ANTICONVULSANT DRUGS

Anti-convulsant drugs

Anti-convulsants or anti-epileptic drugs are used to depress CNS in case of convulsive and seizure disorders (convulsion and seizure are pathological signs that are triggered by excessive inappropriate stimulation of spinal cord and brain respectively). Epilepsy is a complex syndrome of sudden and recurrent seizures that arise as a result of synchronous discharge of cerebral neurons in particular region of CNS which is referred to as primary focus (that may or may not be characterized by anatomical defect). The nature of resultant signs depend upon the cortical portion involved in the course of action. Involvement of motor cortex leads to convulsions (un-controlled, irregular movements) whereas visual (related to vision), auditory (concerned with hearing) or olfactory (smell related) hallucinations reflect the stimulation of parietal or occipital cortex. Normal CNS activity is maintained through the coordinated execution of excitation (performed by the release and receptor occupancy of excitatory neurotransmitters like ACh, Norepinephrine, Serotonin, Aspartate and Glutamate) and inhibition (involving inhibitory neurotransmitters like GABA, Glycine and Dopamine).  Domination of inhibitory or excitatory mechanism (caused by pharmacological or pathological intervention) is manifested as CNS depression (including sedation, hypnosis. narcosis, anesthesia) and CNS stimulation (characterized by convulsions, seizures) respectively.

Pathophysiology of Epileptic disorders: Any of the following mechanisms can be implicated in the occurrence of Epilepsy.

1.     Enhanced availability of excitatory neurotransmitters (due to overproduction, increased release or improper metabolism/uptake)

2.     Diminished accessibility of inhibitory neurotransmitters (due to underproduction, lesser release or enhanced metabolism/uptake)

3.     Altered function of neuronal membrane due to impaired activity of Na⁺-K⁺-ATP_ase pump or distorted permeability (resulting from hypoxia, inflammation, trauma)

4.     Change in extra-cellular K⁺ and Ca⁺² concentration (seizure is associated with rise in K⁺ level and decline in Ca⁺² concentration)

Types of Epilepsy: Epilepsy is divided into following types on the basis of etiology.

Primary Epilepsy: It is caused by inherited anatomical defects of CNS and requires life-long therapy with anti-convulsant drugs.

Secondary Epilepsy: The underlying cause in this type of Epilepsy may be neoplasia (brain tumor), head injury, hypoglycemia, meningeal infection or abrupt alcohol withdrawl.

Classification of Epilepsy on the basis of signs and symptoms

1. Generalized seizures: It is characterized by the loss of consciousness and involvement of both cerebral hemispheres (there is no specific primary focus) and is further subdivided into following categories.

(a) Tonic-clonic seizures (Grand-mal Epilepsy): It is the common type of Epilepsy seen in humans and dogs. It is manifested by the rigidity of extremities followed by jerky movements for several minutes.

(b)  Absence seizures (Petit-mal Epilepsy): It results in momentary loss of consciousness associated with staring, jerking of eyelids and lack of abnormal motor activity.

(c) Myoclonic seizures: It is a brief shock like condition that involves the muscles of limbs/extremities or entire body and no treatment is anticipated for dogs suffering from this type of seizures.

(d) Febrile seizures: This type of Epilepsy is caused by intense fever in children (most common during 3 months to 5 years of age) and is rarely treated as it never leads to neurological damage, cognitive impairment (loss of memory and learning ability) or death.

(e) Status epilepticus: It is a state of frequent or prolonged seizures that involves the appearance of subsequent seizure prior to recovery from the previous one. This can lead to extreme exhaustion, hyperpyrexia and even death.

2. Partial seizures: Consciousness is preserved/retained during this type of seizures. It consists of the following subtypes.

(a) Simple partial seizures: It gives rise to localized sensory or motor disturbances.

(b) Complex partial seizures (Temporal lobe Epilepsy): Consciousness is altered in this case and primary focus is present in temporal lobe. Patient exhibits confused behavior and purposeless movements.

