Category: 1. General Pharmacology

Case Scenario:

Mrs. Jameel, 45 years of age, is a housewife. Since last month she was feeling fatigue of shoulder muscles while combing her hair. She had to perform some unusual physical work when her family was to move into a new residence and all the luggage and house-hold was to be packed for shifting. She felt extremely weak during the activity and was compelled to take rest at short intervals.

Learning Objectives:

• What is Myasthenia gravis?
• Etiology and patho-physiology of the disease.
• Appraoches to pharmacotherapy of MG.
• Classification of anticholinesterases.
• Mechanism of action of anticholinesterases and their control.
• How to distinguish between cholinergic crisis and myasthenic crisis.
• Other uses of anticholinesterases.
• Drugs that may precipitate MG.

Myasthenia Gravis:

It is a disease of neuro-muscular junction caused by immune mediated loss of acetylcholine receptor. It occurs in 30 out of 100,000 persons. Before age of 40 it is more common in women.

65% have thymic hyperplasia , 15% thymona in almost all cases autoimmune bodies against AChR.

In this disease, antibodies are produced against the main immunogenic region found on α1 subunits of nicotinic receptor-channel complex.

Nicotinic receptors are reduced by following processes:

1. Antibody causes cross-linkages of receptors leading to internalization and degradation.
2. Antibody also cause direct postsynaptic membrane damage.
3. Antibody bind to the receptor and preventing agonists from binding.

Nicotinic Receptors:

• Pentamer of four glycoproteins (one subunit is repeated)
• Each subunit has four transmembrane segments.
• Two binding sites are found for agonists, the interface between 2α and 2 adjacent subunits (β,γ,ε).
• Agonist binding causes conformational change that makes it more permeable to cations mainly Na⁺, K⁺ and small amount of Ca⁺⁺.
• Single agonist binding cause negligible conformational change whereas binding of two agonists molecules cause major conformational change.
• Prolonged occupation of the receptor diminishes receptor response.
• Continued presence leads to depolarization blockade.
• Later leads to restoration of resting membrane potential and receptors are desensitized. This state is refractory to the reversal by agonist.

Diagnosis:

1. 2 mg Edrophonium I/V after baseline muscle strength has been recorded.
2. If no reaction in 45 seconds, additional dose of 8mg may be injected.
3. In case of MG, improvement in muscle strength lasting upto 5 mins is seen.

Prognosis:

Again edrophonium is used. (1-2 mg I/V)

If muscarinic overactivity, no improvement or worsening of weakness is seen with dose. (Cholinergic crisis).

If inadequate, improvement with small dose of edrophonium is seen. (Myasthenic crisis)

Treatment:

Ocular MG: Only anticholinesterases are used.

Widespread:

• Anticholinesterases with immunosuppressants are used (steroids, cyclosporine and azathioprine)
• Removal of thymus
• Administration of immunoglobulins
• Plasmaphoresis

Anticholinesterases: Pyridostigmine is drug of choice. Neostigmine and ambemonium are the alternatives. Doses are titrated till effects are controlled and monitored by edrophonium.

Steroids: Cause initial exacerbation of symptoms followed by relief of symptoms.

Steroids act as immunosuppressants in following way:

• Inhibit function of macrophages and antigen presenting cells.
• Production of TNF-α, IL-1, metalloproteinases and plasminogen activators is reduced.
• IL-12 and INF-γ are reduced, which are inducers of TH1 and cellular immunity.
• Reduces leukotrienes, prostaglandins and PAF synthesis.
• Reduces induction of COX-2 enzyme.

Cyclosporine:

• Cyclosporine binds to cyclophilin in T-cells which belong to intracellular proteins called immunophilins.
• Cyclosporine and cyclophilin complex inhibits the cytoplasmic phophatase, calcineurin which is necessary for the activation of T-cell specific transcription factor.
• This transcription factor, NF-AT, is involved in the synthesis of interleukins by activated T-cells.
• IL-2, IL-3, INF-γ are not produced.
• No effect on interaction of T-cells with these factors and with antigen.

Toxicity: Nephrotoxicity, hypertension, hyperglycemia, liver dysfunction, hyperkalemia, altered mental status, seizures and hirsutism.

Azathioprine: It is a prodrug of mercaptopurine. Both appear to produce immunosuppression by interfering with purine nucleic acid metabolism at steps that are required for the wave of lymphoid cell proliferation that follows antigenic stimulation. 2.5 mg/Kg daily.

Plamapheresis: It is reserved for myasthenic crisis and pre-operative control of MG.

IVig: It is the infusion of Immunoglobins collected from 20,000 donors. Possible MOA in autoimmune diseases are¹:

• Reversible blockade of Fc receptors on cells of the reticuloendothelial system by Fc fragments of injected immunoglobulins.

• Fc-dependent feedback inhibition of autoantibody synthesis by B cells and modulation of suppressor or helper T cell functions.
• Interference of IVIg with complement-mediated damage.
• Modulation by IVIg of cytokine secretion.
• V-region dependent modulation by IVIg of the expression of the autoimmune repertoire*.

*Inventory, stock, supply. Clin. exp. Immunol. (1991) 86, 192- 198REVIEWIntravenous immunoglobulins (IVIg) in the treatment of autoimmune diseasesS.-V. KAVERI, G. DIETRICH, V. HUREZ & M. D. KAZATCHKINE

Classification of Cholinergic drugs (Anticholinesterases)

Reversible

Carbamates

i. Tertiary amines:

Physostigmine

ii. Quarternary amines:

Neostigmine

Demecarium

Pyridostigmine

Distigmine

ii. Alcholols

Edrophonium

Irreversible

i. Therapeutically useful

Ecothiophate

ii. War gases

1. i.     Sarin
2. ii.     Soman
3. iii.     Tuban

iii. Insecticides

1. Parathion
2. ii.     Malathion
3. iii.     Diisopropylflurophophate (DFP)
4. iv.     Tetraethylpyrophosphate (TMPP)
5. v.     Octamethylpyrophoramide (OMPA)

Miscellaneous

1. Tacrine
2. Donepezil
3. Galantamine
4. Rivastigmine

Mechanism of Action:

All cholinesterase inhibitors increase the concentration of endogenous acetylcholine at cholineceptors by inhibiting cholinesterases.

Quaternary Alcohols like Edrophonium bind electostatically and through H-bonding to the enzyme and prevent acetylcholine from binding it. Bond formed is weak so blockade is short lived.

Carbamate esters like neostigmine and physostigmine undergoes two-step hydrolysis sequence analogous to acetylcholine, however covalent bond formed is considerably resistant to hydrolysis, this step is considerably prolonged.

Organophophates forms a similar bond with the active site resulting in phophorylation of the enzyme. This phosphorylation is resistant to hydrolysis. If the process of aging occurs that is removal of one of the oxygen-phosphate bond results in even tighter bond between enzyme and phosphorus. Before aging occurs this bonding can be reversed by strong nucleophiles like oximes e.g Pralidoxime, which are called cholinesterase regenerator.

Adverse Effects:

Muscarinic: Miosis, salivation, sweating, bronchial constriction, vomiting and diarrhea.

CNS: Cognitive disturbances, convulsions and coma

Nicotinic: Depolarizing neuromuscular blockade.

Therapy:

• Maintainance of vital signs: respiration is liable to be affected.
• Decontamination to prevent further absorption.
• Atropine parenterally large dose for muscarinic effects.
• Treatment with pralidoxime.
• Benzodiazepines for seizures.

Distinguishing between Cholinergic crisis and Myasthenic crisis:

Edrophonium, improvement means Myasthenic crisis otherwise cholinergic crisis.

Other uses of Anticholinesterases:

• Glaucoma:
  • Contraction of ciliary muscles so as to facilitate outflow of aqueous humour.
  • Decreases its rate of secretion.

