical (physicochemical) antagonism
- Antacids (such as NaHCO3) neutralise gastric acid.
- Chelating agents bind toxic metals: desferrioxamine for iron toxicity, dimercaprol for heavy metals.
4. Physiological antagonism
Two drugs act on different receptors or systems and produce opposite responses.
- Adrenergic vs histaminergic response
- Insulin vs glucagon
- Acetylcholine vs adrenaline
Additive effects, the opposite of antagonism, are covered under pharmacodynamic interactions (C3).
Adverse drug reactions
What an ADR is, how Type A and Type B reactions differ, and how ADRs are classified.
What is an adverse drug reaction?
- Drug
- Response and pharmacological effects
- Desiredbeneficial
- Undesired effects
- Harmlessnot injurious
- Harmful: ADR
- Response and pharmacological effects
An ADR is any response to a drug which is noxious (injurious) and unintended, and which occurs at doses used for prophylaxis, diagnosis or therapy of a disease.
- It is the drug and its dose that separate a useful drug from an adverse drug (toxin). ADRs are linked to increased dosage.
- Side effects are unintended effects that cannot be avoided; they are an inherent property of drugs.
- ADRs may arise from a change in the internal environment, so a drug can act variably. Certain drugs have effects in only a handful of people.
- An ADR that is not controlled may cause death, for example anaphylactic shock.
| Drug | Side effects |
|---|---|
| Aspirin | Gastric stimulation, heartburn |
| Atropine (antispasmodic) | Dryness of mouth, urinary retention |
Common reasons for ADRs
- OTC drugs
- Polypharmacy
- Self-medication
Type A and Type B reactions
By their nature, ADRs are either normal (augmented), Type A, or abnormal (bizarre), Type B.
| Feature | Type A: augmented (normal) | Type B: bizarre (abnormal) |
|---|---|---|
| Nature | An exaggerated, increased response of the drug’s known pharmacological activity: an elevated extension of the pharmacological response. | Abnormal reactions, not expected from the known pharmacology of the drug, occurring at therapeutic doses. |
| Examples |
|
Malignant hyperthermia: an abnormal rise in body temperature. In some cases general anaesthesia may cause it. |
| Other points | Polypharmacy is also a cause. | Results in mortality: raises the mortality rate and worsens the patient’s condition. |
Classification of ADRs
Based on pharmacological activity, ADRs are grouped into five classes.
| Class | Group | Subtypes |
|---|---|---|
| 1 | Pharmacological ADR | Extension of the therapeutic effect; non-therapeutic ADR (effect) |
| 2 | Non-pharmacological ADR | Hypersensitivity / drug allergy; idiosyncrasy (pharmacogenetics); photosensitivity |
| 3 | Disease-related ADR | – |
| 4 | Multiple drug reactions | – |
| 5 | Miscellaneous ADR | Carcinogenicity; teratogenicity; overdosage; drug-induced |
Pharmacological ADR
These result from a greater-than-desired action of a drug, or from more of its secondary effects. The primary (1°) effect is the intended, useful one; the secondary (2°) effect is unwanted or unintended.
Overdosage of a drug usually produces an excessive reaction to its primary effect. Example: tranquillisers used in the daytime, or in excessive doses, may produce more sedation than they usually do.
Drug interactions
Pharmacokinetic (ADME) and pharmacodynamic interactions, with the examples from the class notes.
Overview
Pharmacokinetic interactions
One drug changes how another is absorbed, distributed, metabolised or excreted (A, D, M, E).
Pharmacodynamic interactions
The effects of the drugs add up, are potentiated, or oppose one another (see C3).
Interactions can change:
- Effectiveness
- Toxicity
- Estimation (biological tests)
- In-vitro effects
- Beneficial effects (therapy)
The effects may be potentiated, increased or antagonised, and interactions occur in vitro as well as in vivo.
Penicillin + aminoglycosides: mixing them leads to inactivation of both medicines.