Anti-epileptic drugs are divided into two categories.

1. Primary anti-epileptic drugs: These are the main agents which are specific for the condition.

Phenytoin: It selectively blocks Na⁺ channels and thus interferes with the improper generation and propagation of action potential. Gingival hyperplasia (hyperplasia of gums that can disturb the normal pattern of dental growth) and fetal hydantoin syndrome (characterized by cleft-lip, cleft-palate and congenital heart defets) are common adverse effects reported with the inadequate administration of Phenytoin.

Carbamazepine: Its mode of action is similar to that of Phenytoin. It has the property of auto-induction/self-induction (it stimulates the activity of microsomal enzymes responsible for its own metabolism).

Valproic acid: It is considered to be a broad-spectrum anti-convulsant drug (can be used to treat all types of seizures). In addition to the blockage of Na⁺ channels, it also enhances GABA-mediated inhibitory neurotransmission. Being a hepatotoxic agent, it can lead to inhibition of microsomal enzymes concerned with the biotransformation of most drugs.

2. Adjunct anti-epileptic drugs: These are meant for add-on therapy (combined with primary anti-epileptic drugs to provide better relief).

Felbamate: It blocks Na⁺ channels and NMDA (N-methyl D-aspartate) receptors.

Gabapentin: Although it is an analogue of GABA but it has no action over GABA receptors. It is responsible for the blockage of Ca⁺ channels.

Lamotrigine: It blocks both Na⁺ as well as Ca⁺ channels. It has the potential to cause life-threatening rashes (dermatitis) that are particularly harmful for patients less than 16 years of age.

Drugs modifying abnormal behavior

Veterinary ethology (branch of veterinary sciences that deals with the study of animal behavior in their natural habitat) is relatively a new field of study and the use of drugs to treat behavioral disorders of animals is still uncommon. Behavior is considered as abnormal if it affects owner, other animals or humans in a negative manner. However all behaviors are not physically harmful to other animals or humans.

Classification and treatment of behavioral disorders

1. Genetic-based behavioral problems: These include physiological malfunctions attributed to congenital or inherited defects. For example polydipsia (increased thirst) and polyuria (increased urination) associated with primary (congenital) diabetes insipidus (it results from congenital deficiency of ADH).

2. Developmental and age-related behavioral problems: Senility (old age) predispose the animals to uncontrolled urination/defecation while infantality (young age) deprive them of proper congnitive ability.

3. Instinctive (specie specific) behavioral problems: Coprophagia in rabbits is a common example of this category.

4. Disease-related behavioral problems: Hydrophobia, drooling of saliva from the mouth, self-mutilation (biting) and excessive barking are commonly observed in dogs suffering from rabies.

5. Adaptation-related behavioral problems: Newly acquired pets may exhibit destructive behavior (damaging the property and attempting to escape through the holes of fences), excessive vocalization (such as barking), panic reactions (acting wildly and damaging themselves) or elimination behavior (urinating and defecating at unacceptable sites).

6. Fear and phobias: Some animals get scared/frightened from thunderstorm, gun shots and loud noise such as that produced by auto-mobiles.

7. Displaced/redirected behaviors: It is the appearance of normal reaction on wrong stimulus/object. For instance a dog chases vehicles or bicycle if prey is not found and a male animal displays couplatory attitude towards inanimate objects if a female is not available nearby.

Many of the above mentioned behavioral disorders (except congenital, developmental and instinctive behavioral disorders) can be non-specifically treated with sedatives or tranquilizers to provide transient symptomatic relief.