Not the first line of drugs (First line agents: β- blockers and prostaglandin derivatives)

• Acute angle closure glaucoma:

Combination of direct muscarinic agonist and anticholinesterase before iridectomy.

• Accomodative estropia (Strabismus caused by hypermetropic accommodative error) in young children.
• Postoperative Ileus (atony or paralysis of the stomach or bowel following surgical manipulation)
• Congenital megacolon (hirschsprung’s disease)
• Urinary retention postoperatively or postpartrum secondary to spinal cord injury or disease (neurogenic bladder).
• Reflux esophagitis: Increase tone of lower esophageal sphincter.THERE MUST NOT BE ANY MECHANICAL OBSTRUCTION OTHERWISE PERFORATIONS WILL OCCUR
• Bethanecol: For GIT orally 10-25mg 3 to 4 times daily, for urinary symptoms S/C 5 mg repeated in 30 mins if necessary
• Neostigmine: GIT 0.5-1 mg S/C, Oral 15mg
• Myasthenia Gravis
• Recovery from muscle relaxant
• Paroxysmal supraventricular tachycardia: Edrophonium but replaced by adenosine and Calcium channel blockers verapamil and diltiazem.
• Antimuscarinic drug intoxication: Atropine and Tricyclic antidepressants. Physostigmine is used but has adverse CNS effects.
• Alzheimer’s Disease: Tacrine, donepezil, galantamine and rivastigmine are used.

Neostigmine	Physostigmine
Synthetic	Natural alkaloid obtained from Physostigma venenosum (calabar bean)
Quaternary amine	Tertiary amine
Water soluble	Lipid soluble
Can not cross blood brain barrier	Can cross blood brain barrier
Poorly absorbed GIT	Absorbed readily from GIT
No CNS effect at moderate dose	CNS effect are present
Prostigmine	Eserine
Has direct actions on nicotinic receptors	No known dual action.

A simple way to remember the drugs that should be used with caution in myasthenia gravis is the “14 A’s”:^1-4

ACTH and corticosteroids	prednisone
Analgesics	narcotics
Anesthetics, local	cocaine, procaine, lidocaine, bupivacaine, prilocaine
Antacids or laxatives containing magnesium	Maalox, Mylanta
Antiarrhythmics	quinidine, lidocaine, procainamide
Antibiotics	aminoglycosides, quinolones, telithromycin, azithromycin, erythromycin, clindamycin, ampicillin, imipenem, vancomycin, metronidazole
Anticonvulsants	phenytoin
Antihypertensives	beta-blockers, calcium channel blockers
Antimanics	lithium salts
Antipsychotics	chlorpromazine
Antirheumatic	chloroquine
Arthritis agents	penicillamine-induced myasthenia gravis
All neuromuscular blocking agents
Antimalarials	chloroquine, hydroxychloroquine

Differentials :

• Amyotrophic Lateral Sclerosis
• Basilar Artery Thrombosis
• Brainstem Gliomas
• Cavernous Sinus Syndromes
• Dermatomyositis/Polymyositis
• Lambert-Eaton Myasthenic Syndrome
• Multiple Sclerosis
• Sarcoidosis and Neuropathy
• Thyroid Disease
• Tolosa-Hunt Syndrome

1. Karcic AA. Drugs that can worsen myasthenia gravis. Postgrad Med. 2000;108(2):25.
2. Pascuzzi R. Myasthenic crisis. Postgrad Med. 2000;107(4):211-222.
3. Yarom N, Barnea E, Nissan J, Gorsky M. Dental management of patients with myasthenia gravis: A literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;100(2):158-163.
4. Kuczkowski KM. Labor analgesia for the parturient with neurological disease. Arch Gynecol Obstet.   2006;247(3):41-46.

Case Scenario:

A young female, 26 years old primae underwent C/S. Both mother and baby were clinically stable. She was advised postoperative antibiotic injection to prevent infection. Nursing staff administered her Co-amoxiclav injection, immediately the patient complained of severe difficulty in breathing, abdominal pain and nausea. She was sweating and pulse was weak. Drastic fall in B.P and she fainted.

Learning Objectives:

1. Definition of drug allergy and hypersensitivity.
2. What is anaphylaxis?
3. Other forms of pencillin allergy and their prevention
4. Management of acute anaphylaxis
5. Difference between acute anaphylaxis and anaphylactoid reactions.
6. Definition of physiological antagonism. Clinical settings in which physiological antagonist may be preferred over pharmacological antagonist.

Explanation:

Co-Amoxiclav:

Co-Amoxiclav is British approved name for combination of Amoxicillin trihydrate and Potassium clavulanate, a β-lactam antibiotic and β-lactamase inhibitor. This combination increases the spectrum and restores efficacy against amoxicillin-resistant bacteria, that produce β-lactamase. Trade names include Augmentin, Clavamax, CLAMP, Amoxiclav.

Amoxicillin works by interfering with the ability of bacteria to form cell walls. The cell walls of bacteria are vital for their survival. It inhibits Transpeptidase enzyme responsible for inducing cross-linkages in the peptidoglycan layer of cell wall. This leads to decrease strength and integrity of the cell wall. Only useful when bacteria are actively dividing and synthesizing cell wall.

Prophylaxis:

It is a measure taken for the prevention of a disease or a condition. It is Greek for ‘advance guard’.

The single most important risk factor for postpartrum maternal infections is cesarean section.(Gibbs 1980)

Complications:

Fever, wound infection, endometriosis, bacteremia, pelvic abscess, septic shock, necrotizing fasciitis and septic pelvic vein thrombophlebitis and UTIs.

Sources of infection:

Genital tract and skin.

Organisms:

Polymicrobial: wounds and endometrosis include Escherichia coli, other aerobic gram negative rods, Group B – Streptococcus and other Streptococcus bacteria, Enterococcus faecalis , Staphylococcus aureus and coagulase negative Staphylococci, anaerobes Peptostreptococcus species and Bacteriodes species Gardnorella vaginalis and genital Mycoplasm. (Watts 1991, Robert 1993, Mortoms 1995)

Staphyloccus aureus and coagulase negative arise from contamination of wound with endogenous flora of skin at the time of surgery (Emmon 1981)

Anaphylaxis:

Anaphylaxis is a severe allergic reaction that occurs rapidly and causes a life threatening response involving the whole body. This reaction can lead to difficulty breathing and shock, ultimately leading to death. Sensitizing is required, IgE mediated response.

Drug Allergy:

It is the response of the body in which body’s immune system reacts with the drug.

Irritation, hives, skin rashes, itchy skin or eyes, congestion and swelling in the mouth and throat.

Severe symptoms: Difficulty in breathing , blueness of skin, dizziness, fainting, anxiety, confusion rapid pulse, nausea, diarrhea and abdominal problems.

Other drugs: Sulfa drugs, barbiturates, anticonvulsants, insulin and iodine.

Difficulty in breathing, swelling or spasm in the airways, tongue swelling severe, apnea.

Loss of consciousness due to hypotension.

Cardiac arrest

Skin: Most analphylactic reactions involve the skin.

Hives, welts or wheals, hives can cause severe itching.

Generalized erythema, swelling in the face, eyelids, lips, tongue throat, hands and feet,

Breathing:

Swelling of the surrounding tissues narrows the airways. Difficulty breathing, wheezing, chest tightness, coughing, hoarseness, nasal congestion, sneezing.

Cardiovascular:

Blood pressure may drop dangerously low levels. Rapid or irregular heartbeat, Dizziness, faintness loss of consciousness and collapse.

General:

Tingling or sensation of warmth, difficulty swallowing, nausea, vomiting, diarrhea, abdominal cramping, bloating, anxiety, fear, feeling that you are going to die, Confusion

Management:

Since it is a medical emergency, so ABC is applied

Airways:

Check the patency of the airways.

Breathing:

Use mask or nasal tubes. In serious cases intubation and mechanical ventilator. If required tracheostomy.

