Drugs That Relieve Pain And Inflammation

ANTIMAL ARIALS PRIMAQUINE: •Mode of action: not completely understood, but the intermediates formed causes hemolysis of infected rbc & meth-hemoglobin w/c is toxic to the protozoa •Indication: P. vivax, p. ovale •Adverse effects: hemolytic anemia •Undesirable side effect: n/v, abdominal pain CHLOR OQUINE: •Mode of action: damage mediated by accumulated heme, alkalinization of food vacuole, decreased DNA synthesis •Indication: blood schizontocide. P. falciparum infection •Adverse effects: hepatotoxic •Undesirable side effects: Gastrointestinal upset, pruritus, headache QUININE: •Mode of action: inhibits DNA synthesis •Indication: blood schizontocide •Adverse effects: anemia MEFL OQUINE: •Mode of action: unknown •Indication: P. falciparum •Adverse effects: CNS symptoms PYRIMETH AMINE: •Mode of action: inhibits plasmodial dihydrofolate reductase •Indication: P. falciparum, P. malariae, T. gondii •Adverse effects: megaloblastic anemia AR TEMISININS: •Indication: for multidrug resistant P. falciparum.

Antipar asitic Ag ents

Mebendazole and Albendazole (Benzimidazoles) •MOA: inhibit microtubule polymerization by binding to beta-tubulin → immobilization → death

Mebendazole and Albendazole (Benzimidazoles) Pharmacokinetics –

Mebendazole: poorly and erratically absorbed rapid first-pass hepatic metabolism (both of these cause low systemic bioavailability) *mebendazole is the active drug form and not its metabolites Mebendazole and Albendazole (Benzimidazoles) Pharmacokinetics – Albendazole: metabolized to albendazole sulfoxide which has potent antihelminthic activity

Mebendazole and Albendazole (Benzimidazoles)

•Indications: both drugs effective for Enterobius (pin worm), Ascaris ( ascaris lumbricoides), Trichiuris(whip worm), and hookworms (necatur americanus, ancylostoma doudenale) *albendazole is more effective against hydatid cysts Adverse Effects:

•allergic reactions •Alopecia •reversible neutropenia •agranulocytosis •hypospermia •teratogenic in experimental animals Contraindications pregnant patients children below 2 years old * Albendazole is contraindicated in hepatic cirrhosis Pyrantel pamoate MOA: depolarizing neuromuscular blocking agent releases acetylcholine and inhibits

cholinesterase induces marked, persistent activation of nicotinic receptors spastic paralysis of worms Pyrantel Pamoate Pharmacokinetics: poorly absorbed from the GIT (selective action on the GIT nematodes) Indications: hookworms pinworms Ascaris

*Ineffective against Trichiuris Drug interaction: pyrantel + piperazine = antagonism Contraindications: pregnancy children less than 2 years old

effective against Trichiuris

Oxantel pamoate

Oxantel-pyrantel combination (Quantrel) is available in a fixed dose of each drug Piperazine citrate MOA: blocks the response of Ascaris muscle to acetylcholine causes flaccid paralysis of Nematodes Piperazine Pharmacokinetics: absorbed rapidly from the GIT indications: Enterobius Ascaris Piperazine Contraindications:

pregnancy seizures renal disorders Levamisole (also an imidazole derivative) as efficacious as Piperazine also an immunomodulant Diethylcarbamazine citrate used mainly in lymphatic filariasis and loaisis Pharmacokinetics: readily absorbed in the GIT, skin, and conjunctiva widely distributed Adverse effects: nausea, vomiting, headache, drowsiness allergic reactions arise from the death of the filariae or microfilariae Precaution: adjust doses in renal failure Praziquantel

MOA: increases cell membrane permeability to calcium resulting in marked contraction, followed by paralysis of worm musculature Praziquantel Pharmacokinetics: rapidly and almost completely absorbed from the GIT penetrates the BBB first pass metabolism in liver