8. Schizophrenia: The term schizophrenia is Greek in origin, and in the Greek meant"split mind". It is a psychotic (mental) disorder that arises as a result of inherent brain dysfunction and is characterized by delusions, hallucinations, anhedonia (inability to feel pleasure at normally pleasurable things/occasions), apathy, impaired attention and thinking or speech disturbances. It affects men and women with equal frequency. People suffering from schizophrenia may have the following symptoms:

• Delusions, false personal beliefs held with conviction in spite of reason or evidence to the contrary, not explained by that person's cultural context.
• Hallucinations, perceptions (can be sound, sight, touch, smell, or taste) that occur in the absence of an actual external stimulus (Auditory hallucinations, those of voice or other sounds, are the most common type of hallucinations in schizophrenia.)
• Disorganized thoughts, behaviors and speech.
• Catatonic behavior, in which the affected person's body may be rigid and the person may become unresponsive.

Neuroleptics or Antipsychotics are drugs that are used to treat patients suffering from schizophrenia or other psychotic (mental) disorders.

(a) Typical Neuroleptics (D₂ receptor antagonists): These are subdivided into following two classes.

·         Phenothiazine derivatives (basically used as tranquilizers and anti-emetics) like Chlorpromazine (Largectil) and Acepromazine (Sedastress).

·         Butyrophenone derivatives (also used as anti-emetics) like Droperidol and Haloperidol.

(b) Atypical Neuroleptics (D₂ as well as 5HT₂ receptor antagonists): Resperidone and Clozapine are common agents belonging to this category. Tardive dyskinesia [an involuntary movement disorder involving tongue (fly catching stance) and lateral movement of the jaws] is a frequent side effect associated with Resperidone.

9. Depression: It is a mood disorder that is manifested by intense sadness, hoplessness, frustration/desperation/disappointment, variation in sleep and appetite pattern and suicidal tendencies. Separation or death of a partner or owner, disease or surgical procedures can cause depression in pet animals.

Biogenic amine theory: It states that depression is caused by the deficiency of mono-amines (particularly Serotonin and Norepinephrine) at certain key sites in the brain whereas mania occurs as a result of overproduction of these substances.

Antidepressants are unable to cause CNS stimulation if used in normal/healthy individuals.

Antidepressant drugs are classified into following five groups.

       I.      Selective Serotonin re-uptake inhibitors (SSRI_S): As indicated by their name these agents selectively block the re-uptake of Serotonin and hence indirectly enhance its availability for repeated receptor occupancy. These drugs constitute the mainstay of treatment for patients suffering from depression. Paroxetine (Paraxyl) and Sertraline are common members of this class. In addition to depression these drugs are also administered to relieve Obsessive compulsive disorder (OCD), panic disorder, pre-menstrual dysphoric disorder (a condition marked by severe depression symptoms, irritability, fatigue, sadness or hopelessness, sleep disturbances, disinterest in daily activities and relationships and tension before menstruation) and bulimia nervosa (also called hyperphagia or binge-purge syndrome, a habitual disturbance in eating behavior mostly affecting young women of normal weight, characterized by frequent episodes of grossly excessive food intake followed by self-induced vomiting to avert weight gain). Frequently reported adverse effects linked with the inadequate use of SSRI_S include sedation (sleep disorder) and sexual dysfunction [impotence and delayed ejaculation in males while anorgasmia (absence of orgasm; inability to attain sexual climax/peak despite sufficient stimulation that can lead to sexual frustration) in females]. These drugs are contraindicated in children and teenagers due to the risk of aggravating suicidal thoughts.

    II.      Serotonin-Norepinephrine re-uptake inhibitors: These agents block the re-uptake of Serotonin as well as Norepinephrine and thus improve their availability at respective receptor sites. Venlafaxine and Duloxetine are important members of this category. Nausea, dizziness and sexual dysfunction are probable undesirable effects caused by these agents.

 III.      Atypical Antidepressants: These agents are devoid of a well-defined mode of action and sexual dysfunction (a common adverse effect of almost all Antidepressants). Bupropion (also used for smoking cessation/stoppage) and Mirtazapine are common drugs of this group.