Circulation:

Epinephrine injection. IV line for fluids and drugs like H1 blockers beta agonists etc.

Medications:

Epinephrine to increase blood pressure by opposing vasodilation by histamine and stimulating heart.

H1-receptor blocker/ antihistamine (diphenylhydramine)

Beta-agonist: Like albuterol to relieve bronchospasm.

H2-blocker: Zantac, Tagamat, Cimetidine, Ranitidine.

Corticosteroid: Prednisone to combat inflammation.

Hypotension persists then Dopamine.

After Epipen or Ana-kit, which contains epinephrine in known concentration for self-administration as IM.

Anaphylactoid Reaction:

An analphylactoid reaction doesn’t need the presence of IgE antibodies for a hypersensitivity reaction to occur. Substances initiating the analphylatoid reactions, such as radiopaque contrast media, non-steroidal anti-inflammatory drugs and aspirin cause a direct breakdown of the mast cell and basophil membranes.

Anaphylactoid Reactions causing substances:

Aspirin, NSAIDs, radiopaque contrast media, fluroscem, Dextran, Thiamn, opiates.

Hypersensitivity:

A state of altered reactivity in which body reacts with an exaggerated immune response to what is perceived as a foreign substance.

Types of reaction	Prototypic disorders	Immune mechanism	Pathologic Lesion
Immediate (type 1) hypersensitivity	Anaphylaxis, allergies, bronchial asthma (atopic forms)	Production of IgE antibody leads to immediate release of vasoactive amines and other mediators from mast cell, later recruitment of inflammatory cells.	Vascular dilation, edema, smooth muscle contraction, mucous production, tissue injury, inflammation.
Antibody-mediated (type-II) hypersensitivity	Autoimmune hemolytic anemia ; Good pasture syndrome	Production of IgG, IgM leads to their binding to antigen on target cell or tissue leads to phagocytosis or lysis of target cell by activated complement of Fc receptors; recruitment of leukocytes	Phagocytosis and lysis of cells; inflammation in some diseases, functional derangements without cell or tissue injury.
Immune complex mediated (type III) hypersensitivity	Systemic Lupus Erythmatous; some forms of glomerulnephritis; serum sickness; Arthur reaction	Deposition of antigen binding complexes leads to complement activation leading to recruitment of leukocytes by complement products and Fc receptors leads to release of enzymes and other toxic molecules	Inflammation, necrotizing vasculitis (fibrinoid necrosis)
Cell-Mediated (type IV) hypersensitivity	Contact dermatitis; multiple scelrosis; type I diabetes; rheumatoid arthritis; inflammatory bowel disease; tuberculosis	Activated T lymphocytes leads to: I)Release of cytokines leading to inflammation and macrophage activationII)T cell mediated cytotoxicity	Perivascular cellular infiltrates; edema; granuloma formation; cell destruction.

Action	Mediators
Vasodilation, increased vascular permeability	Histamine, PAF, Leukotrienes C4 D4 E4, Neutral proteases that activate complement and kinins, Prostaglandins D2.
Smooth muscle spasm	Leukotrienes C4 D4 E4, histamine, Prostaglandins, PAF.
Cellular Infiltration	Cytokines, (chemokines, TNF) leukotrienes B4, Eosinophil and neutrophil chemotactic factor.

Events:

1. Exposure to antigen
2. Activation of TH2 cells and IgE class switching in B cells.
3. Production of IgE
4. Binding of IgE to FcεRI on mast cells
5. Repeat exposure to antigen
6. Activation of mast cells, release of mediators

Mediators:

• Vasoactive amines and lipid mediatiors for immediate hypersensitivity reaction
• Cytokines for late phase reaction

Two phases of Type I

Immediate: Vasodilation, vascular leakage, smooth muscle spasm.

Late Phase reaction: Leukocyte infiltration, Epithelial damage, Bronchospasm.

To summarize, immediate hypersensitivity is a complex disorders resulting from an IgE-mediated triggering of mast cells and subsequent accumulation of inflammatory cells at sites of antigen deposition. These events are regulated mainly by the induction of TH2 helper T-cells that stimulate production of IgE (which promotes mast cell activation). Cause accumulation of inflammatory cells (particularly eosinophils) and triggers secretion of mucous. The clinical features result from release of mast cell mediators as well as the eosinophil-rich inflammation.

Allergic reactions:

An allergic reaction occurs when the immune system begins to recognize a drug as something “foreign”. Several different symptoms can indicate that a person is allergic to penicillin. These include hives (raised, intensely itchy spots that come and go over hours) angioedema (swelling of the tissue under the skin, commonly around the face), throat tightness, wheezing, coughing, and trouble breathing from asthma-like reactions (narrowing of the airways into the lungs).

A past history of these types of reactions is important because the person might develop a more severe reaction, such as anaphylaxis, if they were to take the antibiotic again. Mild to moderate allergic reactions to penicillins are common, occurring in 1 to 5 percent of people.

Anaphylaxis:

Anaphylaxis is a sudden, potentially life-threatening allergic reaction. Symptoms include those of an allergic reaction, as well as very low blood pressure, difficulty breathing, abdominal pain, swelling of the throat or tongue, and/or diarrhea or vomiting. Fortunately, anaphylaxis is uncommon.

Definition

The WHO defines drug dependence as:

“A state, psychic and sometimes  physical resulting  from taking a drug characterized by behavioral and other responses that always include a compulsion to take a drug on a continuous or periodic basis in order to experience its psychic effects, and some times to avoid discomfort of its absence”

Body systems become adopted in a way that the person has to take the drug, leading to tolerance and changes of toxicity e.g. morphine like drugs may cause respiratory depression.

Once the drug is stopped, since the body has adopted, it leads to withdrawal or abstinence symptoms, opposite to therapeutic effects. Morphine, an analgesic, producing sedation and calming effects if not provided, may cause pain, irritability and diarrhea. Thus leading to addiction.

CNS drugs are psychoactive drugs, acting by mesolimbic dopaminergic pathway on ventral tegmental areas, involved with behavior and emotion; show the phenomenon of drug dependence. When these drugs are prescribed, in a few percentage of people, produce euphoria, the feeling of well being. This euphoria compels them to take the drugs repeatedly due to which certain changes take place in the homeostasis by virtue of presence of drug.

Components:

1. Euphoria
2. Physical dependence- known now as dependence e.g. antihypertensive drugs have to be taken life long by the patients, bronchodilators and nitrates (glyceryl trinitrate) are other examples. These include non psychoactive drugs, individual is dependent but is not addiction
3. Psychological dependence- known now as addiction, which is the compulsion to take the drug in spite of negative effects. More relapses and compulsion to take drugs occur e.g. cocaine addiction, but has no withdrawal symptoms, opoids have highly troublesome
4. Abstinence/withdrawal syndrome

There are different symptoms and mechanisms of different drug abuse. The main problem is the denial by the patient.

Development of dependence

The first use of a drug is in one of four contexts

1. Therapeutics,
2. Recreational
3. Instrumental,
4. Cultural

The outcomes of use of drugs depend on:

The drug – its availability form and its ability to induce reinforcement

The individual: curious rebellious unhappy, vulnerable types, pleasure seeking, motivation, also the response to the drug

The culture: deprivation, constraints, peer groups, the age of instant gratification.

Commonly abused drugs:

Common abused drugs/substances include

1. Opiates and Narcotics
   Heroin (diacetylmorphine, highly lipophilic and short lived), opium, codeine (used in cough syrups), meperidine, hydromorphin
2. Central Nervous System Stimulants
   Amphetamines (sympathomimetic), cocaine, dextroamphetamine, Methamphetamine, methylphenidate.
   Most commonly used stimulants are caffeine and nicotine, for which craving develops (psychological dependence)
3. Central Nervous System Depressants
   Barbiturates: (amobarbital, Pento barbital, Secobarbital)
   Benzodiazepines: (Valium, Ativan, Xanax)
   Chloral hydrate (was used as sedative hypnotic in young children), paraldehyde

Benzodiazepines are sedatives and anti anxiety drugs, used on continuous basis, which leads to dependence. Sleep cycle is disturbed and cause paradoxical problems in elderly

The most commonly used is alcohol, a social drink, which when taken within limits presents no problems.