Praziquantel Adverse effects: most common – malaise, headache, dizziness, anorexia others – drowsiness, nausea, vomiting, abdominal pain, low grade fever, pruritus Contraindication: ocular cysticercosis children under 4 years old pregnant and lactating mothers Niclosamide MOA: inhibits oxidative phosphorylation Pharmacokinetics: minimally absorbed following oral administration Niclosamide Adverse effects: mild and transient nausea, vomiting, diarrhea, abdominal discomfort; Contraindications/precautions: consumption of alcohol children below 2 years old pregnancy Niridazole MOA: not established Pharmacokinetics: absorbed slowly peak serum concentration attained in 6 hours mainly excreted in the urine, some in feces Niridazole Adverse effects: GIT – nausea, vomiting, diarrhea, abdominal pain headache, dizziness myalgia hematologic and neuropsychiatric effect

DRUGS THA T RELIEV E PAIN AND INFLAMM ATION

•PAIN: Unpleasant sensation •PAIN EXPERIENCE: includes all the emotional sensations (attention, anxiety, fatigue, suggestion, & prior condition) for a particular person under a certain set of circumstances

•PAIN PERCEPTION: Or nociception, is the individuals awareness of the feeling or sensation of pain •PAIN THRESHOLD: it is the point at which the individual first acknowledges or interprets a sensation as being painful

•PAIN TOLERANCE: the individuals ability to endure the pain being experienced •ANALGESICS: drugs that relieve pain w/o producing loss of consciousness or reflex activity.

•WHA T CAUS ES P AIN? ???? ? •THEORIE S: –GATE CONTR OL THE OR Y OF P AIN: Melzak and W •pro poses th at stimulation of the skin evokes ne

all 1 965 rvous im pulses which are

then transmitted to the spin al cord –MELZAK S THE OR Y 1 996: he pro posed that a l arge wid esprea d network of neu rons exist s and consists of loo ps betwe en the th alamus and cortex and betwee n the cortex and the lim bic system (N EUROMA TRIX THEOR Y). This neu rosign ature output with a co nstant stream of input and varyin g patterns, pro duces th e fee lings of the b ody that constantly cha nges. •The gate control theo ry of pai n, put forward by Ronald Melzack and Patrick David Wall in 1962,[1] and again in 1965,[2] is the idea that the perception of physical pain is not a direct result of activation of nociceptors, but instead is modulated by interaction between different neurons, both pain-transmitting and non-pain-transmitting. The theory asserts that activation of nerves that do not transmit pain signals can interfere with signals from pain fibers and inhibit an individual's perception of pain. •NEURO

PHYSI OLO GICAL TRANSMIS SION OF PAIN

•Receptors/Pr imary Af ferent nociceptors: Naked or free ne rve endin gs –fou nd in the nerves to the skin, and to the d eep somatic and visceral

org ans, these maximal ly r espond to intense / p ainful stimuli, they ar e; •A-d elta fibers: smal l myel inated •C-Fib ers: unmye linated –A-beta fibers maximal ly r espond to light touch and movin g stimuli a nd is n ot associated with pain * Insensitive viscera- no pa in fibers: lung alveo li, live r pare nchyma I. Narcotics

OPIATE AGONISTS: •Derived from opium (poppy plant). Also called narcotic analgesic. •3 groups: Morphine- like derivatives, Meperidine-like derivatives, Methadone-like derivatives. •Actions: Combines with opiate receptors in the CNS, these drugs reduces stimuli from nerve endings thus reducing pain threshold & euphoria •Indications: Relieves acute & chronic moderate to severe pain- postoperative pain, renal & biliary colic, AMI & terminal CA •Adverse effects: tolerance, respiratory depression, orthostatic hypotension, cofusion/disorientation •Side-effects: sedation, constipation, n/v, urinary retention, blocks cough reflex •Drug interactions: Phenobarbital, phenytoin, rifampin, chlorpromazine •Drugs: codeine, hydromorphone, fentanyl, levorphanol, morphine, oxycodone, oxymorphone, alfentanyl, meperedine, methadone, tramadol OPIATE PARTIAL AGONISTS: •Action: These drugs can activate an opioid receptor to affect a submaximal response