 IV.      Tricyclic Antidepressants (TCA_S): In addition to the blockage of Serotonin and Norepinephrine re-uptake, these agents also antagonize Muscarinic, Histaminic and Adrenergic receptors. Imipramine and Clomipramine are important drugs included in this class. Imipramine can cause the contraction of internal sphincter of urinary bladder and therefore it is also used to treat enuresis (uncontrolled nocturnal urination also known as bed wetting) in children less than 6 years of age. Besides depression TCA_S are also utilized to alleviate narcolepsy (uncontrolled episodes of sleepiness during day time), cataplexy (loss of muscle tone as a result of narcolepsy), urinary incontinence [inability to retain urine in urinary bladder (probably caused by injury to sacral spinal nerves that are concerned with the regulation of inhibitory action over detrusor muscles of urinary bladder) leading to frequent drop wise flow of urine that is referred to as dribbling] and pruritis (due to presence of antihistaminic activity) in livestock. Antimuscarinic effects (xerostomia, blurred vision, mydriasis, tachycardia, urine retention etc.), antiadrenergic signs (such as orthostatic/postural hypotenstion), antihistaminic responses (like drowsiness and sedation) and sexual dysfunction are possible adverse effects associated with these drugs.

    V.      Mono-amine oxidase (MAO) inhibitors: Tranylcypromine and Selegiline (Deprenyl) are inhibitors of MAO enzyme (which is responsible to carry out the metabolism/break down of biogenic amines) and thus lead to extension of their duration of action at receptor sites. However their administration is subjected to complicated dietary restrictions such as avoidance of food items that are rich in tyramine amino acid (like cheese, chicken liver, beer and wine etc.). MAO inhibition prolongs the duration of action of tyramine (due to failure of metabolism) and excessive accumulation of tyramine leads to the release of high amount of stored catecholamines from nerve terminals which can result in hypertension, tachycardia and headache. In pituitary dependent hyper-adrenocorticism (PDH, also known as Cushing disease or old dog dementia), Selegiline maintains the levels of dopamine and corticotrophin releasing hormone (CRH) to be in balance inside hypothalamus, thereby reducing the amount of adreno-corticotrophic hormone (ACTH). Normally in the hypothalamus, CRH acts to stimulate the production of ACTH in the pituitary, and dopamine acts to inhibit the release of ACTH. But as dogs get older, there is progressive decline in dopamine synthesis that contributes to the development of PDH and associated cognitive dysfunction (known as “old dog dementia”).

10. Mania: It is a completely opposite behavior to depression and involves enthusiasm, rapid thought and speech pattern, extreme self-confidence and impaired judgment.

11. Bipolar disorder: It is a state of mental disturbance that is characterized by alternate episodes of both depression as well as mania. Bipolar disorder was called manic depression in the past, and that term is still used by some people. It is a psychiatric illness that causes major disruptions in lifestyle and health. Everyone has occasional highs and lows in their moods. But people with bipolar disorder have extreme mood swings. They can go from feeling very sad, despairing, helpless, worthless, and hopeless (depression) to feeling as if they are on top of the world, hyperactive, creative, and grandiose (mania). This disease is called bipolar disorder because the mood of a person with bipolar disorder can alternate between two completely opposite poles, euphoric happiness (happiness without any reason) and extreme sadness. Lithium [it inhibits the recycling of phosphotidyl inositol di phosphate (PIP₂) 2^nd messenger system] salts are orally given to treat mania and bipolar disorder but these are highly toxic and can cause polydipsia, polyuria and even diabetes insipidus.

12. Anxiety: It is a state of chronic depression, uneasiness, tension and fear from unknown sources. It leads to frequent tachycardia, diaphoresis (profused sweating) and trembling. Mild anxiety is not an alarming situation and requires no medical treatment but if the problem persists continuously then anxiolytic (anti-anxiety) drugs should be prescribed.

Anxiolytic drugs are classified into following groups.

(a) Benzodiazepines like Diazepam, Lorazepam and Clonazepam etc.

(b) Barbiturates like Phenobarbital, Pentobarbital and Amobarbital etc.