4. Hallucinogens
   LSD, Mescaline Psilocybin (Mushroom), Phencyclidine (Angel dust), Cannabis

Cannabis has medical importance and is anti cancer. They improve the quality of life but lead to distorted perception.

Causes, Incidence and Risk Factors:

Drug abuse can lead to drug dependence or addiction. Drug dependence may also follow the use of drugs for physical pain relief.  The exact cause of drug abuse and dependence is not known. However, the genetic make-up of the individual (e.g. receptors for morphine), the pharmacology of the particular drug, peer pressure, emotional distress, anxiety, depression, and environmental stress are all factor which seem to be involved.

Consequences:

Drug abuse is simply excessive use of a drug or use of a drug for purposes for which it was not medically intended. There are some substances that do not cause addiction but do cause physical dependence e.g. (some blood pressure medications) and substances that cause addiction but not physical dependence (Cocaine).

Symptoms:

Opiates and Narcotics

Symptoms of use:

• The first sign of addiction is denial
• Needle marks on the skin in some cases (because of release of histamine on scratching
• Scars from skin abscesses
• Rapid heart rate
• Constricted pupils (pin point) (dilated in cocaine)
• Relaxed and/or euphoric state
• Coma, respiratory depression leading to coma and death in high doses.

Symptoms of withdrawal:

• Anxiety and difficulty sleeping
• Sweating
• Runny nose (rhinorrhea)
• Stomach cramps or diarrhea
• Dilated pupils
• Nausea and vomiting
• Excessive sweating
• Increase in blood pressure, pulse and temperature

Less potency drugs like methadone are given during withdrawal, otherwise patient may die.

Central Nervous System Stimulants:

Symptoms of cocaine use:

• Euphoria (exaggerated feeling of well being)
• Dilated pupils
• Rapid heart rate
• Restlessness and hyperactivity

Symptoms of cocaine withdrawal:

• Fatigue and malaise
• Depression
• Vivid and unpleasant dreams

Central Nervous System Depressants:

Symptoms of alcohols use:

• Slurred speech
• Lack of coordination
• Decreased attention span
• Impaired judgment

Symptoms of alcohol withdrawal:

• Anxiety
• Tremors
• Seizures
• Increase in blood pressure, pulse, and temperature
• Delirium

Hallucinogens

Symptoms of LSD use:

• Anxiety
• Frightening hallucinations
• Paranoid delusions
• Blurred vision
• Dilated pupils
• Tremors

Drugs are categorized into A, B&C with class A being subject to stiffer control

Class A  Drugs (highly addictive)	Class B Drugs
Alfentanil	Oral Preparations of Amphetamines
Cocaine	Barbiturates
Heroin	Codeine
Lofentamil	Gluthethamide
LSD	Pentazocine
Methadone	Phenmetrazine
Morphine	Pholcodine (cough syrup)
Pethidine
Opium
Phencyclidine
Ingectables of Class B
Class- C Drugs
Phentamine
Meprobamate (muscle relaxant)
Most benzodiazepines
Cannabis – became classified as a class C drug
Mazindol (used in anesthesia, added in January 2004
Diethylpropion

Drug intoxication and drug overdose may be accidental or intentional. Drug withdrawal symptoms can occur when use of substance is stopped or reduced. Withdrawal symptoms vary, depending on the abused substance. The onset of withdrawal symptoms depends on the length of time the drug normally stays within the body. Withdrawal can be life – threatening in some situations.

Treatment of drug dependency

1. Detoxification
2. Support
3. Abstinence

Detoxification is the gradual withdrawal of an abused substance in a controlled environment. Sometimes a drug with a similar action is substituted during the withdrawal process to reduce the unpleasant symptoms and risks associated with withdrawals.

Drug abuse and dependence may lead to a fatal drug overdose. Replace from drug abstinence may occur and lead to recurrent dependence.

Complications of drug abuse

1. Bacterial endocarditis
2. Hepatitis
3. Thrombophlebitis
4. Pulmonary emboli
5. Malnutrition
6. Respiratory infections.
7. Intravenous drug abuse
8. Infection with HIV through shared needles.
9. Drug induced loss of inhibitions may lead to unsafe sexual practices

Increase in various cancer rates e.g. lung and pharynx cancer, are associated with nicotine use, mouth and stomach cancer are associated with alcohol abuse and dependence

Drug Use

Drug is used for therapeutic purposes

Drug Abuse

When the same drug used for therapeutic purposes for treatment of particular condition, because of feeling of reward (e.g. pain relieving effect of analgesics) administered repeatedly is known as drug abuse.

Undesirable or harmful effects which can occur at therapeutic doses and need a reduction of dose or drug withdrawal. Adverse drug effects include:

1. Nausea and vomiting
2. Deafness with gentamycin
3. Death with penicillin

All drugs are poisons until used judicially. Every drug acts on all systems of the body, e.g. aspirin used for headache also acts on GIT and blood producing side effects.

Types of adverse drug reactions

Adverse drug reactions are of five types; A, B, C, D and E

1) Type A reactions

Type A reactions are common and constitute 75 % of all adverse reactions. These are related to pharmacological actions and are dose-dependent. Type A reactions are predictable and can be avoided by adjusting the dosage regimen. Most of them are reversible upon stopping drug. Examples include

–  Hypotension (antihypertensives)

–  Hypoglycaemia (insulin)

a. Excessive therapeutic effect

Unwanted effects related to the main pharmacological actions of the drug that occur when the drug produces greater therapeutic effect than is necessary.

e.g. Warfarin is an anticoagulant but may lead to bleeding tendency.

Insulin is used for normoglycemia but may produce hypoglycaemia

b. Side Effects

Unwanted effects unrelated to the main pharmacological actions of the drug but due to other normal actions of the drug

e.g. morphine may cause constipation during its use as analgesic.

2)  Type B reactions

Type B reactions are bizarre reactions, not related to the normal pharmacological actions of the drug. They are unpredictable and not dose-related. They occur only in minority of patients. Test dose can be given for judgement.

Types

a. Allergic reactions (Hypersensitivity)

b. Genetic disorders (Idiosyncrasy)

a) Hypersensitivity (allergic reactions)

Abnormal response to the drug due to antigen- antibody reactions e.g. Penicillin. These are the allergic responses to a drug.

They include rashes, hypotension and bronchospasm (anaphylactic reaction).

b) Idiosyncrasy

Idiosyncrasy is abnormal response to the drug due to genetic disorders. E.g.

Succinylcholine apnea

Malignant hyperthermia

Favism

Porphyria

Secondary Effects

Unwanted effects that occur secondary to the wanted actions of the drug. Examples include overgrowth of microorganisms following use of broad spectrum antibiotics.

Type C reactions (Continuous reactions)

Type C reactions are due to long term use e.g. NSAIDs causing analgesic nephropathy due to long term usage of drugs and changing doses.

Type D reactions (Delayed adverse reactions)

Teratogenesis Is congenital malformations occurring in the foetus due to exposure to drugs during
pregnancy e.g. Thalidomide may produce phocomelia (abnormal limbs)

Carcinogenesis is the ability of some substances to induce cancer. E.g. Stilbesterol may cause adenocarcinoma of vagina in female off springs.