•Ceiling effect: increasing the dose of these agents after the 1st week of use significantly increases the analgesia but also increases the side effects

•Indications: used for short-term relief (3weeks) of moderate to severe pain associated with, CA, burns, colic •Adverse effects: Hallucinations, sedation, clamminess, respiratory depression •Side effects: constipation, n/v, dizziness •Drug interactions: with CNS depressants: •Drugs: prophoxyphene, codeine OPIATE ANTAGONISTS NALMEFENE: •Actions: a pure opiate antagonist related to naloxone. It has longer duration of action than naloxone •Indication: treatment for respiratory depression caused by opiate overdose

•Adverse effects: apathy, depression •Side effects: n/v NALOXONE: •Action: binds with high affinity to opioid receptors but fail to activate a receptor mediated response. This is a pure opiate antagonist •Indication: Drug of choice for treating respiratory depression caused by opiate overdose •Adverse effects: depression, apathy •Side effects: n/v NALTREXONE: •Action: also a pure opioid antagonist. Can be given enterally & has longer duration of action •Indication: can be given in opiate dependent patients & in alcoholism •Adverse effects: liver damage •Side effects: n/v, headache, anorexia No nnarcotic

Analg esics

SALICYLATES •Action: anti-pyretic & anti-inflammatory. Blocks prostaglandin synthesis at the thermoregulator centers in the thalamus & at peripheral target tissues •Indications: myalgia, headache, RA, TIA, post-AMI •Adverse effects: Inhibits thromboxane A2- causing decreased platelet function (1 tab= 7-10 days platelets loose aggregation ability), Gastric bleeding, salicylism, Reye’s syndrome

•Side effects: n/v •Drug interactions: probenecid, warfarin, phenytoin, oral hypoglycemics, methotrexate, steroids, alcohol •Drug: aspirin, diflunsal, Na salicylate Non Ster oidal Anti Inflammatory Figure 2-12 Kumar p 37

Drugs

CYCLOOXYGENASE PATHWAY INHIBITORS: •Action: inhibits prostaglandin synthesis by inhibiting either the COX 1 arm or Cox 2 arm •types: (a.) Cox 1 inhibitors, (b.) Cox 2 inhibitors •Indications: OA, RA, acute pain •Adverse effects: renal toxicity, liver damage, bone marrow depression •Side effects: lesser GIT irritation, n/v •Drugs: COX 1: celecoxib

COX 2: Rofecoxib, valdecoxib

Anti-G out Medicatio

ns

IMMUNO SUPPR ESSIV E AG ENTS Vaccine and Sera

•Review Immunity •Immunization –Process of artificially stimulating active immunity by exposing the body to weakened or less toxic proteins associated with specific disease causing organisms.

•Vaccines –Comes from Latin word for small pox, vaccinia. –Are immunizations containing weakened or altered protein antigens that stimulate formation of antibodies against specific disease

•Toxoids –Are vaccine that are made from the toxins produced by microorganism Vaccines in the elimination of disease •The purpose of viral vaccine is to utilize the immune response of the host to prevent viral disease. •Vaccination is the administration of a vaccine to stimulate a protective immune response that will prevent disease in the vaccinated person if contact with the corresponding infectious agent occurs subsequently. •Thus vaccination, if successful, results in immunization: the vaccinated person has been rendered immune to disease caused by the infectious pathogen. •In practice, the terms “vaccination”and “immunization” are often used interchangeably.