(c) Other drugs like Zaleplon and Zolpidem [it binds with benzodiazepine₁ (BZ₁) receptors but unlike other Benzodiazepines it lacks the property of muscle relaxation, anti-convulsion, serious withdrawal effects and appearance of tolerance (after excessive administration).

13. Obsessive compulsive disorder (OCD): Obsession means recurrent unwanted thoughts and compulsion means purposeless behavior/activities frequently performed in an attempt to get rid of obsessive thoughts (to achieve mental satisfaction). Obsessions are recurrent and persistent thoughts, impulses, or images that are intrusive and inappropriate. The thoughts cause severe anxiety or distress. The person tries to ignore or suppress the thoughts, impulses, or images, or to neutralize them with some other thought or action. The person recognizes that the obsessional thoughts, impulses, or images are a product of his or her own mind and are not based in reality. Compulsions are repetitive behaviors or mental acts that the person feels they must perform in response to an obsession, or according to rigid rules. Excessive skin picking (i.e., dermatillomania) or hair plucking (i.e., trichotillomania), nail biting (i.e., onychophagia) and unnecessarily collection of huge number of books (i.e., bibliomania) are all on the Obsessive-Compulsive Spectrum. Individuals with OCD are aware that their thoughts and behavior are not rational but they feel bound to comply with them to fend off feelings of panic. People might repeatedly wash their hands or clear their throats, making sure certain items are in a straight line, repeatedly check that their parked cars have been locked before leaving them, constantly organizing in a certain way, turn lights on and off, keep doors closed at all times. In addition to the anxiety and fear that typically accompanies OCD, some people may spend hours performing such tasks (i.e., compulsions) every day. In such situations it can be hard for the person to fulfill their work, family, or social roles. In some cases, these behaviors can also cause adverse physical symptoms. For example, people who obsessively wash their hands with antibacterial soap and hot water to remove what they consider to be contamination can make their skin red and raw with dermatitis. English footballer, David Beckham has been outspoken regarding his struggle with OCD. He has told media that he has to count all of his clothes, and his magazines have to lie in a straight line. It is hypothesized that the serotonin receptors of OCD sufferers may be relatively understimulated. This suggestion is consistent with the observation that many OCD patients benefit from the use of selective serotonin reuptake inhibitors (SSRIs), a class of antidepressant medications that allow for more serotonin to be readily available to other nerve cells. Behavioral therapy or cognitive behavioral therapy and medications should be regarded as first-line treatments for OCD. The specific technique used in behavioral therapy/cognitive behavioral therapy (BT/CBT) is called exposure and ritual prevention (also known as "exposure and response prevention") or ERP; this involves gradually learning to tolerate the anxiety associated with not performing the ritual behavior. At first, for example, someone might touch something only very mildly "contaminated" (such as a tissue that has been touched by another tissue that has been touched by the end of a toothpick that has touched a book that came from a "contaminated" location, such as a school.) That is the "exposure". The "ritual prevention" is not washing. Another example might be leaving the house and checking the lock only once (exposure) without going back and checking again (ritual prevention). The person fairly quickly habituates to the anxiety-producing situation and discovers that their anxiety level has dropped considerably; they can then progress to touching something more "contaminated" or not checking the lock at all—again, without performing the ritual behavior of washing or checking. Medications as treatment include selective serotonin reuptake inhibitors (SSRIs) such as paroxetine, sertraline and the tricyclic antidepressants, in particular clomipramine. SSRIs prevent excess serotonin from being pumped back into the original neuron that released it. Instead, serotonin can then bind to the receptor sites of nearby neurons and send chemical messages or signals that can help to regulate the excessive anxiety and obsessive thoughts.

Chemotherapy

Chemotherapy is the branch of Pharmacology which deals with the use of chemicals/drugs (called chemotherapeutic agents like anti-bacterials, anti-fungals, anti-neoplastic and anti-virals etc.) that are selectively toxic to the foreign cells (pathogens) with minimal or no impact over the normal host cells.