Mechanisms:

1. DNA alteration

Griesofulvin (antifungal) & alkylating cytotoxics (cancer), they are anti-mitotic, acting on spindle formation

2. Immunosuppression

Immunosuppressant increase incidence of cancer e.g. organ transplantation & methotrexate in rheumatoid arthritis

3. Hormonal

Long term use of estrogen replacement in post menopausal therapy may induce endometrial cancer

Type E reactions (Ending of drug)

Sudden discontinuation (abrupt withdrawal) may lead to rebound adrenal insufficiency
e.g. corticosteroids

Treatment should be started with smaller dose, which can be gradually increased. Patient compliance is poor if adverse reactions occur.

Risk benefit ratio

Disease healing is important at the risk of side effects, especially in life threatening situations. This depends on the expertise of the doctor.

A multitude of host & environmental factors influence drug response. Understanding of these factors can guide choice of appropriate drug & dose for individual patient.

Variation in response to the same dose of a drug between different patients and even in the same patient on different occasions will occur. The range of variability may be marked or limited depending on the pharmacokinetic & Pharmacodynamic characteristics of the drug. Drugs mostly disposed by metabolism are most effected (e.g. propanolol) while those excreted by the kidneys are least effected (e.g. atenolol).

1.      Physiological Factors.
2.      Pathological Factors (Diseases)
3.      Genetic Factors
4.      Environmental Factors
5.      Interaction with other drugs

There exists no specific dose. The decision lies with the doctor. Giving optimum dose is mandatory for desired results. Pharmacopoeia gives the guidelines and ranges. All factors affecting absorption and biotransformation may influence the outcomes of drug actions.

1. Physiological Factors

a. Age

The adult dose is for people between 18 and 60 years of age. The tissues of an infant & child are highly sensitive to large number of drugs. Children under 12 yrs require fraction of adult dose because:

1. Drug metabolizing enzyme system is inefficient in them (Glucuronidation takes 3 months to develop)

2. Their barriers are not fully developed (BBB, blood aqueous barrier), thus are more sensitive to CNS stimulants. All parts of the body are affected by the drug.
3. Infants have an immature renal tubular transport system. Penicillin, streptomycin and amino glycosides are not administered. After one year of age, elimination by kidneys is increased.
4. Hepatic metabolizing capacity is also under developed. Chloramphenicol may cause grey baby syndrome.

The dose for a child is calculated from the adult dose up to 8 yrs of age.  The average adult dose is for an individual of medium built.  For very thin or obese individual the dose may be modified using either the body surface area or body weight. i.e.

Surface area is found from height and weight, and is around 1.7-1.8/m².

Dose to be prescribed = Body surface area (m²) x adult dose

1.7

Dose to be prescribed = Wt in kg x A.D

70

Child dose= Body surface area in m2 of child x A.D

1.7 (average body surface area in AD).

Newborns

The drug dosage of newborn is decreased because:

a.      gastric acid secretion are not adequate e.g.

GIT absorption of ampicillin and amoxicillin is greater in neonates due to decreased gastric acidity

b.      liver microsomal enzymes (glucuronyl transferase) are deficient

Administration of Chloramphenicol may lead to Grey baby syndrome because of inadequate glucouronidation of chloramphenicol resulting in drug accumulation

c.       Plasma protein binding is less

d.      GFR & tubular secretions are not adequate.

e.       There is immaturity of blood brain barriers in neonates.

Sulfonamides may lead to hyperbilirubinemia and kernicterus

Children

In children Tetracyclines may cause permanent teeth staining

Corticosteroids may lead to growth & development retardation

Antihistaminics may cause hyperactivity.

Geriatric age group (> 60 yrs)

Patient requires special consideration because physiological changes occur with age are to be kept in mind such as:

1. Reduced body weight

2. Reduced body fat
3. Reduced intestinal motility & mesenteric blood flow.
4. Reduced renal & hepatic functions
5. Altered mental functions

Elderly often require lesser doses than adults because they are prone to suffer from adverse drug reactions. If liquid preparations are available, they should be preferred as are convenient for absorption.

Liver functions are impaired. Drugs like diazepam, theophylline having lower therapeutic index, may have much larger half lives (2 hrs in normal 90 hrs in old)

Kidney functions are also impaired. Drugs like Digoxin, lithium and amino glycosides have decreased excretion

Plasma protein binding is decreased leading to greater amounts of active drugs.

Increased sensitivity to CNS depressants like diazepam, morphine also occurs

b. Sex

Testosterone increases the rate of biotransformation of drugs.

Decreased metabolism of some drugs in female (Diazepam) occurs. Females are more susceptible to autonomic drugs (estrogen inhibits choline esterase). Drugs used for ulcer may cause increased prolactin.

During menstruation, salicylates and strong purgatives should be avoided as they may increase bleeding.

c. Pregnancy

In pregnancy following are to be considered:

1. Cardiac output
2. GFR and renal elimination of drugs.
3. Volume of distribution
4. Metabolic rate of some drugs

Lipophilic drugs cross placental barrier & are slowly excreted. During pregnancy, uterine stimulants, strong purgatives and drugs likely to have teratogenic effects should be avoided, especially during first trimester no drug should be given unless absolutely necessary.

During labour, morphine should be avoided as it crosses placental barrier and depresses respiration in newborn.

d. Plasma Protein Binding

Malnutrition causes decreased amino acids, decreased proteins leading to decreased binding sites for drugs.

e. Body weight

Dose is given per kg body weight. Average muscular weight is between 50 and 100 kg, with 70 kg being the average.

f. Lactation

During lactation, drugs may be excreted through milk and may affect the infant e.g. some purgatives, penicillin, chloramphenicol and oral anticoagulants.

g. Food

Drugs are better absorbed in empty stomach. To prevent gastric irritation most drugs are taken after or between foods, which affects the outcomes. Antimotion drugs are taken on empty stomach. Helminthes (for evacuation of worms) are also taken on empty stomach.

h. Allergy

Allergy is the abnormal response of drug resulting from antigen-antibody reaction, leading to liberation of histamine and histamine-like substances; therefore, there may be skin rashes, urticaria, bronchoconstriction and fall of blood pressure. Allergic reactions may occur immediately or may be delayed for many days.

Immediate and acute allergic reactions lead to acute anaphylactic shock which is dangerous for patient and may even be fatal e.g. penicillin, sera, vaccines. Steps which can be taken include:

1. History taking of previous allergic reactions
2. Test dose should be given first
3. Drugs required to deal with emergency should be kept ready

Sometimes skin rashes or urticaria along with fever and pain in joints and swelling of lymph nodes may occur after a few days. This is delayed type of allergy called serum sickness type reaction.

i. Drug Dependence (Drug addiction)

Drug dependence is a state of periodic or chronic intoxication which is detrimental to person and society. It becomes almost impossible to carry out normal physical functions without the drug.

Components of phenomenon of addiction include:

1. Euphoria- sense of happiness and forgetfulness
2. Tolerance- due to increased production of enzymes
3. Psychic dependence (Habituation)- person desires but in absence of drug no harm occurs
4. Physical dependence-
5. Withdrawal symptoms (Abstinence syndrome)- symptoms opposite pharmacological actions of drug develop in absence of drug

2. Pathological Factors

Diseases cause individual variation in drug response

(A)  Liver Disease

In liver diseases, prolong duration of action occurs because of increased half life. Plasma protein binding for warfarin, tolbutamide is decreased leading to adverse effects

If hepatic blood flow is reduced, clearance of morphine- propanolol may be affected.

Impaired liver microsomal enzymes may lead to toxic levels of Diazepam, rifampicin and theophylline

(B)  Renal Disease

GFR, tabular function and plasma albumin may be affected leading to abnormal effects of digoxin, lithium, gentamycin and penicillin

(C)  Malnutrition

Plasma protein binding of drugs is reduced along with the amount of microsomal enzymes, leading to increased portion of free, unbound drug e.g. Warfarin

3. Genetic Factors

Genetic abnormalities influence the dose of a drug and response to drugs. It affects the drug response in individuals at 2 levels.

