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PHARMACOLOGY: Basic Pharmacology, ANS, Endocrine

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BASIC PHARMACOLOGY

HENDERSON-HESSELBACH EQUATION:

DRUG PERMEATION:

Routes of Administration:

VOLUME OF DISTRIBUTION: The apparent amount of volume that a drug seems to distribute to.

Apparent Vd Apparent Vd

(L / kg)

#Liters in 70kg man % Total Body Weight Example, Explanation
Plasma Water 0.045 L/kg 3 L 4.5% Plasma-Protein-bound drugs, and large drugs that stay in plasma. Concentrates in blood and thus has a small Vd.

Example = Heparin

Extracellular Water 0.2 L/kg 14 L 20% Large water soluble drugs.

Example = Mannitol

Total Body Water 0.6 L/kg 42 L 60% Small water soluble drugs; rapid equil-ibration between body compartments.

Example = Ethanol

Tissue

Concentration

>0.7 L/kg >42 L ----- Drugs that bind to tissue

Example = chloroquine, which intercalates with DNA intracellularly.

Vd may be greater than TBW volume, hence some drug must be bound to plasma.

This is very common and occurs with many drugs.

PLASMA PROTEIN BINDING: Two main plasma proteins carry drugs in the blood.
ALBUMIN alpha1-Acid Glycoprotein

OROSOMUCOID

Negatively Charged, hence it binds primarily to weak acids. Positively Charged, hence it binds primarily to weak bases.
Negative acute-phase protein: its synthesis decreases during time of body insult. Positive acute-phase protein: its synthesis increases during times of body insult.
Examples: Phenytoin, Salicylates Examples: Quinidine, Propanolol


BIOTRANSFORMATION: Alteration of drugs by the liver. Drugs can be metabolized from active to inactive, or from inactive to active. Generally drugs are made more hydrophilic by the process.

CYTOCHROME-P450 COMPLEX:

EXCRETION:

PHARMACOKINETICS:

: Dosage interval. The shorter the dosage interval, the higher the Css

Vd: Volume of Distribution. A high volume of distribution means we're putting the drug into a large vessel, which means we should expect a low Css.

If G = 60%, then we should give the patient 60% of the original dose.

If f is 100%, then the drug is cleared only by the kidney.

PHARMACODYNAMICS:

METABOTROPIC RECEPTOR-COUPLING MECHANISMS:

Gs Stimulates adenylate cyclase (cAMP)
Gi Inhibits adenylate cyclase alpha2-Receptors have Gi ------> inhibit post-synaptic adrenergic neurons
Gq Stimulates Phospholipase-C (IP3/DAG) alpha1-Receptors have Gq ------> Ca+2 in smooth muscle
Go Inhibits Ca+2 channels
Gi Opens K+ channels

IONOTROPIC RECEPTOR-COUPLING MECHANISMS:

DOSE-RESPONSE CURVES:

ADVERSE EFFECTS:

TOLERANCE


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AUTONOMIC NERVOUS SYSTEM



CATECHOLAMINE SYNTHESIS:

SYNTHESIS OF ACETYLCHOLINE: Choline + Acetyl-CoA ------> Acetylcholine (Choline Acetyltransferase)

ACETYLCHOLINE RELEASE: Other neurotransmitters are released along with ACh.

CATECHOLAMINE RELEASE: Other neurotransmitters are released along with NE.

CATECHOLAMINE BREAKDOWN: The primary way to get rid of NE is reuptake back into the pre-synaptic neuron.

AUTONOMIC RECEPTORS: Brief summary
Receptor Location Effect
Nicotinic Ganglionic (NG) ANS Ganglions Activation of parasympathetic and sympathetic post-synaptic neurons.
Nicotinic Neuromuscular Junction (NMJ) Neuromuscular Junction Activation of skeletal muscle
Muscarinic (M1)

IP3 / DAG

Sympathetic post-ganglionics Inhibit sympathetic NE release. This is the way in which ACh causes relaxation of vascular smooth muscle: ACh ------> inhibit NE ------> vasodilation.
Muscarinic (M2)

Inhibitory: cAMP, K+ influx

Heart Lower rate (on SA node) and force (on myocardium)
Eye Pupillary constriction (contract iris muscle); accommodation
GI / UG Contraction of GI smooth muscle and relaxation of sphincters.
Respiratory Bronchoconstriction and increased secretions
Penis Erection (via NO), vasodilation
Muscarinic (M3)

IP3 / DAG

Vascular Vasodilation: Strong indirect vasodilatory effect due to inhibition of sympathetics. At low doses, this leads to a reflex tachycardia.