Antimicrobials: These are substances having natural, semi-synthetic or synthetic origin and are effective against a wide range of micro-organisms (like bacteria, protozoa etc.). Antibacterials, antivirals and antiprotozoals are examples of antimicrobial drugs.

Antibacterials: Their origin may be natural, semi-synthetic or synthetic but their activity is only against bacteria.

Antibiotics: Their origin is always natural (from bacteria or fungi) or semi-synthetic but their activity may be against a wide range of micro-organisms (like bacteria, protozoa etc.).

Bacteriostatic: It is that antibacterial agent which inhibits the growth of susceptible bacteria e.g. Amphenicols, Macrolides and Lincosamides.

Bactericidal: It is that antibacterial agent which causes destruction/lysis of susceptible bacteria e.g. Penicillins, Cephalosporins and Quinolones.

Antimicrobial spectrum: It is the range of micro-organisms covered by a particular chemotherapeutic agent. It is of three types.

1.     Narrow spectrum: It is used for those antibacterial agents that are effective only against gram positive or gram negative bacteria. For example Erythromycin is effective against gram positive while Streptomycin covers only gram negative bacteria.

2.     Broad spectrum: Broad spectrum indicates the activity of concerned antibacterial against a wide range of bacteria, covering gram positive as well as gram negative, e.g. Oxytetracycline and Chloramphenicol.

3.     Extended spectrum: It is subdivided into two types. Extended gram positive spectrum indicates that respective agent is originally active against gram positive bacteria but it also covers sufficient number of gram negative bacteria (but not all) e.g. Amoxycillin. Extended gram negative spectrum shows that concerned drug is basically effective against gram negative but it also covers sufficient number of gram positive bacteria e.g. Nalidixic acid.

Sulphonamides

Sulphonamides are antimicrobial drugs of synthetic origin which are extensively used to treat human and veterinary infections. In 1935, a scientist named, Domagk found that Prontosil dye inhibited the growth of streptococcal bacteria in mice. Later on it was found that Prontosil contained Sulphanilamide and Domagk was awarded with Noble prize for his discovery. The basic structure of Sulphonamides resembles to that of Para amino benzoic acid (PABA) that is used by certain micro-organisms to synthesize Folic acid (an integral component of vitamin B complex). Utilization of Sulphonamide (instead of PABA) depletes the micro-organisms of Folic acid (hence Sulphonamides are said to inhibit the metabolic pathway of micro-organisms especially bacteria). Metabolism of Sulphonamides occurs through acetylation. But this acetylation prolongs their half life as their solubility is diminished (and they get precipitated in tissues). Therefore Sulpha drugs are comparatively safe in slow acetylators and carry a risk of toxicity in fast acetylator species.

Mechanism of action of Sulphonamides PABA + Pteridine Dihydropteroate synthase (inhibited by Sulpha drugs) Dihydropteroic acid                                             Dihydro folate reductase                                                                    Glutamic acid (inhibited by Diaminopyrimidines)                       Dihydro folic acid Tetra hydro folate reductase                Tetrahydro folic acid Thymine            Purines           Methionine         Glycine                                                                         DNA, RNA             DNA                       Proteins

Classification of Sulphonamides

1. Locally acting Sulphonamides: These are further classified into two categories.

(a) Topically acting Sulphonamides (e.g. Sulphacetamide is used for eye infections): These are topically administered to treat dermal infections caused by susceptible micro-organisms.

(b) Gut active Sulphonamides (e.g. Sulphaguinidine): They are poorly absorbed from GIT and thus they are effective for the treatment of enteritis and diarrhea associated with bacterial or protozoal infection (like coccidiosis, colibacilosis etc.).

2. Systemically acting Sulphonamides: They are meant for systemic action and are classified on the basis of their duration of action.