1. At the level of receptors
2. At the level of drugs metabolizing enzyme

Thus, interfering with the functions such as rate of plasma drug clearance.

Pharmacogenetics is the study of the relationship between genetic factors and drug response.

Idiosyncrasy

Idiosyncrasy is the abnormal drug reaction due to genetic disorder. It is the unpredictable response seen on first dose of drug on hereditary basis. This may be due to

1. Acetylation.

2. Oxidation
3. Succinylcholine apnea
4. Glucose 6-phosphate dehydrogenase deficiency.

All individuals do not respond in similar way to same drug. Idiosyncrasy is used to describe abnormal drug response on administration of first dose.

Genetic Polymorphism

The existence in a population of two or more phenotypes with respect to the effect of a drug. E.g. Acetylation enzymes deficiency

Acetyl transferase (non-microsomal) affects Isoniazid, sulphonamides, etc.

Slow acetylator phenotype may show peripheral neuropathy .

Rapid acetylator phenotype may show hepatitis

Pseudocholinesterase deficiency

Succinyl choline is a skeletal muscle relaxant. Succinylcholine apnea may occur due to paralysis of respiratory muscles.

Malignant hyperthermia

Occurs by succinyl choline due to inherited inability  to chelate calcium by sarcoplasmic reticulum resulting in Ca release, muscle spasm and rise in temperature.

Oxidation Polymorphism

In case of Debrisoquine

1. Extensive metabolizers (EM) need larger dose.
2. Poor metabolizers (PM) – need smaller dose.

Deficiency of Glucose-6 phosphate dehydrogenase (G-6-PD)

G-6-PD Deficiency in RBCs leads to haemolytic anaemia upon exposure to some oxidizing agents like

1. Antimalarial drug, primaquine

2. Long acting sulphonamides
3. Fava beans ( favism).

4. Environmental Factors

a. Route of Administration

Some drugs are incompletely absorbed after oral intake, when given intravenously; their dose has to be reduced. Examples include morphine and magnesium sulphate. Magnesium sulphate when given orally is osmotic purgative, but its 20% solution is injected intravenously to control the convulsions in eclampsia of pregnancy.

b. Time of Administration

Hypnotics (producing sleep) act better when administered at night and smaller doses are required. Amonoglycosides like streptomycin when given intravenously cause neuromuscular blockage, which is not observed after intramuscular injection.

c. Effect of Climate

Metabolism is low in hot and humid climate. Purgatives act better in summer while diuretics act better in winters. Oxidation of drugs is low at higher altitudes.

d. Racial Differences

Castor oil, a purgative, is ineffective in Chinese. The dilating effect of ephedrine in fair people on pupil is absent in Negroes.

e. Preparation of Drug

Drugs in solid forms disintegrate slowly. Onset of action is rapid when drug is given in liquid form.

f. Age of Drug

Action may be modified if kept for longer durations. Outdated tetracyclines give rise to excretion of amino acids in urine. Chloroform and carbon tetrachloride become toxic if kept for long durations.

g. Acidic or Basic Medium

If GIT has decreased acidity, acidic drugs like benzyl penicillin are not effective orally.

h. Effect of Disease

Certain drugs are only effective in disease conditions. These include antipyretics like aspirin and paracetamol, which do not reduce temperature in case of healthy individuals.

Iron is better absorbed in iron deficiency anemia. As the anemia improves, it has less response.

Hyper susceptibility to Drugs

Variations in individuals leading to prolonged effects of drugs. Examples include diazepam, 2 mg of which are used as antianxiety producing no hang overs. In hyper susceptible individuals, the drug has prolonged action causing hangovers and hypnotic actions.

Opioids like morphine cause analgesia and sedation in 10 mg dose effective for 4-6 hours. In hyper susceptible individuals, effect might be prolonged to 10-12 hours. These are individual based variations.

Hypersensitivity

Hypersensitivity is the quantitatively abnormal response with certain groups of drugs. Response is seen in sub therapeutic doses not capable of producing pharmacological actions. This has immunological basis, e.g. allergy. 25% of the drugs show hypersensitivity.

Hematological disorders can occur more pronounced in atopic individuals, who are already exposed to antigens, e.g. ashthemics are more prone to allergic reactions.

Nearly all drugs show hypersensitivity in some category, which might be self limiting or even life threatening. Penicillin when administered may cause anaphylactic shock. High molecular weight drugs have a greater tendency to show hypersensitivity. History taking is helpful in predicting hypersensitivity. Test dose can be given intradermally and localized reactions can be seen.

Tolerance

Resistance to normal therapeutic dose of drug, producing lesser response to normal therapeutic dose is known as tolerance. This is acquired character. Examples include morphine, person is initially responsive, if continued, changes occur at cellular and pharmacokinetic level, reducing the action. Thus one has to increase the dose of drug to overcome.

Alcoholics do not respond to hypnotics and analgesics, dose of which has to be increased many folds. In fact they may even tolerate toxic levels.

Cross Tolerance

A person tolerant to drugs resembling in chemical structure is known as cross tolerance. Those drugs resembling in chemical structures show cross tolerance. If a person is tolerant to morphine, he also shows tolerance to pathedine (synthetic derivative) and codeine.

Complete cross tolerance is observed in cases like diazepam and flurezepam

Incomplete cross tolerance occurs with the drugs sharing the same pharmacological properties. Examples include barbiturates and general anesthetics, site of action is CNS, incomplete cross tolerance may be observed although they are not resembling chemically, but having same pharmacological properties.

Tachyphylaxis

Repeated administration of a drug at short intervals of time leads to a rapidly developing tolerance. This occurs with indirectly acting drugs. On repeated administration, depletion of endogenous receptors occurs. It is also known as acute tolerance. Example includes ephedrine, which acts by releasing noradrenalin from adrenergic stores. After repeated administration, these stores are exhausted and pharmacological action is not restored even on increasing the dose.

5. Interactions of Drugs

a. Synergism

Synergism is the facilitation/potentiation of pharmacological response by concomitant use of two drugs.

I. Potentiation

The total effect will be more than the sum of their individual effects. Examples are:

1. Acetylcholine + physostigmine. Physostigmine inhibits the action of esterase prolonging the effect of acetylcholine.
2. Levodopa (Parkinsonism) + carbidopa/benserazide. Levo dopa is decarboxylated peripherally, carbidopa inhibits the decarboxylase.
3. Sulfonamide (effective against some microorganisms) when combined with trimethoprim is effective against a wider range of microorganisms.

The action is more than the normal therapeutic effect.

II. Additive Effect (Summation)

In this case the total pharmacological action of two drugs will be equal to the sum of their individual effect on simultaneous administration. The response is not more than their total algebraic sum.  e.g.

1. Aspirin + paracetamol as analgesic/ antipyretic
2. Ephedrine + theophylline as bronchodilator
3. Nitrous oxide + ether as general anesthetic
4. Antihypertensive drugs
5. Cardiac stimulants

b. Antagonism

When two drugs, administered simultaneously, oppose the action of each other on the same physiological system, the phenomenon is called antagonism. It can be of following types.

1.      Chemical antagonism:

It involves reduction of the biological activity of a drug by a chemical reaction with another agent e.g. between acids and alkalies: BAL and arsenic. Antacids, used for dyspepsia involve administration of sodium bicarbonate to react with hydrochloric acid. In cases of heavy metal poisoning chelating agents are used like dimerzapam.

In iron poisoning deproxamine is given which binds sulphydral groups forming insoluble complexes which can be easily detoxified.