Pharmacokinetic interactions: A, D, M, E
| Stage | Interacting drugs | Result |
|---|---|---|
| AAbsorption | Tetracycline + salts of Ca, Mg, Al, Fe | Reduced absorption of tetracycline (chelation), so its usefulness is lost. |
| Fats and vitamins + liquid paraffin | Reduced absorption of vitamins and fats. | |
| DDistribution | Salicylates or sulfonamides + tolbutamide (a hypoglycaemic agent) | They displace drugs from their binding sites, so there is more hypoglycaemia. |
| Sulfonamide + anticoagulants | Displacement from binding sites gives more bleeding. | |
| MMetabolism | Enzyme inducers (barbiturates) + warfarin | Warfarin does not show its full (100%) effect. |
| Rifampicin + oral contraceptives | Enzyme induction: the contraceptive does not work. | |
| Enzyme inhibitors (e.g. MAO inhibitors) | Metabolism of other drugs is slowed. | |
| EExcretion | Acidic drugs (e.g. aspirin) are more ionised in alkaline medium. | Aspirin is readily absorbed from the stomach because it is acidic. To end its action, make the urine alkaline: this helps its removal. |
| Basic drugs (e.g. morphine) are more ionised in acidic medium. | In toxicity, make the urine acidic and the toxicity goes as the drug is excreted. The reverse holds for acidic drugs. |
Pharmacodynamic interactions and other examples
| Kind | Drugs | Outcome |
|---|---|---|
| Additive action increases |
Halothane, ether and other general anaesthetics | Useful. |
| Paracetamol + aspirin | Useful. | |
| Aminoglycoside + tubocurarine | Too much effect: toxicity. | |
| Beneficial combination | Levodopa + carbidopa | Used for Parkinsonism. |
| Treating toxicity | Morphine toxicity | Give naloxone, an antagonist at opioid receptors. |
| Organophosphorus insecticide toxicity | Atropine is given. | |
| Interference with estimations | Some drugs that raise blood-glucose level | Give false results. |
| Estrogen therapy | Thyroid level rises. |
Drug discovery and clinical evaluation of new drugs
From discovery and preclinical testing through the phases of clinical trials to pharmacovigilance.
Stages of new-drug evaluation
Drug discovery phase
Finding and screening candidate molecules (D2).
Preclinical phase
Toxicity testing before the drug goes into people (D2).
Clinical trial phase
Phases I, II and III, then the New Drug Application (D3).
Phase IV
Post-marketing surveillance and pharmacovigilance (D4).
Cheap, easily available, safe, easy to administer, with few side effects, and with efficacy.
Drug discovery and preclinical phases
Drug discovery phase
Approaches noted:
- Target screening
- Random screening
- Serendipity
- Assay / active-moiety based screening
- Rational drug design
Preclinical phase
Toxicity studies are carried out before the drug is tested in people.
Toxicity studies
- Acute
- Sub-acute
- Chronic (up to 2 years)
- Reproductive
Special toxicity
- Mutagenicity
- Carcinogenicity
- Teratogenicity
Study design noted: 2 species, 3 doses, 4–5 weeks.
Clinical trials
IND (Investigational New Drug, or preclinical new drug): approval is needed from the IRB (Institutional Review Board) and the IEC (Institutional Ethics Committee) before trials in people.
| Phase | Details |
|---|---|
| Phase I | Carried out in healthy volunteers (except in the case of AIDS and cancer). |
| Phase II | Targeted population, about 100–200 patients. Early and late (depends on the number of patients). Blind: the patient does not know the drug. |
| Phase III | Large multicentre, patient-oriented trial in a large population. Double blind: the patient and the observer both do not know the drug. |
| New Drug Application | Has to be filed and submitted. |
| Phase IV | Post-marketing surveillance (see D4). |
Phase IV and pharmacovigilance
- Phase IV is post-marketing surveillance.
- It has no official time range or fixed duration.
- It is time-consuming and expensive.
Pharmacovigilance bodies noted in the class notes:
- CDSCO
- Central Drugs Standard Control Organisation
- IPC
- Indian Pharmacopoeia Commission
- DCGI
- Drugs Controller General of India
Autonomic nervous system
The last pages of the PDF. They fall outside the Unit II syllabus and are kept here for completeness.
Organisation of the nervous system
- Nervous system
- CNSBrain and spinal cord
- PNS
- SensoryAfferent
- MotorEfferent
- SomaticVoluntary; skeletal muscle
- AutonomicInvoluntary; smooth muscle, glands, cardiac
- Neuron
- Cell body (with the nucleus), dendrites, axon (with myelin sheath) and terminal bulb.