Category	Duration of action	Example
Short acting Sulphonamides	< 12 hours	Sulphanilamide Sulphadiazine
Intermediate acting Sulphonamides	12-24 hours	Sulphadimidine Sulphamethoxazole
Long acting Sulphonamides	24-48 hours	Sulphaethoxypyridazine Sulphamethoxypyridazine
Ultra long acting Sulphonamides	> 48 hours	Sulphadoxine

3. Potentiated Sulpha drugs: Di-aminopyrimidines and Sulphonamides block consecutive steps that are crucial for the metabolism of bacteria and if used in combination they show potentiated action.

Brand names of commonly used Potentiated Sulphonamides

Combination	Trade name (s)
Trimethoprim + Sulphamethoxazole = (Co-trimoxazole)	Septran
Trimethoprim + Sulphadiazine = (Co-trimazine)	Tribrissin, Triben
Pyrimethamine + Sulphadoxine	Fansidar (Anti-malarial)

Antimicrobial spectrum of Sulpha drugs: All Sulphonamides are bacteriostatic with broad spectrum antimicrobial activity (only against rapidly multiplying bacteria, those in lag phase are comparatively resistant to Sulphonamides).

Micro-organisms susceptible to Sulphonamides
Gram positive bacteria	Streptococcus, Hemophilus, Bacillus, Actinobacillus
Gram negative bacteria	Enterobacteracae family
Protozoa	Toxoplasma, Eimeria, Plasmodium
Micro-organisms resistant to Sulphonamides
Leptospira, Mycoplasma,  Acid fast bacteria (e.g. Mycobacterium), Pseudomonas, Rickettsiae and Spirocheates

Antagonists of Sulpha drugs: Availability of PABA, Folic acid, thymine, purine or glycine will inhibit the utilization of Sulphonamides by bacteria therefore their concomitant administration should be avoided. Pus and tissue debris also contains these substances (especially PABA) thus Sulpha drugs may prove ineffective if used topically for pyogenic infections. Co-administration of Procaine (precursor of PABA that is used as a local anesthetic) with Sulpha drugs is also contraindicated.

Adverse effects: The toxicity profile of Sulphonamides is manifested in terms of acute or chronic toxicity.

Acute toxicity:

• Crystalluria: Acidic urine causes the precipitation of Sulphonamides in renal tubules of glomerulus (resulting in obstruction of renal tubules) leading to crystalluria that is characterized by hematuria. Carnivores (having acidic P_H of urine) are more vulnerable than omnivores and herbivores. Administration of urinary alkalizer (like sodium bi carbonate), improving the hydration status of patient or using a combination of two or more Sulpha drugs (in this case each Sulphonamide will provide its individual solubility and the overall solubility of the mixture will be enhanced, chances of precipitation will be abolished) can help to avoid this problem.

• Idiosyncratic hemolytic anemia: Individuals with congenital deficiency of glucose-6 phosphate dehydrogenase are unable to produce sufficient level of glutathion (anti-oxidant in RBC_S) therefore they are subjected to hemolytic anemia caused by reactive oxygen species (generated by oxidizing drugs like Sulphonamides, Paracetamol and Primaquin etc.). This may occur within 2-7 days of therapy.

• Hypersensitivity reactions: Allergic skin reactions (such as expoliative dermatitis or cutaneous eruption) are frequent complications of Sulpha therapy. Sulphadiazine containing preparations may promote a reversible immune-mediated polyarthritis in Doberman breed of dogs.

Chronic toxicity:

• Hypoprothrombinemia: Prolonged administration of certain Sulphonamides (like Sulphaquinoxaline) may lead to vitamin K deficiency due to inhibition of vitamin K epoxide reductase enzyme (this commonly occurs in poultry). This results in hypoprothrombinemia and deficiency of vitamin K dependent clotting factors leading to prolongation of bleeding and clotting times.
• Keratoconjuctivitis sicca (KCS):  Some Sulpha drugs possess nitrogen-containing pyridine ring (instead of benzene ring) that is responsible for lacrymotoxic effect (which causes hypolacrimation/dryness of eyes) on lachrymal acinar cells of eyes.