2.      Pharmacological antagonism

Pharmacological antagonism is of two types:

I. Competitive or reversible antagonism.

In this type of antagonism the agonist and antagonist compete with each other for the same receptors. The extent of antagonism will depend on the relative number of receptors occupied by the two compounds. Other features are:

a. Antagonist has chemical resemblance with agonist.

b. Antagonism can be overcome by increasing the concentration of the agonist at receptor site. It means the maximal response to agonist is not impaired.

c. Antagonist shifts the dose response curve to right

d. Emax of agonist is obtained with high concentration of agonist

e. Duration of action is short. It depends on drug clearance

Example is of acetyl choline and atropine antagonism on muscarinic receptors. In presence of antagonist, log dose response curve of agonist shifts to right, indicating a higher concentration of agonist is required for same response. Maximum height of the curve can be attained by overcoming the action of antagonist. This leads to a parallel shift of log dose response curve towards right.

II. Non competitive antagonism:

Here an antagonist inactivates the receptor in such a way so that the effective complex with agonist cannot be formed irrespective of the concentration of the agonist. This can happen by various ways:

1. The antagonist might combine at the same site in such a way that even higher concentration of the agonist can not displace it.
2. The antagonist might combine at a different site of R in such a way that agonist is unable to initiate characteristic biological response
3. The antagonist might itself induce a certain change in R so that the reactivity of the receptor site where agonist should interact is abolished.

Other features of this antagonism are:

1. Antagonist has no chemical resemblance with agonist.

2. Maximum response is suppressed
3. Although antagonist shifts the dose response curve to right, the slope of the curve is reduced.
4. The extent of antagonism depends on the characteristics of antagonist itself and agonist has no influence upon the degree of antagonism or its reversibility
5. Emax of agonist is decreased even with high concentration of agonist
6. Duration of action is long which depends upon new receptor synthesis.

Example is of phenoxybenzamine and adrenaline at alpha adrenergic receptors.

III. Physiological antagonism:

In this interaction of two drugs, both are agonists, so they act at different receptor sites. They antagonize the action of each other because they produce opposite actions. Classical example of physiological antagonism is adrenalin and histamine. Former causes bronchodilatation while later broncho Constriction. So adrenalin is a life saving drug in anaphylaxis.

Clinical significance of drug antagonism

1. It helps to correct adverse effects of a drug e.g. ephedrine and phenobarbitone.
2. It is useful to treat drug poisoning e.g. morphine with naloxone
3. It guides to avoid drug combinations with reduced drug efficacy such a as penicillin and tetracycline combination

Certain drugs do not act through any of the mechanisms already mentioned, they are categorized as miscellaneous. These include:

1. Colchicines, vinca alkaloids
2. Ionizing radiation
3. Levamisole
4. Immunosuppressive:-  Cyclosporine
5. Therapeutic antibodies

1. Colchicines

Colchicines are used in the treatment of acute gout. The symptoms of gout are aggravated by the migration of leukocytes causing phagocytosis of uric acid crystals producing lactic acidosis leading to more inflammation and the cycle continues.  Colchicines binds tubulin of microtubules and prevents the migration of leukocytes.

Vinca alkaloids

Vinca alkaloids are used in cancer chemotherapy. They too bind tubulin of microtubules of cancer cells, thus blocking mitosis.

2. Ionizing radiations

Ionizing radiations are used in cancer chemotherapy.

3. Levamisole

Levamisole is anthelmintic used to expel worms and parasites to treat worm infestation. They also cause stimulation of the immune system. When using immunosuppressive drugs, these are taken as immunostimulant drugs.

4. Immunosuppressive drugs

Immunnosuppressive drugs act by binding cytosolic protein aminophilin and are used in transplantation.

5. Therapeutic antibodies

Therapeutic antibodies are used for isolation of cytokines which are responsible for inflammation.

In drug channel interaction, drug interfere with the flow of ions through the channels specific for these ions. These include the Na+, K+,Ca++ and Cl- channels. Examples include:

1. Sodium Channels:-      Quindine Procainamide, Local anesthetics
2. Calcium channels:-      Nifedipine, Verapamil, Diltiazem
3. Potassium Channels:-   Amiodarone, sulfonylureas
4. Chloride Channels:-     Benzodiazepines

1. Sodium Channels

Sodium channel drugs are used in cardiac arrhythmias and act by blocking the sodium channels. These include the local anesthetics which produce anesthesia in a localized area. Thus depolarization does not take place and there is no nerve conduction in that localized area.

2. Calcium channels

Calcium channel drugs are used in the treatment of hypertension and arrhythmias. They block the voltage gated calcium channels and release the vascular stiffness.

3. Potassium channels

Potassium channel drugs include amiodarone used in arrhythmias and block potassium channels. Thus there is a prolonged refractory period. Sulfonylureas are antidiabetic and block the ADP mediated potassium channels in the beta cells of pancreas.

4. Chloride channels

Chloride channel  drugs include benzodiazepines which produce sedation, used in epilepsy and are muscle relaxants. They increase the entry of chloride ions through the chloride channels causing hyper polarization.

Drug enzyme interaction is similar to drug receptor interactions. The drugs resemble the natural substrates, bind enzymes and cause change in their activity. This may take place by:

1. Activation of enzymes
2. Inhibition of enzymes

In therapeutic drugs causing inhibition on enzymes are generally used. This combination of drugs with the enzyme may be:

1. Competitive
2. Non competitive

Non competitive response is irreversible until new enzyme is generated.

Examples of Competitive Inhibition

1. ACE inhibitors e.g., captopril
2. Carbidopa——-Levodopa
3. Ethanol———-Methanol
4. Reversible anticholinestrases e.g., Neostigmine, physostigmine
5. Disulfiram——Alcohol
6. Allopurinol

1. ACE inhibitors(angiotensin converting enzyme inhibitors)

ACE inhibitors convert angiotensin I into angiotensin II, which is a potent vasoconstrictor. ACE inhibitors are used in the treatment of hypertension.

2. Levo dopa

Levo dopa is metabolized by dopa decarboxylase in the periphery. Carbidopa competes with levo dopa for the dopa decarboxylase enzyme. Thus peripheral metabolism of levo dopa is decreased, more levo dopa enters brain producing more efficacy.

3. Ethanol

Ethanol (alcohol) undergoes metabolism in body in two steps:

a. Ethanol is converted into acetaldehyde by alcohol dehydrogenase

b. Acetaldehyde is converted into water and carbon dioxide by aldehdyde dehydrogenase.

4.    Neostigmine

Neostigmine acts as a reversible acetylcholine esterase inhibitor. Thus in treatment of myasthenia gravis, acetyl choline levels are reversibly increased in the NMJ.

5. Disulfiram

Disulfiram is used in alcohol aversion therapy. It inhibits aldehyde dehydrogenase enzyme. When patient takes alcohol, increase in plasma levels of acetaldehyde cause bad symptoms like nausea, vomiting and flushing.

6. Allopurinol

Allopurinol is used in treatment of gout. Xanthine oxidase is inhibited which converts xanthine and hypoxanthine into uric acid.

Non Competitive Inhibition

The effects of non competitive inhibition are prolonged. These include:

1. Irreversible anticholinestrases e.g., Organophosphate compounds
2. Aspirin
3. MAO Inhibitors e.g., Iproniazid, Phenelzine
4. Proton Pump Inhibitors e.g., Omeprazole, Esomeprazole

1. Irreversible anticholinestrases

These include the insecticides and the war gases. These are toxic compounds which can be absorbed through the skin.

2. Aspirin

Aspirin is an analgesic used in headache, it inhibits cyclooxygenase enzyme in the platelets. It inhibits the synthesis of prostaglandins especially thromboxane A2. Life of platelets is only seven days. On maintenance therapy, aspirin is taken in low doses by cardiac patients.

3. Monoamine oxidase inhibitors

These are used to treat depression. They inhibit the monoamino oxidase enzyme which breaks down catecholamines. Thus decreased levels of noradrenalin and serotonin are coped by MAO inhibitors and increased levels are achieved.

4. Proton pump inhibitors

Proton pump inhibitors inhibit the hydrogen potassium ATPase in parietal cells of stomach, thus inhibit HCl secretion.