•Highly effective method of preventing certain infectious diseases. •Prevention is better and more cost-effective than cure. •Generally very safe and serious adverse reactions are uncommon. •Routine immunization programmes protect most of the world’s children from a number of infectious diseases. •For travellers, offers the possibility of avoiding a number of dangerous diseases that may be encountered abroad. Killed-virus vaccines •Inactivated vaccine (killed-virus) are made by purifying viral preparations to a certain extent & then inactivating viral infectivity in a way that does minimal damage to the viral structural proteins

•Prepared from whole virions generally stimulate the development of circulating antibody against the coat proteins of the virus, confering some degree of resistance. Advantages •No reversion to virulence by the vaccine virus Disadvantage •Extreme care is required: no residual live virulent virus is present in the vaccine

•Immunity conferred is often brief & must be boosted •Parenteral administration: limited protection because of local resistance •Cell mediated response generally poor •Can induce hypersensitivity reaction Attenuated live-virus vaccines •Utilize virus mutants that antigenically overlap with wild-type virus but are restricted in some step in the pathogenesis of disease •The genetic basis is not known Advantage •Acting like the natural infections with regard to their effect on immunity.

•They multiply in the host & tend to stimulate longer lasting antibody production to induce a good cell-mediated response & to induce antibody production & resistance at the portal of entry Disadvantage •Risk of reversion to greater virulence

•Limited storage & shelf life •Interference by coinfection with a naturally occuring wild-type virus may inhibit replication of the vaccine virus & decrease its effectiveness. Vaccines for routine use •DIPHTHERIA Disease •caused by Corynebacterium diphtheriae. •Commonly affects the throat and may lead to obstruction of the airways and death. Exotoxininduced damage occurs to organs such as the heart. •Transmission is from person to person, through droplets and close physical contact, and is increased in overcrowded and poor socioeconomic conditions. Vaccin e •Usually given as “triple vaccine” – DTP (diphtheria/tetanus/pertussis or diphteria/tetanus/acellular pertussis). After the initial course of three doses, additional doses may be given as DT until 7 years of age, after which a vaccine with reduced diphtheria content

•(Td) is given. Since both tetanus toxoid (see below) and diphtheria toxoid can reasonably be given on a booster basis about every 10 years •acellular pertussis (TdaP) are being introduced in some country. TETANUS Disease •Acquired through environmental exposure to the spores of Clostridium tetani •Disease caused by the action of a potent neurotoxin (tetanospasmin) •Clinical symptoms are muscle spasms, initially of the muscles of mastication causing trismus or “lockjaw”, which results in a characteristic facial expression – risus sardonicus. •Trismus can be followed by sustained spasm of the back muscles (opisthotonus) and by spasms of other muscles. •Finally, mild external stimuli may trigger generalized, tetanic seizures, which contribute to the serious complications of tetanus (dysphagia, aspiration pneumonia) and lead to death unless intense supportive treatment is rapidly initiated. Vaccin e •Available as single toxoid (TT), combined with diphtheria toxoid (DT) or low-dose diphtheria toxoid (Td), and combined with diphtheria and pertussis vaccines (whole pertussis wP or acellular pertussis aP) (DTwP, DTaP, or TdaP). •In some countries, combination vaccines with Haemophilus influenzae type b and/or IPV exist. Vaccines containing DT are used for children under 7 years of age and dT-containing vaccines for those aged 7 years and over. •A childhood immunization schedule of 5 doses is recommended. The primary series of 3 doses of DTP (DTwP or DTaP) should be given in infancy, with a booster dose of a tetanus toxoid-containing vaccine ideally at age 4–7 years and another booster in adolescence, e.g. at age 12–15 years. • For adult travellers, an extra tetanus toxoid-containing dose will provide additional assurance of long-lasting, possibly lifelong, protection. •No booster is needed if the last dose of tetanus vaccine was given less than 5 (for dirty wounds) to 10 years (for clean wounds) previously. PERTUSSIS Disease •Pertussis (whooping cough) is a highly contagious acute bacterial disease involving the respiratory tract and caused by Bordetella pertussis. •It is transmitted by direct contact with airborne discharges from the respiratory mucous membranes of infected persons. •It causes a severe cough of several weeks’ duration with a characteristic whoop, often with cyanosis and vomiting. In young infants, the cough may be absent and disease may manifest with spells of apnoea. •most serious cases and fatalities are observed in early infancy •Major complications include pneumonia, encephalitis and malnutrition (due to repeated vomiting). •Vaccination is the most rational approach to pertussis control. Vaccin e