Some direct vasodilatory effect (especially when exogenous ACh is given)

Exocrine glands Increased sweating in non-adrenergic sweating areas (regular eccrine sweat glands). Under sympathetic control, but they are M3 muscarinic receptors.
Adrenergic (alpha1)

IP3 / DAG ------> Ca+2

Vascular smooth muscle Vasoconstriction (via IP3 / DAG, increased Ca+2)
GI / UG Smooth muscle relaxation and contraction of sphincters
Eye Pupillary dilation (contract radial muscle)
Adrenergic (alpha2)

Gi ------> cAMP

Post-ganglionics Inhibitory on sympathetic and parasympathetic post-ganglionic neurons. For sympathetics, this is auto-regulatory feedback.

Gi ------> inhibit cAMP

Pancreatic beta-Cells NE Inhibits the release of insulin ------> hyperglycemia
Adrenergic (beta1)

Adenyl Cyclase / cAMP

Heart Increase rate (SA node) and inotropic state (myocardium)
Lipocytes Increase lipolysis
Brain NE stimulatory CNS effects.
Kidney Increased Renin release ------> higher b.p. ultimately
Adrenergic (beta2)

Adenyl Cyclase / cAMP

Vascular Relaxation of vascular smooth muscle in skeletal muscle and brain.
Pancreatic beta-Cells Stimulate release of insulin in Pancreatic beta-Cells. Thus beta-Blockers can lead to hyperglycemia as side-effect.
Dopamine (D1)

G-Protein, cAMP

Vasculature Vasodilation, especially in Kidney ------> higher Renal Blood Flow.
Dopamine (D2)

G-Protein, cAMP

Anterior Pituitary Inhibit Prolactin Release
CNS Various stimulatory effects.


VASCULATURE: There are little or no parasympathetics innervating the vasculature.

SWEAT GLANDS:



MUSCARINIC AGONISTS:

ORGANOPHOSPHATE POISONING:

ANTI-MUSCARINIC AGENTS:

GANGLIONIC BLOCKERS: Trimethaphan and Hexamethonium.

ADRENERGIC AGONISTS: Catecholamine, catecholamine-like compounds.

beta-AGONISTS:

MAO-INHIBITORS: Mono-Amine Oxidase Inhibitors. MAO has two isozymes.

alpha-ANTAGONISTS:

beta-ANTAGONISTS:


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ENDOCRINE PHARMACOLOGY



GROWTH HORMONE (GH):

THYROID HORMONE:

ADRENAL HORMONES:

CORTISOL:

GONADOTROPINS:

ESTROGEN:

PROGESTINS: They generally modulate the effects of estrogens (and lessen their side-effects) when used in oral contraceptives.

DIABETES:
Diabetes Type I (IDDM) Diabetes Type II (NIDDM)
Mechanism Insulin is defective or is never formed. Antibodies against pancreatic beta-cells. Insulin resistance; down-regulation of insulin receptors; failure of pancreas to release insulin even though it being formed.
Survival Insulin is absolutely required for survival. Patient will survive without insulin
Synonyms Ketosis-Prone Diabetes

Juvenile-Onset Diabetes

Ketosis-Resistant Diabetes

Adult-Onset Diabetes

Onset Sudden, often discovered by ketoacidosis. Childhood polydipsia, polyphagia, polyuria. Gradual, insidious. Often discovered incidentally, or when chronic complications arise.
Nutrition Often thin. Failure of action of insulin. Usually obese.
Ketoacidosis Frequent Seldom or never
Treatment (order of importance) Insulin always required

Diet

Never oral hypoglycemics

Diet and exercise

Oral hypoglycemics

Insulin

PARATHYROID HORMONE (PTH): It increases serum Ca+2 and promotes resorption of Ca+2 in bone.

VITAMIN-D:

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Copyright 1999, Scott Goodman, all rights reserved