- Synapse
- The junction between a presynaptic and a postsynaptic neuron, across the synaptic cleft. Neurotransmitters carry the signal across.
Topics listed in the notes for this section:
- Sympathomimetics
- Sympatholytics
- Parasympathomimetics
- Parasympatholytics
- Glaucoma
- Local anaesthetics
- NMBA (neuromuscular blocking agents)
Only parasympathomimetics and parasympatholytics have notes in this PDF.
Sympathetic and parasympathetic divisions
Sympathetic
- Thoracolumbar outflow
- Neurotransmitter: noradrenaline (norepinephrine)
Parasympathetic
- Craniosacral outflow
- Neurotransmitter: acetylcholine
Together they are responsible for the normal (physiological) functioning of the body.
| Target | Sympathetic | Parasympathetic |
|---|---|---|
| Eyes | Pupil dilated | Pupil constricted |
| Blood vessels | Vasoconstriction | – |
| Lacrimal gland | – | Tear secretion |
| Salivary gland | Saliva reduced | Saliva increased (watery) |
| Heart | Heart rate increases | Heart rate decreases |
| Bronchi (lungs) | Bronchodilation | Bronchoconstriction |
| Stomach | Reduces peristalsis | Increases peristalsis |
| Adrenal medulla | Increases secretion | – |
| Kidney | Decreased urine | Increased urine |
| Bladder | Relaxed, sphincter closed | Sphincter open, bladder contracted |
| Liver | Glucose increased | – |
Parasympathomimetics (cholinomimetics)
- They mimic the parasympathetic nervous system and release acetylcholine.
- They are cholinergic drugs (cholinomimetics) and act on both muscarinic and nicotinic receptors.
Acetylcholine: synthesis and termination
- ACh acts on post-synaptic and pre-synaptic receptors.
- ACh is hygroscopic and has a short half-life.
| Receptor | Subtypes | Found in |
|---|---|---|
| Muscarinic | M1, M2, M3, M4, M5 | Heart, glands |
| Nicotinic | NM, NN | Neuromuscular junctions (NM) and autonomic ganglia (NN) |
Classification
| Kind | Drugs | Notes |
|---|---|---|
| Direct-acting | Acetylcholine, nicotine, methacholine, pilocarpine, carbachol | Synthetic and natural alkaloids. |
| Indirect: reversible | Physostigmine, rivastigmine, neostigmine | Reversible inhibitors of ACh esterase. |
| Indirect: irreversible | Organophosphorus compounds and insecticides: ecothiopate, parathion, malathion | Irreversible inhibitors of ACh esterase. Used as insecticides (e.g. killing head lice). |
Organophosphorus toxicity causes paralysis of the respiratory muscles. Drugs that restore ACh esterase activity are used: pralidoxime and obidoxime.
Tremorine and oxotremorine are agonists that cause a Parkinson’s-like state; they are not used clinically.
Parasympatholytics (anticholinergics)
- Cholinergic antagonists: they act on muscarinic receptors and block them.
- Also called antimuscarinic agents, anticholinergic drugs or atropine-like drugs. They are competitive antagonists.
| Source | Drugs |
|---|---|
| Natural alkaloids | Atropine, scopolamine |
| Semi-synthetic | Homatropine |
| Synthetic | Benztropine, cyclopentolate |
CNS effects: slightly stimulating at first, later depression; they produce convulsions and anxiety. In severe cases: respiratory failure and circulatory collapse.
Uses
- Motion sickness (atropine, scopolamine)
- Parkinson’s disease
- Diagnosis of Alzheimer’s (memory loss is due to ACh reduction)
- Mydriatic, dilating the pupil (avoid in narrow-angle glaucoma)
- Bronchodilator in asthma: relaxes bronchial muscle
- Reduce GIT, salivary, lacrimal and bronchial secretions: useful in peptic ulcer, COPD and asthma
- Pre-anaesthetic medication
- Antispasmodic
- Mushroom poisoning and organophosphate poisoning
Adverse effects
- Constipation
- Decreased sweating
- Blurred vision
- Urinary retention
- Dryness of mouth
Too much reduction of secretions leads to toxicity.
Physostigmine (IV) is used to prevent or treat the toxicity of these drugs.