•Whole-cell (wP) and acellular (aP) pertussis vaccines provide excellent protection. •Three doses are required for initial protection. •Protection declines with time and probably lasts only a few years. •Booster dose administered 1–6 years after the primary series is warranted. •Only aP or dTaP vaccines are used for vaccination of older children and adults. HAEMO PHILUS INFLUENZAE

TYP E B

Disease •Haemophilus infl uenzae type b (Hib) is a common cause of bacterial pneumonia and meningitis and of a number of other serious and potentially life-threatening conditions, including epiglottitis, osteomyelitis, septic arthritis and sepsis in infants and older children. Vaccin e •All children who are not up to date with this vaccine should be offered it.

•Conjugate Hib vaccines have dramatically reduced the incidence of Hib meningitis in infants and of nasopharyngeal colonization by Hib. •Given as a combined preparation with DTP or poliomyelitis vaccine in routine immunization programmes, but is available as a single antigen preparation for use in children HEP ATIT IS B Vaccin e •Produced both from plasma and by recombinant DNA technology (usually in yeast) is available; the two types are equally safe and effective. •Three doses of vaccine constitute the complete series; the first two doses are usually given 1 month apart, with the third dose 1–12 months later. •Immunization provides protection for at least 15 years and, according to current scientific evidence, probably for life. •Because of the prolonged incubation period of hepatitis B, •The standard schedule of administration is three doses, given as follows: day 0; 1 month; 6–12 months.

•A rapid schedule of administration of monovalent hepatitis B vaccine has been proposed by the manufacturer as follows: day 0; 1 month; 2 months. An additional dose is given 6-12 months after the first dose. HUMAN P APILLOM AVIRUS •Human papillomavirus (HPV) is a family of viruses that are very common all over the world. Although most HPV infections cause no symptoms and are selflimited,persistent genital HPV infection can cause cervical cancer in women (as well as other types of anogenital cancers, head and neck cancers, and genital warts in both men and women). INFLUENZA •Influenza viruses constantly evolve, with rapid changes in their antigenic characteristics. •To be effective, influenza vaccines need to stimulate immunity to the principal strains of virus circulating at the time.

•The internationally available vaccines contain three inactivated viral strains, with the composition

being modified every 6 months to ensure protection against the strains prevailing in each influenza season. Since the antigenic changes in circulating influenza viruses occur very rapidly. •One dose is given i.m. for individuals over 9 years of age. Two doses at least 4 weeks apart for immunocompromised people and for children aged 6 months – 9 years; those aged 3–36 months should receive half the adult vaccines injections. •Mild local and/or systemic reactions are common. Vaccination is contraindicated in case of egg allergy. MEASL ES Disease •Highly contagious infection; before vaccines became available. •Affected most people by the time of adolescence. •Common complications include middle-ear infection and pneumonia. Transmission, which is primarily by large respiratory droplets, increases during the late winter and early spring in temperate climates, and after the rainy season in tropical climates. Vaccin e •The measles/mumps/rubella triple (MMR) or measles/rubella (MR) vaccine is given in many countries instead of monovalent measles vaccine. •In industrialized countries, vaccination is usually given at the age of 12–15 months, •In most developing countries,high attack rates and serious disease among infants necessitate early vaccination, usually at 9 months of age. •All children should be given a second opportunity for measles immunization. •Although generally administered at school entry (age 4–6 years), the second •dose may be given as early as one month following the first dose. MUMPS Disease •Mumps, or parotitis epidemica, is a viral infection that primarily affects the salivary glands. Although mumps is mostly a mild childhood disease, the virus may also affect adults, in whom complications such as meningitis and orchitis are relatively common. Encephalitis and permanent neurological sequelae are rare complications of mumps. Vaccin e •The mumps vaccine is usually given in combination with measles and rubella vaccine (MMR). •Different attenuated strains of the mumps virus are used for the production of live mumps vaccines, all of which are considered safe and efficacious, except for the Rubini strain. In order to avoid possible interference with persistent maternal antibodies. •The recommended one dose of the vaccine is usually given at 12–18 months of age. A single dose of mumps vaccine, either as single antigen or in combination, has a protective efficacy of 90– 96%, and the second dose given at age 4–6 years. RUBE LLA Disease