Receptor:

Macromolecules protein in nature which are target sites for drugs. Most drugs have to bind receptors to produce effects. Receptors are located mostly on the cell membrane but certain intracellular receptors are found as well.

There are three forms of binding to receptors:

1. Agonists
2. Antagonists
3. Partial agonists

Ligands

Ligands are the endogenous substances, molecules or compounds which bind with receptors present in the body e.g. acetyl choline, adrenaline, noradrenalin, neurotransmitters like glutamate, aspartate and GABA. They produce various effects and interfere with the flow of ions through channels called ligand gated channels. Their action may:

1. Resemble with natural ligand
2. Block the natural ligand

Agonists

Agonists are the drugs which when bind receptors, cause activation of receptors. They have the capacity to produce chain reactions in the receptors which ultimately bring about the effects. Agonists have two properties:

1. Affinity for receptor
2. Capability to produce chain reactions in the cells having capability of intrinsic activity or efficacy

Coupling

Transduction process between occupancy of the receptor by agonist and response to occur is called coupling. Most agonists when bind to receptors cause activation. Most of them alter the second messenger systems in the cells.

There are three second messenger systems:

1. Cyclic AMP
2. Cyclic GMP
3. Calcium and phosphoinositol second messenger system

The levels of these second messenger systems may increase or decrease. This may occur in three steps:

1. Drug binds receptor
2. Stimulation of g-regulatory protein occurs. G-regulatory protein exists in two forms; GS (stimulatory g-protein) and GI (inhibitory g-protein).
3. This causes change in the effector element-enzyme or ionic channel depending on GS or GI.

Drug Receptor Interactions

cAMP Second Messenger System

Beta 1, beta 2,alpha 2, and dopamine 1 are the receptors associated with cAMP second messenger system.

Ligands include ACTH, catecholamines (beta adrenoreceptors), hCG, FSH, glucagon, histamine (H2 receptors), LH, MSH, PTH, serotonin, etc.

Calcium and Phospho-inositol system

Muscarinic and alpha 1 receptors are associated with calcium phospho-inositol system. Ligands include acetylcholine (muscaranic receptors), angiotensin, serotonin, vasopressin (V1 receptors), and catecholamines (alpha 1 adrenoreceptors).

Mechanism of Action of Nitrates

Types of Receptors:

There are four main types of receptors:

	Type 1Ligand gated ion channels	Type 2G-protein coupled receptors	Type 3Kinase linked receptors	Type 4Nuclear receptors
Location	Membrane	Membrane	Membrane	Intracellular
Effectors	Ion channel	Channel or enzyme	Enzyme	Gene transcription
Coupling	Direct	G-protein	Direct	Via DNA
Examples	Nicotinic acetylcholine receptor (nAchR), GABA type A	Muscarinic acetylcholine receptor (mAchR), adrenoceptors	Insulin, growth factor, cytokine receptors	Steroid, thyroid hormone receptors
Structure	Oligomeric assembly of subunits surrounding central pore	Monomeric (occasionally dimeric) structure comprising seven transmembrane helices	Single transmembrane helix linking extracellular receptor domain to intracellular kinase domain	Monomeric structure with separate receptor and DNA binding domains

When drug binds the receptor, activation occurs, and the response gradually increases until it reaches the peak, then the response decreases, although agonist still binds. This is due to desensitization of receptors, which might be overcome by removing the agonists from the receptor. Example includes suxamethonium (succinyl choline), which produces relaxation of skeletal muscles by:

1. Activation of nicotinic receptors
2. Desensitization of receptors in the neuromuscular junction

The reason for desensitization is not clear. In beta blockers (which act by cAMP), ultimately phosphorylation of proteins and accumulation of phosphosilines occurs, which increases the binding of beta receptors with proteins, known as beta arrestin. This beta arrestin interferes with the activity, ultimately leading to inhibition of adenyl cyclase enzyme.

The binding of drug with receptor may by of two types:

1. Reversible binding
2. Irreversible binding

In reversible binding, the bond between the drug and receptor is very weak ionic, hydrogen or van der wall. This the effect is short lived.

In irreversible binding, very strong covalent bonds are present, which prolongs the effects of drug. The effect continues until the drug is excreted or new receptor is generated.

Prolong contact of tissues with the agonists results in decreased number of receptors in the tissues called down regulation of receptors. Example includes the patients suffering from bronchial asthma, in whom by prolong usage of beta agonists down regulation occurs. This the effect is reduced.

Spare Receptors

Sometimes it is seen, especially in isolated tissues, that when various amounts of drugs are added e.g. when in intestines of rabbits acetyl choline is added, this may lead to maximum effect. Only one percent of receptors might be occupied but maximum response might be seen. This is due to the vast reserve. There are spare receptors, only very small amounts of drugs are required for maximum effect.

Antagonists:

Binding of drug with receptor is the same. Most of the drugs binding receptors resemble the agonists but they cannot activate the receptors, and also prevent agonist binding. Thus opposite effect occurs in case of agonists and antagonists. They have two properties:

1. Affinity
2. Do not have efficacy or intrinsic activity

Examples include atropine, which is antagonist of acetyl choline. Propanolol is antagonist of beta receptors.

The binding of antagonist with receptor is of two types:

1. Reversible binding
2. Irreversible binding

Reversible binding is also known as competitive antagonism. E.g. atropine.

Non competitive antagonism occurs when binding effect of antagonist is prolonged until drug is excreted or new receptor is generated. Example includes phenoxy benzamine, which non-competitively blocks action of catecholamines at beta receptors. Second generation H1 histamines are also non-competitive blockers.

Prolonged contact of tissues with the antagonists results in up regulation of receptors or increase in the number of receptors in the tissues. Example includes patients suffering from arrhythmias or angina taking beta blockers, if we abruptly withdraw them, there will be reversing of the arrhythmia and angina. Up regulation of catecholamines occurs which worsens the conditions.

Partial Antagonists

Partial antagonists have intermediate levels of efficacy. They bind with the receptors but have very small intrinsic activity and efficacy. It can be seen that even on 100 percent occupation of the receptors, the response is sub maximal. Examples include beta blockers like pindolol and oxpranolol. They have ISA property (intrinsic sympathomimetic property) and are used in patients suffering from diabetes mellitus, peripheral vascular diseases and bronchial asthma.

Inverse Agonists

When inverse agonists bind receptors, they cause activation of receptors but produce effect opposite to the agonists. Examples include benzodiazepines used as sedative hypnotics. They produce sedation, relieve anxiety and relaxation of muscles. When beta carbolines are administered, they bind benzodiazepines receptors causing the activation of receptors, producing stimulation, increase in tone, anxiety and convulsions.

Drugs having agonist effect at receptors have positive efficacy.

Drugs having inverse agonist effect at receptors have negative efficacy.

Drugs having antagonist effect at receptors have zero efficacy.

In chemical mechanisms, drugs act by producing chemical reactions in the body. These include:

1. Chemically acting antacids– NaHCO₃
2. Chelating agents– Dimercaprol, penicillamine, desferrioxamine
3. Pralidoxime

1. Chemically acting antacids

Chemically acting antacids react chemically with HCl of stomach, causing neutralization. Sodium bicarbonate chemically binds HCl forming NaCl and water.

2. Chelating agents

Chelating agents are the drugs used to treat poisoning with various metals. They incorporate or chelate  metal ions into inner ring structure and in this way inactivate or neutralize the effects of metals.

3. Pralidoxime

Pralidoxime is a choline esterase reactivator. Poisoning of drugs like acetyl choline esterase inhibitors or organophosphate poisoning (insecticides, war gases) irreversible cause inactivation of acetyl choline esterase enzyme. This drug reacts chemically with phosphate of organophosphate compounds causing dephosphorylation. Thus acetyl choline esterase is released