•Occurs worldwide and is normally a mild childhood disease. However, infection during early pregnancy may cause fetal death or congenital rubella syndrome (CRS) which is characterized by multiple defects, particularly of the brain, heart, eyes and ears. •CRS is an important cause of hearing and visual impairment and mental retardation in countries where acquired rubella infection has not been controlled or eliminated Vaccin e •Strain of the rubella virus and propagated in human diploid cells, have proved to be safe and efficacious. •Rubella vaccine is commercially available in a monovalent form, in a bivalent combination with either measles or mumps vaccine, and in the trivalent measles/mumps/rubella (MMR) vaccine •Rubella vaccination of pregnant women should be avoided, and pregnancy should be avoided within one month of receiving the vaccine PNEUM OCOCC AL DISE ASE Disease •Caused by the bacterium Streptococcus pneumoniae.

•Invasive pneumococcal infections include pneumonia, meningitis and febrile bacteraemia; the common non-invasive conditions include otitis media, sinusitis and bronchitis. •Infection is acquired by direct person-to-person contact via respiratory droplets or oral contact. Vaccin e •The current 23-valent polysaccharide vaccine represents pneumococcal serotypes that are responsible for 90% of pneumococcal infections and is immunogenic in those over 2 years of age. Children under 2 years of age and immunocompromised individuals do not respond well to the vaccine. •Vaccination provides protection against invasive pneumococcal disease in healthy elderly individuals. •Pneumococcal polysaccharide vaccine is recommended for selected groups, over the age of 2 years, at increased risk of pneumococcal disease •In USA, routine vaccination is recommended for everyone aged over 65 years. •A conjugate vaccine containing seven serotypes of the pneumococcus is now available and is safe and immunogenic also in infants and children under 2 years. This vaccine is recommended by WHO as part of routine immunization in infants and has been introduced in some countries. POLIOM YELITIS Disease •Disease of the central nervous system caused by three closely related enteroviruses, poliovirus types 1, 2 and 3. •The virus is spread predominantly by the faecal–oral route, although rare outbreaks caused by contaminated food or water have occurred. •After the virus enters the mouth, the primary site of infection is the intestine, although the virus can also be found in the pharynx. Poliomyelitis is also known as “infantile paralysis” because it most frequently caused paralysis

•in infants and young children in the pre-vaccine era in industrialized countries. In developing

countries, 60–70% of cases currently occur in children under 3 years of age and 90% in children under 5 years of age. The resulting paralysis is permanent, although some recovery of function is possible. •There is no cure. •Two types of vaccine: inactivated (IPV), which is given by injection, and oral (OPV). •OPV is composed of the three types of live attenuated polioviruses. Because of the low cost and ease of administration of the vaccine and its superiority in conferring intestinal immunity, •OPV has been the vaccine of choice for controlling epidemic •Vaccine-associated paralytic poliomyelitis (VAPP) is more common in individuals who are immunocompromised, for whom IPV is the vaccine of choice. •Following the first dose, unvaccinated older children and adults receive the second dose is given 1–2 months, and the third dose 6–12 months, after the first dose. •A booster dose is recommended after 4–6 years. •IPV is also the vaccine of choice to protect travellers with no history of OPV use, as well as for immunocompromised individuals and their contacts and family members.